SKIN AND INTEGUMENTARY MODULE

VIRUS CAUSING SKIN AND

INTEGUMENTARY INFECTION

FERA IBRAHIM

DEPARTMENT OF MICROBIOLOGY, FMUI

THE STRUCTURE OF THE SKIN
• Healthy intact skin protects
underlying tissues and provides excellent
defense against invading microbes
• Factors controlling the skin’s microbial
load
– the limited amount of moisture present
– acid pH of normal skin
– surface temperature <optimum for many
pathogens
– salty sweat
– excreted chemicals such as sebum, fatty acids and
urea
– competition between different species of the
normal flora
If the organism breach the stratum
corneum

the host defenses are mobilized

the epidermal Langerhans’ cells elaborate

cytokines, neutrophiles are attracted to the
site of invasion, and complement is activated
via the alternative pathway
 Normal Microbial Flora of Skin

• The skin is a generally dry, acidic

environment that does not support the
growth of most microorganisms.
• However, moist areas, especially around
sweat glands, are colonized by gram-positive
Bacteria and other members of the skin
normal flora. Environmental and host factors
influence the quantity and quality of the
normal skin microflora.
 Normal Microbial Flora of Skin

• The normal flora of the skin consists of

transient or resident populations of
microorganisms.
• The skin is continually being inoculated with
transient microorganisms, virtually all of
which are unable to multiply and usually die.
• Resident microorganism are able to multiple,
not merely survive, on the skin.
 Normal Flora of Skin

Two types of skin flora:

• The resident flora: always present on the whole skin
surface (S. epidermidis, micrococci,diphtheroids,
small number of anaerobic cocci, propionibacterium)

• The transient flora: contact with the superficial

aspects of the skin from the environment, another
person or from the person’s own alimentary tract
Microbial disease of the skin may result
from any of three lines of attack

• Breach of intact skin

• Skin manifestations of systemic infections
• Toxin-mediated skin damage
THE PATHOGENESIS OF MUCOCUTANEOUS LESIONS
 MUCOCUTANEOUS LESIONS CAUSED BY VIRUSES
VIRUS LESION VIRUS SHEDDING
FROM LESION
NO SYSTEMIC PAPILLOMA (WART) COMMON WART +
SPREAD PLANTAR WART
GENITAL WART
MOLUSCUM CONTAGIOSUM FLESHY PAPULE +
(POXVIRUS)
ORF (POXVIRUS FROM PAPULOVESICULAR +
SHEEP, GOATS)

SYSTEMIC HERPES SIMPLEX, VESICULAR (NEURAL +

SPREAD VARICELLA-ZOSTER SPREAD AND LATENCY
COXSACKIEVIRUS A (9,16,23) VESICULAR IN MOUTH +
(HEPARNGINA)
COXSACKIEVIRUS A16 VESICULAR (HAND, FOOT +
AND MOUTH DISEASE)

ERYTHROVIRUS (FORMERLY FACIAL MACULOPAPULAR -

(ERYTHEMA INFECTIOSUM)
HUMAN PARVOVIRUS) B19 EXANTHEM SUBITUM -
(ROSEOLA INFANTUM)
MEASLES MACULOPAPULAR SKIN RASH -
RUBELLA, ECHOVIRUS (4,6,9,16) MACULOPAPULAR NOT -

DENGUE AND OTHER DISTINGUISHABLE CLINICALLY -

ARTHROPOD TRANSMITTED MACULOPAPULAR
VIRUSES
 DIAGNOSIS OF VIRAL INFECTION
BASED ON RASH APPEARANCE (VIRAL TYPE)

MACULAR/MACULOPAPULAR
MEASLES, RUBELLA, ENTEROVIRUSES, PARVOVIRUS B-19,
MONONUCLEOSIS, CYTOMEGALOVIRUS, HEPATITIS B, ROSEOLA, HIV

VESICLES
HERPES SIMPLEX, VARICELLA-ZOSTER, ECZEMA HERPETICUM,
HAND-FOOT AND MOUTH DISEASE

PETECHIAE, PURPURA OR PUSTULES

VIRAL HAEMORRHAGIC FEVERS, ENTEROVIRUS
 THE DIFFERENTIATION OF
MACULES, PAPULES, VESICLES AND PUSTULES
HERPES SIMPLEX VIRUS

