Viral Zoonosis (Rabies)Titiek DjannatunBagian Mikrobiologi- Fakultas Kedokteran Universitas YARSI

DefinitionZooneses are diseases of vertebrate animals that can be transmitted to man: either directly or indirectly through an insect vector. When an insect vector is involved, the disease is also known as an arboviral disease. However, not all arboviral diseases are zoonosis: where the transmission cycle takes place exclusively between insect vector and human e.g. dengue and urban yellow fever.Examples of viral zoonoses that can be transmitted to man directly include rabies, hantaviruses, lassa and ebola fevers.

KLASIFIKASI, TAKSONOMI & NOMENKLATURFamilia : RhabdoviridaeGenus : Lyssavirus Ephemerovirus VesiculovirusSpesies : Rabies virus, lagos bat, Mokola virus, Devenhage virus, European bat virus 1 & 2, Australian bat virus (Lyssavirus)Virus RNA, SS, Polaritas negatif, Non segmented

Infeksi akut SSP dan mematikanVirus Dditularkan melalui gigitan binatang buas (GILA)Tersebar luas diantara reservoar binatang

SIFAT PENTING RHABDOVIRUS

VIRIONBerbentuk seperti peluru, Diameter 75X180nmKOMPOSISIRNA (4%), Protein (67%), Lipid (26%), KH (3%)GENOMSS RNA, Lurus, Non segmented, - SENSE, BM 4,6 juta, 12 kbPROTEIN1 Glikoprotein envelopeREPLIKASISitoplasma, virion bertunas dalam plasmaENVELOPEAdaCIRI KHASBarisan virus yang lebar dengan kisaran inang luas merupakan grup virus yang mematikan

Rabies Virusmember of the Lyassavirus of the Rhabdoviridae.ssRNA enveloped virus, characteristic bullet-shaped appearance with 6-7 nm spike projections.virion 130-240nm * 80nm-ve stranded RNA codes for 5 proteins; G, M, N, L, SExceedingly wide range of hosts.There are 5 other members of Lyassavirus : Mokola, Lagosbat, Duvenhage, EBL-1, and EBL-2.Duvenhage and EBL-2 have been associated with human rabies.

STRUKTUR VIRUSUKURAN Pj 180 nm, Lebar 75 nmGenom mengkode 5 protein Nukleoprotein (N)Phosphoprotein (P)matrix protein (M)Glikoprotein (G)Polymerase (L)Komponen struktural core Ribonukleoprotein (RNP) dikelilingi envelope.Genom RNA nukleoprotein/kapsid (heliks)N, L, P genom RNAM envelope membranG tonjolan glikoprotein envelope

Rabies VirusStructure of rabies virus (Source: CDC)Rabies virus particles

5.bmp

6.bmp

Viral Structure

SIFAT FISIKA- KIMIAPada 40C Tahan selama seminggu

Diinaktivasi oleh CO2

Penyimpanan dalam vial bertutup gelas pada dryice

Mati Sinar UV atau sinar matahari Pemanasan (1 jam pada 500C) Lemak (Ether , 0,1% Natrium deoksikholat) Tripsin Deterjen pH extrim

REPLIKASI

EpidemiologyRabies is a zoonosis which is prevalent in wildlife. The main animals involved differs from continent to continent.Europe fox, batsMiddle Eastwolf, dog AsiadogAfricadog, mongoose, antelopeN Americafoxes, skunks, raccoons, insectivorous batsS Americadog, vampire bats

KERENTANAN HEWAN THD RABIES VIRUS

SANGAT TINGGITINGGISEDANGRENDAHRubahHamsterAnjingTupaiCoyoteMusangLembuSerigalaRakunDombaAnjing hutanKucingKambingKelelawarKudaKelinciPrimata bukan manusia

