INFEKSI VIRUS DI

KULIT
Modul Kulit & Jaringan
Penunjang

Andriansjah, M. Biomed., PhD

dr. T. Mirawati S., PhD
dr. Mardhia

References:
Jawetz, Melnick, and Adelbergs : Medical
Microbiology, ed. 23, Appleton and Lange,
California, 2003 (chapters 33, 34, 43)

Shanson, DC. Microbiology in Clinical Practice.

Butterworth Heinemann, Oxford, 1999

Murray. PR, et al. : Medical Microbiology, The

CV Mosby Company, St Louis, 2002 (chapters
54, 55 )

PORT DE ENTREE
Mild trauma
Virus group Produce local symptoms at Produce generalized infection
portal of entry
+ specific organ diseases
Papillomavirus

most types

Herpesvirus herpes simplex virus

Poxvirus
Retrovirus

molluscum contagiosum virus

Human immunodeficiency
virus
17

Injection
Virus group Produce local symptoms at
Produce generalized infection
portal of entry
+ specific organ diseases
Hepadnavirus

Hepatitis B virus

Flavivirus

Hepatitis C virus

Retrovirus

HIV

Bites
Virus group
Produce local symptoms at
Produce generalized infection
portal of entry
+ specific organ diseases
Flavivirus
Rhabdovirus

dengue virus
yellow fever virus
rabies virus

Systemic infection with skin manifestation

Disease

Virus

Route of infection

Measles Measles virus

(Paramyxoviridae)

Respiratory

Rubella

Respiratory, transplacental

Togaviridae

Fifth Disease Parvovirus

Roseola

Respiratory

Roseolovirus
Oral secretions
(Herpesviridae)

Varicella/ Varicella zoster Respiratory, close contact

Zoster
virus (herpesviridae)
Hemorrhagic fever :
Dengue virus, Chikungunya virus, Hantaan virus, etc
5

THE PATHOGENESIS OF MUCOCUTANEOUS LESIONS

HERPESVIRIDAE
Ukuran besar (120-200nm), berselubung, ikosahedral,

double-stranded DNA

HERPESVIRIDAE

Herpesviruse have a large, enveloped icosahedral capsids

containing double-stranded DNA genome.
Transcription :
3 phases

Immediate early proteins

Early proteins

Late proteins

Encode a large number of

proteins involved in DNA
synthesis (e.g. DNA
polymerase, thymidine kinase)
Cytolitic
8

HERPESVIRIDAE (1)
Karakteristik
Menyebabkan infeksi laten
Bertahan pada pasien terinfeksi dorman
Reaktivasi oleh immnuosupresi

Herpesviruses
Primary target Site of
Cells
Latency

Alphaherpesvirinae
Herpes simplex type 1

Mucoepithelial

Herpes simplex type 2

Mucoepithelial

Varicella zozter virus

Gammaherpesvirinae
Epstein-Barr virus
Kaposis sarcoma
related virus

Means of
spread

Neuron

Neuron
(sexually transmitted)
Mucoepithelial
Neuron
Close contact

B cells &
B cells
epithelial cells
B cells &other cells
B cells
saliva?

Close contact
Close contact
Respiratory and

Saliva
Close contacts (sexual),

Betaherpesvirinae
Cytomegalovirus
Monocytes, lympomonocytes.
Close contacts, transfussion,
cytes, epithelial cells lymphcytes
Tissue transplants,
and?
Transplacental
Herpes lymphotropic
T cells and?
T cells & ?
Respiratory & close contac
virus
Human herpesvirus 7
T cells and?
T cells & ?
?

