Virus and bullous Virus and bullous dermatosesdermatoses

Lector: Shkilna M.

CONENTCONENT

1.Clinical types of pemphigus1.Clinical types of pemphigus Pemphigus vulgarisPemphigus vulgaris Pemphigus foliaceusPemphigus foliaceus Pemphigus vegetansPemphigus vegetans Pemphigus erythematousPemphigus erythematous2. Classification2. Classification3.Diagnosis of HSV Infections3.Diagnosis of HSV Infections4. Epidemiology4. Epidemiology5. Disease caused by Herpes Simplex Viruses5. Disease caused by Herpes Simplex Viruses6. Disease caused by Herpes Zoster6. Disease caused by Herpes Zoster7. Other human Herpes Viruses Disease7. Other human Herpes Viruses Disease8. Diagnosis and treatment8. Diagnosis and treatment

Skin layersSkin layers

Bulla formed dueBulla formed due to fluid in the skin and fluid to fluid in the skin and fluid collection occurs at sites where the cohesion on collection occurs at sites where the cohesion on the skin is weak:the skin is weak:

subcornealsubcorneal intra – epidermal,intra – epidermal, due due

to individual to individual keratinocyteskeratinocytes

dermo –dermo – epidermalepidermal junctionjunction

A circumscribed collection of free fluid more than

0,5 sm in diameter

Pemphigus ( from the Greek Pemphigus ( from the Greek pemphixpemphix) -) -

meaning blister is a rare, of autoimmune, intraepidermal blistering meaning blister is a rare, of autoimmune, intraepidermal blistering diseases involving the skin and mucous membranes.diseases involving the skin and mucous membranes.

It is a particular group of bullous dermatoses presenting with a distinct It is a particular group of bullous dermatoses presenting with a distinct histopathology characterized by intraepidermal bulla and histopathology characterized by intraepidermal bulla and acantholysis.acantholysis.

AcantholysisAcantholysis

Normally the cells of the spinous Normally the cells of the spinous cell layer are kept together by the cell layer are kept together by the of desmosomes and a series of desmosomes and a series extracellular proteins known as extracellular proteins known as cadherins.cadherins.

Autoantibodies, (IgG) are Autoantibodies, (IgG) are directed against the extracellular directed against the extracellular protein desmoglein 3 which is one protein desmoglein 3 which is one of the cadherins. Desmoglein 3 is of the cadherins. Desmoglein 3 is treated as an antigen and this treated as an antigen and this process produces the separation of process produces the separation of the cells of the spinous cell layer the cells of the spinous cell layer with consequent formation of with consequent formation of vesicles and bullae. The process vesicles and bullae. The process of destruction (lysis) of the of destruction (lysis) of the intercellular connections intercellular connections (desmosomes) of the epithelial (desmosomes) of the epithelial cells is known as acantholysis. cells is known as acantholysis.

AcantholysisAcantholysis

Acantholytic cellsAcantholytic cells

is (which are present is (which are present both in the blister both in the blister cavity and at the edge cavity and at the edge of the blister) are of the blister) are rounded keratinocytes. rounded keratinocytes. The cytoplasmThe cytoplasm

is condensed in the is condensed in the periphery resulting in periphery resulting in a perinuclear pale a perinuclear pale halo.halo.

Four clinical types of pemphigusFour clinical types of pemphigus

1.1. Pemphigus vulgarisPemphigus vulgaris – cleft is deeply situated – cleft is deeply situated between the basal layer and the rest of epidermis between the basal layer and the rest of epidermis and there is sufficient fluid to produce the and there is sufficient fluid to produce the characteristic bulla.characteristic bulla.

2. Pemphigus vegetans2. Pemphigus vegetans – superficial cleft and – superficial cleft and proliferate changes producing papillomatous proliferate changes producing papillomatous masses.masses.

3. Pemphigus foliaceus3. Pemphigus foliaceus – subcorneal cleft and little – subcorneal cleft and little fluid.fluid.

4. Pemphigus erythematous4. Pemphigus erythematous – – abortive phase of abortive phase of Pemphigus foliaceusPemphigus foliaceus. .