WABAH RABIESIndonesia 2004-2008 15.000 digigitBadung, Bali Vaksin 20.000 anjingTahun 2008 14.106 orang: 9565 diberi vaksin dan obat; 85 RabiesBali 1700 orangPenyebab: Populasi anjing tidak terkendali karena lemahnya sistem deteksi dini dan evaluasi periodik survey srologi antibodi dari hewan sumber penularan harusnya dilakukan periodik

PathogenesisThe commonest mode of transmission in man is by the bite of a rabid animal, usually a dog. Rabies is an acute infection of the CNS which is almost invariably fatal. Following inoculation, the virus replicates in the striated or connective tissue at the site of inoculation and enters the peripheral nerves through the neuromuscular junction. It then spreads to the CNS in the endoneurium of the Schwann cells. Terminally, there is widespread CNS involvement but few neurons infected with the virus show structural abnormalities. The nature of the profound disorder is still not understood.

Viral cycle

Viral cycle

Viral Pathogenesis

PATOGENESA & PATOLOGIVirus berkembang-biak pada otot/jaringan, kadang tanpa replikasi lokal saraf tepi (Neuromuscular junction) SSP berkembang-biak di sel otak saraf tepi kelenjar ludah dan jaringan lain.

Virus dapat ditemukan Kelenjar ludah sub maxilla (titer tertinggi)Pankreas, GIinjal, Hati , Retina, Kornea

Virus belum pernah diisolasi dari darah pasien terinfeksi

Virus membentuk badan inklusi intra sitoplasma, asidofilik pada sel saraf terinfeksiI BADAN NEGRI

PATOGENESA & PATOLOGIKerentanan & Masa Inkubasi tergantung:Umur pasienLatar belakang genetikStatus imunStrain virus Patogenitas virusJumlah inokulum Jumlah virus yang masukBeratnya laserasi Dalam dan parahnya lukaBekas gigitan, jumlah luka gigitan, jumlah saraf disekitar gigitanJarak dari Port DEntry SSP (Lokasi luka)

Gigitan di kepala/wajah Masa inkubasi pendek, serangan tinggi

Gigitan pada kaki Kematian rendah

GEJALA KLINISEnsefalitis akut, fulminan, fatal

Masa inkubasi 1 Minggu, 1-2 Bulan, Beberapa tahun (> 6 Tahun) :Hewan Timbul gejala > 2 Minggu (20 Hari - 8 Minggu)Manusia Timbul gejala 2-3 Minggu sampai satu tahun

Fase Klinis Fase Prodomal PendekFase Neurologi akutKoma

GEJALA KLINISFASE PRODOMAL PENDEK :2-10 HariMalaise, Anorexia, Nyeri kepala, Fotopobia, Mual, Mmuntah, Nyeri tenggorokan, demam

FASE NEUROLOGI AKUT :Gelisah, cemas. halusinasi, lakrimasi, dilatasi pupil, salivasi (aktivasi menelan menyebabkan spasme dan nyeri otot tenggorokan), berkeringat, sebagian hidrophobia KEJANG/KOMA kematian (2-7 hari setelah onset) karena kelumpuhan pernafasan

Rabies paralitik terjadi sekitar 20% pasien akibat terinfeksi virus Rabies kelelawarBeberapa bertahan 30 hari, tapi jarang yang dapat sembuh dan bertahan hidup

GEJALA PADA HEWANBENTUK GANAS (FURIOS RABIES):Masa eksitasi panjang, umumnya akan mati 2-5 hari setelah tanda-tanda terlihat Hewan menjadi galak dan penakut, Membangkang perintah tuannya, Nafsu makan hilang, Hipersalivasi, Ekor diantara 2 paha

BENTUK DIAM (DUMB RABIES):Masa eksitasi pendek, Paralisa cepat terjadi bersembunyi di tempat gelap dan sejuk,kejang-kejang dalam waktu singkat, lumpuh tidak dapat menelan, hipersalivasi