10

Herpes simplex virus infection

Primary herpetic gingivostomatitis

Cold sores of recurrent herpes

labialis
Herpetic
whitlow

11

HSV-1
Site of latency
ganglia

HSV-2

Trigeminal ganglia

Age of primary infection Young children

Transmission

Contact (often saliva)

Sacral
Young adults
Sexual

12

MEKANISME PENYAKIT
Kontak langsung
Kelainan sitopatologi
Terhindar dari antibodi penyebaran via sel

pembentukan sinsitia
Bersifat laten di neuron
Reaktivasi imunosupresi, stress
Cell mediated immunity resolusi
Cell mediated immunopathologic gejala

13

PATHOGENESIS

14

15

Keratoconjunctivitis

Primary herpetic gingivostomatitis

Herpes simplex virus

infection

Herpetic whitlow

Cold sores of recurrent herpes

labialis
16

HERPES SIMPLEX TYPE 1

Primary gingivostomatitis in a chlid, acute gingivostomatitis in an Herpetic lesion on the tongue

of an adult, heavily coated and
thin-walled vesicles on an
adult (primary infection)
small round vesicles
erythematous base rupture-ulcers

Herpetic whitlow,
nurses and doctors
Primary infection of the skin,
by direct contact to any part of body
Stomatitis with secondary lesion
on skin, the face, neck and chest

Hepes simplex
mimicking
herpes zoster

Recurrent infection
vesicles on
an erythematous
base, pustules,
heal without scars
17

HERPES SIMPLEX TYPE 2

Genital herpes adult man

on the vulva of an
adult woman

on cervix of an adult woman

Genital herpes lesions
may be found on the vulva,
vagina or cervix,
perineum or buttocks

Herpetic infection of the eye (HSV 1 or 2),

primary, recurrent or neonatal eye infections
Vulvovaginitis in a child

18

Laboratory diagnosis
Cytopathology

Tzanck smear, pewarnaan giemsa :

Sel raksasa multinukleus,
Cowdry type A acidophilic intranuclear inclusion body.

Viral isolation and identification

Isolasi virus dari lesi, tenggorokan, SSP,feses infeksi
akut & reaktivasi
Isolasi pada kultur jaringan identifikasi dengan
pewarnaan immunofuloresence dengan antibody spesifik
PCR : membedakan HSV-1 & HSV-2

19

Serology
Antibodi muncul 4-7 hari setelah infeksi, puncak 2-4
minggu
Digunakan untuk studi epidemiologi

20

Tatalaksana

Antiviral dapat mencegah atau mempersingkat masa

infeksi primer atau rekuren herpes

tidak ada obat yang bisa menghilangkan infeksi laten

Pilihan obat untuk HSV-1 dan HSV-2:

- Acyclovir
- Penciclovir
- Valacyclovir
- Famciclovir
- Adenosine arabinoside
- Iododeoxyuridine
- Trifluridine

21

Pencegahan

Hindari kontak dengan lesi

Tenaga kesehatan:
Menggunakan hand scoen, mencuci tangan dengan sabun

Pasien dengan herpes genital :

Hindari berhubungan selama gejala muncul
Gunakan kondom

Wanita hamil sectio cesaria

Belum tersedia vaksin

22

LABORATORY EXAMINATION OF HERPES SIMPLEX

SEL NEURON ANTIBODI FLUORESEN

HERPES ENSEFALITIS FATAL

23

HISTOLOGI VESIKEL
A= VESIKEL INTRAEPIDERMAL
B= SEL RAKSASA BERINTI BANYA
C= DERMIS

24

25

VARICELLA ZOSTER VIRUS

26

Varicella-zoster virus

27

Spread of VZV in the body

Respiratory
tract

Lymphatics

Liver, spleen,
RES

Viremia

Fever
Malaise
Headache

Skin
Vesicle proggression:
Macule
Papule
Vesicle
Pustule
crust

Latency in neurons

28

Varicella (chickenpox, cacar air) Penyakit dengan

tingkat penularan tinggi,
Karakteristik : erupsi kulit dan mukosa
Immunosupresi, dewasa Lebih berat

Zoster (shingles)
Karakteristik : erupsi kulit terbatas satu gangglion
sensorik
Lesi sama dengan varicella

29

Mekanisme varicella-zoster virus

Port de entre sistem respirasi

Replikasi awal sistem respirasi

VZV menginfeksi sel epitel, fibroblas, sel T dan saraf

VZV membentuk sinsitia dan menyebar antar sel

Viremia lesi di kulit

VZV dapat bebas dari antibodi, cell-mediated

immune berperan dalam mengontrol infeksi

30

Mekanisme varicella-zoster virus (1)

