Infectii virale cutanate

transcript

INFECTII CUTANATEVIRALE

Conflict de interese

• Astellas Pharma• Glaxo SmithKline• Hoffman LaRoche• Janssen Pharma• Schering AG• Schering Plough• L’Oreal

• Sir Samuel Scott ofYews Trust

• European DermatoEpidemiologyNetwork

• Archives ofDermatology

Foarte variateDepind de:

Tipul virusuluiLocalizarea infectieiRaspunsul imun al gazdei

Unele virusuri pot doar coloniza epidermul, fara aproduce manifestari clinice (ex: HPV, v.molluscumului contagiosum)

Manifestari clinice

Virusuri care produc infectiicutanate (I)

Papilomavirusuri umaneVirusuri herpetice

Virusul herpes simplex 1, 2Virusul varicelo-zosterianVirusul Epstein-BarrHerpesvirusul uman 6, 7, 8

Pox-virusuriVirusul molluscumului contagiosumVirusul nodulilor mulgatorilorVirusul ectimei contagiosum (orf)

Virusuri care produc infectiicutanate (II)

Virusurile bolilor eruptive ale copilariei(rujeola, rubeola, varicela)Virusul hepatitei B (vasculite, urticariecronica)

Despre ce voi vorbi...

• Papilomavirusuri umane• Herpes simplex• Herpes zoster• Poxvirusuri• Pitiriazis rozat• Sarcom Kaposi• Manifestari cutanate in infectia HIV

Papilomavirusuri umane

Caractere generaleGrup de >100 virusuri ADNProduc proliferarea epiteliilor pielii simucoaselorDetermina de obicei leziuni benigneUnele tipuri pot produce leziuni displazicesau neoplazice

Papilomavirusuri umanemanifestari clinice (I)

Veruci vulgareVeruci plantare

ProfundeSuperficiale (in mozaic)

Veruci plane (juvenile)Papiloame (veruci filiforme/digitate)

Papilomavirusuri umanemanifestari clinice (II)

Condiloame (veruci) anogenitaleCondiloame acuminateCondiloame plane ale colului uterinCondilomatoza giganta

Papuloza bowenoidaEpidermodisplazia veruciforma

Papilomavirusuri umane tratament

Acid salicilic 15-25%Acid mono-, tricloracetic 25-30%Podofilina 25%/podofilotoxina 0,5%CrioterapieSensibilizanti de contact (DNCB, DCP)Citostatice topice/intralezionaleMetode chirurgicale: curetaj,electrocoagulare, laser CO2

Papilomavirusuriinfectii genitale (I)

Cea mai frecventa ITSIncidenta in crestere: ↑25% barbati,↑28% femei - 1999 vs. 199390% din condiloame sunt produse detipuri neoncogene (PVU 6, 11)Majoritatea celor infectati nu aucondiloame vizibile (posibil doar 1%dintre cei infectati)

Papilomavirusuriinfectii genitale

Cu risc oncogen mare (16, 18)Majoritatea cazurilor de carcinom de col uterin secoreleaza cu PVU 16, 18; frecvent produc infectiiasimptomatice

Cu risc oncogen mic (6, 11)Produc un carcinom spinocelular neagresiv (Buschke-Loewenstein)

Sunt posibile coinfectii cu mai multe tipuri

Papilomavirusuriinfectii genitale

Testarea ADN-ului pentru tipurilorcu risc mare:

Utilitatea testarii depinde de Sb, Sp siprevalenta infectiei cu risc mareCel mai utilizat test (Digene) are Sb90%, Sp 15-20% → rata mare defals+testul este autorizat de FDA pentruprobe recoltate din colul uterin

Papilomavirusuri - infectii genitaleepidemiologie

Transmiterea este facilitata de existentaleziunilor (dar nu exclusiva)Transmiterea mediata de obiecte esteposibila, dar nedoveditaTransmiterea cu ocazia nasterii este rara(papiloame laringiene sau condiloameanogenitale la luni de zile post-partum)Infectivitatea inter-parteneri: 60%Utilizarea prezervativului reducetransmiterea

Papilomavirusuri - infectii genitalefactori de risc

Numarul partenerilor sexualiFrecventa contactelor sexualePrezenta condiloamelor la partenerFumatul (factor de risc independent)