Pemphigus vulgarisPemphigus vulgaris

It is an autoimmune disease caused by drugsIt is an autoimmune disease caused by drugs,, chemicals chemicals and infections.and infections.

Pathology.Pathology.1.1. The bulla of Pemphigus vulgaris are intra-dermal and The bulla of Pemphigus vulgaris are intra-dermal and

irregular in shape with acute lateral margins .irregular in shape with acute lateral margins .2.2. They are formed by the separation of acantholytic They are formed by the separation of acantholytic

epidermal cells( Tzanck cells ).epidermal cells( Tzanck cells ).3. Acantholytic cells may be in the bulla cavity.3. Acantholytic cells may be in the bulla cavity.4.4. Dermis beneath the bulla shows number of inflammatory Dermis beneath the bulla shows number of inflammatory

cells including a few lymphocytes and plasma cells.cells including a few lymphocytes and plasma cells.

Skin lesions predominantly present Skin lesions predominantly present on:on:

AxillaeAxillae TrunkTrunk

Skin lesionsSkin lesions

Tense of flaccid bulla appear Tense of flaccid bulla appear on normal skin.on normal skin.

The lesions may be few and The lesions may be few and sparse, or extensive.sparse, or extensive.

The eruption is usually The eruption is usually symmetrical.symmetrical.

They are usually irregular in They are usually irregular in shape.shape.

On rupturing, form painful On rupturing, form painful erosions which have a erosions which have a tendency to spread .tendency to spread .

Positive Nikolsky’s sign.Positive Nikolsky’s sign.

Nikolsky's signNikolsky's sign

application of tangential application of tangential pressure on normal skin pressure on normal skin results in formation of anew results in formation of anew bulla or if applied to pre-bulla or if applied to pre-existing bulla results in the existing bulla results in the spread of bullaspread of bulla (Nikolsky’s (Nikolsky’s sign).sign).

where the epidermis is where the epidermis is detached and slipping free detached and slipping free from the dermis with slight from the dermis with slight pressurepressure

Mucosal lesions:

Eventually present in all patients; oral mucosa moat frequently involved.Eventually present in all patients; oral mucosa moat frequently involved. The mouth is often involved, but denuded areas may be seen on conjunctive, The mouth is often involved, but denuded areas may be seen on conjunctive,

vagina, nose.vagina, nose. Patients have painful raw areas with detachable shreds of epithelium in the Patients have painful raw areas with detachable shreds of epithelium in the

mouth, these may extend to the pharynx and larynx resulting in dysphagia and mouth, these may extend to the pharynx and larynx resulting in dysphagia and hoarsenesshoarseness..

Pemphigus foliaceusPemphigus foliaceus

Pathology:Pathology:

It is superficial pemphigus (in granular cell layer or is superficial pemphigus (in granular cell layer or under the stratum corneum).under the stratum corneum).

Skin lesions:Skin lesions:

Flaccid bulla and exfoliating scales.Flaccid bulla and exfoliating scales. Usually flaccid bulla develop first on the face.Usually flaccid bulla develop first on the face. Slowly the disease spreads symmetrically till the whole of Slowly the disease spreads symmetrically till the whole of

the integument is covered with bulla (when it looks like the integument is covered with bulla (when it looks like erythroderma).erythroderma).

Bulla rapture rapidly and produce a moist, red, raw, and Bulla rapture rapidly and produce a moist, red, raw, and oedematous surface and flake-like plaques of imperfectly oedematous surface and flake-like plaques of imperfectly keratinized, horny cells.keratinized, horny cells.

The conjunctivae and mucosa may be affected.The conjunctivae and mucosa may be affected. The scalp may also be involved; it is covered with moist, The scalp may also be involved; it is covered with moist,

yellowish scales. The hair may fall.yellowish scales. The hair may fall.

Pemphigus vegetansPemphigus vegetans

It is the rarest variety of It is the rarest variety of pemphigus.pemphigus.

Individuals of anyIndividuals of any

group may begroup may be

affected. affected.

