Viral Zoonosis (Rabies)

Titiek Djannatun Bagian Mikrobiologi- Fakultas Kedokteran Universitas YARSI

Definition
Zooneses 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 & NOMENKLATUR

FAMILIA : Rhabdoviridae GENUS : Lyssavirus Ephemerovirus Vesiculovirus SPESIES : 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 MEMATIKAN VIRUS DITULARKAN MELALUI GIGITAN BINATANG BUAS (GILA) TERSEBAR LUAS DIANTARA RESERVOAR BINATANG

SIFAT PENTING RHABDOVIRUS

VIRION BERBENTUK SPT PELURU, DIAMETER 75X180NM

KOMPOSISI RNA (4%), PROTEIN (67%), LIPID (26%), KH (3%)

GENOM
PROTEIN REPLIKASI ENVELOPE CIRI KHAS

SS RNA, LURUS, NON SEGMENTED, - SENSE, BM 4,6 JUTA, 12 kb

1 GLIKOPROTEIN ENVELOPE SITOPLASMA, VIRION BERTUNAS DI M PLASMA ADA BARISAN VIRUS YG LEBAR DG KISARAN INANG LUAS MRPK GRUP VIRUS YG MEMATIKAN

Rabies Virus
member 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, S Exceedingly 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 VIRUS
UKURAN Pj 180 nm, Lebar 75 nm Genom 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 RNA M envelope membran G tonjolan glikoprotein envelope

Rabies Virus

Structure of rabies virus (Source: CDC)

Rabies virus particles

Viral Structure

SIFAT FISIKA- KIMIA

PADA 40C TAHAN SELAMA SEMINGGU
DIINAKTIVASI OLEH CO2 PENYIMPANAN DALAM VIAL BERTUTUP GELAS PADA DRY ICE MATI SINAR UV ATAU SINAR MATAHARI PEMANASAN (1 JAM PADA 500C) LEMAK (ETHER, 0,1% NATRIUM DEOKSIKHOLAT) TRIPSIN DETERJEN pH EXTRIM

REPLIKASI

Epidemiology
Rabies is a zoonosis which is prevalent in wildlife. The main animals involved differs from continent to continent.
Europe Middle East Asia Africa N America
S America

fox, bats wolf, dog dog dog, mongoose, antelope foxes, skunks, raccoons, insectivorous bats dog, vampire bats

KERENTANAN HEWAN THD RABIES VIRUS

SANGAT TINGGI
RUBAH COYOTE

TINGGI
HAMSTER MUSANG

SEDANG
ANJING LEMBU

RENDAH
TUPAI

SERIGALA
ANJING HUTAN

RAKUN
KUCING KELELAWAR

DOMBA
KAMBING KUDA

KELINCI

PRIMATA BUKAN MANUSIA

WABAH RABIES
INDONESIA 2004-2008 15.000 DIGIGIT BADUNG, BALI VAKSIN 20.000 ANJING TH 2008 14.106 ORANG: 9565 DIBERI VAKSIN DAN OBAT; 85 RABIES BALI 1700 ORANG PENYEBAB: POPULASI ANJING TDK TERKENDALI KRN LEMAHNYA SISTEM DETEKSI DINI DAN EVALUASI PERIODIK SURVEY SEROLOGI ANTIBODI DARI HEWAN SUMBER PENULARAN HARUSNYA DILAKUKAN PERIODIK

Pathogenesis
The 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 & PATOLOGI

VIRUS OTOT/JAR IKAT (BKBG BIAK) , KADANG TANPA REPLIKASI LOKAL SARAF TEPI (NEUROMUSCULAR JUNCTION) SSP BERBIAK DI OTAK SARAF TEPI KEL LUDAH & JAR LAIN.
VIRUS DAPAT DITEMUKAN KEL LUDAH SUBMAXILLA (TITER TERTINGGI) PANKREAS, GINJAL, HATI , RETINA, KORNEA VIRUS BLM PERNAH DIISOLASI DARI DARAH PASIEN TERINFEKSI