Famili : HERPESVIRIDAE
SubFamili : ALPHAHERPESVIRINAE
Genus : SIMPLEX VIRUS
PROPERTIES OF VIRUS

Morphologically identical to herpes simplex virus

The virus causess chickenpox and zoster → same, no significant
genetic variation
Virion : spherical, 150-200 nm in diameter (icosahedral)
Genome : ds DNA, linear, 124-235 kbp
Replication : Nucleus, bud from nuclear membrane

Outstanding characteristics:
Establish latent infections
Persist indefinitely in infected hosts
Frequently reactivated in immunosuppressed hosts
some are cancer-causing
PATHOGENESIS
SITES OF EVENTS IN HERPESVIRUS INFECTIONS
 HERPES SIMPLEX TYPE 1

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

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

Herpetic whitlow,
nurses and doctors

Primary infection of the skin,

by direct contact to any part of body
Recurrent infection
Stomatitis with secondary lesion vesicles on
on skin, the face, neck and chest Hepes simplex an erythematous
mimicking base, pustules,
herpes zoster heal without scars
 HERPES SIMPLEX TYPE 2

on the vulva of an on cervix of an

Genital herpes – adult man adult woman
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
 LABORATORY DIAGNOSIS

HHV 1 & 2 → Clinical Diagnosis (typical lesions)

Cytology & Histology → vesicles
Isolation of virus → culture of vesicular fluids
(sel Hep2, Hela ect)
PCR - LCS herpes encephalitis
Serology → primary infection, epidemiology,
not for recurent infection diagnosis
LABORATORY EXAMINATION OF HERPES SIMPLEX

SEL NEURON –ANTIBODI FLUORESEN

HERPES ENSEFALITIS FATAL

HISTOLOGI VESIKEL
A= VESIKEL INTRAEPIDERMAL
B= SEL RAKSASA BERINTI BANYAK
C= DERMIS
TREATMENT, PREVENTION & CONTROL

In the normal host, acyclovir reduces the duration of symptoms and

viral shedding in primary herpetic gingivostomatitis

Treatment prevents or shortens the course of primary or

recurrent disease.
None of the drug treatment can eliminate latent infection

Th/ antiviral (FDA approved) → acyclovir, valacyclovir,

penciclovir, famciclovir.
Vidarabine, idoxuridine, and trifluridine are less effective

Avoidance of direct contact with lesions reduces the risk of infection

No vaccine is currently available for HSV
VARICELLA-ZOSTER VIRUS

Varicella (chickenpox) is a mild, highly contagious disease

characterized clininically by a generalized vesicular eruption
of the skin and mucous membranes
→ children

the disease may be severe in adults and in immunocompromised children

Zoster (shingles) is a sporadic, incapacitating disease of adults or

immunocompromised individuals, is characterized by a rash limited in
distribution to the skin innervated by a single sensory ganglion

The lesion are similar to those of varicella

 PATHOGENESIS AND PATHOLOGY

VARICELLA
The virus → inoculation of the mucosa of the upper respiratory
tract or conjuctiva → viral replication in regional nodes →
virus infected cells into capillaries → blood →
localizes in the skin

Focal cutaneous and mucosal lesions → swelling of epithelial cells,

ballooning degeneration and the accumulation of tissue fluids
→ vesicle formation, eosinophilic inclusion bodies are found
in the nuclei of infected cells
Virus replication and spread is limited by host humoral and cellular
immune responses
ZOSTER
The skin lesions → histologically identical to those of varicella

an acute inflammation of the sensory nerves and ganglia

(often only a single ganglion)

The distribution of lesions in the skin corresponds closely to the areas

of innervation of latent varicella-zoster virus infections in ganglia

Virus → the nerve → the skin → vesicle formation

 VARICELLA-ZOSTER

Close up of
Pustules
(zoster)

Close up of rash
on light skin, vary greatly Close up of rash on dark skin,
in size and shape a petechial element

Close up of vesicle
(zoster),
Scarring
the vesicles develop
in clusters on an
erythematous base
 CLINICAL FINDINGS
VARICELLA
Subclinical varicella <<<
Incubation period : 10-21 days
The earliest symptoms : malaise, fever → The rash, 1st on the trunk
on face, the limbs, the buccal and pharyngeal mucosa in the mouth
→2-4 days, fresh vesicles appear in the crops, all stages of macules,
→Papules, vesicles and crusts may be seen at one time

