Rim2

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  1. 1. TINJAUAN PUSTAKA IMUNOLOGIASPEK KLINIS DAN LABORATORIS (SEROLOGIS) PADA INFEKSI VIRUS HERPES SIMPLEK Oleh: Binawati / Endang Retnowati 1
  2. 2. PENDAHULUAN (1)• Infeksi Herpes simplex disebabkan oleh herpes simplex virus (HSV)• HSV ada dua tipe : 1. HSV-1  herpes labialis 2. HSV-2  herpes genitalis 2
  3. 3. PENDAHULUAN (2)• Infeksi HSV menjadi masalah karena: 1. transmisi virus dapat terjadi dari penderita yang asimtomatik, 2. pengaruhnya terhadap kehamilan dan bayi / janin dalam kandungan, 3. pengaruh pada penderita imunokompromais, 4. dampak kejiwaan, 5. serta kemungkinan timbulnya resistensi virus 3
  4. 4. HSV (1)• HSV merupakan virus DNA anggota dari famili Herpesviridae• HSV  ds (double stranded) DNA enveloped viruses• Virion terdiri dari empat struktur yaitu envelope, tegumen, nucleocapsid dan DNA yang berisi inti (core)• Genom virus terbentuk dari protein ikosahedral 4
  5. 5. HSV (2)Structure of Herpes Simplex Virus 5
  6. 6. HSV (3)• Struktur genom dari kedua subtipe sama dan derajad homologinya 50-70%• HSV-1 dan HSV-2 masing-masing memiliki region spesifik yang digunakan untuk membedakan kedua tipe HSV• Perbedaan kedua tipe terletak pada komposisi molekuler genomnya dan terefleksi pada struktur glikoprotein dari peptidanya. 6
  7. 7. PATOGENESIS (1)• Permukaan mukosa atau bagian kulit yang mengalami abrasi : - tempat masuknya virus HSV - tempat multiplikasi virus• infeksi primer : infeksi pada seseorang yang sebelumnya belum pernah terinfeksi dengan HSV-1 atau HSV-2 (seronegatif)• Respon humoral pada tahap awal meliputi Ig M yang bersifat sementara dan Ig G yang bersifat menetap 7
  8. 8. PATOGENESIS (2)• Setelah virus masuk  replikasi (sel epidermis dan dermis) fusi, nucleocapsid masuk  virus dilepaskan dari virion  DNA virus yang tereplikasi tersebut, selanjutnya dipaket dalam capsid yang diberi envelope pada membran dalam dari inti sel inang  ditransportasi melalui aparatus golgi ke bagian ekstraselular• Dari sel epitel HSV dapat menginfeksi syaraf sensoris atau otonomik regional, dan menyebar melalui axon syaraf menuju ke neuron 8
  9. 9. PATOGENESIS (3)• Keadaan laten : genom virus terpelihara dalam keadaan represi oleh sel normal dan tidak menimbulkan efek pada neuron inang• Reaktivasi : virus yang keluar dari neuron ke sel epitel menyebabkan replikasi virus dan penampakan kembali virus pada permukaan mukosa• Kedua mekanisme infeksi laten dan reaktivasi HSV belum diketahui secara jelas 9
  10. 10. PATOGENESIS (4)Gambar 1 : Establishment dan reaktivasi infeksi laten virus herpes(diambil dari animal viruses) 10
  11. 11. PATOGENESIS (5)• Beberapa pencetus yang memicu terjadinya reaktivasi : 1. stress fisik atau stress psikis, 2. infeksi pneumokokus, 3. infeksi meningokokus, 4. panas, 5. irradiasi, termasuk sinar matahari, 6. menstruasi.• Infeksi HSV pada otak terutama melalui transmisi neuronal yang berasal dari syaraf trigeminal atau olfaktorius 11
  12. 12. PATOGENESIS (6)• Daerah otak yang paling sering terinfeksi HSV adalah lobus temporalis media dan lobus frontalis inferior• Kerusakan jaringan syaraf otak disebabkan destruksi langsung oleh virus atau tidak langsung melalui mekanisme imunologis 12