Imunosupresi mengancam jiwa

Virus dorman ganglion dorsal dan ganglion saraf

kranial

Herpes zoster rekuren replikasi virus daerah

dermatom

Rekuren imunosupresi

31

ATENCY AND REACTIVATION OF

VARICELLA-ZOSTER VIRUS

32

Laboratorium
Cytology : similar to HSV

Tzanck smear

Samples : lesi kulit, spesimen respirasi, biopsi organ

Imunofluoresen

Antigen detection and PCR : sensitive

Virus isolation
Jarang dilakukan
Tingkat replikasi in vitro rendah
Serology
Deteksi antibodi untuk melihat imunitas terhadap VZV

33

Varicella zoster (VZV)

Gejala klinis
- lesi kulit berupa vesikel (chicken pox)
- Herpes zoster (bentuk lain manisfestasi infeksi
varicella zoster):
- lesi kulit yang amat nyeri di daerah dermatom tertentu,
biasanya unilateral
- Daerah yang tersering terkena adalah badan,
kepala, leher dan daerah oftalmik saraf trigeminus
- Dapat diikuti dengan neuralgia
Infeksi pada kehamilan
- Mempengaruhi kehamilan:
- persalinan prematur
- menyebabkan sindrom varisela kongenital (jarang
terjadi)
34

Varicella zoster (VZV)

Bayi dengan sindrom varisela kongenital
- sikatriks, atrofi ekstremitas
- tanda-tanda yang sesuai dengan kelainan sistem
saraf otonom
- mikrosefali dan atrofi kortikal
- kejang dan retardasi mental
- kelainan pada mata:
korioretinitis, mikroftalmia dan katarak.
Pengobatan
- acyclovir intravena

35

Varicella zoster (VZV)

36

Tatalaksana
Anak tidak diperlukan terapi
Dewasa dan pasien dengan imunosupresi atau infeksi
herpes zoster
Antiviral : acyclovir, famciclovir, valacyclovir

Control and prevention

Pasien imunosupresi :
Varicella-zoster immunoglobulin (VZIg) mencegah
viremia, inefektif untuk terapi
Live attenuated vaccine :
Oka strain : menginduksi antibodi dan cell mediated
immunity

37

Epidemiologi
Tersebar luas
Varicella menyebar melalui udara dan kontak langsung

38

HUMAN PAPILLOMA VIRUS

39

Human papillomavirus
- >100 types
HPV genome :
- dsDNA, circular
- regulatory region, early and
late
genes

40

HPV proteins
Protein

Function

E1
Binds DNA at ori, has helicase activity,
promotes viral DNA replication
E2
Binds DNA, helps E1, regulates mRNA synthesis
E4
Disrupts cytokeratin to promote release
E5
activates EGF receptor to promote growth
E6
binds to tumor supressor protein p53
E7
binds to tumor supressor protein p105RB

41

Replikasi
virus:
HPV tidak dapat
dikultur pada
jaringan
monolayer
HPV hanya dapat
dikultur pada
kultur
keratinocyte
cultured on raft
system
42

Replikasi Virus

Immune response
Innate dan cell mediated immunity penting untuk mengontrol
HPV; Koilocytes HPV bersembunyi

43

Clinical syndromes associated with HPVs

Syndromes
Common

HPV types
Rare

Cutaneous syndromes
Plantar wart
1,2
Common wart
2,4
Flat wart
3, 10
Epidermodysplasia
5, 8, 17
verruciformis
20, 36
Mucosal syndromes
Laryngeal papilloma
Oral papilloma
6,
Conjunctival papilloma
Condyloma acuminatum
Cervical intraepithelial
44
neoplasia, cancer

4, 63
1,7,26,29
27, 28, 41
9, 12, 14, 15, 19
21-25, 38, 47, 50

6, 11
11
6, 11
16, 18

2, 16
1, 2, 10, 16, 30, 44, 45
11, 31, 33, 35, 42-

44

Oncogenic potential :
High risk HPV
types 16, 18, 30, 31, 33,
35, 39, 45, 51, 52, 56
(cervical cancer)
Types 5, 8, etc (skin
cancer)

HPV oncogene is
necessary but not
sufficient to cause cancer

85% of cervical cancers

contain integrated HPV
genome. Breaking of E1
or E2 will inactivate
them, while the
expression of other
45
genes continues.

echanisms of spread of papillomavirus within the bod

Papilomavirus

Inoculation of
epithelium

Wart

Resolution
(latency)

Hand, foot,
throat, cervix
Local
multiplication

Cell transformation (?)