Condiloame acuminatediagnostic

Clinicutilizarea acidului acetic (aceto-whitening) nerecomandabila, pt caSb↓, Sp↓, 25% rezultate fals+ (CDC)

HistopatologicReactie de amplificare genica

cercetare, beneficiu minim pt dg sitratamentul de rutina

Condiloame acuminate evolutie naturala

Pot spontan regresa, creste, ramaneneschimbateNetratate, 10-30% dispar spontan incca 3 luni

Condiloame acuminateprincipii de tratament

Nu exista o metoda terapeutica unica sisatisfacatoare in toate cazurileRatele de succes initiale sunt 50-75%cu majoritatea tratamentelorRecurentele sunt obisnuiteVaccinuri anti-PVU pot preveni infectia

Condiloame acuminatetratament

Metode aplicabile de catre pacientPodofilotoxina (Condyline) 3/7, 4-6 saptImiquimod (Aldara) 3/7, max 16 sapt

Metode aplicabile de personal medicalCrioterapiePodofilinaAcid tri-, bi-cloraceticCuretareElectrocauterizareFotovolatilizare laser

Vaccin anti-PVU (Gardasil)

Vaccinul este impotriva celor mai frecvente tulpinide PVU (6, 11, 16, 18)Este puternic imunogen - induce un raspuns imunfoarte intens, de 50 de ori mai mare decat raspunsulimun obtinut prin contactul natural cupapilomavirusul.Vaccinul nu are nici un risc din punct de vedere alinfectiozitatii sau riscului oncogenic, intrucat esteobtinut prin recombinare genica.Este in prezent autorizat si pentru vaccinareabaietilor (FDA 2010)

Vaccin anti-PVU - limitariLipsa datelor referitoare la durata raspunsului imunDate insuficiente referitoare la intensitatearaspunsului imun (titrul Ac este un marker surogat alraspunsului imun)Posibile infectii cu alte tipuri, deci screening-ultrebuie sa continueAcceptabilitatea sociala a vaccinuluiVaccinarea barbatilor (vaccinarea exclusiva afemeilor este cu 60-75% mai putin eficienta inprevenirea cancerului de col decat vaccinareaambelor sexe)

Tratamentrezultate asteptate

Scopul nu este eradicarea PVU (imposibila dincauza infectiei clinice subiacente)Tratarea leziunilor vizibile poate reduceinfectiozitatea si transmiterea (nedemonstrat)Tratamentul este exclusiv simptomatic si poatecontribui la cresterea perioadelor fara leziuniRecurentele sunt > 25% in primele 3 luniTratamentul este mai eficace pentrucondiloamele recente (< 1an)

Duct tape therapy for warts.Jerry Litt, 1978.

Tratamentul verucilor cu bandaadeziva (“duct tape”)

Metoda nedureroasa, lipsita de riscuri, ieftina sieficace pt verucile peri- si subunghiale

Tehnica:Infasurati complet veruca cu banda adezivapentru a realiza ocluzie completaLasati banda 6,5 zile, apoi faceti o pauza de12 ore; se repeta pana la disparitia veruciiDupa cateva sapt, veruca se micsoreaza, semacereaza si dispare

Don’t Excise - Exorcise.Duct tape therapy for warts.

Jerry Litt. Cutis 1978; 22: 673-76.

Ce este “duct tape”?

• Duct tape, or duck tape, is a polyethylene, reinforced,multi-purpose pressure sensitive tape with a soft andflexible shell and pressure sensitive adhesive. It isgenerally silver or black in color but many othercolors have recently become available. With astandard width of 1+7⁄8 inches (48 mm), duct tapewas originally developed during World War II in 1942as a water resistant sealing tape for ammunitioncases.

(http://en.wikipedia.org/wiki/Duct_tape)

Duct tape for the treatment of commonwarts in adults: a double-blind RCT

Arch Dermatol 2007• 90 immunocompetent adult volunteers with at least 1

wart measuring 2 to 15 mm enrolled. 80 completedthe study.

• There were no statistically significant differences inthe proportions of patients with resolution of thetarget wart (8 [21%] of 39 patients in the treatmentgroup vs 9 [22%] of 41 in the control group).