VIRUS MEMBENTUK BADAN INKLUSI INTRASITOPLASMA, ASIDOFILIK PD SEL SARAF TERINFEKSI BADAN NEGRI

PATOGENESA & PATOLOGI

KERENTANAN & MASA INKUBASI TERGANTUNG : UMUR PASIEN LATAR BELAKANG GENETIK STATUS IMMUN STRAIN VIRUS PATOGENITAS VIRUS JUMLAH INOKULUM JUMLAH VIRUS YANG MASUK BERATNYA LASERASI DALAM DAN PARAHNYA LUKA BEKAS GIGITAN, JUMLAH LUKA GIGITAN, JUMLAH SYARAF DI SEKITAR GIGITAN JARAK DARI PORT DTRY SSP (LOKASI LUKA) GIGITAN DI KEPALA/WAJAH MASA INKUBASI PENDEK, SERANGAN TINGGI

GIGITAN PADA KAKI KEMATIAN RENDAH

GEJALA KLINIS
ENSEFALITIS AKUT, FULMINANT, FATAL
MASA INKUBASI 1 MINGGU, 1-2 BULAN, BBRP TH (> 6 TH) : HEWAN TIMBUL GJL > 2 MINGGU (20 HARI-8 MINGGU) MANUSIA TIMBUL GJL 2-3 MINGGU SMP 1 TAHUN FASE KLINIS FASE PRODOMAL PENDEK FASE NEUROLOGI AKUT KOMA

GEJALA KLINIS
FASE PRODOMAL PENDEK : 2-10 HARI MALAISE, ANOREXIA, NYERI KEPALA, FOTOPOBIA, MUAL, MUNTAH NYERI TENGGOROKAN, DEMAM

FASE NEUROLOGI AKUT : GELISAH, CEMAS, HALUSINASI, LAKRIMASI, DILATASI PUPIL, SALIVASI (AKTIVITAS MENELAN SBBK SPASME & NYERI OTOT TENGGOROKAN), BERKERINGAT, SEBAG HIDROPOBIA KEJANG/KOMA KEMATIAN (2-7 HARI STLH ONSET) KRN KELUMPUHAN PERNAFASAN
RABIES PARALITIK TERJADI SEKITAR 20% PASIEN AKIBAT TERINFEKSI VIRUS RABIES KELELAWAR BBRP BTHN 30 HARI, TP JARANG YANG DPT SEMBUH & BTAHAN HIDUP

GEJALA PADA HEWAN

BENTUK GANAS (FURIOS RABIES):
MASA EKSITASI PANJANG, UMUMNYA AKAN MATI 2-5 HR STLH TANDA-TANDA TERLIHAT HEWAN MENJADI GALAK DAN PENAKUT, MEMBANGKANG PERINTAH MAJIKAN, NAFSU MAKAN HILANG, HIPERSALIVASI, EKOR DIANTARA 2 PAHA

BENTUK DIAM (DUMB RABIES):

MASA EKSITASI PENDEK, PARALISA CEPAT TERJADI BERSEMBUNYI DI TEMPAT GELAP DAN SEJUK, KEJANG2 DALAM WKT SINGKAT, LUMPUH TDK DAPAT MENELAN, HIPERSALIVASI

BENTUK ASYMPTOMATIS:
TANPA GEJALA, TIBA-TIBA MATI

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

GEJALA PADA MANUSIA

NAFSU MAKAN HILANG, SAKIT KEPALA, TIDAK BISA TIDUR, DEMAM TINGGI, MUAL DAN MUNTAH2 RASA PANAS PADA TEMPAT GIGITAN TAKUT AIR, SUARA KERAS, CAHAYA DAN ANGIN AIR LIUR, AIR MATA KELUAR BERLEBIHAN KEJANG2 DISUSUL KELUMPUHAN BIASANYA MENINGGAL DALAM WAKTU 4-6 HR SETELAH GEJALA KLINIS PERTAMA TIMBUL

