Oleh : Dr.dr.Hj.Efrida Warganegara, M.Kes., Sp.

MK
august 2003 dn

HERPES VIRUSES
1. HERPES SIMPLEKS VIRUS TYPE 1

2. HERPES SIMPLEKS VIRUS TYPE 2

3. VARICELLA ZOSTER VIRUS

4. EPSTEIN BARR VIRUS

5. CYTOMEGALO VIRUS 6. HUMAN HERPES VIRUS TYPE 6 7. HUMAN HERPES VIRUS TYPE 7 8. HUMAN HERPES VIRUS TYPE 8

HERPES VIRUSES
KEY CONCEPS

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

HERPES VIRUSES
KEY CONCEPS
Kebanyakan infeksi adalah asymptomatik Secara 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 VIRUSES
CLASSIFICATION FAMILY HERPESVIRIDAE

Subfamily
Alphaherpesvirinae
Human herpes virus 1 Human herpes virus 2 Human herpes virus 3

Virus
Herpes simplex type 1 Herpes simplex type 2 Varicella-zoster virus

Abbreviation
HSV-1 HSV-2 VZV

Gammaherpesvirinae
Human herpes virus 4 Human herpes virus 8 Epstein-Barr virus Kaposis sarcoma related virus EBV HHV-8

Betaherpesvirinae
Human herpes virus 5 Human herpes virus 6 Human herpes virus 7 Cytomegalovirus Herpes lymphotropic virus Human herpes virus 7 CMV HHV-6 HHV-7

HERPES VIRUSES
TRANSMISSION OF HUMAN HERPES VIRUSES
VIRUS MEANS OF TRANSMISSION PORTAL OF ENTRY INITIAL TARGET CELLS

HSV-1 HSV-2 VZV CMV EBV HHV-6 HHV-7 HHV-8

Direct contact Direct contact Inhalation, direct contact Saliva, blood, urine ? Semen ? Saliva, blood Respiratory, close contact ? Saliva

Mucous membrane, skin Mucous membrane, skin Respiratory tract mucous membranes ? Blood stream, mucous membranes Mucous membranes, blood stream ? ? ? ?

Epithelial Epithelial Epithelial Neutrophils, monocytes, others B lymphocytes, salivary glands T lymphocytes T lymphocytes ?

HERPES VIRUSES
VIRAL REPLICATION

HERPES SIMPLEX VIRUS

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 VIRUS

TRANSMISI

Kedua virus berbeda dalam cara transmisinya :

HSV-1 disebarkan mel. kontak, biasanya melibatkan saliva yg terinfeksi

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

HERPES SIMPLEX VIRUS

INFECTIONS ASSOCIATED WITH HERPES SIMPLEX VIRUS
Infection Predominant Frequency Age virus type group
Ocular herpes 1 Common All

Usual outcome

Recurrence

Oral herpes Genital herpes

1>2 2>1

Neonatal herpes 2 > 1 Meningoencephalitis Encephalitis Disseminated herpes 2 1 1 >2

Resolution Yes visual impairment Very common All Resolution Yes Common Adolescence, Resolution Yes adults Very rare 0 4 weeks Developmental No impairment Un Adolescence, Resolution No common adults Very rare All Severe neurologic No impairment Rare All Resolution or No death

HERPES SIMPLEX VIRUS

CLINICAL 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 categories
Primary infection Reactivation
HSV-1 : oropharyngeal area HSV-2 genital

HERPES SIMPLEX VIRUS

CLINICAL FINDINGS

CLINICAL
Primary infection Primary Recurrent or infection recurrent infection
Gingivostomatitis Cutaneous Cold sores,herpes fever blisters Pharyngotonsilitis Skin above the waist Keratitis Keratoconjunctivitis Skin below the waist Neonatal infections Hands or arms Herpetic whitlow Eczema herpeticum Genital herpes Herpes encephalitis Herpes meningitis

HSV-1
+ ++ + ++ - + + + + +

HSV-2
-+ + + + + +

HERPES SIMPLEX VIRUS

CLINICAL FINDINGS RECURRENT INFECTION

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

HERPES SIMPLEX VIRUS

Reactivation Provocation : Common cold UV Underlying disease Stress Hormonal (menstrual cycle) HSV-2 : Oncogenic virus Ca-cervix & vulva transformation of cell culture inoculation of animal tumor