46

CLINICAL SYNDROMES
Skin warts
Usually on the hands and feet
Occur frequently in childhood or early adolescence
Deep plantar warts (verrucae plantaris), common
warts
(verrucae vulgaris), plane warts (verrucae planae).
Usually asymptomatic, although they may bleed &
can
be painful when located over weight bearing surface
or
point of friction.
Spontaneous resolution in 50% and 90% of children
whithin 1 and 5 years, respectively.

47

Epidermodysplasia verruciformis
- An autosomal recessive genodermatosis linked to gene
loci on chromosome 17
- Associated with many HPV types, mainly types :
2,3,10,5,,9,12,14,15, 17
- May resemble flat warts but more commonly resemble
Pithyasis versicolor, covering the torso and upper
extremities
- Mostly appear tn the first decade of life
- Highly correlated with malignant transformation, especially
in sun-exposed area
- Lesions are not contagious to healthy individuals.
48

GEJALA KLINIK
Anogenital warts
Genital warts (condyloma acuminata) terjadi pada epitelium
genitalia eksterna dan area perianal
90% disebabkan HPV tipe 6 dan 11
Jarang menjadi maligna

Cervical dysplasia, neoplasia

Infeksi traktus genitalia wanita oleh HPV tipe 16 dan 18,
berhubungan dengan cervical intraepithelial
neoplasia (CIN) dan kanker
Mild dysplasia : 40-70% spontaneously regress
Mild CIN moderate to severe dysplasia carcinoma

in situ cancer

49

GEJALA KLINIK (1)

Benign head and neck tumors
Oral papillomas
Laryngeal papilloma
- HPV-11
- Benigna
- Mengancam jiwa
- Pada anak atau dewasa
- Transmisi dari ibu ke bati saat melahirkan
- Rekurensi tinggi

50

Seed warts of the fingers

THE VARIOUS KINDS OF WARTS

Plantar warts
PLANTAR WARTS

Flat wart
FLAT WARTS
Condyloma acuminata
Genital warts
51

Patogenesis HPV

Menginfeksi jaringan kutaneus dan sel skuamos epitelia

Menginduksi tumor jinak
Beberapa lesi bisa menjadi karsinoma
DNA spesifik HPV terdapat di tumor

52

Diagnosis
Laboratorium:
Mendeteksi HPV dan
high risk HPV
Cytology
(keilocytotic
cells)
Electron Microscope
Immunofluorescent
dan immunostaining
Nucleic acid
hybridization
Polymerase chain
reaction (PCR)
PCR and hybridization
:
for type
determination
53

54

Terapi

Pembedahan
Caustic agents
Cryotherapy
DNA synthesis inhibitor(5-fluorouracil)

Pencegahan
Kontak langsung
Vaccine :
- Empty virus-like particle consist of L1 & L2 protein
- Bivalent (HPV-16 & 18), or tetravalent (HPV-16,18, 6,11)
- Prophylactic
Vaccine for cutaneous HPV is not yet available

55

POXVIRUS

56

POXVIRUSES

Orthopoxvirus

Parapoxvirus
57

MEMBERS
VIRUS

GENUS
Orthopoxvirus

Parapoxvirus

Moluscipoxvirus
Yatapoxvirus

PRIMARY HOST

Variola

Human

Vaccinia

Vaccine strain/human

Buffalopox

Water buffalo

Monkeypox

MOnkey

Cowpox

Cow

Orf

Sheep

Pseudopoxvirus

Cow

Bovine papular
stomatitis
Molluscum
contagiosum
Tanapox

Cow

Yabapox

Monkey

Human
Monkey

58

59

STRUKTUR
Virus terbesar dan komplek
Virion : oval atau brick-shaped, 400nm x 230 nm,
Genome : double-stranded DNA, linear
Proteins : lebih dari 100 polypeptides, banyak enzim
terdapat di inti, termasuk sistem transkripsi