GEJALA PADA MANUSIA

KALAU DIGIGIT DEKAT LEHER/KEPALA AKUT: DEMAM TINGGI KEJANG2 OTOT MULUT BERBUSA FOTOPHOBIA KESADARAN MENURUN BERTERIAK-TERIAK

Human rabies
Hospitalized human rabies, who was restrained while bedridden

Human rabies Hospitalized human rabies victim in restrains

Laboratory Diagnosis
Histopathology - 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 LABORATORIUM
ANTIGEN RABIES/ASAM NUKLEAT IMMUNOFLUORESCENS, PCR (JAR OTAK/KORNEA ISOLASI VIRUS INTRACEREBRAL PADA TIKUS YG BLM DISAPIH ENSEFALITIS & KEMATIAN SEROLOGI IMMUNOFLUORESCENS, TES Nt OBSERVASI HEWAN SELAMA 10 HARI PADA HEWAN RESERVOAR

Diagnosis of Rabies

Negri Body in neuron cell (source: CDC)

Positive DFA test (Source: CDC

Characteristic Negri Bodies

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

Management and Prevention

Pre-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 Prophylaxis
Wound 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.

PENANGGULANGAN
KASUS NON AKUT: CUCI LUKA DG SABUN/DETERGEN SLM 510 MENIT DI BAWAH AIR BERI ALKOHOL 70%/YODIUM BERI Ig ANTI RABIES DAN VAKSIN HEWAN KIRIM KE DINAS PETERNAKAN ORANG YANG DIGIGIT RS KHUSUS INFEKSI

PENANGGULANGAN
KASUS AKUT: VAKSIN EFEK SAMPING: MENINGITIS + GJL SEPERTI RABIES YODIUM TDK MEMBANTU KRN VIRUS SDH MSK Ig ANTI RABIES CEGAH VIRUS TDK MENYEBAR KE SYARAF OTAK ISOLASI PENDERITA BISA MENULARKAN OBAT TDK ADA, TERAPI SYMPTOM: ANTI KEJANG, OBAT CEGAH INFEKSI SEKUNDER, OBAT PENENANG

Rabies Vaccines
The 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 & PENCEGAHAN

VAKSINASI : VAKSIN SEL DIPLOID MANUSIA (HDCV) VAKSIN RABIES TERABSORPSI (RVA) VAKSI SEL EMBRIO AYAM DIMURNIKAN (PCEC) VAKSIN JARINGAN SARAF VAKSIN EMBRIO BEBEK VIRUS HIDUP DILEMAHKAN
TIPE ANTIBODI RABIES : Ig RABIES MANUSIA (HRIG) SERUM ANTIRABIES KUDA

IMMUNITAS & PENCEGAHAN

PENCEGAHAN SEBELUM PEMAPARAN : VAKSINASI PADA INDIVIDU BERESIKO TINGGI PENCEGAHAN SETELAH PEMAPARAN : PENATALAKSANAAN & PENGENDALIAN :

Control of Rabies
Urban - 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 animals

Wildlife - 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 meningkat Jumlah vaksin terbatas Vaksin rabies pasca paparan mahal (VeroRab 4x suntikan/bulan Sumber: muntah, ludah pasien Sulit edukasi masyarakat untuk:
Eradikasi anjing liar Henti makan daging anjing

Skor LARAT
LARAT: nama titik terluar NKRI, yang berbatasan langsung dengan Samudra Hindia Probability/Peluang kejadian Rabies pada pasien gigitan anjing saat KLB Rumus
1 1 + e-(F)

Skor LARAT
F = 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
No 1 2 3 4 Variasi Selisih waktu gigitan anjing Lokasi luka gigitan anjing Karakteristik anjing (ada 7 karakteristik) Akibat kematian anjing < 2 bulan 2 bulan Kepala, wajah, leher, dada, punggung Lengan, tangan, perut, tungkai, kaki Dominan Rabies ( 4 sifat) Tidak dominan Rabies (< 4 sifat) Anjing 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 Kategori Skor 2 0 1 0 3 0

3 0 9 0

Skor maksimum Skor minimum

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