  13. 13. MANIFESTASI KLINIS (1)• Ada tiga episode herpes : 1. episode primer / infeksi primer 2. infeksi reaktivasi 3. episode pertama infeksi non primer• Infeksi pada satu daerah tidak dapat mencegah daerah lain terhadap infeksi berikutnya• Infeksi berulang biasanya berlokasi pada atau dekat infeksi primer 13
  14. 14. MANIFESTASI KLINIS (2) Tabel 1 : Keadaan klinis infeksi HSV-1 dan HSV-2 CONDITIONVIRUSHSV-1 Cold Sores / Oral Herpes Neonatal HSV Genital Herpes Herpes Keratitis Herpes Encefalitis Herpes Dermatitis Herpetic WhitlowHSV-2 Neonatal HSV Genital Herpes Herpes Dermatitis Herpetic Whitlow 14
  15. 15. MANIFESTASI KLINIS (3)• HSV ensefalitis  gejala serebral umum dan fokal• HSV oral-fasial  panas, malaise, mialgia, malas makan, irritabilitas, dan adenopati servikal• HSV genital (lokal)  nyeri, itching, disuria, urethral dan vaginal discharge ,limfadenopati inguinal• HSV neonatal  1. Infeksi lokal pada kulit, mata dan mulut 2. Infeksi lokal SSP 3. Infeksi diseminata 15
  16. 16. MANIFESTASI KLINIS (4)Tabel 2 : Manifestasi klinis Herpes genitalis (diambil dari TheHerpes Monitor) 16
  17. 17. MANIFESTASI KLINIS (5)Gambar 2 : Perjalanan klinis infeksi herpes genital primer(diambil dari pathophysiology) 17
  18. 18. MANIFESTASI KLINIS (6)Gambar 3 : Perjalanan petanda serologi pada infeksi herpes(diambil dari DiaphroMed) 18
  19. 19. PEMERIKSAAN SEROLOGI HSV (1) Gambar 4 : Alur diagnosis infeksi HSV 19
  20. 20. PEMERIKSAAN SEROLOGI HSV (2)• Gold standard deteksi antibodi terhadap HSV  western blot (WB)• Indikasi pemeriksaan imuoasai HSV : 1. konfirmasi adanya infeksi primer 2. kasus dicurigai ensefalitis karena HSV 3. penderita immunosuppressed dan unknown febris lama dengan penyebab belum diketahui 4. bayi dengan kelainan kongenital yang tidak diketahui penyebabnya 5. skrining kesehatan (penderita routine sexual) 6. ibu hamil atau suaminya dicurigai menderita HSV genital 20
  21. 21. PEMERIKSAAN SEROLOGI HSV (3)Gambar 6 : Alur pemeriksaan HSV-1 dan HSV-2 pada wanitahamil dan pasangannya 21
  22. 22. PEMERIKSAAN SEROLOGI HSV (4)Gambar 5 : Alur pemeriksaan HSV-2 pada wanita hamil 22
  23. 23. PEMERIKSAAN SEROLOGI HSV (5)• IgM spesifik HSV tidak membantu diagnosis infeksi primer karena IgM HSV dapat ditemukan pada reaktivasi• Pada infeksi virus, pemeriksaan IgG avidity spesifik  untuk mengetahui infeksi primer atau infeksi lampau• Hasil IgG avidity spesifik : - rendah  infeksi primer - tinggi  infeksi lampau atau rekuren 23
  24. 24. PEMERIKSAAN SEROLOGI HSV (6)IMUNOASAI ENZIM (EIA)• Prinsip dasar dari EIA : ELISA tidak langsung (indirect)• Keuntungan : sensitif, praktis dan cepat• Kerugian : dibutuhkan pengalamanan yang cukup untuk mengkonstruksi ELISA• Uji ELISA tidak spesifik kecuali dipakai glikoprotein G1 (gG1) dan gG2 sebagai antigen 24
  25. 25. PEMERIKSAAN SEROLOGI HSV (7)UJI HEMAGLUTINASI TAK LANGSUNG (IHA)• Prinsip dasar : SDM domba yang disensitisasi antigen HSV bila direaksikan dengan serum penderita (mengandung antibodi terhadap HSV)  aglutinasi• Keunggulan IHA : - hasil diperoleh dalam satu hari - dapat melacak antibodi yang baru diproduksi pada infeksi primer maupun antibodi stabil pada infeksi laten, dan menahun 25
