1. herpesviridae-unimal.ppt

Oleh :

Dr.dr.Hj.Efrida Warganegara, M.Kes., Sp.MK

august 2003dn

1. HERPES SIMPLEKS VIRUS TYPE 1


3. VARICELLA ZOSTER VIRUS

4. EPSTEIN BARR VIRUS

5. CYTOMEGALO VIRUS

6. HUMAN HERPES VIRUS TYPE 6





3. VARICELLA ZOSTER VIRUS

4. EPSTEIN BARR VIRUS

5. CYTOMEGALO VIRUS




HERPES VIRUSES

Mengandung bbp patogen yg paling penting pd manusia

Dikharakteristikkan dgn adanya infeksi latent yg diikuti infeksi primer

Masa latent menghasilkan gejala-gejala rekurent yang tetap persisten sepanjang kehidupan individu yang terinfeksi

Adalah “ubiquitous” pada manusia, misal hampir semua individu telah terinfeksi dengan HSV type-1

KEY CONCEPS

HERPES VIRUSES

Kebanyakan infeksi adalah asymptomatikSecara klinik :

Memperlihatkan suatu spektrum dr penyakit

Bbp memp. host yg luas, sedangkan yg lain memp. host yg sempit

Kemampuannya utk tetap sbg infeksi yg persisten sepanjang hidup dan mengalami reaktivasi secara periodeik

Dapat diobati dgn antiviral, namun antiviral tak dpt mencegah rekurent

Terakhir, vaksin vericella telah tersedia

HERPES VIRUSESKEY CONCEPS

Subfamily Virus Abbreviation

Alphaherpesvirinae Human herpes virus 1 Herpes simplex type 1 HSV-1Human herpes virus 2 Herpes simplex type 2 HSV-2Human herpes virus 3 Varicella-zoster virus VZV

Gammaherpesvirinae Human herpes virus 4 Epstein-Barr virus EBVHuman herpes virus 8 Kaposi’s sarcoma HHV-8

related virus

BetaherpesvirinaeHuman herpes virus 5 Cytomegalovirus CMVHuman herpes virus 6 Herpes lymphotropic virus HHV-6Human herpes virus 7 Human herpes virus 7 HHV-7

HERPES VIRUSESCLASSIFICATION FAMILY HERPESVIRIDAE

VIRUS MEANS OF PORTAL OF ENTRY INITIALTRANSMISSION TARGET CELLS

HSV-1 Direct contact Mucous membrane, skin EpithelialHSV-2 Direct contact Mucous membrane, skin EpithelialVZV Inhalation, Respiratory tract Epithelial direct contact mucous membranes ? CMV Saliva, blood, Blood stream, Neutrophils, urine ? mucous membranes monocytes, Semen ? othersEBV Saliva, blood Mucous membranes, B lymphocytes,

blood stream salivary glandsHHV-6 Respiratory, ? T lymphocytes close contact ?HHV-7 ? ? T lymphocytesHHV-8 Saliva ? ?

HERPES VIRUSESTRANSMISSION OF HUMAN HERPES VIRUSES

HERPES VIRUSESVIRAL REPLICATION

Sangat tersebar luas dlm populasi Memperlihatkan host yg luas, mampu

bereplikasi dlm banyak tipe sel Tumbuh dgn cepat dan sifat cytolytic

yg tinggi Bertanggungjawab pd penyakit-

penyakit : gingivostomatitis keratoconjunctivitis encephalits genital herpes infections of newborn

Seringkali latent dlm sel syaraf

HERPES SIMPLEX VIRUSHERPES SIMPLEX VIRUS

Kedua virus berbeda dalam Kedua virus berbeda dalam cara transmisinya :cara transmisinya : HSV-1 disebarkan mel. kontak, HSV-1 disebarkan mel. kontak,

biasanya melibatkan saliva yg biasanya melibatkan saliva yg terinfeksiterinfeksi

HSV-2 ditransmisikan mel. HSV-2 ditransmisikan mel. hubungan seksual atau dari ibu hubungan seksual atau dari ibu yang terinfeksi pada genitalnya yang terinfeksi pada genitalnya ke bayinyake bayinya


