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 SS RNA, LURUS, NON SEGMENTED, - SENSE, BM 4,6

JUTA, 12 kb

PROTEIN 1 GLIKOPROTEIN ENVELOPE

REPLIKASI SITOPLASMA, VIRION BERTUNAS DI M PLASMA

ENVELOPE ADA

CIRI KHAS 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 fox, bats

Middle East wolf, dog

Asia dog

Africa dog, mongoose, antelope

N America foxes, skunks, raccoons,

insectivorous bats

S America dog, vampire bats

KERENTANAN HEWAN THD RABIES VIRUS

SANGAT

TINGGI

TINGGI SEDANG RENDAH

RUBAH HAMSTER ANJING TUPAI

COYOTE MUSANG LEMBU

SERIGALA RAKUN DOMBA

ANJING

HUTAN

KUCING KAMBING

KELELAWAR 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 D’TRY 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

Negri Body in neuron cell

(source: CDC)

Positive DFA test (Source: CDC

Diagnosis of Rabies

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 5-

10 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 Variasi Kategori Skor

1 Selisih waktu gigitan anjing < 2 bulan ≥ 2 bulan

2 0

2 Lokasi luka gigitan anjing Kepala, wajah, leher, dada, punggung Lengan, tangan, perut, tungkai, kaki

1 0

3 Karakteristik anjing (ada 7 karakteristik)

Dominan Rabies (≥ 4 sifat) Tidak dominan Rabies (< 4 sifat)

3 0

4 Akibat kematian anjing 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

3 0

Skor maksimum Skor minimum

9 0

Analisis sensitivitas dan

spesifisitas pada ROC curve, skor

≥ 5 memberikan prediksi Rabies

sehingga perlu mendapat prioritas

vaksinasi di saat KLB