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Educao Mdica Continuada / Continuing Medical Education
Herpes simples * Herpes simplex *

Omar Lupi 1
Resumo: Herpes simples molstia infecciosa de etiologia viral, tendo o HSV como agente etiolgico. As duas cepas do vrus produzem quadros de localizao genital e extra-genital, muito prevalentes na populao mundial. O controle efetivo do herpes simples difcil de ser obtido devido capacidade de latncia do HSV, alm das recorrncias crnicas e variveis. Novos quadros tm sido descritos em pacientes imunodeprimidos, tais como formas mais crnicas ou disseminadas da doena. Tcnicas sorolgicas mais especficas j permitem diagnstico preciso e eficiente da doena. As drogas antiherpticas tm ao efetiva contra o vrus, poucos efeitos colaterais e esquemas posolgicos cada vez mais cmodos aos pacientes com primoinfeco herptica ou recorrncia. Novas vacinas especficas, incluindo as de subunidades e as gnicas, devem facilitar o controle da doena nos prximos anos. Palavra-chave: Herpes genital; herpes labial; herpes simples; drogas anti-herpticas; vacinas. Summary: Herpes simplex is an infectious disease of viral etiology that has the HSV (herpes simplex virus) as the agent. Two strains of the virus lead to symptoms located in the genital and extra-genital areas, and these are highly prevalent among the world population. The effective control of Herpes simplex is hard to achieve due to the latent capacity of HSV, besides the chronic and variable recurrences. New symptoms have been described in immunodepressed patients, such as chronic and disseminated forms of the disease. Specific serologic techniques now permit a precise and effective diagnosis. Anti-herpes drugs effectively act against the virus, rarely produce adverse effects, and afford more comfortable therapeutic regimens for patients with a first herpes infection or recurrences. New specific vaccines, including those of subunits and genic, may facilitate the control of the disease in the next few years.
INTRODUO O herpes simples molstia infecto-contagiosa crnica e, por vezes, recorrente, tendo como agente etiolgico duas cepas diferentes do vrus herpes simples (HSV ). Dois quadros distintos podem ser individualizados: o herpes simples extragenital, cujo principal agente o HSV do tipo 1 (HSV-1), e as formas perigenitais, com preponderncia do HSV-2. A molstia ganhou um novo e especial destaque com o advento da AIDS e com o aumento do nmero de
INTRODUCTION Herpes simplex is a chronic infectious-contagious disease and, sometimes, recurrent. The etiology is from two different strains of herpes simplex virus (HSV), of which there are two distinct manifestations: extragenital herpes simplex, of which the principal agent is HSV type 1 (HSV -1), and the perigenital form, where there is a predominance of HSV -2. The disease has gained special attention since the outbreak of AIDS, resulting in a higher number of immunodepressed individuals, with clinical manifestations that were once atypical and
Recebido em 30.12.1999. /Received in December, 30th of 1999. Aprovado pelo Conselho Consultivo e aceito para publicao em 26.5.2000. /Approved by the Consultive Council and accepted for publication in May, 26th of 2000. * Trabalho realizado no Curso de Ps-graduao em Dermatologia - UFRJ e Servio de Dermatologia do HUCFF/UFRJ. Work done at Curso de Ps-graduao em Dermatologia / UFRJ and Servio de Dermatologia do HUCFF/UFRJ.
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Mestre; Doutor em Dermatologia - UFRJ. Mdico - HUCFF / UFRJ. Professor Titular - UNIG. Professor Adjunto - IPGMCC / PGRJ. Professor Assistente - UGF. Master; Doctor of Dermatology - UFRJ. Doctor - HUCFF / UFRJ. Professor - UNIG. Assistant Professor - IPGMCC / PGRJ. Assistant Professor - UGF. 2000 by Anais Brasileiros de Dermatologia
An bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.
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indivduos imunodeprimidos, pois as manifestaes clnicas tornaram-se atpicas e inusitadas. Outro fato importante, nesse contexto, foi o surgimento de novas opes de drogas anti-herpticas e das modernas tcnicas de imunoprofilaxia envolvendo a biologia molecular. Assim sendo, o herpes simples passou a ser um dos campos da Medicina de maior evoluo na ltima dcada. DISCUSSO 1. Etiopatogenia O HSV um DNA-vrus pertencente subfamlia Alphaherpesvirinae, apresentando quatro componentes bsicos: a estrutura helicoidal de DNA em dupla hlice, envolvida por capsdeo icosadrico e circundada por uma substncia amorfa (tegumento), alm do envelope lipdico, em que se expressam as glicoprotenas de superfcie do HSV.1 A transmisso do HSV ocorre atravs das superfcies mucosas ou das solues de continuidade na pele. Os principais stios incluem a mucosa oral, ocular, genital e anal. O HSV-2 tem como via preponderante de contgio a relao sexual ou o canal do parto, nas gestantes infectadas.1,2 A replicao viral inicia-se na epiderme aps a ligao do vrus s molculas de heparan sulfato da membrana celular. O perodo de incubao de cerca de sete dias. A infeco propaga-se para as terminaes nervosas livres com disseminao intra-axonal atravs de transporte retrgrado dos vrions, partculas infectantes bsicas dos vrus, para os gnglios sensoriais paravertebrais. A replicao viral prossegue no gnglio sensorial e nos tecidos neurais contguos, com o estabelecimento da latncia viral. Os gnglios sacrais e trigeminais so os mais acometidos, mas outros gnglios paravertebrais tambm podem servir de epicentro nas recorrncias clnicas.1,2 O ciclo biolgico do HSV controlado por suas glicoprotenas (g) de superfcie. As glicoprotenas gC, gB e gD so indispensveis para a replicao viral nas clulas infectadas, participam da adsoro ao heparan sulfato, alm da liberao de vrions. Mutaes virais, com translocao no gene codificador da g B, produzem vrions no infecciosos. Quando a translocao afeta a g e a gD B conjuntamente, o vrion efetua a adsoro, mas no penetra a clula. As glicoprotenas gE e gI codificam receptores para a frao Fc da IgG, enquanto a g C atua como receptor para o fragmento C3b do complemento.1,3 2. Latncia viral O HSV apresenta tropismo por ceratincitos e neurnios. Enquanto os primeiros so altamente permissveis replicao do vrus, os neurnios no o so. Curiosamente, o HSV beneficia-se ao infectar essas clulas imunes a seu efeito citoptico, pois, por no a poder destruir, acaba integrando-se a seu DNA ; o resultado final o estabelecimento da infeco latente.4,5 Parece que, no caso do HSV, ocorre a restrio da transcrio do gene IE durante a
unknown. Another important fact was the development of new antiherpes drugs and modern techniques of immunoprophylaxis, including molecular biology. In this way, herpes simplex became in the last decade one of the fields of medicine with the greatest evolution. DISCUSSION 1. Etiopathogenesis HSV is a DNA -virus belonging to the subfamily Alphaherpesvirinae, presenting four basic compounds: a helicoidal structure of DNA with a double-stranded helix, covered by an icosahedral capsid and surrounded by an amorphous substance (tegument), and a lipid envelope, where the surface HSV glycoproteins are expressed.1 The transmission of the HSV occurs through the mucous surfaces or the continuous solutions on the skin. The main spots include oral, ocular, genital, and anal mucosa. The primary route of HSV-2 transmission is via sexual intercourse, or the birth canal, in infected pregnant women. 1,2 The viral replication starts on the epidermis after the virus link to the heparitin sulfate molecules of the cell membrane. The incubation period is about 7 days. The infection propagates to the free nervous terminations with intra-axonal dissemination through retrograde transport of the virions, basic infectious particles of the virus, to the paravertebral sensorial ganglia. The viral replication continues in the sensorial ganglion and in the surrounding neural tissues, establishing viral latency. Sacral and trigeminal ganglia are most often attacked, but other paravertebral ganglia can also serve as an epicenter in clinical recurrences.1,2 The biological cycle of HSV is controlled by its surface glycoproteins (g). Glycoproteins gC, g B and g D are indispensable to viral replication in the infected cells, they participate in the adsorption of heparitin sulfate, besides the liberation of virions. Viral mutations with translocation on the codifier gene of gB produces noninfective virion. When the translocation affects g and gD altogether, the B virion makes the adsorption, but does not penetrate the cell. Glycoproteins gE and gI codify receptors to Fc fraction of IgG, while gC acts as a receptor to the C3b fragment of the complement.1,3 2. Viral Latency HSV presents tropism for keratinocytes and neurons. While the former are highly subject to virus replication, the neurons are not. Curiously, HSV infects cells that are immune to its cytopathic effect; since it cannot destroy them, it integrates itself into the DNA of the cells; and the final result is the development of latent infection. 4,5 It seems that HSV is restricted to transcription of the IE gene during neuronal infection. Tissue factors necessary to the expression of the IE gene are rare in the nervous tissue, but