It is more common in It is more common in females than in females than in males.males.

Skin lesionsSkin lesions The initial lesions, in the form of broken bullae, The initial lesions, in the form of broken bullae,

appear on the mucosa of the lips, angle of appear on the mucosa of the lips, angle of mouth or nose.mouth or nose.

Later, they develop in the axillae, groins and Later, they develop in the axillae, groins and some-times on the other parts of the body.some-times on the other parts of the body.

When ruptured, the bulla develop into moist, When ruptured, the bulla develop into moist, superficial ulcers.superficial ulcers.

The ulcers undergo proliferative changes The ulcers undergo proliferative changes producing fungoid vegetations with producing fungoid vegetations with malodorous discharge.malodorous discharge.

The vegetations may also seem to arise de The vegetations may also seem to arise de novo on the normal skin.novo on the normal skin.

Nikolsky’s sign is often positive.Nikolsky’s sign is often positive.

Pemphigus erythematousPemphigus erythematous

Skin lesionsSkin lesions The early lesions which are The early lesions which are

erythematous and crusted, appear erythematous and crusted, appear on the nose and ears, resembling on the nose and ears, resembling lupus erythematosus both in their lupus erythematosus both in their location and appearance.location and appearance.

However, the lesions exhibit a However, the lesions exhibit a moist, raw surface when the crust moist, raw surface when the crust is removed.is removed.

The greasy crust may indicate The greasy crust may indicate seborrhoeic dermatitis.seborrhoeic dermatitis.

These lesions may appear along These lesions may appear along with bullae on the chest and with bullae on the chest and extremities.extremities.

The eruption is symmetrical in The eruption is symmetrical in distribution.distribution.

DiagnosisDiagnosis

Laboratory diagnosis of pemphigus Laboratory diagnosis of pemphigus is based on :is based on :

1.1. Tzanck Smear.Tzanck Smear.

2.2. Histology.Histology.

3.3. Immunopathology.Immunopathology.

Preparation of Tzanck smearPreparation of Tzanck smear

The vesicle should be unroofed or the crust removed, and the base scraped The vesicle should be unroofed or the crust removed, and the base scraped with a scalpel or the edge of a spatula.with a scalpel or the edge of a spatula.

The material is transferred to a glass slide by touching the spatula to the The material is transferred to a glass slide by touching the spatula to the glass slide repeatedly but gently. glass slide repeatedly but gently.

The slide should be clean, since cells will not adhere to a slide marred by The slide should be clean, since cells will not adhere to a slide marred by fingerprints.fingerprints.

In the case of blistering disorders:In the case of blistering disorders: The intact roof of a blister is opened along one side, folded back The intact roof of a blister is opened along one side, folded back

and the floor gently scraped. and the floor gently scraped. The material thus obtained is smeared onto a microscopic slide, The material thus obtained is smeared onto a microscopic slide,

allowed to air dry, and stained with Giemsa or any of the allowed to air dry, and stained with Giemsa or any of the Romanowsky’s stains.Romanowsky’s stains.

Tzanck Smear findings in Tzanck Smear findings in bullous disordersbullous disorders

Pemphigus Pemphigus ((Acantholytic cellsAcantholytic cells));; Bullous pemphigoidBullous pemphigoid (Predominantly eosinophils);(Predominantly eosinophils); Chronic bullous disease of childhood Chronic bullous disease of childhood

(Predominantly polymorphs);(Predominantly polymorphs); Varicella zoster infection (Multinucleated giant Varicella zoster infection (Multinucleated giant

cells);cells); Herpes simplex infection (Multinucleated giant Herpes simplex infection (Multinucleated giant

cells);cells); Toxic epidrmal necrolysis (Necrotic cells).Toxic epidrmal necrolysis (Necrotic cells).

ImmunopathologyImmunopathologyTwo classes of tests areTwo classes of tests are

available:available:

1.1. Direct immunofluorescence Direct immunofluorescence (DIF):(DIF): Done on the skin of the Done on the skin of the patient, shows intercellular patient, shows intercellular deposits of Ig G and C3 giving a deposits of Ig G and C3 giving a fish net appearance.fish net appearance.