TRANSMISI


Infection Predominant Frequency AgeInfection Predominant Frequency Age Usual Usual RecurrenceRecurrence virus typevirus type group outcome group outcome

INFECTIONS ASSOCIATED WITH HERPES SIMPLEX VIRUS

Ocular herpes Ocular herpes 1 1 Common Common AllAll Resolution Resolution YesYes visual impairmentvisual impairment

Oral herpesOral herpes 1 1 >> 2 2 Very common Very common AllAll Resolution Resolution YesYesGenital herpes 2 Genital herpes 2 >> 1 1 Common Common Adolescence, ResolutionAdolescence, Resolution

YesYes adultsadults

Neonatal herpes 2 Neonatal herpes 2 >> 1 1 Very rare Very rare 0 – 4 weeks Developmental0 – 4 weeks Developmental NoNoimpairmentimpairment

Meningo-Meningo- 2 2 Un Un Adolescence, ResolutionAdolescence, ResolutionNoNo

encephalitisencephalitis common common adults adultsEncephalitisEncephalitis 1 1 Very rare Very rare AllAll Severe neurologic Severe neurologic NoNo

impairmentimpairmentDisseminated Disseminated 1 1 >> 2 2 Rare Rare AllAll Resolution or Resolution or NoNoherpesherpes death death


CLINICAL FINDINGSCLINICAL FINDINGS

Vesicular eruption at the skin or mucous membrane

Incubation period is short : 3 – 5 days, with a range of 2 – 12 days Clinical manifestation 2 categoriesPrimary infectionReactivation

HSV-1 : oropharyngeal areaHSV-2 “ genital

CLINICALCLINICAL HSV-1HSV-1 HSV-HSV-22

Primary infectionGingivostomatitis + -Pharyngotonsilitis + -Keratoconjunctivitis + -Neonatal infections ± +



Recurrent infection

Cold sores, fever blisters + -

Keratitis + -

Primary or recurrent infectionCutaneous herpes

Skin above the waist + -Skin below the waist - +Hands or arms + +

Herpetic whitlow + +Eczema herpeticum + -Genital herpes ± +Herpes encephalitis + -Herpes meningitis + +



• Oropharyngeal disease : cluster of vesicles, most commonly localized at the border of the lip, painful, 4 – 5 days

• Keratoconjunctivitis : common & appear as dendritic keratitis or corneal ulcers or vesicles on the eyelids

• Genital herpes : common & tend to be mild, a limited number of vesicles, heal in 10 days

RECURRENT INFECTION


Reactivation

Provocation :• Common cold

– UV• Underlying disease

– Stress• Hormonal (menstrual cycle)

HSV-2 : Oncogenic virus Ca-cervix & vulva

transformation of cell cultureinoculation of animal tumor


IMMUNITY

• Many newborns acquire passively transferred maternal Abs, lost during 6 months, not totally protected against infection of newborns

• During primary infections, IgM Abs appear transiently, and followed by IgG & IgA that persist for long period

• Abs do not prevent reinfection or reactivation of latent virus, but maybe subsequent disease


LABORATORY DIAGNOSIS

• ISOLATION & IDENTIFICATIONSpecimens : swab or vesicle fluidHSV has a wide host range ------------- many cell culture system are susceptible Appearance of CPE in cell cultures in 2 – 3 days identified by Nt test or immunofluorescence staining Hybridization using DNA probes & DNA

amplification

• SEROLOGY Abs appear in 4 – 7 days after infection, reach a peak after 2 – 4 weeks

can be measured by Nt, CF, ELISA, RIA, IF


TREATMENT

• Inhibitors of viral DNA synthesis

• The drugs inhibits virus replication & suppress clinical manifestation

• HSV remain latent in sensory ganglia

• Acyclovir (acycloguanosine) : topical, intravenous, oral

• Vidarabine : more toxic

Virus Syndrome Frequency Age group Tissue Usual involved outcome

INFECTIONS ASSOCIATED WITH OTHER HERPES VIRUSESINFECTIONS ASSOCIATED WITH OTHER HERPES VIRUSES

Cytomegalo Congenital Common Newborn Brain, eye, Developmental virus infection liver, spleen, problems,

