Infeksi Epstein Barr Virus Disusun Oleh: Rahmatillah, S. KG PEMBIMBING: Dr. Drg. Maharani Laillyza Apriasari, Sp. PM Epstein Barr Virus (EBV) Famili : Herpesviridae Subfamili : γ-herpesviridae; HHV-4 Pertama kali diisolasi oleh Epstein et al. (1964) dari sel Burkitt limfoma orang Afrika. Genus : Lymphocryptovirus (Khammisa dkk, 2016; Kikuchi dkk, 2017; Muhlis R, 2017; Smatti dkk, 2018; Zanella, 2019) Genom EBV: ● DNA untai ganda linier ● panjang ∼172 kb dengan lebih dari 100 gen pengkode sekitar 85 protein dan EBV sekitar 50 RNA non-pengkode. berdasarkan sekuens DNA (alel pada gen EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C) EBV- 1 (Tipe A) EBV-2 (Tipe B) e.g B95-8, GD1, Akata e.g AG876 dan P3HR-1 (Khammisa dkk, 2016; Kikuchi dkk, 2017; Smatti dkk, 2018; Zanella, 2019) Epidemiologi EBV-1 (paling umum) Eropa, Asia, Amerika Utara & Selatan. Sekitar 90% -95% orang di seluruh dunia terinfeksi EBV dan 50% anak terinfeksi pada usia 5 tahun. EBV-2 Alaska, Papua New Guinea, Afrika Tengah, Kenya (Houldcroft & Kellam, 2015; Kikuchi dkk, 2017; Zanella dkk, 2019) Transmisi EBV 1. Rute oral (saliva) 2. Transplantasi organ 3. Transfusi darah 4. Aktivitas seksual 5. Menyusui (penelitian sebelumnya melaporkan bahwa bukan faktor risiko yang signifikan) (Houldcroft & Kellam, 2015; Khammissa dkk. 2016; Smatti dkk, 2018) EBV Entry Glikoprotein EBV dan Reseptor Permukaan Sel Host (Kikuchi dkk, 2017) gp350 (/gp220) CD21 (/CD35) gH/gL/gB gp24 Makropinositosis Endositosis HLA c. II gH/gL/gB ɑvβ6 & ɑvβ8 kapsid bertegumen masuk ke sel B fusi membran (sel B) fusi membran (sel epitel) Infeksi Primer Siklus litik Siklus hidup bifasik kapsid bertegumen masuk ke sel epitel (Diefenbach, 2015; Houldcroff & Kellam, 2015; Khammissa dkk. 2016; Sathiyamoorthy dkk, 2016; Kikuchi dkk, 2017) Siklus laten Tropisme primer EBV adalah sel B dan sel epitel tetapi juga dapat menginfeksi sel NK, sel T, dan sel otot polos, dengan kemampuan untuk menyebabkan onkogenesis di semua jenis sel ini. (Shannon-Lowe C, Rowe M, 2014; Khammissa dkk. 2016; Kikuchi dkk, 2017) Siklus hidup virus Epstein-Barr (EBV) pada carrier yang sehat. (Smatti dkk, 2018) (Andrei dkk, 2019) EBV-associated Diseases ● Infeksi mononukleosis ● Oral hairy leukoplakia ● Limfoma ● Karsinoma epitel ● EBV-LPD (Kikuchi dkk, 2016; Möhl dkk, 2016; Münz, 2019) Limfoma Hodgkin limfoma Non-Hodgkin limfoma • Burkit Limfoma Karsinoma Epitel Carsinoma lymphoepitheliomalike g. parotid Karsinoma epitel tiroid Paru-paru Nasofaring Gastric (Kikuchi dkk, 2016; Möhl dkk, 2016; Münz, 2019) Infeksi Mononukleosis ● limfoproliferatif jinak & self limiting ● Gambaran klinis yang khas: ○ sakit tenggorokan yang tiba-tiba, limfadenopati ○ Malaise, mialgia dan kelelahan (Balfour dkk, 2015; Houldcroff, 2015) Diagnosa & Terapi IM EBV Terapi Diagnosa ● Pada serologi non spesifik yaitu ● diberikan 3x dalam sehari uji Monospot clinical selama 7-10 hari mononucleosis didapatkan positif antibodi heterophile. ● Uji serologi spesifik Methisoprinol 500 mg 3x1 ● Antibiotik untuk mencegah penyebaran dan perluasan penyakit (Morrison dkk, 2015; Apriasari, 2016; Apriasari, 2019) Oral Hairy Leukoplakia ● lesi hiperkeratotik jinak putih atau putih keabuan ● Berbatas tegas ● Terutama mengenai batas lateral lidah ● Unilateral / bilateral ● Permukaannya datar, berombak vertikal, atau hairy ● Asimtomatik (Khammisa dkk, 2016; Pujiastuti, 2016) Diagnosa & Terapi OHL ● ● Kriteria