BENTUK ASYMPTOMATIS:Tanpa gejala, tiba-tiba mati

Dumb RabiesDumb Rabies, manifested as depresion and an attempt at self-imposed isolation

GEJALA PADA MANUSIANafsu makan hilang, Sakit kepala, Tidak dapat tidur, Demam tinggi, Mual dan muntah-muntahRasa panas pada tempat gigitanTakut air, suara keras, cahaya dan anginAir liur, air mata keluar berlebihanKejang-kejang disusul kelumpuhanBiasanya meninggal dalam waktu 4-6 hari setelah gejala klinia pertama timbul

GEJALA PADA MANUSIAKalau digigit dekat kepala / leher:Demam tinggiKejang-kejang ototMulut berbusaFotophobiaKesadaran menurunBerteriak-teriak

Human rabiesHospitalized human rabies, who was restrained while bedridden

Human rabiesHospitalized human rabies victim in restrains

Laboratory DiagnosisHistopathology - Negri bodies are pathognomonic of rabies. However, Negri bodies are only present in 71% of cases.Rapid virus antigen detection - in recent years, virus antigen detection by IF had become widely used. Corneal impressions or neck skin biopsy are taken. The Direct Fluorescent Antibody test (DFA) is commonly used.Virus cultivation - The most definitive means of diagnosis is by virus cultivation from saliva and infected tissue. Cell cultures may be used or more commonly, the specimen is inoculated intracerebrally into infant mice. Because of the difficulties involved, this is rarely offered by diagnostic laboratories.Serology - circulating antibodies appear slowly in the course of infection but they are usually present by the time of onset of clinical symptoms.

DIAGNOSA LABORATORIUMAntigen Rabies/Asam NukleatImmunofluorenscens, PCR (Jaringan Otak/Kornea)Isolasi VirusIntracerebral pada tikus yang belum disapih Ensefalitis dan kematianSerologi Immunofluorenscens, Tes NtObservasi HewanSelama 10 hari pada hewan reservoar

Negri Body in neuron cell (source: CDC)Positive DFA test (Source: CDCDiagnosis of Rabies

7.bmp

8.bmp

Characteristic Negri BodiesHistopathologic features of rabies, brain. Characteristic Negri Bodies are present within a Purkinye cell of the cerebellum; patient died of rabies

Management and PreventionPre-exposure prophylaxis - Inactivated rabies vaccine may be administered to persons at increased risk of being exposed to rabies e.g. vets, animal handlers, laboratory workers etc.Post-exposure prophylaxis - In cases of animal bites, dogs and cats in a rabies endemic area should be held for 10 days for observation. If signs develop, they should be killed and their tissue.Wild animals are not observed but if captured, the animal should be killed and examined. The essential components of postexposure prophylaxis are the local treatment of wounds and active and passive immunization.Once rabies is established, there is nothing much that could be done except intensive supportive care. To date, only 2 persons with proven rabies have survived.

Postexposure ProphylaxisWound treatment - surgical debridement should be carried out. Experimentally, the incidence of rabies in animals can be reduced by local treatment alone. Passive immunization - human rabies immunoglobulin around the area of the wound; to be supplemented with an i.m. dose to confer short term protection. Active immunization - the human diploid cell vaccine is the best preparation available. The vaccine is usually administered into the deltoid region, and 5 doses are usually given. There is convincing evidence that combined treatment with rabies immunoglobulin and active immunization is much more effective than active immunization alone. Equine rabies immunoglobulin (ERIG) is available in many countries and is considerably cheaper than HRIG.