other death Mononucleosis Common Adolescent, Lymph Resolution

adult nodes, liver

Hepatitis Uncommon Adolescent Liver Resolution adult

Pneumonia Common in All Lung Death immunosuppressed patients

Retinitis Common in All Eye Blindness immunosuppressed patients



Epstein- Mononucleosis Very common All Lymph ResolutionBarr nodes, liver,virus spleen

Lymphomas Very rare All Lymph Death nodes, liver, spleen, brain

VZV Chickenpox Very common All Skin, others Resolution, uncommon rarely death

Shingles Common Older Skin, nerves Resolution, (Zoster) adults others chronic pain,

uncommon rarely deathHHV-6 Roseola Very common Infants Skin Resolution

Febrile Common Infants Brain Resolution, convulsions developmental

problems



HHV –7 RoseolaHHV –7 Roseola Common Common Infants SkinInfants Skin Resolution Resolution

Kaposi’s Kaposi’s CommonKaposi’s Kaposi’s Common AdultsAdults Skin Death Skin Death

Sarcoma sarcoma ? in immuno-Sarcoma sarcoma ? in immuno- “metastatic” “metastatic”Associated suppressedAssociated suppressedVirus patientsVirus patients

(HHV-8) Lymphomas Uncommon Adults Body(HHV-8) Lymphomas Uncommon Adults Body Death Death in immuno-in immuno- cavities cavities suppressedsuppressed patientspatients

– Varicella (chickenpox) :Varicella (chickenpox) :a mild, highly contagious disease a mild, highly contagious disease

chiefly in childrenchiefly in children characterized clinically by a characterized clinically by a

generalized vesicular eruption of the generalized vesicular eruption of the

skin & mucous membranesskin & mucous membranes– The disease may be severe in adults & The disease may be severe in adults &

immunocompromised childrenimmunocompromised children

VARICELLA-ZOSTER VIRUS (VZV)VARICELLA-ZOSTER VIRUS (VZV)

Zoster (shingles) a sporadic, incapacitating disease of

adults or immunocompromised individuals

characterized by rash limited to distribution to the skin innervated by a single sensory ganglion

lesions similar to those of varicella


Varicella : route of infection is the mucosa of the upper respiratory tract or conjunctiva

blood multiple cycle of replication

skin


PATHOGENESIS

Zoster skin lesion histopathologicaly identical to

varicella

acute inflammation of the sensory nerve & ganglia

often only a single ganglion may be involved

as a rule the distribution of lesions in the skin corresponds closely to the areas of innervation from an individual dorsal root ganglion


Varicella Herpes Zoster Varicella Herpes Zoster


• Previous infection with varicella is believe to confer lifelong immunity to varicella

• However, zoster can occur in the presence of relatively high level of Nt Ab to varicella


IMMUNITY


Laboratory diagnosis

Stained smear of scraping or swabs of the base vesicles :multinucleated giant cells

Virus isolated from vesicle fluid using culture of human cells 3 – 7 days

Cytopathic effects develop more slowly


Treatment

Gamma globulin of high VZV Ab titer (VZ Ig) can be used to prevent the development of the illness of immunocompromised patients exposed to varicella

It has no therapeutic value once varicella has started

Antiviral : acyclovir, valacyclovir, vidarabine

Dr.dr. Efrida Warganegara, M.Kes., Dr.dr. Efrida Warganegara, M.Kes., Sp.MKSp.MK

INTRODUCTIONINTRODUCTIONThe largest & most complex of viruses knownSmallpox first appeared in China and the Far East at least 2000 years ago.The family encompasses a large group of agents,

morphologically similar, share a common nucleoprotein

antigenThe group includes variola virus

etiologic agent of smallpox, disease has most affected humans throughout the worldrecorded history until elimination in 1977