• Of patients with complete resolution, 6 (75%) in thetreatment group and 3 (33%) in the control group hadrecurrence of the target wart by the sixth month.

Arch Dermatol. 2007 Mar;143(3):309-13.

If the patient is you, try aplacebo or two.

Herpes simplex

Virus ADN - 2 tipuri antigenice (VHS1,VHS2)Produce infectie cronica, persistenta aggl nervilor senzitivi si recurentemucoase variabile si imprevizibile

Herpes simplex manifestari clinice

• A. Primo-infectia herpeticaF. inaparente (80-95% din infectiile VHS1)Gingivostomatita herpeticaHerpesul genital primarAlte forme:

Panaritiu herpeticKeratoconjunctivita

Forme graveEczema herpeticumHerpesul neonatalHerpesul la imunodeprimati

• B. Herpesul recurent

Herpes simplex - diagnostic

• Clinic - suficient pt cazurile tipice• Paraclinic

CitodiagnosticIFDCultura viralaSerologia - nu este utila pt dg. recurentelor

Herpes simplex - tratament

1.Antivirale care inhiba ADN-polimerazavirala dupa o fosforilare prealabilamediata de timidinkinaza (TK)herpetica (*ciclovir-uri)

2.Antivirale care inhiba ADN-polimerazavirala independent de timidinkinazaherpetica

Efectele tratamentului antiviral

Tratamentul recurentelor (intermitent)Scurteaza durata si severitate recurenteirespectiveNu influenteaza durata frecventa, duratasi severitatea recurentelor ulterioare

Tratamentul continuuReduce frecventa (cu >60-70%) siseveritatea recurentelor si ↓ eliminarileasimptomatice de virus

Indicatiile tratamentului antiviralcontinuu

Recurente frecvente (>6/an)Recurente complicateImunodeprimatiGravide la risc, dupa saptamana 36

Rezistenta la antivirale

Nu se dezvolta la persoaneimunocompetenteRisc mare de dezvoltare a rezistenteila imunodeprimatiMecanism: mutatii ale genei TK cudisparitia completa a genei →rezistenta incrucisata la *ciclovir-uri

AciclovirAnalog ciclic al guanozineiBiodisponibilitate 15%Trat recurentelor: 200 mg x 5/ziTrat continuu: 800 mg/zi in 1-2 prize

ValaciclovirEsterul L-valil al acicloviruluiBiodisponibilitate 54%Trat recurentelor: 500 mg x 2/ziTrat continuu: 500 mg/zi in 1-2 prize

FamciclovirTransformat in penciclovir (f. activa)Biodisponibilitate 77%Trat recurentelor: 250 mg x 3/ziTrat continuu: 125 mg x 2/zi

La persoanele cu rezistenta la antiviraleleclasice:Foscarnet

Nu se absoarbe oral, se adm i-vIndicat in infectiile cu VHS1,2 VVZ, CMV laimunodeprimati

CidofovirEficace topic si sistemic pe mutantii rezistenti laaciclovir si foscarnet

Herpes zoster

Reactivarea dermatomerica a virusuluivaricelo-zosterian → nu poate apareadecat la cei care au avut varicela

98% din adulti in decada 3 au Ac anti-VVZEruptia este unilaterala, formata dinvezicule grupate pe fond eritematos

Herpes zoster

VarstaIncidenta: < 1/1000 la copii vs. 12/1000 lapersoane > 65 ani

Factori de risc:↓ imunitatii la VVZ cu inaintarea in varstaImunosupresiaInfectia HIV

Varstnicii sunt mai expusi, deoarece odata cu inaintareain varsta are loc o reducere a imunitatii fata de virusul V-Z. De aceea, 66% dintre pacienti au peste 50ani

Mult mai rar, zosterul afecteaza si copii (5% dintre cei sub15 ani).

Alti factori de risc suntimunosupresia (mai ales cea indusa de bolilimfoproliferative si/sau tratmente chimioterapice)Infectia HIV (creste de 8 ori riscul de zoster).