Fever ~ new lesions appear ~ severity of the rash

Complications are rare in normal children

The mortality rate is very low
 Petechiae on
the palate

Chickenpox rash on dark skin

Distribution of rash, first on the body

and inner aspects, to the face, scalp and
Pleomorphic rash (macule, papule,
proximal parts of the limbs vesicle, pustule and crust)
COMPLICATIONS

Chickenpox pneumonia
(miliary calcification)

Haemorrhagic
chickenpox

Varicella and disturbed immunity Chickenpox pneumonia (the most common)

 ZOSTER

Usually starts with severe pain in the area of skin or mucosa

supplied by one or more groups of sensory nerves and ganglia
→A crop of vesiclesappears over the skin supplied by the
affected nerves

The eruption is usually unilateral, the trunk,head and neck are

most commonly involved

The duration and severity of cutaneous eruption ~

the age of the patient

Complication → postherpetic neuralgia

LATENCY AND REACTIVATION OF
VARICELLA-ZOSTER VIRUS
 DERMATOMES
THE BANDS OF SKIN INNERVATED
BY A SINGLE SENSORY NERVE
HERPES ZOSTER

THORACIC

HERPES ZOSTER CERVICAL

IN A CHILD
 Herpes zoster and leukemia
(disturbed immunity)

Secondary staphylococcal infection

LABORATORY DIAGNOSIS

Staining smears of scrapings or swabs of the base of vesicles →

multinucleated Giant cells

Isolation and identification of virus → cells culture → vesicular

fluids

Serology → CF, Nt, Indirect Immunofluorescence, ELISA

 Zoster
Giant cell in human Histology (A=IEV
amnion cell culture of vesicle B=MNGC
C=dermis)

Early
In human (B=multi
amnion cells Nucleated
Giant cell)

Histology of Mature
Peripheral nerve (A=intra
Epidermal
Vesicle, B=
Dermis)
Histology of the dorsal root ganglion
(A=undegenerate neurones,B= degenerate neurones
C=mononuclear cells)
EPIDEMIOLOGY

Varicella and zoster occur worldwide

Varicella/chickenpox is highly communicable and is a common
epidemic disease of childhood (peak incidence, age 2-6 years)
Zoster occurs sporadically, chiefly in adult

Varicella spreads by airborne droplets and direct contact

TREATMENT, PREVENTION & CONTROL

Varicella in normal children requires no treatment

Gamma immunoglobulin of high varicella-zoster antibody titer →

Prevent the development of the illness in immunocompromised patient
Exposed to varicella

Th/ antiviral → acyclovir, valacyclovir, vidarabin and

leukocyte interferon

A live attenuated varicella vaccine

 POXVIRIDAE

Molluscum contagiosum
Genus : Molluscipoxvirus

Variola & Vaccinia (smallpox vaccine)

Genus : Orthopoxvirus
→ smallpox (now eliminated)
GENOME OF VIRUS
REPLICATION OF
VIRUS
 CLINICAL MANIFESTATION

the lesions are small, pink, Molluscum contagiosum

wart-like tumors on the face
arms, back and buttocks
the typical lesion is un umbilicated
papule
 EPIDEMIOLOGY
Geographic >> : Fiji, Papua New Guinea, Zaire

Sporadic, epidemic

Spreading : children > adults

Mode of Transmission : direct contact or indirect contact

( by barbers, Common use of towels, swimming pools)

Young adult → as a Sexually Transmitted Diseases, is

increasing
 LABORATORY DIAGNOSIS

The diagnosis of molluscum contagiosum can usually

be made clinically

PCR → can detect viral DNA sequences

Electron microscopy → can detect poxvirus particles

The virus is apoor immunogen, about one-third of patient

never produce antibodies against it
 PATHOGENESIS

Molluscum contagiosum → Hypertrophi epidermal keratocytes and

hyperplasia basal cells
in AIDS patient the skin may be covered
with many papules and recurrent