  26. 26. PEMERIKSAAN SEROLOGI HSV (8)UJI HAMBATAN HEMAGGLUTINASI (IHA INHIBITION)• Prinsip dasar:didasarkan kemampuan antigen homolog menghambat antibodi secara lengkap dan antigen yang heterolog hanya memberikan hambatan parsial• Kekemahan : baik antigen IHA maupun SDM domba yang disensitisasi harus diproduksi secara lokal 26
  27. 27. PEMERIKSAAN SEROLOGI HSV (9)Penentuan tipe HSV antisera dengan uji hambatan IHA : IHA dengan sel yang IHA dengan sel yang Tipe Ab HSV tersensitisasi HSV-1 tersensitisasi HSV-2 setelah absorbsi serum setelah absorbsi serum dengan dengan HSV-1 HSV-2 Kontrol HSV-1 HSV-2 Kontrol 1 O + + O O + 2 O O + + O + 1 dan 2 O + + + O +Tipe tidak tentu O O + O O + + = aglutinasi (penurunan titer kurang dari 4 kali dibandingkan kontrol) O = hambatan (penurunan titer lebih dari 4 kali dibandingkan kontrol) 27
  28. 28. INTERPRETASI HASIL (1)• Kasus dicurigai infeksi primer  konfirmasinya diperiksa interval 10 hari-3 minggu• Imunoasai antibodi HSV tidak banyak berguna pada infeksi berulang• Kasus dicurigai ensefalitis HSV  antibodi dalam CSF 6% diatas kadarnya dalam darah, berarti amat besar kemungkinan adanya produksi lokal antibodi dan infeksi SSP yang baru terjadi 28
  29. 29. INTERPRETASI HASIL (2)• Bayi dengan kelainan kongenital belum jelas penyebabnya  penentuan IgM anti- HSV, mengkonfirmasi atau menyingkirkan HSV sebagai penyebabnya• Risiko penularan pada bayi amat besar dari ibu hamil (sero-HSV yang negatif)  kenaikan titer IgG 4 kali dengan interval 10-21 hari, perlu tindakan 29
  30. 30. INTERPRETASI HASIL (3)• Hasil IgG dan IgM positif dengan aviditas IgG yang rendah, menunjukkan bahwa adanya infeksi terjadi kurang dari empat bulan• Hasil IgG dan IgM positif dengan aviditas IgG yang tinggi menunjukkan infeksi terjadi lebih dari empat bulan 30
  31. 31. INTERPRETASI HASIL (4)Tabel 5 : Klasifikasi infeksi HSV genital berdasar klinis, virologi dan serologi Detection of HSV antibodies Clinical Type of virus Acute phase serum Convalescent phase Classification of designa isolation serum infection tion First HSV-2 None HSV-2 Primary HSV-2 episode HSV-1 None HSV-1 Primary HSV-1 HSV-2 HSV-1 HSV-1 and HSV-2 Nonprimary HSV-2 HSV-1 HSV-2 HSV-1 and HSV-2 Nonprimary HSV-1 HSV-2 HSV-2 with or HSV-2 with or First symptoms of without HSV-1 without HSV-1 prior HSV-2 infection ; recurrent HSV- 2 HSV-2 HSV-2 with or HSV-2 with or recurrent HSV-2 without HSV-1 without HSV-1 HSV-1 HSV-1 with or HSV-1 with or recurrent HSV-1 without HSV-2 without HSV-2 31
  32. 32. TERIMA KASIH 32
  33. 33. MANIFESTASI KLINISINFEKSI ORAL-FASIAL• Tanda dan gejala klinis  hari ke 3-14, meliputi panas, malaise, mialgia, malas makan, irritabilitas, dan adenopati servikal• Sebelum terjadi lesi  peningkatan sensitivitas, kesemutan dan rasa terbakar ringan• Reaktivasi HSV  ganglia trigeminal• 50-70% penderita seropositif mengalami dekompresi trigeminal nerve root dan 10- 15% penderita terinfeksi setelah kira-kira 3 hari post ekstraksi gigi 33
  34. 34. MANIFESTASI KLINISINFEKSI GENITAL• Herpes genital primer episode pertama ditandai dengan panas, pusing, dan mialgia• gejala lokal yang menonjol : nyeri, itching, disuria, urethral dan vaginal discharge serta limfadenopati inguinal• Tingkatan lesi dapat bervariasi, meliputi vesikel, pustula, atau ulkus eritema yang sangat nyeri 34