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infeco dos neurnios. Fatores tissulares necessrios expresso do gene IE so escassos no tecido nervoso, mas os neurnios produzem inibidores especficos para a transcrio do gene IE .6,7 A transcrio do genoma viral depende da protena Oct-1, presente na maioria das clulas humanas. Alguns neurnios so dotados, no entanto, de uma protena octamrica correlata, a Oct-2, que promove efeito contrrio ao da Oct-1, reprimindo a transcrio dos nucleotdeos codificados pelo locus gnico IE , impedindo assim a reativao das cepas latentes do HSV .7 Os neurnios em que predomina a protena Oct-2 tm como caracterstica principal a dependncia do fator de crescimento neuronal (FCN). A recorrncia herptica observada aps injria tecidual pode ter sua origem na reduo do nvel de fator de FCN dos neurnios com excesso da Oct-2, permitindo que a Oct-1 se torne predominante e permita a transcrio do genoma do HSV. 7,8 Os neurnios no so clulas sujeitas mitose; assim sendo, o DNA do HSV no precisa ser replicado durante a latncia, e os produtos virais necessrios replicao no precisam ser expressos. A total ausncia de sntese protica permite que o HSV fique completamente invisvel ao sistema imunolgico. O nico produto viral detectado durante a latncia conhecido como LAT (latencyassociated transcript), representando um fragmento de RNA sintetizado pelo vrus. 8,9 3. Reativao viral A latncia persiste at que ocorra qualquer alterao estrutural na clula infectada, tal como injria ou diferenciao celular; esses fatos, acredita-se, poderiam alterar a condio de no-permissibilidade da clula. O gene IE ativado aps estmulo apropriado e permite a replicao viral. O LAT , por ser a nica frao viral presente durante toda a latncia, parece promover a reativao do HSV.7,8 Os fatores capazes de estimular a reativao do HSV so variados, com destaque para imunodepresso, alteraes hormonais, radiao ultravioleta (UV) e leso traumtica do nervo acometido. A latncia viral nos gnglios pode, hipoteticamente, ser afetada pela presena dos neurotransmissores envolvidos nos estados de ansiedade, depresso e distrbios comportamentais, tambm comuns nas recorrncias.1,4 4. Epidemiologia O HSV produz pandemia sem precedentes, disseminando-se por todo o mundo. Estudos soroepidemiolgicos confirmam que mais de 90% da populao, em geral na quarta dcada de vida, possui anticorpos sricos contra pelo menos uma das cepas do HSV.10,11 O contato com leses clnicas do herpes a forma usual de contgio. Admite-se, no entanto, a participao dos portadores assintomticos na transmisso do HSV. Excreo salivar do HSV-1 em assintomticos pode ser observada em at 9% dos adultos e 5% das crianas
the neurons produce specific inhibitors to IE gene transcription.6,7 The viral genome transcription depends on the Oct-1 protein, present in the majority of human cells. Some neurons present a correlate octameric protein, the Oct-2, that promotes a contrary effect of the Oct-1, repressing the transcription of the nucleotides codified by the IE genetic locus, impairing the reactivation of latent strains of HSV. 7 Neurons where the Oct-2 protein predominates have as a principal characteristic a dependency on the neuronal growth factor ( NGF ). The herpetic recurrence observed after tissue injury may originate in the reduction of the levels of NGF on the neurons with an excess of Oct-2, permitting Oct-1 to become predominant, and then allowing the transcription of the HSV genome.7,8 Neurons are not subjected to mitosis, therefore, the DNA of the HSV does not need to be replicated during latency, and the viral products necessary for replication do not need to be expressed. The total absence of protein synthesis permits HSV to remain completely invisible to the immune system. The only viral product detected during latency is known as LAT (latencyassociated transcript), representing a fragment of RNA synthesized by the virus.8,9 3. Viral reactivation The latency persists until any structural alteration occurs in the infected cell, such as injury or cell differentiation; it is believed that these facts could alter the condition of nonpermissibility of the cells. The IE gene is activated after an appropriate stimulus and allows viral replication. The LAT , as the unique viral fraction present during the whole latency, seems to promote the reactivation of HSV .7,8 Many factors are capable of stimulating HSV reactivation, the main ones are immunodepression, hormonal alterations, ultraviolet radiation (UV ), and traumatic lesion of the affected nerve. The viral latency of the ganglia may hypothetically be affected by the presence of the neurotransmitters involved in the states of anxiety, depression, and behavior disturbances, also common in recurrences.1,4 4. Epidemiology HSV produces pandemics with no precedents, disseminating itself around the world. Serumepidemiological studies confirmed that more than 90% of the population, generally around their fourth decade of life, presents plasmatic antibodies to at least one HSV strain. 10,11 The usual form of contagion is contact with herpes clinical lesions. However, transmission by asymptomatic carriers of HSV is considered. The excretion of HSV -1 in the saliva of asymptomatic carriers can be observed in up to 9% of the adults and 5% of the children infected. Around
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infectadas. Cerca de 50% dos casos de herpes neonatal ocorrem em mulheres sem evidncias clnicas de herpes genital durante o parto. Estima-se que apenas 10 a 20% dos pacientes infectados se definam como portadores de herpes simples; at 60% dos indivduos soropositivos para o HSV apresentam quadros assintomticos ou oligossintomticos no reconhecidos pelos prprios pacientes como herpes simples. 12 Essa avaliao ajuda a entender como ocorre a disseminao do vrus na populao, pois provveis recidivas so interpretadas como estados gripais, aftas ou infeces genitais inespecficas. A infeco pelo HSV-1 tem-se tornado cada vez mais precoce na populao de classe mdia europia e norteamericana, estando presente na forma latente em indivduos cada vez mais jovens. A incidncia de casos novos do HSV1 de aproximadamente 1,5% por ano, at a idade de 50 anos.11 A prevalncia para o HSV-1 oscila de 70%, na maioria dos pases europeus, at 95%, na Amrica Central, frica e sia. Observa-se prevalncia de 86% na populao da cidade do Rio de Janeiro, em estudo de 1998. As menores prevalncias situam-se no Japo (48%) e nos pases escandinavos.11,13 O aumento na incidncia da infeco herptica genital pelo HSV -1 , tambm, tendncia mundial. O HSV1 o agente causal de 28,5% das ulceraes genitais de certas populaes amaznicas. Essa incidncia pode chegar a 50% em certas regies da Inglaterra.13 A observao dos autores no Rio de Janeiro detectou cerca de 8% dos pacientes com recorrncia comprovada de herpes genital, mas soronegativos para o HSV-2.14 Visto que as duas cepas virais podem causar infeco genital ou orolabial, importante ressaltar que a freqncia da reativao do vrus influenciada pelo stio anatmico envolvido. O HSV-2 apresenta acentuada tendncia recorrncia (mdia de quatro episdios/ano), superior observada na infeco herptica genital causada pelo HSV-1 (mdia < um episdio/ano). A infeco extragenital causada pelo HSV-1 recorre mais do que a causada pelo HSV-2, em qualquer regio.13 A prevalncia do HSV-2 nos diversos pases bastante diferente, sendo maior nos EUA (13-52%) do que na Europa (10-27%) e bastante alta na frica (30-40%). Austrlia (14-40%) e Formosa (14%) apresentam taxas semelhantes s observadas nos pases ocidentais mais desenvolvidos. As mais altas prevalncias para o HSV -2 ocorrem em Ruanda (33,3%), no Zaire (40,8%) e no Haiti (54%). O extremo Oriente caracteriza-se por prevalncias mais baixas (2-7%).11,13,15 Estudo realizado no Brasil, na cidade do Rio de Janeiro, demonstrou que, numa populao de doadores de sangue voluntrios, a soroprevalncia para o HSV-2 foi de 29,1%, mas, desse total, apenas 7% referiram histria prvia de herpes genital.14 Outras avaliaes similares em doadores de sangue dos EUA detectaram prevalncia varivel de 1% a 20% para o HSV-2.15 A prevalncia do HSV -2 aumenta com a idade, com
50% of neonatal herpes cases occur in women with no clinical evidence of genital herpes during delivery. It is believed that only 10% to 20% of infected patients define themselves as herpes simplex carriers; up to 60% of the individuals with plasmatic positivity to HSV are asymptomatic or oligosymptomatic, unrecognized by themselves as herpes simplex. 12 This evaluation helps to understand how the virus dissemination occurs among the population, since possible recurrences are interpreted as flu, aphthae, or unspecified genital infections. The HSV-1 infection has become more precocious in the European and North-American middle-class populations, presenting in the latent form in even younger individuals. The incidence of new cases of HSV-1 is approximately 1.5% a year, until the age of 50 years.11 The prevalence of HSV-1 varies from 70% in the majority of the European countries to 95% in Central America, Africa, and Asia. In a study performed in 1998, the prevalence rate of 86% was observed among the population of Rio de Janeiro. The lowest prevalence rates were observed in Japan (48%) and in the Scandinavian countries.11,13 The increase in the incidence of genital herpes infection by HSV-1 also shows a worldwide trend. HSV-1 is the causal agent of 28.5% of genital ulceration among certain Amazonian populations. This incidence rises to 50% in certain regions of England.13 The authors observed in Rio de Janeiro that around 8% of the patients with proved genital herpes recurrence presented plasmatic negativity to HSV-2.14 Since both strains may cause genital or orolabial infection, it is important to point out that the frequency of virus reactivation is influenced by the anatomical location involved. HSV-2 presents high tendency of recurrence (average of 4 episodes/year), superior to the one observed in the genital herpetic infection caused by the HSV-1 (average < one episode/year). The extragenital infection caused by HSV-1 reoccurs more often than the one caused by HSV-2, in any region. 13 The prevalence of HSV -2 varies between countries: it is higher in the USA (13%-52%) than in Europe (10%-27%), and very high in Africa (30%-40%), Australia (14%-40%), and Formosa (14%), which present similar rates to those observed in developed occidental countries. The highest prevalence of HSV-2 occurs in Rwanda (33.3%), Zaire (40.8%), and Haiti (54%). Oriental countries present a lower prevalence (2%-7%).11,13,15 A study carried out in Rio de Janeiro, Brazil, showed that in a population of volunteer blood donors, the plasmatic prevalence to HSV -2 was 29.1%, but out of this total, only 7% reported a history of genital herpes.14 Some other similar evaluations in American blood donors revealed a variable prevalence of 1% to 20% of HSV -2.15 The prevalence of HSV-2 increases with age, with a cumulative increase after puberty. Genital herpes