2. Indirect immunofluorescence 2. Indirect immunofluorescence (IIF):(IIF): Done on patient serum to Done on patient serum to detect autoantibody; titers detect autoantibody; titers correlate with the clinical activity correlate with the clinical activity and may be a useful guide to the and may be a useful guide to the dose of oral steroids needed.dose of oral steroids needed.

TreatmentTreatment

Supportive treatment Local hygiene of mucosal Local hygiene of mucosal

and skin lesions. and skin lesions. TherapeuticTherapeutic

as well as prophylactic as well as prophylactic use of antibiotics (foruse of antibiotics (forcoetaneous infection) and coetaneous infection) and anticandidal agents (foranticandidal agents (formucosal lesions).mucosal lesions).

Maintenance of water Maintenance of water and electrolyte balance.and electrolyte balance.

Specific treatmentSpecific treatment

Specific treatment Specific treatment depends on the depends on the judicious use of judicious use of corticosteroids and corticosteroids and immunosuppressive immunosuppressive drugs since drugs since pemphiguspemphigus

is an autoimmune is an autoimmune disorder.disorder.

TreatmentTreatment

CorticosteroidsCorticosteroidsTwo regimes are commonly usedTwo regimes are commonly used::Daily doseDaily dose of 1 -2 mg / kg body weight of of 1 -2 mg / kg body weight of

prednisoloneprednisoloneequivalent is used to suppress disease equivalent is used to suppress disease activity andactivity andsteroids are tapered when the disease is steroids are tapered when the disease is controlled;controlled;this form of steroid therapy is associated this form of steroid therapy is associated withwithsubstantial adverse events.substantial adverse events.

Monthly steroid therapyMonthly steroid therapy.. Monthly 1-2 mg / kg of betamethasone Monthly 1-2 mg / kg of betamethasone

orally /orally /dexamethasone intravenous is given.dexamethasone intravenous is given.

Usually combined with Usually combined with immunosuppressiveimmunosuppressivetherapy.therapy.

>> May induce remissions with May induce remissions with less side effects.less side effects.

Immunosuppressive therapy:Immunosuppressive therapy:

Drug regimes:Drug regimes:

Azathioprine:Azathioprine: Usually along with oral Usually along with oral steroidsteroidtherapy. 2-3 mg/kgtherapy. 2-3 mg/kg of body of body weight till clearing ofweight till clearing ofdisease: maintain on 1 mg / kg.disease: maintain on 1 mg / kg.

Methotrexate:Methotrexate: Usually along with oral Usually along with oral steroidsteroidtherapy; given as weekly 20-25 therapy; given as weekly 20-25 mg.mg.

Cyclophosphamide:Cyclophosphamide: Usually along Usually along with oral steroidwith oral steroidtherapy. As daily dose (50-200 therapy. As daily dose (50-200 mg) or monthlymg) or monthlybolus dose (500-1000 mg) bolus dose (500-1000 mg) intravenously.intravenously.

Human Herpes VirusesHuman Herpes Viruses

Latent VirusesLatent Viruses

Vesicle Vesicle

DescriptionDescription

Circumscribed Circumscribed collection of free collection of free fluidfluid

Up to 0.5 cm in Up to 0.5 cm in diameterdiameter

Herpes zoster

EROSIONEROSION

DescriptionDescription

A focal loss of epidermis; erosions do not penetrate

below the dermoepidermal

junction; and therefore heal

without scarring

Toxic epidermal necrolysis

CRUSTCRUST

DescriptionDescriptionIs a collection of dried Is a collection of dried

serum and cellular serum and cellular debris- a scabdebris- a scab

ExamplesExamples– Acute eczematious Acute eczematious

inflammationinflammation

– Atopic on the faceAtopic on the face

– Impetigo- golden or Impetigo- golden or honey coloredhoney colored

– Tinea capitisTinea capitisImpetigo. A thick, honey-yellow adherent crust covers the entire eroded surface.