  35. 35. MANIFESTASI KLINISINFEKSI SSP DAN PERIFER• HSV ensefalitis yang khas  penyakit akut dengan gejala serebral umum dan fokal• Gejala prodromal : malaise, demam dan mual• Gejala ensefalopati : letargi, kebingungan dan delirium• Kejang  kejang umum atau kejang fokal• HSV ensefalitis harus dibedakan dengan meningitis aseptik herpes simplex, yang terjadi bersamaan dengan infeksi genital HSV-2 35
  36. 36. MANIFESTASI KLINIS• Metode paling sensitif dan non invasif untuk diagnosis dini HSV ensefalitis  pemeriksaan HSV DNA pada cairan serebrospinal dengan PCR• Adanya HSV antibodi dalam CSF dan HSV DNA yang persisten dalam CSF dapat membantu menegakkan diagnosis 36
  37. 37. MANIFESTASI KLINISINFEKSI HSV NEONATAL• Populasi yang terinfeksi HSV  neonatus (bayi <6 bulan) mempunyai frekuensi kejadian infeksi pada viseral dan / atau CNS paling tinggi• Angka kematian herpes neonatal 65%, <10% neonatus dengan infeksi CNS berkembang normal• Manifestasi dibagi : 1. Infeksi lokal pada kulit, mata dan mulut 2. Infeksi lokal SSP 3. Infeksi diseminata 37
  38. 38. MANIFESTASI KLINISTabel 3 : Faktor risiko kejadian morbiditas dan mortalitaspada infeksi HSV neonatus 38
  39. 39. MANIFESTASI KLINISTabel 4 : Faktor-faktor yang berhubungan dengan risikopenularan secara vertikal 39
  40. 40. MANIFESTASI KLINIS• Risiko terkena herpes neonatal pada : - wanita HSV-1 seropositif (awal hamil)  1/3800 - wanita HSV-2 seropositif  1/4600 karena ibu HSV-2 seropositif mengimunisasi janinnya secara transplasenta dengan IgG anti HSV-2 dan bayi dilahirkan cara operasi caesar  diperlukan pendekatan preventif dengan pemeriksaan serologi selama kehamilan 40
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  43. 43. Testing with symptoms: viral cultureIf symptoms of herpes appear, they can vary widely fromperson to person. If a person does experience signs ofinfection, we recommend obtaining a culture test (a swabfrom the symptom) within the first 48 hours after a lesionappears. Results are usually available in about a weekstime.The major advantage of the culture is its accuracy in givinga positive result. A culture can also be “typed” to determinewhether the infection is caused by HSV-1 or HSV-2. If youtest positive by viral culture, you can be sure you have thevirus.The major disadvantage of the culture is its high rate offalse negatives. Because a culture works by requiring virusthat is active, if a lesion is very small, or is alreadybeginning to heal, there may not be enough virus presentfor an accurate culture. Beyond 48 hours of the symptomsappearing, there is a risk of receiving a false negative testresult. Viral culture is even less accurate during recurrences(positive in only about 30% of recurrent outbreaks). 43
  44. 44. • When an individual contracts herpes, the immune system responds by developing antibodies to fight the virus: IgG and IgM. Blood tests can look for and detect these antibodies, as the virus itself is not in blood. IgG appears soon after infection and stays in the blood for life. IgM is actually the first antibody that appears after infection, but it may disappear thereafter. 44