TREATMENT AND PREVENTION

No spesific treatment, lesi → surgery, cryotherapy

 VARIOLA VIRUS INFECTION → SMALLPOX

Smallpox rash, macules-papules-

vesicles-pustules-crusts-pink scars
that faded slowly.
The lesion were generally found in
the same stage of development
(in contrast to chickenpox)
SMALLPOX was officially declared eliminated in 1980
HUMAN PAPOVAVIRIDAE
- Genus:
- Polyomavirus : BK virus and JC virus
- Papillomavirus

FAMILY : PAPILLOMAVIRIDAE
Important properties of papillomavirus

Small icosahedral capsid virion, 55 nm in diameter

Genome : Double stranded DNA, circular
Envelope : none
Human papilloma virus (HPV) → > 100 types, using
molecular criteria
Outstanding characteristics :
Stimulate cell DNA synthesis
Restricted host range and tissue tropism
Significant cause of human cancer, especially cervical cancer
Viral oncoproteins interact with cellular tumor suppressor proteins
Papillomavirus cannot be cultivated in laboratory

Replication of virus
Schematic representation of a skin wart (papilloma)

Viral replication depends on the epithelial cells differentiation stage;

it is persistent in the basal layer and active in differentiated
keratinocytes
ORGANIZATION OF HPV GENOME
PATHOGENESIS

TRANSMISSION :
DIRECT CONTACT ,
SEXUAL CONTACT
Immune Response
* Important, cell-mediated immunity

Clinical Manisfestation
Asymptomatic shedding

- Skin wart
- Epidermodysplasia Verruciformis
- Genital Infection
- Anogenital wart
- Cancer cervix
- Papilloma laringeal
- Papilloma nasal
- Focal epithelial hyperplasia
- Papilloma skuamosa
- Papilloma conjungtiva
- Other malignancies
CLASSIFICATION OF HPV TYPES BY
CERVICAL ONCOGENICITY
(data from Munoz et al 2003)

RISK CLASSIFICATION HPV TYPES

HIGH RISK 16, 18, 31, 33, 35,

39, 45, 51, 52, 56,
58, 59, 68, 73, 82

PROBABLE HIGH RISK 26, 53, 66

LOW RISK 6, 11, 40, 42, 43, 44,

54, 61, 70, 72, 81, CP6108

UNDETERMINED RISK 34, 57, 83

 SEED WARTS OF
THE FINGERS

THE VARIOUS KINDS OF WARTS

PLANTAR WARTS

FLAT WARTS

CONDYLOMA ACUMINATA
GENITAL WARTS
 Epidemiology
Viruses are found worldwide, Virus persist in host and
asymptomatic shedding

Transmission : direct contact, sexual contact (STD) for certain

virus types, passage through infected birth canal for laryngeal
papillomas (type 6 & 11)
→the virus can be transmitted on fomites such as the surfaces
of counters or furniture, bathroom floors and towels

The virus can be acquired by close contact and infects the

epithelial cells of the skin or mucous membranes

HPV infection is acquired by :

-Direct contact through small breaks in the skin or mucosa
-During sexual intercouse
-While an infant is passing through an infected birth canal
-as the result of chewing warts (children habit)
Laboratory Diagnosis
Histology → Papanicolaou
smears (koilocytotic cells)

Electron Microscopy

Immunofluorescent and immunoperoxidase

staining

Nucleic acid Detection Technique

Polymerase Chain Reaction (PCR)

Fera Ibrahim, Department of Microbiology, Medical Faculty, University of Indonesia, Dec 2007
Serological assays are not recommended for diagnosis
in individual women due to low sensitivity, but they are
useful in comparisons of groups in epidemiological and
ecological studies (Dillner 1999).
Treatment And Prevention :
Warts spontaneously regress → take many months to years
No spesific treatment
- Antiproliferative agents : Podophyllin/podophyllotoxin, 5-Fluorouracil,
Cidofovir
- Destructive/excision therapies : Trichloracetic acid, currette or Surgery,
electrosurgical, laser therapy, photodynamic therapy (5-aminolevulinic
acid/haematoporphyrins –red light laser)
- Cryotherapy
- Immunomodulators (IFN alpha, imiquimod/imidazoquinolines)/Vaccines

Vaccines :
-Prophilaxis Vaccines are available → L1 & L2
-Vaccines are in clinical trial → Therapeutic Vaccines : E6 & E7