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incremento cumulativo aps a puberdade. O herpes simples genital, como esperado para uma DST, tem alta prevalncia em pacientes com vida sexual promscua. Dois estudos realizados no Brasil por Lupi e cols.10,14 entre os anos de 1995 e 1998 avaliaram uma populao de 105 pacientes, com idade variando entre 12 e 70 anos. O grupo estudado incluiu homossexuais e bissexuais com histria de multiplicidade de parceiros; a prevalncia do HSV-2 atingiu 72% nesses pacientes, enquanto nos do grupo controle no ultrapassou 29%. A avaliao comparativa desses dois estudos no deixou perceber influncia significativa da faixa etria na soroprevalncia para o HSV-2. 10,16 Observaram-se, como causas estatisticamente significativas da disseminao do HSV -2, iniciao sexual precoce, histria prvia de DST (uretrites gonoccicas, uretrites pela Chlamydia trachomatis e sfilis), multiplicidade de parceiros sexuais, prtica do sexo orogenital, coito anal e relaes homossexuais com penetrao. Mertz17 destaca, tambm, o grau de alfabetizao e a renda familial como fatores importantes. Todas essas variveis so, provavelmente, mais importantes na caracterizao de um grupo de risco para a aquisio do HSV-2 do que fatores diretamente implicados na infeco viral. 5. Manifestaes clnicas do herpes simples As manifestaes clnicas do herpes simples dependem, fundamentalmente, do stio da inoculao viral, da imunidade do hospedeiro e da cepa viral adquirida. A primoinfeco herptica , geralmente, assintomtica ou manifesta-se por meio de sintomatologia inespecfica. Muitos dos quadros infecciosos da infncia e adolescncia, erroneamente imputados a outros vrus e infeces bacterianas da orofaringe, so, na verdade, primoinfeces herpticas. At 95% dos pacientes expostos primariamente ao HSV no apresentam sintomatologia suficiente para a plena caracterizao do quadro.18 Essa primeira manifestao do herpes simples pode
simplex, as expected of a sexually transmitted disease, has a high prevalence in patients with a promiscuous sex life. Two Brazilian studies by Lupi and colleagues,10,14 between 1995 and 1998, evaluated a population of 105 patients with ages varying from 12 to 70 years. The study population included homosexuals and bisexuals with a history of multiple partners. The prevalence of HSV -2 reached 72% in these patients, while the control group did not go over 29%. The comparative evaluation of these two studies did not show any significant influence of the age range in the plasmatic prevalence of HSV -2.10,16 The following were observed to be statistically significant causes of HSV-2 dissemination: premature sexual initiation, history of STD (gonococcal urethritis, urethritis by Chlamydia trachomatis, and syphilis), multiple sexual partners, orogenital sex, anal intercourse, and homosexual relationships with penetration. Mertz1 7 also emphasizes the alphabetization level and family income as important factors. All these variables are probably more important in characterizing a group at risk for acquiring HSV-2 than the factors directly implied in viral infection. 5. Clinical manifestations of herpes simplex Clinical manifestations of herpes simplex depend, fundamentally, on the viral inoculation location, on the host's immunity, and the viral strain acquired. The first herpetic infection is generally asymptomatic or presents as unspecified symptomatology. In many infants and adolescents, infectious manifestations are erroneously considered infections caused by other viruses and oropharyngeal bacterial infections, but they truly are first herpetic infections. Up to 95% of the patients primarily exposed to HSV do not present enough symptomatology to fully characterize the manifestation.18 This first manifestation of herpes simplex may occur in healthy patients that will develop the characteristic
Figura 1: Primoinfeco herptica em adulto, acometendo o An bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.
Figura 2: Herpes simples genital
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Figura 3: Herpes orolabial recorrente
Figure 3: Recurrent orolabial herpes0
ocorrer em pacientes hgidos que desenvolvero a sintomatologia prpria da chamada primoinfeco herptica benigna (Figura 1). O quadro clssico de primoinfeco benigna freqentemente precedido por febre, cefalia, mialgias e adinamia. Em cerca de 24 horas surgem mculas eritematosas no local da inoculao, acompanhadas de ardor, prurido e dor. Sobre a base eritematosa surgem vesculas agrupadas, que permanecem ntegras por cerca de quatro a cinco dias. Erosam, para depois haver a reparao; esse quadro perdura por perodo de duas a trs semanas (Figuras 2 e 3). Ocorre poliadenomegalia regional em at 75% dos casos.18,19 A complicao local mais comum no herpes genital so as infeces secundrias; nos homens no circuncisados pode ocorrer o quadro de fimose ou parafimose. 2,4,18 O herpes extragenital ou labial menos associado complicaes durante a primoinfeco, apesar da suspeita de que o HSV -1 esteja associado a quadros de paralisia de Bell e sndrome de Guillain-Barr. Itzhaki e cols. detectaram partculas do DNA do HSV -1 no crebro de portadores da doena de Alzheimer; 20 indivduos geneticamente predispostos parecem, em presena do vrus, produzir quantidades excessivas da apolipoprotena E (ApoE), envolvida no quadro demencial. 20,21 Os quadros de primoinfeco maligna ocorrem nos pacientes imunodeprimidos, especialmente quando o inculo viral grande, cursando com manifestaes mais graves e duradouras. Portadores de dermatoses eritmatodescamativas extensas ou que cursem com soluo de continuidade da pele, tais como o eczema atpico, pnfigo foliceo, sndrome de Szary, doena de Darier e doena de Hailey-Hailey, esto expostos a formas disseminadas de infeco herptica, em especial a erupo variceliforme de Kaposi. 22,23 Portadores de neoplasias hematolgicas, com exceo do mieloma mltiplo, e crianas com aplasia tmica congnita podem desenvolver herpes simples crnico e recorrente. Infeces pelo HSV em gestantes, pacientes geritricos e recm-natos, que pela imaturidade do sistema imunolgico funcionam como imunodeprimidos, podem apresentar-se de maneira extensa e com disseminao visceral. importante tambm o considervel aumento da morbidade dos grandes queimados com infeco herptica concomitante e de indivduos em crise de cetoacidose
symptomatology of the benign first herpetic infection (Figure 1). The classical manifestation of the benign first herpetic infection is frequently preceded by fever, headache, myalgia, and asthenia. In about 24 hours some erythematous macules break out, accompanied by burning, pruritus, and pain. Over the erythematous base appear some grouped vesicles that remain intact for 4 to 5 days. They first erupt, then begin to heal, a process which lasts for 2 to 3 weeks (Figures 2 and 3). Regional polyadenomegaly occurs in up to 75% of the cases.18,19 The most common local complications in genital herpes are the secondary infections; in noncircumsized men, phimosis or paraphimosis may occur. 2,4,18 The extragenital or lip herpes are associated less with complications during the first infection, however, there is some evidence of an association between HSV-1 and manifestations of Bells paralysis and Guillain-Barre syndrome. Itzhaki and colleagues detected DNA particles of HSV -1 in the brain of Alzheimers patients.20 Individuals genetically predisposed seem to produce, in the presence of the virus, excessive quantities of apolipoprotein E (ApoE), a substance involved in the manifestation of dementia.20,21 The manifestations of the first infection occur in immunodepressed patients, especially when the viral inoculum is large, resulting in more severe and longer manifestations. Individuals presenting extensive erythematous-scaly dermatoses or who have continuous skin manifestations, such as atopic eczema, pemphigus foliaceus, Sezary syndrome, Darier disease, and HaileyHailey disease, are exposed to disseminated forms of herpetic infections, especially the varicelliform of Kaposi's eruption.22,23 Individuals presenting hematological neoplasias, except for multiple myeloma, and children with congenital aplasia of the thymus may develop chronic and recurrent herpes simplex. HSV infections in pregnant women, geriatric patients, and new-borns, who can be considered immunodepressed due to the immaturity of the immune system, can present in an extensive way and with visceral dissemination. It is also important to note the considerable increase in morbidity of extensively burned individuals with concomitant herpetic infection and individuals in diabetic ketoacidosis crises induced by herpes.24,25
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diabtica precipitada pelo herpes.24,25 Corticoterapia sistmica e utilizao de imunossupressores, durante longos perodos, associam-se com a ecloso do HSV . O herpes simples mais comum nos pacientes com pnfigo, principalmente com acometimento perigenital. Os pnfigos formam grupo de alta morbidade no que se refere infeco pelo HSV, pois, como dermatoses vesicobolhosas, tm seu quadro clnico confundido com a prpria erupo cutnea provocada pelos herpes.25 O herpes neonatal outro tipo de primoinfeco maligna, com mortalidade de 70%. Caracteriza-se pela contaminao no momento do parto, visto que o HSV no se relaciona com infeco intra-tero. O concepto apresentar hepatite e encefalite macia, com taxa de mortalidade superior a 70%. A incidncia do herpes neonatal francamente crescente, visto o aumento da prevalncia do HSV-2. Cerca de 0,2% das gestantes avaliadas no momento do parto apresentam viremia pelo HSV, sem manifestaes clnicas. Apenas 30% dos casos de transmisso maternofetal apresentam histria prvia de herpes genital.26 A AIDS , no entanto, a molstia mais associada s infeces herpticas malignas. O herpes simples mucocutneo ou de acometimento visceral (brnquico, pulmonar ou esofagiano) com mais de um ms de durao doena definidora da AIDS; admite-se que, em grande parte dos casos, ocorre a reativao do HSV latente (Figuras 4 e 5). Os autores acompanharam 100 pacientes HIV positivos por um ano e detectaram soroprevalncia para o HSV-1 de 82% e de 73% para o HSV-2 em doentes subclassificados no estdio I da AIDS (soropositivo para o HIV, mas sem manifestaes clnicas da molstia). Efetuaram a mesma avaliao em pacientes do estdio IV (mais de 50% do tempo hospitalizados por complicaes relacionadas AIDS), e a soroprevalncia para o herpes foi de 100% para as duas cepas do HSV. 14 O herpes genital no curso da AIDS pode manifestar-