  45. 45. IgM tests are not recommended because of three serious problems:1. Many assume that if a test discovers IgM, they have recently acquired herpes. However, research shows that IgM can reappear in blood tests in up to a third of people during recurrences, while it will be negative in up to half of persons who recently acquired herpes but have culture- document first episodes. Therefore, IgM tests can lead to deceptive test results, as well as false assumptions about how and when a person actually acquired HSV.2. 2. In addition, IgM tests cannot accurately distinguish between HSV-1 and HSV-2 antibodies, and thus very easily provide a false positive result for HSV-2. This is important in that most of the adult population in the U.S. already has antibodies to HSV-1, the primary cause of oral herpes. A person who only has HSV-1 may receive a false positive for HSV-2.3. 3. IgM tests sometimes cross-react with other viruses in the same family, such as varicella zoster virus (VZV) which causes chickenpox or cytomegalovirus (CMV) which causes mono, meaning that positive results may be misleading. 45
  46. 46. DIA-DIA- HSV 1/2-IgG and DIA- HSV 2-IgG 1/2- DIA- 2- 46
  47. 47. DIA-DIA- HSV 1/2-IgG and DIA- HSV 2-IgG 1/2- DIA- 2-• Principle of the method: two stage ELISA based on «IgM- cupture» principle• Clinical materials: human serum or plasma• DIA-HSV ½-IgM: Detection of specific IgM antibodies to herpes simplex virus 1 and 2 types DIA-HSV 2-IgM: Detection of specific IgM antibodies to herpes simplex virus 2 type• Immunosorbent – monoclonal antibodies to human IgM• Conjugate: DIA-HSV ½-IgM: specific purified recombinant antigens gG1 HSV1 and gG2 HSV2 conjugated with horseradish peroxidase; DIA-HSV 2-IgM: specific purified recombinant antigen of herpes simplex virus 2 (gG2) conjugated with horseradish peroxidase• Packing configuration: strip (lockwell) microplate TMB chromogen 96 tests• Incubation time: 2 hours• Shelf life: 12 months 47
  48. 48. DIA-DIA- HSV 1/2-IgG and DIA- HSV 2-IgG 1/2- DIA- 2-Assay principle• wells coated with antigens of herpes simplex virus 1 and 2• adding of sera and controls• incubation for 60 minutes, 37°С• adding of conjugate• incubation for 30 minutes, 37°С• adding of chromogen• incubation for 30 minutes, 18-25°С• reaction termination• result reading 48
  49. 49. DIA-DIA-HSV 1/2-IgМ and DIA-HSV 2-IgM 1/2- DIA- 2- 49
  50. 50. DIA- DIA-HSV 1/2-IgМ and DIA-HSV 2-IgM 1/2- DIA- 2-• Principle of the method: two stage ELISA procedure based on «IgM-capture» principle• Clinical materials: human serum or plasma• Detection of specific to Rubella virus IgM antibodies• Immunosorbent – monoclonal antibodies to human IgM• Conjugate – purified antigen of Rubella virus conjugated with horseradish peroxidase• Packing configuration: strip (lockwell) microplate TMB chromogen 96 tests• Incubation time: 1,5 hours• Shelf life: 12 months 50
  51. 51. DIA- DIA-HSV 1/2-IgМ and DIA-HSV 2-IgM 1/2- DIA- 2-• Assay principle• wells coated with monoclonal antibodies to human IgM• adding of sera incubation for 60 minutes, 37°С• adding of conjugate• incubation for 30 minutes, 37°С• adding of chromogen• incubation for 30 minutes, 18-25 °С• reaction termination• result reading 51