60

POXVIRIDAE

Molluscum contagiosum
Genus : Molluscipoxvirus

61

Replikasi Poxvirus

62

VIRUS-ENCODED HOSTMODIFIER GENES

Virus menghasilkan growth factor mirip EGF
Beberapa gen poxvirus menghasilkan proteins
mirip gamma interferon receptor, IL-1 receptor,
dan complement binding protein

63

SMALLPOX CONTROL AND ERADICATION

Variolation : mortality rate 25% 1%

1798 : Edward Jenner memperkenalkan vaksinasi dengan

live cowpox

1967 : smallpox endemik pada 33 negara, 10-15 juta kasus/tahun

WHO mengkampanyekan eradikasi smallpox

Cases of smallpox were traced, and contact of the patient

and those in the immediate area were vaccinated

1975 : last case in Asia

1977 : Last case in Somalia

1979 : Smallpox was officially declared eliminated

64

SPREAD OF POXVIRUS WITHIN THE BODY

Virus

Inhalation or
Transmission by scabs
(less effective)

Lymph nodes

Multiplication in
upper respiratory tract

Lymphatics
(macrophages)

Primary viremia (blood)

Hemorrhage of
Spleen
2nd
Small vessel of dermis viremiaBone marrow
Additional lymph nodes
Rash & pox
65

GEJALA KLINIK
Smallpox
Inkubasi 5-17 hari
Variola major : mortality 15% - 40%
Variola minor : mortality ~1%
Febris, sakit kepala, nyeri punggung
Karakteristik lesi:
- Lesi dalam stadiumyang sama
- Sentrifugal
Involvement of visceral organ : spleen, liver, lung

66

Molluscum contagiosum

Inkubasi : 2 8 minggu
Kontak langsung
Lesi : nodular to wartlike : papul jernih
(pearly), umbilicated nodules
Predileksi : Trunk, genitalia dan ekstremitas
proximal
Molluscum contagiosum
epidermal keratinocyte
hypertrophy basal cell
hyperplasia,
in AIDS patient can be
generalize and recurrent

67

Variola / smalpox/ cacar

68

69

IMMUNITAS

There is serologic cross-reactivity among viruses

within a genus

Attack of smallpox complete protection

Vaccination with vaccinia protects at least 5 years

Antibody alone are not sufficient for recovery from

infection

Cell-mediated immunity is probably more important

70

LABORATORY DIAGNOSIS
Isolation and identification of virus

Specimen : skin lesion / vesicular fluid

Stability : remain viable in specimen for weeks, even

without refrigeration

inoculation onto the chorioallantoic membrane of

chick embryo 2-3 days :
- Vaccinia pocks : large, with necrotic center
- Variola pocks : smaller
- Cowpox and monkeypox : hemorrhagic pocks

Moluscum contagiosum : unculturable

71

Electron microscopy
Viral antigen detection
PCR
Serology
Cannot differentiated orthopoxviruses
Antibodies appear the first week of infection
HI, Nt, ELISA, RIA, Immunofluorescence

72

TREATMENT
Vaccinia immunoglobulin
- Indication : accidental inoculation of
vaccine in the eye or
eczema
vaccinatum

Methisazone : for prophylaxis

73

Vaccination with vaccinia

Potential for vector for introducing foreign gene for

immunization

Time of vaccination :
- 1st : between 1 2 y.o.
- Revaccination : 3 years interval

Reactions of vaccination

- 1st : papule with hyperemia

size increase
vesicle
pustule
dessication (complete in 12
days)
- revaccination : vesicular or pustular lesion or
indulation surrounding a central lesion (scab or ulcer)

Complication of vaccination
74

Selamat belajar

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