Systemic corticotherapy and the use of immunosuppressants for prolonged periods are associated with the outbreak of HSV . Herpes simplex is more common in patients with pemphigus, especially with perigenital occurrence. Pemphigus forms a high morbidity in regard to HSV infection, since, as vesicobullous dermatoses, their manifestations may be misinterpreted as the cutaneous eruption provoked by herpes.25 Neonatal herpes is another type of malignant first infection, with 70% mortality. It is characterized by contamination during delivery, since HSV is not related to intrauterine infection. The new born will present hepatitis and acute encephalitis, with a mortality rate greater than 70%. The incidence of neonatal herpes is increasing, considering the increase in the prevalence of HSV-2. Around 0.2% of pregnant women evaluated at the time of delivery present HSV viremia, with no clinical manifestations. Only 30% of the cases of maternal-fetal transmission have a history of genital herpes.26 AIDS is, however, the disease most frequently associated with malignant herpetic infections. The mucocutaneous or visceral herpes simplex that affect the bronchi, lungs or esophagus and last more than a month, is a defining disease of AIDS ; it is believe that in a vast number of cases reactivation of the latent HSV occurs (Figures 4 and 5). The authors f ollowed 100 HIV-positive patients for 1 year and detected a plasmatic prevalence to HSV -1 of 82% and 73% to HSV-2 in patients subclassified as having stage-I of AIDS (plasmatic positivity to HIV , but no clinical manifestations of the disease). They performed the same evaluation in stage- IV patients (greater than 50% of the time spent in the hospital due to complications related to AIDS), and the plasmatic prevalence to herpes was 100% for both strains of HSV. 14 Genital herpes in AIDS may manifest itself by ulcerated lesions of wide dimension, without
Figura 4: Herpes orolabial em paciente HIV+ Figure 4: Orolabial herpes in HIV-positive patient
Figura 5: Detalhe da leso labial pelo HSV-1 em paciente HIV+ Figure 5: Detail of labial lesion due to HSV-1 in HIV-positive
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se por leses ulceradas de grandes dimenses, sem tendncia cicatrizao espontnea. Ocorrem com maior freqncia na regio anorretal ou perigenital, cursando com edema e aumento do volume do pnis ou dos grandes lbios e lceras na bolsa escrotal. So espontaneamente dolorosas e de crescimento rpido, no apresentando sinais evidentes de reparao tecidual. As leses da face apresentam tendncia especial ao crescimento centrfugo, surgimento de crostas hemticas e necrose. A cronicidade das leses, por vezes presentes durante vrios meses, pode gerar quadros de herpes simples de aspecto verrucoso. 25,27 As recorrncias clnicas subentrantes representam a manifestao mais comum do herpes simples no curso da AIDS. Safrin e cols.28 detectaram a mdia de recorrncias de 10 episdios/ano, superior observada na populao hgida. O tempo mdio de manifestaes clnicas foi de 12,3 dias (9,5 - 15 dias), tambm superior ao observado na populao imunocompetente (5 - 12 dias). So tpicas de fase avanada da linfopenia, ocorrendo quando a contagem de clulas CD4+ inferior a 50 clulas/mm3 . Herpes simples visceral e encefalite herptica tambm so mais comuns nos pacientes com AIDS gravemente imunodeprimidos. Os rgos mais acometidos so o pulmo, esfago, fgado e as glndulas suprarenais. O trato gastrointestinal , no entanto, de importncia fundamental, dadas sua extenso e a dificuldade no diagnstico diferencial com outras infeces oportunsticas, tais como o CMV e o sarcoma de Kaposi.25,27 Outro padro completamente diferente a infeco herptica recorrente, que se manifesta, quase sempre, na mesma topografia. O herpes simples, em especial o herpes orolabial, chega a acometer 10% da populao. As manifestaes prodmicas so mais discretas do que as observadas na primoinfeco, com ardor e dor. Seguem-se eritema e vesculas agrupadas, eroses, crosta e reparao. A durao de todo o processo , em mdia, de uma semana; a adenite regional restringe-se a 5% dos casos.18 A seqncia das recorrncias associa-se, raramente, com o desenvolvimento de eritema polimorfo subentrante. O HSV j foi isolado em todos os stios mucocutneos e viscerais. A correlao entre eritema polimorfo acral recorrente e infeco herptica amplamente reconhecida; a superposio temporal das duas molstias no imprescindvel ao diagnstico (Figura 6).18,29 6. Diagnstico O HSV produz alteraes citopticas prprias no tecido infectado ou em cultura de clulas. As clulas balonizadas multinucleadas, de citoplasma homogneo e eosinoflico, podem ser evidenciadas tanto pelo teste de Tzanck quanto pelo exame histopatolgico.30 O padro ouro no diagnstico da infeco pelo HSV continua sendo o isolamento do vrus em cultura de clulas; de execuo mais fcil com material proveniente das
spontaneous healing. They occur more frequently in the anorectal or perigenital region, coursing with edema and an increase in penis volume or in the labium majorus, and ulcers on the scrotum. They are spontaneously painful and rapidly increase, not presenting evident signs of tissue repair. Facial lesions especially show a tendency for centripetal growth, with the appearance of hematic crusts and necrosis. The lesion chronicity, presenting many times ver several months, may originate herpes simplex manifestations with a verrucose aspect.25,27 Clinical recurrences represent the most common manifestation of herpes simplex in the course of AIDS. Safrin et al. 28 detected an average recurrence of 10 episodes/year, greater than that observed in a healthy population. The mean duration of clinical manifestations was 12.3 days (9.5 to 15 days), also greater than the time observed among an immunocompetent population (5 to 12 days). The recurrences are typical of an advanced phase of lymphopenia, occurring when the CD4+ cell count is less than 50 cells/mm3 . Visceral herpes simplex and herpetic encephalitis are also more common in patients severely depressed with AIDS. The organs attacked more frequently are the lungs, esophagus, liver, and adrenal glands. The gastrointestinal tract is, however, of fundamental importance, due to its extension and the difficulty in the differential diagnosis with other opportunistic infections, such as CMV and Kaposis sarcoma.25,27 Another completely different pattern is recurrent herpetic infection that almost always manifests in the same location. Herpes simplex, especially orolabial herpes, affects almost 100% of the population. The prodromal manifestations are more discreet than those observed in the first infection, with burning and pain, followed by erythema and grouped vesicles, erosions, crusting, and repair. The average duration of the entire process 1 week; regional adenitis is restricted to 5% of the cases.18 The sequence of recurrences is rarely associated with the development of a polymorphous erythema. HSV already has been isolated in all mucocutaneous and visceral sites. The correlation between recurrent acral polymorphous erythema and herpetic infection is widely recognized; the temporal superposition of both diseases is not necessary to diagnose. (Figure 6).18,29 6. Diagnosis HSV promotes exclusive cytopathic alterations in the infected tissue or cell culture. Bullous multinuclear cells, with homogeneous and eosinophilic cytoplasm, can be seen both by the Tzanck test or histopathologic exam.30 The gold standard in the diagnosis of HSV infection is still the isolation of the virus in cell culture, which is easier to perform with material from intact vesicles. 31 The cytopathic effect is observed after a period that varies between 4 and 7 days in 95% of the cases. The DNA
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Figura 6: Herpes simples na ndega acompanhado de eritema polimorfo acral, com leso em ris nos quirodctilos
Figure 6: Herpes simplex on the buttock with acral polymorph erythema, with lesion in iris on fingers
vesculas ntegras.31 O efeito citoptico observado aps perodo que varia de quatro a sete dias, em 95% dos casos. O mtodo de amplificao do DNA, conhecido como PCR, apresenta sensibilidade de 98% no diagnstico da infeco pelo HSV. A utilizao do PCR no diagnstico da infeco herptica latente ou do eritema polimorfo induzido pelo HSV conseguem, por vezes, detectar o vrus.29,32 Ainda no existe, no entanto, sob a forma comercial. A extrema sensibilidade dessa tcnica , por vezes, prejudicial ao diagnstico da infeco herptica como causadora do eritema polimorfo recorrente, uma vez que o HSV vrus disseminado e de alta prevalncia na espcie humana. Sua identificao em uma bipsia da pele de eritema multiforme no significa, necessariamente, que seja a causa dessa leso.18,31 As avaliaes sorolgicas so teis no diagnstico diferencial com as buloses, o herpes-zster e as farmacodermias. So, talvez, o mtodo diagnstico mais til na prtica do consultrio, em que pese o fato de a maioria dos casos de herpes simples ter firmado seu diagnstico apenas na avaliao clnica. Utiliza-se o mtodo de ELISA por seu custo reduzido, rapidez, sensibilidade (96%) e especificidade (100%). O ELISA presta-se perfeitamente para detectar um episdio de infeco aguda, demonstrando Ig M especfica para a gG HSV ( Ig M-anti-g G HSV). De modo semelhante, a deteco da Ig G-anti-gG HSV permite identificar a existncia de infeco prvia pelo vrus, mesmo em pacientes com latncia ou recorrncia do HSV .33 A tcnica de Western blot fornece especificidade de at 100% na deteco da g G HSV2. A sensibilidade do mtodo de 95%, podendo ser ampliada quando a anlise sorolgica utiliza a densitometria. Teste imunoenzimtico de deteco direta dos antgenos do HSV, conhecido como Herpchek, chega mesmo a ter mais sensibilidade do que o PCR.34 A imunofluorecncia direta tambm mtodo altamente sensvel (92%). A restrio para o uso dessas duas tcnicas decorre da necessidade da existncia de leses clnicas ativas para a obteno do material a ser examinado. A imunofluorescncia realizada na cultura viral, utilizando anticorpos monoclonais com especificidade para a gG HSV , tambm capaz de fornecer uma identificao fidedigna do vrus.35 7. Tratamento O aciclovir a droga de escolha no tratamento do herpes simples. um anlogo acclico do nucleosdeo 2'An bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.