  52. 52. CYTOLOGY TESTSIn the past, cytology was also used as a diagnostictool for genital herpes.Cellular changes caused by HSV can be recognized incervical scrapings after Papanicolaou stain, and inlesion scrapings in Tzanck preparations.However, using these changes to diagnose HSV is notappropriate as they do not differentiate between HSV-1and HSV-2, or between HSV and other viralinfections. Furthermore, the cytological techniques areonly 30%-80% as sensitive as cultures for HSV, andhave a low but significant false positive rate. 52
  53. 53. EHSBelum jelas, ada kemungkinan :- Infeksi primer akibat transmisi virus secara langsung melalui jalur neuronal dari perifer ke otak melalui saraf Trigeminus atau Offactorius. Faktor precipitasi adalah penurunan sistim imun host.- Reaktivitas infeksi herpes virus laten dalam otak.- Pada neonatus penyebab terbanyak adalah HSV- HSV-2 yang merupakan infeksi daapatan dari secret genital yang terinfeksi pada saat persalinan. 53
  54. 54. EHSLaboratorium :• Analisis CSS : Pada minggu pertama dapat normal, pleositosis mononuclear, peningkatan ringan protein, kadar glucose normal/menurun ringan, jumlah sel normal.• Kultur CSS dapat dapat positif pada neonatus• PCR : sensitive dan spesifik.Radiologi : MRI : pilihan utama : lesi bermakna pada lobus temporalis bagian medial dan bagian inferior lobus frontalius.EEG : cukup sensitive tapi tidak spesifikBiopsi otak : pemeriksaan definitive untuk menegakkan diagnosis 54
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  57. 57. Recurrences and triggers• Following active infection, herpes viruses establish a latent infection in sensory and autonomic ganglia of the nervous system. The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the nucleus of a nerves cell body. HSV latency is static—no virus is produced—and is controlled by a number of viral genes, including Latency Associated Transcript (LAT). 57
  58. 58. Alzheimers disease• Scientists discovered a link between Herpes Simplex Type I and Alzheimer’s disease in 1979. In the presence of a certain gene variation (APOE-epsilon4 allele carriers), HSV type 1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease. The virus interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimers disease. This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s.• Without the presence of the gene allele, HSV type 1 does not appear to cause any neurological damage and thus increase the risk of Alzheimer’s. 58
  59. 59. Bells palsy• A type of facial paralysis called Bells palsy has been linked to the presence and reactivation of latent HSV-1 inside the sensory nerves of the face (geniculate ganglia), particularly in a mouse model. This is supported by findings that show the presence of HSV-1 DNA in saliva at a higher frequency in patients with Bells palsy relative to those without the condition.• However, since HSV can also be detected in these ganglia in large numbers of individuals that have never experienced facial paralysis, and high titers of antibodies for HSV are not found in HSV- infected individuals with Bells palsy relative to those without, this theory has been contested.[36] Other studies, which fail to detect HSV-1 DNA in the cerebrospinal fluid of Bells palsy sufferers, also question whether HSV-1 is the causative agent in this type of facial 59 paralysis.