Herpes zoster

Cele mai afectate teritorii:Ramurile trigemenuluiNervii intercostali

Complicatii:Forme severe hemoragice/necroticeVaricelizareSuprainfectie bacterianaAlgii post-zosteriene - cea mai frecventa

Varstnicii sunt mai expusi, deoarece odata cu inaintareain varsta are loc o reducere a imunitatii fata de virusul V-Z. De aceea, 66% dintre pacienti au peste 50ani

Mult mai rar, zosterul afecteaza si copii (5% dintre cei sub15 ani).

Alti factori de risc suntimunosupresia (mai ales cea indusa de bolilimfoproliferative si/sau tratmente chimioterapice)Infectia HIV (creste de 8 ori riscul de zoster).

Herpes zoster - tratament

Prevenire - prin imunizarea impotrivaVVZ sau prin vaccinarea adultilorVaccinarea persoanelor de >60 ani aredus:

Incidenta h. zoster cu 51.3%Incidenta algiilor postherpetice cu 66.5%Severitatea totala a h. zoster cu 61%

(NEJM 2005; 352: 2271-2284)

Exista vaccin cu virus viu atenuat (Varilrix, Varivax) - cu oeficienta de 80% in prevenirea infectiei simptomatice cuVVZ. 5% dintre copiii vaccinati fac rash. Vaccinul produceatat un raspuns mediat celular cat si unul umoral.

La adulti, care au venit deja in contact cu VVZ, vaccinul arputea fi util ca un rapel de reactivarea a imunitatii umoralesi celulare si ar putea contribui la reducerea incidenteiherpesului zoster.

A Vaccine to Prevent Herpes Zoster and PostherpeticNeuralgia in Older Adults (NEJM, June 2, 2005)

Background. The incidence and severity of herpes zosterand postherpetic neuralgia increase with age inassociation with a progressive decline in cell-mediatedimmunity to varicella–zoster virus (VZV). We tested thehypothesis that vaccination against VZV would decreasethe incidence, severity, or both of herpes zoster andpostherpetic neuralgia among older adults.

Methods. We enrolled 38,546 adults 60 years of age orolder in a randomized, double-blind, placebo-controlledtrial of an investigational live attenuated Oka/Merck VZVvaccine ("zoster vaccine"). Herpes zoster was diagnosedaccording to clinical and laboratory criteria. The pain anddiscomfort associated with herpes zoster were measuredrepeatedly for six months. The primary end point was theburden of illness due to herpes zoster, a measure affectedby the incidence, severity, and duration of the associatedpain and discomfort. The secondary end point was theincidence of postherpetic neuralgia.

Results. More than 95 percent of the subjects continued inthe study to its completion, with a median of 3.12 years ofsurveillance for herpes zoster. A total of 957 confirmedcases of herpes zoster (315 among vaccine recipientsand 642 among placebo recipients) and 107 cases ofpostherpetic neuralgia (27 among vaccine recipients and80 among placebo recipients) were included in theefficacy analysis. The use of the zoster vaccine reducedthe burden of illness due to herpes zoster by 61.1 percent(P<0.001), reduced the incidence of postherpeticneuralgia by 66.5 percent (P<0.001), and reduced theincidence of herpes zoster by 51.3 percent (P<0.001).Reactions at the injection site were more frequent amongvaccine recipients but were generally mild.

Conclusions. The zoster vaccine markedly reducedmorbidity from herpes zoster and postherpetic neuralgiaamong older adults.

Herpes zoster - tratament

Tratament etiologic:Aciclovir 800 mg x 5/zi, 7 zileValaciclovir/Famciclovir/Brivudin -

echivalente ca eficacitate cu aciclovirulcomplianta mai buna pt ca se administreazamai rarmai scumpe

Tratamentul algiilor

Exista vaccin cu virus viu atenuat (Varilrix, Varivax) - cu oeficienta de 80% in prevenirea infectiei simptomatice cuVVZ. 5% dintre copiii vaccinati fac rash. Vaccinul produceatat un raspuns mediat celular cat si unul umoral.

La adulti, care au venit deja in contact cu VVZ, vaccinul arputea fi util ca un rapel de reactivarea a imunitatii umoralesi celulare si ar putea contribui la reducerea incidenteiherpesului zoster.