amplification method, known as PCR , presents 98% sensitivity in the diagnosis of an HSV infection. The use of PCR in the diagnosis of latent herpetic infection or in polymorphous erythema induced by HSV can, sometimes, detect the virus, 29,32 however, it does not yet exist yet in a commercial form. The extreme sensitivity of this technique is sometimes harmful to the diagnosis of the herpetic infection as the cause of the recurrent polymorphous eryth ema, since HSV is a disseminated virus with high prevalence in humans. Its identification in a skin biopsy from a multiform erythema does not mean necessarily that this is the cause of the lesion. 18,31 Plasmatic evaluations are useful in the differential diagnosis with bullae, herpes zoster, and pharmacodermias. It is probably the most useful method for diagnosis in the office, where the majority of herpes simplex cases have been diagnosed only by clinical evaluation. The ELISA method is utilized due to its reduced cost, quickness, sensitivity (96%) and specificity (100%). The ELISA method is perfect for detecting an episode of acute infection, demonstrating IgM specificity to g G HSV (IgM-anti-gG HSV). Similarly, the detection of IgG -anti-g G HSV allows identification of previous infection by the virus, also seen in patients with latent or recurrent HSV. 33 The Western blot technique has specificity of up to 100% in the detection of g G HSV -2. The sensitivity of this method is 95%, and it may be amplified when plasmatic analysis utilizes densitometry. Immunoenzymatic tests, used for direct detection of HSV antigens, known as Herpchek, sometimes have greater sensitivity than PCR.34 Direct immunofluorescence is also a very sensitive method (92%). These two techniques are restricted, however, in the necessity of extracting material from clinically active lesions for examination. The immunofluorescence performed on the viral culture, using monoclonal antibodies with specificity to g G HSV , is also capable of reliably identifying the virus.35 7. Treatment Acyclovir is the drug of choice for the treatment of herpes simplex. It is an acyclic analog of the nucleoside 2deoxyguanosine and acts as a selective inhibitor of HSV
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deoxiguanosina. Age como inibidor seletivo da replicao do HSV , sendo administrado sob a forma de pr-droga inativa. Sua posterior fosforilao (monofosfato de aciclovir) efetuada por uma enzima viral, conhecida como timidina cinase. Esse novo composto volta a ser fosforilado pelas enzimas celulares, transformando-se, finalmente, na forma ativada (trifosfato de aciclovir).36 A droga ativada concentra-se apenas nas clulas infectadas, reduzindo os efeitos colaterais observados em antivirais mais antigos. O aciclovir trifosforilado inibe, especificamente, a replicao do DNA do HSV ao competir com o trifosfato de desoxiguanosina pela DNA polimerase viral. A molcula de aciclovir ligada ao genoma do HSV atravs da DNA polimerase; a ausncia do grupo 3'- hidroxila impede a incorporao dos novos nucleotdeos necessrios para a sntese da cadeia de DNA viral, efetuando assim sua terminao obrigatria.36,37 O aciclovir apresenta interao medicamentosa mnima com outras drogas, facilitando a administrao em pacientes idosos, hipertensos, diabticos ou hospitalizados e em uso de prescrio mltipla. A biodisponibilidade de aproximadamente 30%, com meia-vida plasmtica de trs horas, sendo excretado na urina. A dose preconizada na primoinfeco benigna de 1g/dia, fracionada em cinco tomadas. O tempo de tratamento pode estender-se por perodo de at 10 dias. O uso endovenoso do aciclovir, na dose de 10mg/kg/dose administrada de 8 em 8 horas, est indicado nos casos de primoinfeco maligna. 36 As recorrncias eventuais do herpes simples so facilmente controladas com doses semelhantes s administradas na primoinfeco, porm utilizadas por perodo mais curto (cinco dias). O uso tpico do aciclovir apresenta poucas vantagens em relao ao placebo. A freqncia das recorrncias no , no entanto, estatisticamente modificada pelo uso episdico do aciclovir, sugerindo que o tratamento episdico da recidiva clnica no a opo teraputica ideal. A utilizao racional do aciclovir indica que deve ser empregado em todos os casos de primoinfeco herptica e nos casos graves, especialmente o herpes neonatal e a encefalite herptica. Acredita-se que o uso precoce do aciclovir na primoinfeco preveniria o estabelecimento da latncia viral. 36,38 O uso do aciclovir na gravidez tem sofrido modificaes nos ltimos anos. A droga foi originalmente proscrita durante a gestao pelo risco aparentemente bvio de induzir defeitos congnitos ao atuar no DNA celular. O estudo de Smith e cols. 39 demonstrou, no entanto, a segurana da droga quando ministrada no final da gravidez e a vantagem econmica dessa estratgia em detrimento do parto cesariano, mais caro e de maior morbidade. Spangler e cols.40 advogam que todas as mulheres grvidas, portadoras de herpes genital, deveriam utilizar o aciclovir no ltimo trimestre da gravidez, na tentativa de minimizar o
replication. It is administered as an inactive prodrug. Its posterior phosphorylation (acyclovir monophosphate) is performed by a viral enzyme, known as timidina kinase. This new compound is phosphorylated once again by the cell enzymes, transforming itself into the activated form (acyclovir triphosphate).36 The activated drug concentrates exclusively in the infected cells, reducing the adverse effects observed with older antiviral drugs. The triphosphorylated acyclovir specifically inhibits DNA replication of HSV competing with the desoxyguanosine triphosphate for the viral DNA polymerase. The acyclovir molecule is bonded to HSV by the DNA polymerase; the absence of the 3-hydroxil group impairs the incorporation of new nucleotides necessary to the synthesis of the DNA viral strand, making its obligatory terminal end.36,37 Acyclovir produces few interaction with other drugs, facilitating its administration in older, hypertensive, diabetic, or hospitalized patients, or in those on multiple medications. The bioavailability is approximately 30%, with a plasma half-life of 3 hours, and excretion in the urine. The recommended dose for the first benign infection is 1mg/day, divided into 5 doses. Treatment may be extended for up to 10 days. Intravenous acyclovir, 10mg/kg per dose, administered every 8 hours, is indicated for the first malignant infection.36 The eventual recurrences of herpes simplex are easily controlled with doses similar to those administered for the first infection, but for a shorter period (5 days). The topical use of acyclovir presents small advantages to placebo. The frequency of the recurrences is not statistically modified by the episodic use of acyclovir, suggesting that this treatment for clinical recurrence is not the ideal therapy. The rational use of acyclovir indicates that it must be used in all cases of first herpetic infection and in severe cases, especially in neonatal herpes and herpetic encephalitis. It is believed that early use of acyclovir for the first infection will prevent the establishment of viral latency. 36,38 The use of acyclovir during pregnancy has undergone modifications in the last few years. The drug was originally banned during pregnancy due to its apparent obvious risk for inducing congenital problems by acting on the cell DNA . The study of Smith and colleagues39 demonstrated, however, the drug's safety when administered at the end of pregnancy, as well as economic advantages of this strategy by deterring cesarean delivery, which is more expensive and related to higher morbidity. Spangler and colleagues40 believe that all pregnant women presenting with genital herpes should use acyclovir in the last three months of pregnancy, in order to minimize the risk for neonatal herpes.