INTRODUCTIONINTRODUCTIONEradication & vaccination all over the world started by WHO (1967)Smallpox has been declared eradicated from the world (May 1980) after an extensive campaign coordinated by WHOVaccinia virus is under intensive study as a vector for introducing active immunizing genes as live-virus vaccines for a variety of viral diseases of humans & domestic animals

POXVIRUSES CAUSING DISEASE IN HUMANSPOXVIRUSES CAUSING DISEASE IN HUMANS

Genus Virus Primary Disease

hostOrthopoxvirus Variola Humans Small pox (now extinct)

Vaccinia Humans Localized lesion, usedfor smallpox vaccination

Buffalopox Water buffalo Human infection rare, local

Monkeypox Monkeys Human infection rare,general

Cowpox Cows Human infection rare, local

Parapoxvirus Orf Sheep Human infection rare, local

Pseudocowpox Cows Milkers’ nodes

Bovine papular Cows

stomatitis

Molluscipoxvirus Molluscum Humans Many benign skin nodules

contagiosum

Yatapoxvirus Tanapox Monkeys Human infection rare, local

Yabapox Monkeys Human infection very rare, accidental, localized skin tumor

Subfamily: Genus: Members:

Chordopoxvirinae

Avipoxvirus fowlpox virus

Capripoxvirus sheeppox virus

Leporipoxvirus myxoma virus

Molluscipoxvirus Molluscum contagiosum

Orthopoxvirus vaccinia virus

Parapoxvirus orf virus

Suipoxvirus swinepox virus

Yatapoxvirus Yaba monkey tumor virus

Entomopoxvirinae

Entomopoxvirus AMelolontha melolontha entomopoxvirus

Entomopoxvirus B Amsacta moorei entomopoxvirus

Entomopoxvirus CChironomus luridus entomopoxvirus

VIRUS MORPHOLOGYVIRUS MORPHOLOGY

VIRUS REPLICATIONVIRUS REPLICATION Multiplication cycle takes place in the

cytoplasm, in which they form inclusion bodies

Nuclear factors involved in transcription and virion assembly

Propagation in the laboratory :most poxviruses can be propagated on the chorioallantoic membrane of the 10 – 12 days old chick embryo, form

circumscribed pocks, Ø 2 - 3 mm or in cell cultures

Molluscum contagiosum virus has not so far been grown in the laboratory

VIRUS REPLICATIONVIRUS REPLICATION

POXVIRUS INFECTIONS IN POXVIRUS INFECTIONS IN HUMANS : VACCINIA & VARIOLAHUMANS : VACCINIA & VARIOLA

Control & eradication of smallpox :Control & eradication of smallpox : Edward Jenner (1798) introduced

vaccination with live cowpox virus In 1967 WHO introduced a worldwide

campaign to eradicate smallpox The last Asiatic case occurred in

Bangladesh (1975) The last natural victim was diagnosed

in Somalia (1977)

The main reasons for outstanding The main reasons for outstanding success of vaccination & eradication ;success of vaccination & eradication ;

The vaccine was easily prepared, stable, safe and effective

It could be given simply by personnel in the field

Humans are the only natural host

Only I type of smallpox virus

Comparison of vaccinia & variola virus :Comparison of vaccinia & variola virus :

Vaccinia virus :Vaccinia virus :

Used for smallpox vaccine

Has a broad host range

Nucleotide sequences 192 kb

Variola virus :Variola virus :