The best way to prevent transmission of warts is to avoid

coming in direct contact with infected tissue
The use of condoms can prevent the sexual transmission of HPV
 MEASLES VIRUS INFECTIONS

Close up of rash, maculopapular

→ form irregular blotches
KOPLIK’S SPOTare pathognomonic of measles

behind the ears and

along the hairline,
quickly affects the face

Measles rash on first day Rash on 3rd day, confluent over most body,
some discrete spot remain especially on the limbs
EXANTHEMATOUS DISEASE (ECHOVIRUS INFECTION)
Maculopapular rashes have been found in
infection with echovirus 4, 11, 16, and 19

Petechial rash in echovirus type 9 infection,

pinkish macules which fade quickly on the trunk,
persists on the face, more blotchy

Maculopapular rash on face

in echovirus type 19 infection

rash on trunk – echovirus type 19,

maculopapular, vesicular, petechial and pleomorfic
 EXANTHEMATOUS DISEASE (COXSACKIEVIRUS INFECTION)

Maculopapular, petechial and vesicular eruptions

have been described in infections with coxsackievirus
notably A9, A16, A10, A5, B3, and B5

Herpangina, is predominantly
a disease of children and is caused
by type A coxsackievirus,
fever, sore throat, dysphagia, headache,
myalgia, throat is inflamed and
small discrete vesicles, each surrounded
by a band of erythema

Maculopapular rash on face

in coxsackievirus infection,

Herpex simplex-Herpangina,
similar lesions,tend to affect the anterior half of the buccal cavity,
herpangina is confined to the posterior
 HAND, FOOT AND MOUTH DISEASE
is a mild illness caused by coxsackieviruses type A16, A10 and A5
fever, slight malaise, a sore mouth, characteristic lesion appears in the mouth, on the hands and feet

lesion in the mouth, are bright red

macules, small vesicles on an
vesicle on hand vesicle on finger vesicle on toe erythematous base or painful,
shallow ulcers (seldom seen on the
tonsil, pharynx and the skin round the
lips are not affected)

herpetic lesions
are usually confined
vesicle on heel to one finger,
HFM is more widespread
gonococcal rash,
a vesicular or
pustular eruption
(a history of urethritis
or vaginal discharge)
rash on buttocks,
a maculopapular
 ROSEOLA INFANTUM
EXANTHEM SUBITUM
SIXTH DISEASE
is caused by HHV6 infection
fever, may have a convulsion,
throat inflamed but no exudate,
erythematous macular rash
(persists for 36 hours then fade)

Rash on trunk
ERYTHEMA INFECTIOSUM (SLAPPED-CHEEK SYNDROME)
→ FIFTH DISEASE

is a mild infection caused by a parvovirus

mild fever, headache, sore throat, slight
gastrointestinal disturbance, rash on the
face (a blotchy apprearance, the mark
of slapped cheeks)

Rash on trunk,
morbilliform, annular, or confluent
RUBELLA (GERMAN MEASLES)VIRUS INFECTIONS

maculopapular, measles

a morbiliform rash (maculopapular,

Throat : painful, slightly no pathognomonic) on the face,
inflamed, koplik’s spot the trunk and extremities
are never found (form and duration of rash)
Rash on tight

Conjunctivitis

Rash on 1st day,

discrete, delicate pink macules
sometime maculopapular and Rash on 2nd day, rash may be arrested Purpura (petechiae,
haemorrhagic elements at the macular stage, eccchymoses)
coalesce to produce a pinkish flush
 CONGENITAL RUBELLA

Purpuric rash (4-8th week,

mortality ~30%)

Cloudy cornea

Cataract

Congenital heart disease

Purpura and
hepatosplenomegaly Glaucoma
 HUMAN CYTOMEGALOVIRUS INFECTION
PRIMARY INFECTION →
INFECTIOUS MONONUCLEOSIS

Enanthem - petechiae

Patient with infectious mononucleosis, Rash on trunk, pinkish maculopapular

slight puffiness of the eyelids and (character may be mistaken for Rubella)
a pinkish flush to their cheeks

Anginose
inflamed throat
without exudate
Rash on upper limb, the rash tends
to patchy and is heavier on the limb
abnormal mononuclear cells (contrast with the rash of Rubella)