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risco do herpes neonatal. A supresso da recorrncia do herpes simples pode ser obtida, em 85% dos casos, com a administrao oral de aciclovir, em doses que variam de 400mg/dia a 600mg/dia, por perodos superiores a seis meses. A droga estaria indicada em pacientes sujeitos a mais de seis recorrncias por ano. 36,41 Novas opes teraputicas incluem anlogos dos nucleosdeos com melhor biodisponibilidade e maior meiavida intracelular, o que permite esquemas posolgicos mais cmodos. 42 O valaciclovir, derivado ster L-valina do aciclovir, talvez seja um dos mais promissores entre os novos compostos derivados dos nucleosdeos acclicos. 43 A boa tolerabilidade e a raridade de efeitos colaterais so as mesmas do aciclovir, mas as concentraes mdias do pico j so observadas aps 1,75 horas da ingesto do medicamento. A biodisponibilidade do aciclovir a partir do valaciclovir de 54%, e sua ligao com protenas plasmticas mnima. A primoinfeco herptica pode ser tratada com 500mg a cada 12 horas. 43,44 Teraputica de supresso das recorrncias do herpes simples com valaciclovir tem sido efetuada com doses variando de 500mg a 1g/dia, obtendo controle das recidivas de perfil similar ao do aciclovir. Acompanhamento por um ano demonstrou raros efeitos colaterais (0,02%) em mais de 2.100 pacientes, comprovando a segurana do frmaco. Seu uso durante a gestao permanece controverso.36,44 O penciclovir, outro anlogo purnico, tem baixa biodisponibilidade quando tomado por via oral, sendo, portanto, administrado sob a forma do famciclovir. A transformao no frmaco ativo rpida, e o penciclovir atinge altas concentraes intracelulares, mantendo meiavida de 12 horas, enquanto o aciclovir restringe-se a uma hora. 36,45 Tambm trifosforilado graas ao da timidina cinase, mas sua afinidade pela DNA polimerase do HSV menor do que a do aciclovir. Os estudos demonstram que no promove o trmino obrigatrio da cadeia de DNA qual est incorporado. A dosagem preconizada de 250mg, de 8/8 horas na primoinfeco herptica, por perodo de cinco a sete dias. A posologia preconizada para as recorrncias do herpes simples de 125mg a cada 12 horas, por cinco dias. Diaz-Mitoma e cols.46 estudaram a introduo da terapia de supresso durante intervalo de at 52 semanas com o famciclovir nas dosagens de 125mg de 8/8 horas e de 250mg a cada 12 horas, sem perceber diferenas significativas. O uso de megadoses do famciclovir (750mg/dia) j permite o tratamento da primoinfeco com dose nica diria.36,47 A teraputica em pacientes imunossuprimidos controversa. O surgimento de cepas de HSV resistentes ao aciclovir e seus derivados tem sido, no entanto, uma grande barreira introduo da profilaxia contnua nesses indivduos. Mutantes virais, desprovidos da timidina cinase, tm sido observados em portadores da AIDS, transplantados e nas deficincias imunolgicas congnitas.
Suppression of the recurrence of herpes simplex can be achieved in 85% of the cases with the oral administration of acyclovir, in doses that vary from 400mg to 600mg/day for more than 6 months. The drug is indicated for patients prone to more than six recurrences a year. 36,41 New therapeutic options include nucleoside analogs with better bioavailability and a longer intracellular half-life, which allows easier posologic plans.42 Valacyclovir, a derived ester of L-valine of acyclovir, is perhaps one of the most promising among the new compounds derived from acyclic nucleosides.43 The high tolerability and rarity of adverse effects are the same as acyclovir, but the mean peak concentrations are observed only 1.75 hours after administration of the drug. The bioavailability of acyclovir from valacyclovir is 54% and its plasma protein binding is minimum. The first herpetic infection can be treated with 500mg every 12 hours.43,44 For recurrence-suppression therapy of herpes simplex with valacyclovir, doses have varied from 500mg to 1g/day, controlling recurrences in a similar way to acyclovir. A 1-year follow-up demonstrated only rare adverse effects (0.02%) in more than 2,100 patients, proving the drugs safety. Its use during pregnancy remains controversial. 36,44 Pencyclovir, another analog of purine, has low bioavailability when taken orally, administered as famciclovir. The transformation of the active drug is rapid and pencyclovir reaches high intracellular concentrations, with a 12-hour half-life, while acyclovir is restricted to 1 hour. 36,45 It is also triphosphorylated due the action of timidine kinase, but its affinity for HSV DNA polymerase is inferior than that of acyclovir. The studies demonstrated that it does not promote the obligatory end of the DNA strand to which it is incorporated. The recommended dosage is 250mg every 8 hours for the first herpetic infection for 5 to 7 days. The recommended dosage regimen to herpes simplex recurrences is of 125mg every 12 hours for 5 days. Diaz-Mitoma46 and colleagues studied the introduction of suppression therapy with famciclovir for up to 52 weeks, in the doses of 125mg every 8 hours and 250mg every 12 hours, without noticing significant differences. The use of megadoses of famciclovir (750mg/day) allows the treatment of the first infection with a single daily dose. 36,47 The therapy used in immunosuppressed patients is controversial. The appearance of HSV strains resistant to acyclovir and its products has been, however, a great barrier to the introduction of continuous prophylaxis in these individuals. Viral mutants lacking timidina kinase have been observed in AIDS and transplanted patients, and in immunologic congenital diseases. The resistance of HSV to acyclovir can also be caused
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A resistncia do HSV ao aciclovir tambm pode ser causada por cepas que sintetizem a enzima DNA polimerase alterada.36,48 O foscarnet (cido fosfonofrmico trissdico) a opo no caso dos HSV resistentes ao aciclovir, sendo eficaz na destruio dos vrus desprovidos da timidina cinase. O foscarnet deve ser institudo 10 dias aps a utilizao ineficiente do aciclovir e mantido at a cura clnica. 25,36 O foscarnet , no entanto, ineficaz para o HSV portador da DNA polimerase, responsvel por cerca de 10% das resistncias comprovadas ao aciclovir. A despeito da reconhecida nefrotoxicidade induzida pelo frmaco, Tachedjian e cols.49 utilizaram-no por perodo de at dois anos em pacientes HIV+, sem induzir o surgimento de HSV resistente ao foscarnet. Existem dois esquemas posolgicos do foscarnet que oferecem bons resultados. O primeiro com 40mg/kg/dose EV , correndo em duas horas, a cada oito horas. O outro utiliza doses de 60mg a cada 12 horas, e o tempo de tratamento para ambos os esquemas varia de 14 a 26 dias. 36 8. Profilaxia As primeiras tentativas de vacinao anti-herptica utilizavam o vrus morto ou atenuado, aps sucessivas passagens em cultura de clulas. So as chamadas vacinas de primeira gerao e predominaram at o fim da dcada de 1970. Frank50 tentou, j em 1938, efetuar a imunizao com o HSV inativado em formalina, observando resultados discretos. Muitos estudos semelhantes foram efetuados entre 1946 e 1982, mas os critrios de melhora clnica foram mal definidos, e faltavam os grupos controle utilizando um placebo. 51 O primeiro estudo caso-controle srio, envolvendo o acompanhamento da coorte em estudo por perodo de at 36 meses, foi efetuado por Kern & Schiff. 52 Eles observaram que a melhora no grupo que recebeu o HSV inativado foi de 70%, sendo menor do que a melhora clnica relatada entre os que receberam apenas o placebo (76%). A primeira evoluo real nesse campo ocorreu, curiosamente, por razes erradas. Durante a dcada de 1970, acreditava-se que o HSV-2 poderia ser a causa ou um co-fator importante para o desenvolvimento do carcinoma no colo do tero. Sabe-se hoje que essa funo cabe s cepas oncognicas do HPV, mas, considerando as dvidas existentes naquela poca, procurou-se sintetizar uma nova vacina anti-herptica que congregasse apenas pores virais importantes na imunogenicidade, mas evitando o uso de todo o vrus. Estavam lanadas as bases para as vacinas glicoproticas de segunda gerao.53 Skinner54,55 sintetizou uma vacina que leva seu nome, misturando diversas dessas glicoprotenas, mas no obteve os resultados esperados. Ainda faltavam modelos animais que apresentassem infeco pelo HSV similar ao quadro de herpes simples humano; faltavam tambm conhecimentos mais aprofundados sobre a funo de cada glicoprotena
by strains that synthesize the altered DNA polymerase enzyme.36,48 Foscarnet (trisodium phosphonophormic acid) is the choice in patients with HSV resistant to acyclovir, as it is effective in destroying the virus lacking timidina kinase. Foscarnet must be administered 10 days after the ineffective use of acyclovir and maintained until clinical cure is achieved.25,36 Foscarnet is, however, ineffective against HSV porting DNA polymerase, responsible for around 10% of proved resistance to acyclovir. Despite its known nephrotoxicity induced by the drug, Tachedjian and colleagues49 used it for up to 2 years in patients who were HIV -positive, without inducing HSV resistant to Foscarnet. There are two posologic plans of Foscarnet that present good results. The first one with intravenous 40mg/kg per dose, running for 2 hours, every 8 hours. The other one uses 60mg every 12 hours, and the time treatment for both plans vary from 14 to 26 days.36 8. Prophylaxis The first attempts of antiherpetic vaccination used the dead or attenuated virus, after successive passages in cell cultures, called first generation vaccines, which predominated until the end of the 1970s. Frank50 tried, in 1938, to perform the immunization with HSV inactivated in formol, observing discreet results. Many similar studies were carried out between 1946 and 1982, but the criteria for clinical improvement were badly defined and missed control groups using placebo.51 The first reliable case-control study involving the follow-up of the coorte study for up to 36 months, was carried out by Kern & Schiff.52 They observed that 70% of the group that received the inactivated HSV improved, which was less than the clinical improvement reported among those receiving placebo only (76%). The first real evolution in this field occurred, curiously, for the wrong reasons. During the 1970s, it was thought that HSV -2 could be the cause or an important cofactor in the development of uterine or colon carcinoma. Today it is known that this function belongs to the oncogenic strains of HPV, but considering the doubts existing at that time, a new antiherpetic vaccine was intended to be developed that would have only viral portions important to immunogenicity, but avoiding use of the whole virus. Those were the bases of the glycoproteic 'second generation' vaccines. 53 Skinner 54,55 synthesized a vaccine carrying his name, mixing many of these glycoproteins, but did not obtain the expected results. Animal models presenting HSV infection similar to that of humans lacked as well as the knowledge of the function of each HSV glycoprotein.