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  63. 63. Diagnosis• Diagnosis is based on the physical examination and patient history. Helpful (but nondiagnostic) measures include laboratory data showing increased antibody titers, smears of genital lesions showing atypical cells, and cytologic preparations (Tzanck test) that reveal giant cells.• CONFIRMING DIAGNOSIS Diagnosis can be confirmed by demonstration of the herpes simplex virus in vesicular fluid, using tissue culture techniques, or by antigen tests that identify specific antigens. 63
  64. 64. Limitations of Type-Specific Serology Type-• Tests vary in their reliability and reproducibility.• A positive test merely implies that the person has been infected with one or both of these viruses at some time in the past.• Positive tests provide information about previous exposure to one or both of these viruses, but do not provide specific information about whether particular genital symptoms are due to herpes.• A positive test does not imply that the person is infectious, although evidence suggests that the majority of individuals who have antibodies to one or the other of these viruses may shed the virus asymptomatically or from unrecognised lesions from time to time.• Some patients appear to lose HSV-2 antibodies with time using the current ELISAs 64
  65. 65. • PCR sensitivity rates vary from 75% to 100%• The use of serology in the diagnosis of neonatal HSV infection is hampered by several factors. First, transplacental IgG antibodies cannot be differentiated from IgG produced by the infant. Second, the ability of some severely affected infants to make antibody is impaired. Third, the commercially available assays for HSV IgM antibodies have variable and limited reliability. 65
  66. 66. Direct Testing• Direct Testing (DFA and Viral Culture) is indicated in active infections, but requires accurate collection of specimens from lesions and so cannot be used for asymptomatic genital herpes infections.• Specimens: DFA: Collect infected cells from the base of the vesicle or ulcer using an HSV DFA collection kit. Viral Culture: collect infectec cells and vesicle fluid using a viral transport swab• Request: HSV DFA and/or HSV culture Note: if DFA is positive, no further testing is required; if DFA is negative and a viral transport swab has been collected, viral culture will be performed. 66
  67. 67. Serology• Anti-HSV IgG is usually detectable 2-4 weeks after primary infection. Specific IgM is detectable in primary infections, but may also ocurr in reactivation and so is not diagnostically helpful. Serology is not recommended for the diagnosis of acute HSV infections.• However type specific HSV IgG serology for immune status may be useful for:• Epidemiology and couselling for in contact or at-risk patients.• classification of HSV immune status in patients with gential blisters or ulcers which are culture negative• prognosis (eg HSV-1 genital infectoin is not as likely to recur as HSV-2 infection) 67
  68. 68. HSV Virology• The HSV type 1 and 2 (HSV-1 or HSV-2) is a large, double-stranded DNA virus with an icosahedral nucleocapsid. The herpes virus belongs to the Herpesviridae family, the Alphaherpesvirinae subfamily, and the Simplexvirus genera. The genomes of HSV-1 and HSV-2 exhibit great homology, but the HSV-2 genome has an inherently higher mutation rate than HSV-1. Important viral glycoproteins include1: (1) gD, which is a potent inducer of neutralizing antibody and is important in viral attachment and entry into cells; (2) gB, which is required for infectivity; (3) gH through gL, which are important in viral attachment and entry into cells; and (4) gG, which provides antigenic specificity, allowing serologic differentiation of HSV-1 from HSV-2 (gG-1 and gG-2, respectively). 68
  69. 69. HSV Virology• After initial infection, HSV virions spread by retrograde axonal flow to sensory ganglia, where the virions establish latency.1 The neurovirulence of HSV is attributable to the thymidine kinase gene.1 Reactivation of the virus occurs periodically in response to stressors (eg, illness, fatigue, ultraviolet light, tissue damage1) despite host humoral and cellular immunity. 69
  70. 70. Several alternative cell types have beensuggested as origins of HSV excreted inthe oral cavity. Oral epithelium and, morespecifically, gingival sulcular epitheliumand ocular and salivary tissues have allbeen proposed as sites of HSV replication.Extra-oral persistence of HSV DNA in non-neuronal tissues has been demonstratedin skin, blood, and ocular tissue. 70

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