definitif adanya EBV: histopatologi, Terapi: sitologi eksfoliativa, hibdridisasi in situ/ PCR. ● Pembedahan Temuan histopatologi: Hiperplasia epitel, ● Antivirus sistemik hiperkeratosis, parakeratosis, ballooning, ● Terapi topikal: kombinasi podofilin vakuoalisasi, sel epitel koilositik, dan nukleus 25% dan krim asiklovir 5%. Adapun dengan gambaran groundglass & nuclear agen lain, gentian violet (2%) & beading. Retinoid (Brasileiro dkk, 2014; Khammisa dkk, 2016; Pujiastuti, 2016) EBV dan Oral Burkitt’s Lymphoma ● Tumor yang berkembang agresif ● di area ekstranodal ● Subtipe: endemik, sporadis, terkait HIV ● BL oral : BL endemik dimana sekitar setengahnya muncul di rahang. (Kim dkk, 2016; Guidry dkk, 2018) Diagnosa & Terapi BL ● ● Serologi: peningkatan level antibodi EBV-VCA & ● Terapi EBV-EA ● Kemoterapi R-CHOP (Rituximab + Histologi: pola BL klasik “langit berbintang”, proliferasi Cyclophosphamide, Doxorubicin, difus sel limfoid neoplastik berukuran sedang, dengan Vincristine and Prednisolone) sitoplasma basofilik sedikit dan 1-3 nukleolus yang jelas ● Imunohistokimia: positif CD45, CD20, CD79a, CD10, Bcl6 ● ISH: positif EBER (Van den bosch, 2012; Rebelo Pontes dkk, 2014) EBV dan Nasopharyngeal Carsinoma ● Peningkatan titer antibodi EBV kira-kira tiga tahun sebelum deteksi NPC. ● NPC menunjukkan infeksi EBV laten tipe II yang ditentukan oleh ekspresi onkogen virus LMP1, LMP2, EBNA1, dan viral non-coding RNA. (Kadriyanto & Noegroho, 2015; Guidry dkk 2018) Diagnosa & Terapi NPC Terapi: Diagnosa ● Peningkatan titer IgA (EBV-EA & VCA) dan ● radiotherapy) IgG (produk gen EBV BRLF1 Rta) ● Pengukuran mRNA BRLF1 dengan teknik ● minggu Hibridisasi in-situ (ISH) untuk deteksi RNA EBV. Kemoterapi: Ciplastin 30-40 mg setiap minggu/100 mg setiap 3 RTqPCR ● IMRT (Intensity-modulated ● Bedah diseksi leher (Morrison dkk, 2015; Estania dkk, 2017; Muhlis; 2017) Diagnosa Infeksi EBV Serologi Non Spesifik Uji Monospot Marker: Antibodi Heterophile Molekuler Spesifik PCR ELISA, EIA, IFA, chemoluminescence, imunoblot, aviditas IgG Marker: VCA-IgG, VCA-IgM, EA, EBNA-IgG (Morrison dkk, 2015; Guidry dkk, 2018; Smatti dkk, 2018; AbuSalah dkk, 2020) ISH Marker: EBERs Penatalaksanaan Infeksi EBV ● ● Antivirus dalam kombinasi dengan imunomodulator (e.g Kortikosteroid: metilprednisolon) Inosine pranobex (IP)/ isoprinosine atau methisoprinol (sifat immunomodulator dan antiviral). Medication Possible Doses Antivirals Acyclovir 600-800 mg po 5 times/day x 7-10 days 10 mg/kg IV q8h x 7 days Valacyclovir 3g/day x 14 days 20 mg/kg tid x 14 days Corticosteroid Prednisone 60mg po daily followed by 10 day taper Prednisolone 0,7 mg/kg po x 4 days, followed by tapered doses (0.1 mg/kg/day over 6 days) Dexamethasone 0,3 mg/kg x 3 doses Methisoprinol 500 mg po 3 times/day x 7 days (Hellwig dkk, 2013; Apriasari, 2016; Andrei dkk, 2019; Sliva dkk, 2019) Referensi Andrei G, Trompet E, Snoeck R. Novel Therapeutics for Epstein⁻Barr Virus. Molecules. 2019;24(5):997. Apriasari ML. Methisoprinol as an immunomodulator for treating infectious mononucleosis. Dental Journal (Majalah Kedokteran Gigi). 2016; 49(1): 1–4 Apriasari ML. Ulserasi Mukosa Mulut. Yogyakarta: Pustaka Panasea; 2019. p. 12. AbuSalah MAH, Gan SH, Al-Hatamleh MAI, Irekeola AA, Shueb RH, Yean Yean C. Recent Advances in Diagnostic Approaches for Epstein-Barr Virus. Pathogens. 2020; 9(3): 226. 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