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do HSV. As vacinas glicoproticas s se tornaram realidade depois que Stanberry e cols. 56,57 descobriram que os porcosda-guin apresentavam quadro clnico e recorrncias que mimetizavam o herpes genital em humanos. De forma concomitante, os avanos na biologia molecular permitiram produzir grande quantidade das glicoprotenas virais de forma rpida e barata. As glicoprotenas g e gD so fundamentais na B estimulao da imunidade celular especfica, ativando a populao de linfcitos T citotxicos. Vacinao em cobaias soronegativas para o HSV-1, com um concentrado de glicoprotenas do vrus, sensibilizou linfcitos T a reconhecer a gB e gD e apresentou ao profiltica contra a infeco herptica. 58 Zheng e cols. 59 observaram que eptopos provenientes da g D, quando expressos no material genmico de adenovrus vetores, poderiam constituir um mtodo seguro de imunizao contra o HSV . As vacinas de 'segunda gerao' encontram-se em fase avanada de estudo clnico em cobaias, mas no esto liberadas para uso no ser humano. Apesar de apresentarem resultados encorajadores, tm algumas restries, como potncia imunognica reduzida, durabilidade curta e necessidade de incorporao a adjuvantes. Seu custo e eficcia ainda no se comparam aos da teraputica supressiva com o aciclovir.53 As vacinas gnicas ou de DNA, ainda em fase experimental e de padronizao, podem tornar-se extremamente teis no combate infeco pelo HSV. A diferena fundamental nessa nova gerao de vacinas est na forma de apresentar o antgeno ao sistema imunolgico. Isola-se a seqncia de DNA que codifica antgenos imunodominantes ou um fator de virulncia com a potencialidade de induzir o sistema imunolgico produo de anticorpos especficos ou de estimular a populao de linfcitos T auxiliares. O processo de vacinao envolve a inoculao intramuscular do DNA viral, que leva a mensagem para a sntese intracelular do antgeno apropriado. Evitam-se, assim, a inoculao do patgeno vivo ou atenuado que ocorre nas vacinas de 'primeira gerao' e, tambm, os problemas proporcionados pelos adjuvantes necessrios ao funcionamento das vacinas de segunda gerao.53,60 Existem, no entanto, fatores restritivos ao uso das vacinas gnicas. No se sabe ao certo a exata possibilidade de o plasmdeo modificado integrar-se ao genoma da clula hospedeira, causando mutaes ou levando ao aparecimento de oncogenes. Especula-se tambm que essas vacinas poderiam induzir tolerncia imunolgica ou formao de anticorpos contra o plasmdeo administrado.53 A possibilidade de mutaes do DNA humano so o ponto principal de questionamento dessa tcnica, mas estudos em cobaias demonstraram que o risco de esse evento ocorrer
The glycoproteic vaccines only became reality after Stanberry and colleagues56,57 found that guinea pigs presented the clinical manifestations and recurrences similar to those of human genital herpes. Concurrently, the progress in molecular biology permitted the production of large amounts of viral glycoproteins inexpensively and quickly. The glycoproteins g B and g D are fundamental to the stimulation of specific cell immunity, activating a population of cytotoxic T lymphocytes. The vaccination of guinea pigs plasma negative to HSV -1, with a concentration of glycoproteins of the virus, sensitized T lymphocytes to recognize gB and gD, and presented prophylactic action against the herpetic infection.58 Zheng and colleagues59 observed that epitopes derived from g D, when expressed in the genomic material of adenomic vectors, could constitute a safe method of immunization against HSV. The second generation vaccines are in the advanced phase of clinical study in guinea pigs, but are not yet approved for use in humans. Although they present encouraging results, there are some restrictions, such as reduced immunogenic potency, short durability, and the need to incorporate some adjuvants. The cost and efficacy cannot yet be compared to suppression therapy with acyclovir. 53 Genetic or DNA vaccines, in an experimental and patterned phase, may become very useful in combating HSV infection. The fundamental difference in this new generation of vaccines relies on the means of presenting the antigen to the immune system. It isolates a sequence of DNA that codifies the immunodominant antigens or a virulence factor with the potential to induce the immune system to produce specific antibodies or to stimulate the auxiliary T lymphocyte population. The vaccination process involves the intramuscular inoculation of viral DNA, which carries the message to the intracellular syntheses of the appropriate antigen. Thus, inoculation with the live pathogen is avoided, which occurs with the first generation vaccines and, also, the problems generated by the adjuvant treatments necessary to the function of the second generation vaccines.53,60 There are, however, restrictive factors in the use of genetic vaccines. The exact possibility of the modified plasmid of integrating the host cell genome is unknown, possibly causing mutations or leading to the appearance of oncogenes. There are also speculations that these vaccines may induce immunologic tolerance or development of antibodies to the plasmid administered.53 The possibility of mutations on human DNA is the main point in question of this technique, but studies in mice demonstrated that the risk of this occurring is less than for the spontaneous DNA mutation. q
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REFERNCIAS / REFERENCES
1. Lupi O, Pereira Jr. AC. Herpesvrus humanos, consideraes estruturais e imunopatognicas. An Acad Nac Med 1994;27-9. 2. Sokol DM, Garry RF. Herpesviruses. In: Borchardt K A, Noble MA. Sexually transmitted diseases: epidemiology, pathology, diagnosis, and treatment. New York: CRC Press, 1997:217-43. 3. Olofsson S, Lundstrm M, Marsden H et al. Characterization of a HSV-2 specific glycoprotein and affinity for acetylgalactosamine- specific lectins and its identification as 92K or gG. J Gen Virol 1986;67:737-44. 4. Pereira Jr. AC, Lupi O. Herpes simples genital. In: Passos MRC. Doenas Sexualmente Transmissveis. 4a ed. Rio de Janeiro: Cultura Mdica, 1995:162-70. 5. Gressens P, Martin JR. HSV-2 DNA persistence in astrocytes of the trigeminal root entry zone: double labeling by in situ PCR and immunohistochemistry. J Neuropathol Exp Neurol 1994;53(2):127-35. 6. Lillycrop KA, Liv YZ, Theil T et al. Activation of the herpes simplex virus immediate-early promoters by neuronally expressed POU family transcription factors. Biochem J 1995;307:581-4. 7. Pereira FA. Herpes simplex: evolving concepts. J Am Acad Dermatol 1996;35(4):503-20. 8. Wagner EK, Guzowski JF, Singh J. Transcription of the HSV genome during productive and latent infection. Prog Nucleic Acid Res Mol Biol 1995;51:123-65. 9. Wood JN, Lillycrop KA, Dent CL. Regulation of expression of the neuronal POU protein Oct-2 by nerve growth factor. J Biol Chem 1992;267:1787-91. 10. Lupi O. Fatores de risco na aquisio do vrus herpes simples do tipo 2 (HSV-2) em populaes de baixo e alto risco para doenas sexualmente transmissveis. Tese. Faculdade de Medicina: Universidade Federal do Rio de Janeiro, 1995. 11. Lupi O, Silva AG, Pereira Jr. AC. Herpes simples genital: uma pandemia. An bras Dermatol 1996;71(1):59-61. 12. Wald A. Subclinical shedding of herpes simplex virus in the genital tract: implications for transmission. Herpes 1997;4(2):30-5. 13. Lupi O, Semenovitch I, Pereira Jr. AC. Epidemiologia dos Herpesvrus. In: Lupi O, Silva AG, Pereira Jr. AC. Herpes: clnica, diagnstico e tratamento. Rio de Janeiro: Medsi, 2000:15-32. 14. Lupi O. Herpes simples e infeco pelo vrus da imunodeficincia humana: anlise de 650 pacientes. Tese. Faculdade de Medicina: Universidade Federal do Rio de Janeiro, 1998. 15. Nahmias AJ, Lee FK, Beckman-Nahmias S. Seroepidemiological and sociological patterns of herpes simplex virus infection in the world. Scand J Infect Dis 1990;69:19-36. 16. Lupi O, Silva AG, Pereira Jr. AC. Herpes simplex virus type 2 in Brazil: seroepidemiologic survey. Int J Dermatol 1996;35(11):794-6. 17. Mertz GJ. Epidemiology of genital herpes infections. Infect Dis Clin North Am 1993;7(4):825-39. 18. Lupi O, Pereira Jr. AC. Herpes simples. In: Lupi O, Silva AG, Pereira Jr. AC. Herpes: clnica, diagnstico e tratamento. Rio de Janeiro: Medsi, 2000:43-70. 19. Lupi O, Silva AG, Pereira Jr. AC. Herpes simples genital, uma doena sexualmente transmissvel. F Med (BR) 1995;110:77-98. 20. Itzhaki RF, Lin WR, Wilcock GK et al. HSV-1 and risk of Alzheimer's disease. Lancet 1998;352:238. 21. Corder E, Lannfelt L, Mulder M. Apolipoprotein E and HSVAn bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.