ClassificationClassification There are 25 families in the Herpeotoviridae There are 25 families in the Herpeotoviridae

but only 6 of them infect man with any but only 6 of them infect man with any regularity.regularity.

Herpes Simplex virus Type 1 (HSV-1)Herpes Simplex virus Type 1 (HSV-1)

Herpes Simplex virus Type 2 (HSV-2)Herpes Simplex virus Type 2 (HSV-2)

Epstein Barr virus (EBV)Epstein Barr virus (EBV)

Cytomegalovirus (CMV)Cytomegalovirus (CMV)

Varicella Zoster virus (VZV)Varicella Zoster virus (VZV)

Human Herpes virus 6Human Herpes virus 6

Human Herpes virus 8 Human Herpes virus 8

Herpes Simplex Virus (HSV)Herpes Simplex Virus (HSV)

These are very large viruses and their These are very large viruses and their genome encodes at least 80 proteins.genome encodes at least 80 proteins.

Half are not directly involved in the virus Half are not directly involved in the virus structure.structure.

Almost any human cell type can be Almost any human cell type can be affected by HSV.affected by HSV.

EpidemiologyEpidemiology

HSV-1 and 2 infections are life-long.HSV-1 and 2 infections are life-long. The virus is found in the lesions on the skin The virus is found in the lesions on the skin

but can be present in body fluids including but can be present in body fluids including saliva and vaginal secretions.saliva and vaginal secretions.

As a result of poor hygiene in underdeveloped As a result of poor hygiene in underdeveloped countries, HSV-1 antibodies are found in more countries, HSV-1 antibodies are found in more than 90% of children.than 90% of children.

Epidemiology 2Epidemiology 2

HSV-2 is normally spread sexually and is found HSV-2 is normally spread sexually and is found in the anus, rectum and upper alimentary tract as in the anus, rectum and upper alimentary tract as well as the genital area.well as the genital area.

An infant can be infected at birth by a genitally-An infant can be infected at birth by a genitally-infected mother.infected mother.

The infant can also be infected in The infant can also be infected in uteroutero if the if the mother’s infection spreads.mother’s infection spreads.

Because of the infant’s underdeveloped immune Because of the infant’s underdeveloped immune system, the resulting infection can be very severe system, the resulting infection can be very severe and sometimes be deadly.and sometimes be deadly.

Disease caused by Herpes Simplex VirusesDisease caused by Herpes Simplex Viruses

Oral Herpes - Cold soresOral Herpes - Cold sores– Herpetic gingiovostomatitis, the infection, often initially on the lips Herpetic gingiovostomatitis, the infection, often initially on the lips

spreads to all parts of the mouth and pharynx.spreads to all parts of the mouth and pharynx.

Disease caused by Herpes Simplex VirusesDisease caused by Herpes Simplex Viruses

Eczema HerpeticumEczema Herpeticum– This is found in children with active eczema.This is found in children with active eczema.

– The virus can spread to other organs such as the liver and adrenals.The virus can spread to other organs such as the liver and adrenals.

Disease caused by Herpes Simplex Disease caused by Herpes Simplex VirusesViruses

Genital HerpesGenital Herpes– Is usually the result of HSV-2.Is usually the result of HSV-2.– Primary infection is often asymptomatic but Primary infection is often asymptomatic but

many painful lesions can be developed on the many painful lesions can be developed on the shaft of the penis and vulva, vagina, cervix shaft of the penis and vulva, vagina, cervix and perianal region of women.and perianal region of women.

Genital HerpesGenital Herpes

Genital HerpesGenital Herpes

In both sexes, the urethra can be In both sexes, the urethra can be involved.involved.

Genital Herpes infections can be Genital Herpes infections can be accompanied by a variety of accompanied by a variety of symptoms including fever, symptoms including fever, myalgia, glandular myalgia, glandular inflammation of the groin area inflammation of the groin area (inguinal).(inguinal).

Some patients have only Some patients have only infrequent recurrences but infrequent recurrences but others experience recurrences as others experience recurrences as often as every 14-21 days.often as every 14-21 days.