A Vaccine to Prevent Herpes Zoster and PostherpeticNeuralgia in Older Adults (NEJM, June 2, 2005)

Background. The incidence and severity of herpes zosterand postherpetic neuralgia increase with age inassociation with a progressive decline in cell-mediatedimmunity to varicella–zoster virus (VZV). We tested thehypothesis that vaccination against VZV would decreasethe incidence, severity, or both of herpes zoster andpostherpetic neuralgia among older adults.

Methods. We enrolled 38,546 adults 60 years of age orolder in a randomized, double-blind, placebo-controlledtrial of an investigational live attenuated Oka/Merck VZVvaccine ("zoster vaccine"). Herpes zoster was diagnosedaccording to clinical and laboratory criteria. The pain anddiscomfort associated with herpes zoster were measuredrepeatedly for six months. The primary end point was theburden of illness due to herpes zoster, a measure affectedby the incidence, severity, and duration of the associatedpain and discomfort. The secondary end point was theincidence of postherpetic neuralgia.

Results. More than 95 percent of the subjects continued inthe study to its completion, with a median of 3.12 years ofsurveillance for herpes zoster. A total of 957 confirmedcases of herpes zoster (315 among vaccine recipientsand 642 among placebo recipients) and 107 cases ofpostherpetic neuralgia (27 among vaccine recipients and80 among placebo recipients) were included in theefficacy analysis. The use of the zoster vaccine reducedthe burden of illness due to herpes zoster by 61.1 percent(P<0.001), reduced the incidence of postherpeticneuralgia by 66.5 percent (P<0.001), and reduced theincidence of herpes zoster by 51.3 percent (P<0.001).Reactions at the injection site were more frequent amongvaccine recipients but were generally mild.

Conclusions. The zoster vaccine markedly reducedmorbidity from herpes zoster and postherpetic neuralgiaamong older adults.

The young physician starts life withtwenty drugs for each disease,

andthe old physician ends life withone drug for twenty diseases.

(W. Osler)

Pox-virusuri

Virusul ectimei contagiosum (orf)Virusul nodulilor mulgatorilorVirusul moluscumului contagiosum

Ectima contagiosumNodulii mulgatorilor

Produse de parapoxvirusuri ale carorgazde sunt:

Oile si caprele (ectima contagiosum)Bovinele (nodulii mulgatorilor)

Contaminarea umana are lor prininoculare directa de la animalelebolnave

Ectima contagiosumNodulii mulgatorilor

Manifestari clinice f. asemanatoarePapule rosii → noduli fermi, sensibili→ pustule/bule hemoragice, uneoriombilicate→ crustaLocalizare pe mainiFrecvent limfangita si adenopatiesatelitaSe vindeca spontan, fara cicatrice, in4-6 saptamani

(colectia dr. G. Turcu)

Molluscum contagiosum

Afectiune comuna, apare la oricevarsta, mai frecvent la copiiLa adult se localizeaza genital siperigenital (ITS)Transmiterea: hetero- si autoinoculare

Molluscum contagiosum

Manifestari:Papule de culoarea pielii, hemisferice, cucentrul ombilicatCresc lent si ating 5-10 mm in 6-12 saptPrin exprimarea continutului → “grauntiide molluscum”

Molluscum contagiosumtratament

CuretareCrioterapieExprimarea continutului + alcool iodatSol KOH 5%

Never underestimate thepower of body to heal

Pitiriazis rozat

• Robert Willan 1798• Camille Gibert 1860 (f. maculara)• Pierre Bazin 1862 (f. inelara, cea mai

frecventa)• Louis Brocq 1887 - placa heraldica

Epidemiologie

• Incidenta 0.39-4.80/100 pacienti dedermatologie

• 172/100.000 pers-ani in populatia generala• Majoritatea sunt tineri: 10-35 ani• Barbati-femei: 1:1.43• Variatii sezoniere ale frecventei• Agregari spatio-temporale ale cazurilor

Etiologie

Infectioasa (virala, HHV-7?)• Evolutie similara exantemelor virale• Absenta recidivelor• Asocierea cu infectii respiratorii• Gruparea spatio-temporala a cazurilor• Aparitia de PR dupa contact cu PR