Has narow host range

Nucleotide sequences 186 kb

PATHOGENESIS & PATHOLOGY OF PATHOGENESIS & PATHOLOGY OF SMALLPOXSMALLPOX

Portal of entry : mucous membranes of respiratory tract

1. Primary multiplication in lymphoid tissue draining the site of entry

2. Transient viremia & infection of RE cells throughout the body

3. Secondary phase of multiplication4. Secondary & more intense viremia5. Clinical disease

Smallpox was transmitted by respiratory route Smallpox was transmitted by respiratory route from lesions in the respiratory tract of patients from lesions in the respiratory tract of patients in the early stage of the disease. in the early stage of the disease. During the 12 day incubation period, the virus During the 12 day incubation period, the virus was distributed initially to the internal organs was distributed initially to the internal organs and then to the skin. and then to the skin. Variola major caused severe infections with Variola major caused severe infections with 20-50% mortality, variola minor with <1% 20-50% mortality, variola minor with <1% mortality. mortality. Management of outbreaks depended on the Management of outbreaks depended on the isolation of infected individuals and the isolation of infected individuals and the vaccination of close contacts.vaccination of close contacts. The vaccine was highly effective. If given The vaccine was highly effective. If given during the incubation period, it either during the incubation period, it either prevented or reduced the severity of clinical prevented or reduced the severity of clinical symptoms. symptoms.

At least 9 different poxviruses cause disease in humans, but variola virus (VV) and vaccinia are the best known. VV strains are divided into variola major (25-30% fatalities) and variola minor (same symptoms but less than 1% death rate).

"Variolation" = the administration of material from known smallpox cases (hopefully variola minor!!!) to protect recipients - practiced for at least 1000 years (Chinese) but risky - Jenner was nearly killed by variolation in 1756!

IMMUNITYIMMUNITYAn attack of smallpox complete protection against re-infectionVaccination with vaccinia induced immunity against variola virus at least 5 years & sometimes longerNeonates of vaccinated, immune mother receive maternal antibody transplacentally, persists for several months. After that time, artificial immunity can be produced by vaccination

Molluscum contagiosum virusMolluscum contagiosum virus Molluscum contagiosum is a specifically human disease of worldwide distribution. The incubation period varies from 1 week to 6 months.

The lesion begins as a small papule and gradually grows into a discrete, waxy, smooth, dome-shaped, pearly or flesh-coloured nodule. Usually 1-20 lesions but occasionally they may be present in

hundreds. In children, the lesions are found on the trunk and the proximal extremities. In adults they tend to occur on the trunk, pubic area

and thighs. Individual lesions persist for about 2 months, but the disease usually lasts 6 to 9

months. Constitutional disturbance is rare.

Molluscum contagiosum virusMolluscum contagiosum virusThe disease occurs world-wide and is spread by direct contact or fomites. In general it tends to occur in children. The disease by may transmitted from skin to skin after sexual intercourse. A diagnosis can usually be made on clinical appearance

alone. The diagnosis can be supported by EM. Unlike other poxviruses, molluscum have not been demonstrated to grow in cell culture. Infection is usually benign and painless, with spontaneous recovery in most cases. Where treatment is required for cosmetic reasons, various procedures are available such as curretage, cryotherapy with liquid nitrogen, silver nitrate etc. which are routinely used for the removal of warts.

SYMPTOMSSYMPTOMS

Molluscum contagiosum is a superficial skin infection.

The virus invades the skin causing the appearance of firm, flesh-colored, doughnut-shaped bumps, about 2-5 mm in diameter.

Their sunken centers contain a white, curdy-type material. The bumps can occur almost anywhere on the body including the buttocks

CAUSECAUSE

Molluscum contagiosum is caused by a virus belonging to the poxvirus family. Close physical contact is usually necessary

for transmission; indirect transmission from shared towels, swimming pools, etc., may also be responsible for

infection. The incubation period varies from several weeks to several months. Shaving or scratching may cause the infection to spread.

COMPLICATIONS

If scratched, the bumps can become infected with bacteria.

DIAGNOSIS

The diagnosis is based on the typical appearance of the bumps.

No diagnostic test for this virus is available.

TREATMENTAvoid shaving infected areas. Treatment is done for aesthetic reasons and to

prevent spread of the virus. The goal of treatment is to remove the soft center, after which the bump goes away. Your health care provider may use a curette (sharp, spoon-shaped instrument) to remove the

centers. Freezing the lesion with liquid nitrogen or nitrous

oxide is an alternative treatment.

RISKS OF TREATMENT

There is a slight risk of minimal scarring.

Observe for signs of infection that include redness, swelling, pus-like drainage, or increased

soreness at the site.

1. herpesviridae-unimal.ppt

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