HERPES SIMPLEX VIRUS

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

HERPES SIMPLEX VIRUS

LABORATORY DIAGNOSIS

ISOLATION & IDENTIFICATION

Specimens : swab or vesicle fluid HSV 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

HERPES SIMPLEX VIRUS

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

INFECTIONS ASSOCIATED WITH OTHER HERPES VIRUSES

Virus Syndrome Frequency Age group Tissue involved
Common Newborn

Usual outcome

Cytomegalo Congenital virus infection

Brain, eye, Developmental 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

INFECTIONS ASSOCIATED WITH OTHER HERPES VIRUSES

Virus Syndrome Frequency Age group Tissue involved
Very common All

Usual outcome

Epstein- Mononucleosis Barr virus Lymphomas

Very rare

All

VZV

Chickenpox Shingles (Zoster)

Very common Common

All Older adults

HHV-6

Roseola Febrile convulsions

Very common Infants Common Infants

Lymph Resolution nodes, liver, spleen Lymph Death nodes, liver, spleen, brain Skin, others Resolution, uncommon rarely death Skin, nerves Resolution, others chronic pain, uncommon rarely death Skin Resolution Brain Resolution, developmental problems

INFECTIONS ASSOCIATED WITH OTHER HERPES VIRUSES

Virus Syndrome Frequency Age group Tissue involved Common Common Infants Adults Skin Skin Usual outcome Resolution Death

HHV 7 Roseola Kaposis Kaposis

Sarcoma sarcoma ? in immunoAssociated suppressed Virus patients (HHV-8) Lymphomas Uncommon Adults in immunosuppressed patients

metastatic

Body cavities

Death

VARICELLA-ZOSTER VIRUS (VZV)

Varicella (chickenpox) : a mild, highly contagious disease chiefly in children characterized clinically by a generalized vesicular eruption of the skin & mucous membranes The disease may be severe in adults & immunocompromised children

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-ZOSTER VIRUS (VZV)

PATHOGENESIS

Varicella : route of infection is the mucosa of the upper respiratory tract or conjunctiva blood multiple cycle of replication skin

VARICELLA-ZOSTER VIRUS (VZV)

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-ZOSTER VIRUS (VZV)

Varicella Herpes Zoster

VARICELLA-ZOSTER VIRUS (VZV)

IMMUNITY

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

VARICELLA-ZOSTER VIRUS (VZV)

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

VARICELLA-ZOSTER VIRUS (VZV)

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., Sp.MK

INTRODUCTION
The largest & most complex of viruses known Smallpox 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 antigen The group includes variola virus etiologic agent of smallpox, disease has most affected humans throughout the world recorded history until elimination in 1977

INTRODUCTION
Eradication & 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 WHO Vaccinia virus is under intensive study as a vector for introducing active immunizing genes as livevirus vaccines for a variety of viral diseases of humans & domestic animals

POXVIRUSES CAUSING DISEASE IN HUMANS

Genus
Orthopoxvirus

Virus
Variola Vaccinia

Primary host
Humans Humans

Disease
Small pox (now extinct)
Localized lesion, used for 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: Avipoxvirus
Capripoxvirus Leporipoxvirus
Molluscipoxvirus

Members: fowlpox virus

sheeppox virus myxoma virus Molluscum contagiosum vaccinia virus orf virus swinepox virus

Chordopoxvirinae

Orthopoxvirus Parapoxvirus Suipoxvirus

Yatapoxvirus
Entomopoxvirus A Entomopoxvirinae Entomopoxvirus B Entomopoxvirus C

Yaba monkey tumor virus Melolontha melolontha entomopoxvirus Amsacta moorei entomopoxvirus Chironomus luridus entomopoxvirus

VIRUS MORPHOLOGY

VIRUS 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, 2 - 3 mm or in cell cultures Molluscum contagiosum virus has not so far been grown in the laboratory

VIRUS REPLICATION

POXVIRUS INFECTIONS IN HUMANS : VACCINIA & VARIOLA

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 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 :

Vaccinia virus : Used for smallpox vaccine Has a broad host range Nucleotide sequences 192 kb Variola virus :

Has narow host range Nucleotide sequences 186 kb

PATHOGENESIS & PATHOLOGY OF SMALLPOX

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 multiplication 4. Secondary & more intense viremia 5. Clinical disease

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

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

Molluscum 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 virus

The 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.

SYMPTOMS
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

CAUSE
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.

 TREATMENT
Avoid 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.