Eruptiile pitiriazis rozat-like induse demedicamente sunt clasificate separat

Manifestari clinice

• Placa heraldica - 40-76%• Interval placa heraldica-eruptie: 2-84

zile (de obicei 7-14)• Eruptie eritemato-scuamoasa, ovalara,

cu descuamare “in coleret”, cu scuamemai aderente la periferia leziunii si maidetasate in centrul ei

Manifestari clinice

• Eruptia secunda: leziuni similara placiiheraldice, dar de dimensiuni mai mici

• Distributia leziunilor cu axul lung paralelcu liniile de tractiune ale pielii

• Localizata pe trunchi si radacinamembrelor

• Traditional respecta fata

Forme atipice

• Relativ frecvente• Forme: veziculoase, purpurice,

hemoragice, cu placi gigante, cu placifoarte mici, inversata (afect reg axilare,inghinale, fata)

• Afectarea cav orale - posibila

Chuh AA. JEADV 2003;17:101-3.

Tratament

• Nici un tratament• Eritromicina (sau alte macrolide)• Antivirale (aciclovir ? - eficacitate

redusa pe HHV-7)• Fototerapie (naturala, UVB)

Sarcomul Kaposi

• Tumora multifocala, indusa de infectia cuHHV-8, cu numeroase forme clinice

• Frecventa a crescut dupa aparitia HIV/SIDA• Riscul bolii la cei cu SIDA care au ca factor

de risc homosexualitatea este de 106.000 orimai mare decat in populatia generala, iar lacei cu alti factori de risc pentru SIDA de13.000 ori mai mare.

Sarcomul Kaposi - investigatii

• Biopsie (ptconfirmare)

• test HIV• investigatii uzuale• investigatii de

extensie (echo, CT)

Kaposi - forma clasica

• Barbat, >60 ani• Placi violacee• Debut mb inferioare• Hiperkeratoza• Pot dezvolta noduli• Pot ulcera

Forme de sarcom Kaposi

• Forma clasica (europeana) - la barbati varstnici,mai frecvent in zona mediteraneana, evol lenta &neagresiva; sex ratio B:F=15:1

• Forma endemica africana - la negri, are 4subtipuri (benigna nodulara, agresiva localizata,florida, limfadenopatica); sex ratio 1:1

• Forma epidemica (sidatica) - la pacienti cu SIDA,cea mai specifica manifestare in HIV/SIDA; sexratio B:F=3:1

• Forma iatrogenica (imunodeprimati) - sex ratio 1:1

Kaposi clasic vs. Kaposi sidatic

• pred barbati• de obicei > 60 ani• debut mb inferioare• leziuni putine• evolutie lenta• rareori afecteaza 1/2

superioara corp• nu afecteaza

mucoasele

• pred la homosexuali• in faza de SIDA• fara zone electie• leziui numeroase• evolutie rapida• afect extracutanata

precoce• afect mucoasa

frecventa• Kobnerizare

Diagnostic diferential

• Angiom• Granulom piogenic• Angiokeratom• Insuficienta venoasa severa (pseudo-Kaposi)• Sindromul Blue Rubber Bleb Nevus• Nevi• Dermatofibrom

Evolutie

• Variabila - de la afectare exclusivcutanata la afectare cutanata siextracutanata rapid progresiva.

• Influentata de forma de boala si deteren.

Tratament

• Conservator (watchful waiting)• Excizia/cauterizarea ariilor sever afectate• Radioterapie• Antivirale (foscarnet, HAART)• Chimioterapie intralezionala (eg vincristina) sau

sistemica (vinblastina, paclitaxel, docetaxel)• Intreruperea imunosupresoarelor la cei

imunosupresati iatrogen

The therapist walks a tight ropebetween faith and skepticism,

but should he fall, let if betoward faith.

Manifestari cutanate in HIV/SIDA

• Neoplazice: Kaposi, limfoame, epitelioame• Infectioase:

– virale (herpes extins, zoster necrotic, HPV, molluscum)– bacteriene (angiomatoza bacilara, mycobacterioze atipice,

sifilis)– fungice (candidoze, criptococoza, coccidioidomicoza)– ectoparazitare (scabie norvegiana)– parazitare (pneumocistoza extrapulmonara, toxoplasmoza)

• Neclasificabile: d. seboreica, eruptii papuloase, afectautoimune, reactii postmedicamentoase

Infectii virale cutanate

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