PENANGGULANGANKasus non akut:Cuci luka dengan sabun/detergen selama 5- 10 menit dibawah air Beri alkohol 70%/YodiumBeri Ig Anti Rabies dan vaksinHewan dikirim ke dinas peternakanOrang digigit RS khusus infeksi

PENANGGULANGANKasus Akut:Vaksin Efek samping: meningitis + gejala seperti RabiesYodium tidak membantu karena virus sudah masukIg Anti Rabies Cegah virus tidak menyebar ke syaraf otakIsolasi penderita dapat menularkanObat tidak ada, terapi symptom: anti kejang, obat untuk mencegah infeksi sekunder, obat penenang

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Rabies VaccinesThe vaccines which are available for humans are present are inactivated whole virus vaccines.Nervous Tissue Preparation e.g. Semple Vaccine - associated with the rare complication of demyelinating allergic encephalitis. Duck Embryo Vaccine - this vaccine strain is grown in embryonated duck eggs This vaccine has a lower risk of allergic encephalitis but is considerably less immunogenic.Human Diploid Cell Vaccine (HDCV) - this is currently the best vaccine available with an efficacy rate of nearly 100% and rarely any severe reactions. However it is very expensive. Other Cell culture Vaccines - because of the expense of HDCV, other cell culture vaccines are being developed for developing countries. However recent data suggests that a much reduced dose of HDCV given intradermally may be just be effective.

IMMUNITAS & PENCEGAHANVAKSINASI :Vaksin sel diploid manusia (HDCV)Vaksin Rabies terabsorpsi (RVA)Vaksin sel embrio ayam dimurnikan (PCEC)Vaksin jaringan sarafVaksin embrio bebekVirus hidup dilemahkan

TIPE ANTIBODI RABIES :Ig Rabies manusia (HRIG)Serum anti rabies kuda

IMMUNITAS & PENCEGAHANPencegahan sebelum pemaparan:Vaksinasi pada individu beresiko tinggiPencegahan setelah pemaparan:

Penatalaksanaan dan pengendalian:

Control of RabiesUrban - canine rabies accounts for more than 99% of all human rabies. Control measures against canine rabies include;stray dog control.Vaccination of dogs quarantine of imported animalsWildlife - this is much more difficult to control than canine rabies. However, there are on-going trials in Europe where bait containing rabies vaccine is given to foxes. Success had been reported in Switzerland.

KLB Rabies Jumlah yang digigit meningkatJumlah vaksin terbatasVaksin rabies pasca paparan mahal (VeroRab 4x suntikan/bulanSumber: muntah, ludah pasienSulit edukasi masyarakat untuk:Eradikasi anjing liarHenti makan daging anjing

Skor LARATLARAT: nama titik terluar NKRI, yang berbatasan langsung dengan Samudra HindiaProbability/Peluang kejadian Rabies pada pasien gigitan anjing saat KLBRumus

1 1 + e-(F)

Skor LARATF = 6,3 + 1,6 (selisih waktu gigit anjing < 2 bulan) + 1,3 (lokasi luka gigitan di kepala, wajah, leher, dada, atau punggung) + 2,5 (karakteristik anjing dominan ciri rabies) + 2 (anjing mati sendiri/dibunuh namun diketahui telah digigit anjing yang mati sendiri berasal dari korban).

e = Hasil analisis multivarian model epidemiologi

Sistem skoring prediksi rabies pada pasien gigitan anjing saat KLB Rabies

NoVariasiKategoriSkor1Selisih waktu gigitan anjing< 2 bulan 2 bulan202Lokasi luka gigitan anjingKepala, wajah, leher, dada, punggungLengan, tangan, perut, tungkai, kaki103Karakteristik anjing (ada 7 karakteristik)Dominan Rabies ( 4 sifat)Tidak dominan Rabies (< 4 sifat)304Akibat kematian anjingAnjing mati sendiri, atau anjing dibunuh namun diperoleh informasi bahwa anjing tersebut mati telah digigit anjing lain yang mati sendiri Anjing dibunuh, tidak mati, tidak tahu

30Skor maksimumSkor minimum90

Analisis sensitivitas dan spesifisitas pada ROC curve, skor 5 memberikan prediksi Rabies sehingga perlu mendapat prioritas vaksinasi di saat KLB

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