– Is usually the result of Is usually the result of HSV-2.HSV-2.

– Primary infection is Primary infection is often asymptomatic but often asymptomatic but many painful lesions can many painful lesions can be developed on the be developed on the shaft of the penis and shaft of the penis and vulva, vagina, cervix vulva, vagina, cervix and perianal region of and perianal region of women.women.

Diagnosis of HSV InfectionsDiagnosis of HSV Infections

Cells may be obtained from Cells may be obtained from the base of the lesion the base of the lesion (called a Tzank smear) and (called a Tzank smear) and histochemistry performed.histochemistry performed.

These can be seen in the These can be seen in the smears as multinucleated smears as multinucleated giant cells and contain giant cells and contain Cowdry type A inclusion Cowdry type A inclusion bodies.bodies.

The cells can also be stained The cells can also be stained with specific antibodies in with specific antibodies in an immunofluorescence test.an immunofluorescence test.

It can also be detected by It can also be detected by viral DNA by in situ viral DNA by in situ hybridization.hybridization.

Type-specific antibodies can Type-specific antibodies can distinguish between HSV-1 distinguish between HSV-1 and HSV-2.and HSV-2.

Diagnosis of HSV InfectionsDiagnosis of HSV Infections

HERPES ZOSTERHERPES ZOSTER Reactivation of HVZReactivation of HVZ dermatomal distributiondermatomal distribution may recurmay recur can disseminate in immunocompromised patientscan disseminate in immunocompromised patients complicationscomplications

– post herpetic painpost herpetic pain

– ophthalmic zoster -corneal scarring and loss of visionophthalmic zoster -corneal scarring and loss of vision

DIAGNOSIS

CLINICALEM of vesicle fluid

SEROLOGYIgM detection

Pain and hyperaesthesia

Pain and hyperaesthesia

Pain and hyperaesthesia

OTHER HUMAN HERPES OTHER HUMAN HERPES VIRUSESVIRUSES

HHV6HHV6virus replicates in T and B cellsvirus replicates in T and B cells– infection occurs in first 3 years of infection occurs in first 3 years of

lifelife

– ClinicalClinical Exanthem subitum Exanthem subitum

(roseola infantosum(roseola infantosum)) mild acute febrile illnessmild acute febrile illness incubation period of 2 weeksincubation period of 2 weeks fever lasts several daysfever lasts several days macular papular rash appears macular papular rash appears

within 2 days of feverwithin 2 days of fever– 85% of adults carry virus in saliva85% of adults carry virus in saliva

HHV7HHV7– isolated from CD4 positive isolated from CD4 positive

cellscells– virus present in saliva of virus present in saliva of

>75% of adults>75% of adults– role in disease unclearrole in disease unclear– Evidence of infection Evidence of infection

present (seroconversion)present (seroconversion)

HHV8HHV8– detected in epithelial cells of detected in epithelial cells of

Kaposi sarcomaKaposi sarcoma– also present in semenalso present in semen– postulated as cause of postulated as cause of

KaposiKaposi sarcomasarcoma

Exanthem subitum (roseola infantosum)

TreatmentTreatment

AcyclovirAcyclovir– A Safe and extremely well-A Safe and extremely well-

tolerated drug.tolerated drug.

– More than 35 million patients More than 35 million patients have been consistent and have been consistent and reassuring.reassuring.

– Some authorities have Some authorities have proposed making acyclovir proposed making acyclovir available as a non-available as a non-prescription drug.prescription drug.

– Adverse effects, usually mild, Adverse effects, usually mild, include nausea, vomiting, include nausea, vomiting, rash and headache.rash and headache.

ValacyclovirValacyclovir– New antiviral agentNew antiviral agent

– Is the 1-valine ester Is the 1-valine ester prodrug of acyclovir.prodrug of acyclovir.

– It has an oral It has an oral bioavailability three to bioavailability three to five times greater than five times greater than that of acyclovir.that of acyclovir.

– Several large trials have Several large trials have shown that it is safe and shown that it is safe and well tolerated.well tolerated.

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