1 in Alzheimer's disease. Lancet 1998;13(3):1312-3. 22. Miranda MF, Brito AC, Medeiros JL et al. Erupo variceliforme de Kaposi em paciente com pnfigo foliceo. An bras Dermatol 1999;74(3):239-43. 23. Schirren H, Schirren CG, Schlupen EM et al. Exacerbation of Hailey-Hailey disease by infection with herpes simplex infection. Detection with the PCR. Hautarzt 1995;46(7):494-7. 24. Tesfaye S, Cullen DR, Wilson RM et al. Diabetic ketoacidosis precipitated by genital herpers infection. Diabetis Res Clin Pract 1991;13(1-2):83-4. 25. Lupi O. Herpesvrus e imunodepresso. In: Lupi O, Silva AG, Pereira Jr. AC. Herpes: clnica, diagnstico e tratamento. Rio de Janeiro: Medsi, 2000:157-78. 26. Weinberg RA, Canto CL, Pannuti CS et al. Herpes simplex virus type 2 infection in pregnancy: asymptomatic viral excretion at delivery and seroepidemiologic survey of two socioeconomically distinct populations in So Paulo, Brazil. Rev Inst Med Trop So Paulo 1993;35(3):285-90. 27. Stewart JA, Reef SE, Pellett PE et al. Herpesvirus infection in persons with human immuno-deficiency virus. Clin Infect Dis 1995;21(1):114-20. 28. Safrin S, Ashley R, Houlihan C et al. Clinical and serological features of herpes simplex virus infection in patients with AIDS. AIDS 1991;5(9):1107-10. 29. Kokuba H, Imafuku S, Burnett JW. Longitudinal study of a patient with HSV associated erythema multiforme: viral gene expression and T cell repertoire usage. Dermatology 1999;198(3):233-42. 30. Beard JS, Frishberg DP, Sau P et al. Ominous Tzanck smear in primary herpes simplex virus infection. Arch Dermatol 1993;129:966-8. 31. Nahass GT, Goldstein BA, Zhu WY et al. Comparision of Tzanck smear, viral culture, and DNA diagnostic methods in detection of HSV and varicella zoster infection. JAMA 1992;268:2541-4. 32. Cone RW, Hobson AC, Brown Z et al. Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women. JAMA 1994;272(10):792-6. 33. Cone R, Swenson P, Hobson A et al. HSV detection from genital lesions: a comparative study using antigen detection (Herpchek) and culture. J Clin Microbiol 1993;31:1774-6. 34. Ho DW, Field PR, Irving WL et al. Detection of immunoglobulin M antibodies to glycoprotein G-2 by western blot (immunoblot) for diagnosis of initial HSV-2 genital infections. J Clin Microbiol 1993;31(12):3157-64. 35. Zirn JR, Tompkins SD, Huie C et al. Rapid detection and distinction of cutaneous herpesvirus infection by direct immunofluorescence. J Am Acad Dermatol 1995;33:724-8. 36. Lupi O. Teraputica anti-herptica. In: Lupi O, Silva AG, Pereira Jr. AC. Herpes: clnica, diagnstico e tratamento. Rio de Janeiro: Medsi, 2000:233-54. 37. Elion GB. Acyclovir: discovery, mechanism of action, and selectivity. J Med Virol 1993;1:2-6. 38. Darby G. Acyclovir and beyond. J Intern Med Research 1994;22(suppl.1):33-42. 39. Smith JR, Cowan FM, Munday P. The management of HSV infection in pregnancy. Br J Obstetrics Gynaecology 1998;105:255-60. 40. Spangler JG, Kirk JK, Knudson MP. Uses and safety of
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acyclovir in pregnancy. J Fam Pract 1994;38(2):186-91. 41. Goldberg LH, Kaufman R, Kurtz TO et al. Long-term supression of recurrent genital herpes with acyclovir. Arch Dermatol 1993;129:582-7. 42. Lupi O, Silva AG, Pereira Jr. AC. Novas perspectivas no tratamento do herpes simples. J Bras DST 1995;7(3):9-12. 43. Easterbrook P, Wood MJ. Successors to acyclovir. J Antimicrob Chemother 1994;34(3):307-11. 44. Reitano M, Tyring S, Lang W et al. Valaciclovir for the supression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. J Infect Dis 1998;178(3):603-10. 45. Jarvest RL, Sutton D, Hodge RAV. Famciclovir. Discovery and development of a novel antiherpesvirus agent. Pharm Biotechnol 1998;11:313-43. 46. Diaz-Mitoma F, Sibbald RG, Shafran SD et al. Oral famciclovir for the supression of recurrent genital herpes: a randomized controlled trial. JAMA 1998;280(10):887-92. 47. Spruance SL, Rowe NH, Raborn GW et al. Peroral famciclovir in the treatment of experimental ultraviolet radiation-induced HSV labialis: a double-blind, dose-ranging, placebo-controlled, multicenter trial. J Infect Dis 1999;179(2):303-10. 48. Wade JC, Mclaren C, Meyers JD. Frequency and significance of acyclovir-resistant HSV isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis 1983;148:1077-82. 49. Tachedjian G, Hoy J, Mcgavin K et al. Long-term foscarnet therapy not associated with the development of foscarnet-resistant human immunodeficiency virus type 1 in an acquired immunodeficiency syndrome patient. J Med Virol 1994;42(2):207-11. 50. Frank SB. Formolized herpes virus therapy and the
neutralizing substance in herpes simplex. J Invest Dermatol 1938;1:267-82. 51. Lupi O, Pereira Jr. AC. Perspectivas quanto ao desenvolvimento de vacinas antiherpticas especficas. F Med (BR) 1996;113(2):185-7. 52. Kern AB, Schiff BL. Vaccine therapy in recurrent herpes simplex. Arch Dermatol 1964;89:844-5. 53. Lupi O. Vacinas anti-herpticas. In: Lupi O, Silva AG, Pereira Jr. AC. Herpes: clnica, diagnstico e tratamento. Rio de Janeiro: Medsi, 2000:255-68. 54. Skinner GR, Fink C, Melling J et al. Report of 12 years experience in open study of Skinner herpes simplex vaccine towards prevention of herpes genitalis. Med Microbiol Immunol 1992;180(6):305-20. 55. Skinner GR, Buchan A, Davies J et al. A virus-particle vaccine prepared from bovine mammillitis virus against herpes genitalis. Comp Immunol Microbiol Infect Dis 1991;14(2):133-50. 56. Stanberry LR. Herpes immunization - on the threshold. J Eur Acad Dermatol Venereol 1996;7:120-8. 57. Stanberry LR. Herpes simplex virus vaccines as immunotherapeutic agents. Trends Microbiol 1995;3(6):244-7. 58. Straus SE, Wald A, Kost RG et al. Immunotherapy of recurrent genital herpes with a recombinant HSV-2 glycoproteins D and B: results of a placebo-controlled vaccine trial. J Infect Dis 1997;176:1129-34. 59. Zheng B, Graham FL, Johnson DC et al. Immunogenicity in mice of tandem repeats of na epitope from herpes simplex gD protein when expressed by recombinant adenovirus vectors. Vaccine 1993;11(12):1191-8. 60. Aguado T, Bazin H, Rabinovich R et al. International meeting on nucleic acid vaccine for prevention of infectious diseases. Vaccine 1996;15(8):7-9.
ENDEREO PARA CORRESPONDNCIA: / MAILING ADDRESS: Omar Lupi Av. Lineu de Paula Machado, 76 / 302 Rio de Janeiro RJ 22470-040 E-mail: omarlupi@rj.sol.com.br
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Questes e Resultado das Questes / Questions and Answers to Questions
QUESTES 1. A infeco virtica decorre de um mecanismo do tipo 'chave-fechadura', em que a chave so as protenas de superfcie do vrus, e a fechadura, as molculas de membrana da clula permissvel. Assinale a opo correta quanto a esse mecanismo no caso do herpes simples. a) Chave: gC, gB, gD; fechadura: heparan sulfato. b) Chave: gC, gD , gE; fechadura: CD4+. c) Chave : gB, gE, gI; fechadura: CD8+. d) Chave: gD, gE, gI; fechadura: heparan sulfato. e) Chave: gA, gI, gE; fechadura: sinapses neuronais. 2. Quanto ao stio preferencial de latncia do HSV: a) os gnglios paravertebrais so todos acometidos na mesma freqncia. b) predomina nos gnglios faciais e pudendos. c) predomina nos gnglios oftlmicos e gustativos. d) afeta gnglios motores e sensitivos. e) predomina nos gnglios trigeminais e sacrais. 3. As recorrncias herpticas tm como uma das causas a capacidade do HSV em evitar a lise celular das clulas infectadas pela IgG e pelos fatores do complemento. Que estruturas virais so responsveis por essa propriedade do HSV, respectivamente? a) gA e gD. b) gE e gG. c) gC e gE. d) gE e gC. e) gC e gI. 4. Qual o fator fundamental na transcrio intracelular do genoma do HSV? a) Oct-1 (protena octamrica 1). b) Oct-2 (protena octamrica 2). c) Oct-3 (protena octamrica 3). d) FCN (fator de crescimento neuronal). e) TNF (fator de necrose tumoral). 5. Qual o nico produto do HSV possvel de ser detectado durante o perodo de latncia? a) LAT. b) Oct-1. c) Oct-2. d) FCN. e) Gene IE.
6. Quanto freqncia das recorrncias no herpes simples, assinale a melhor opo. a) HSV-1 oral>HSV-1 genital> HSV-2 genital> HSV-2 oral. b) HSV-1 genital>HSV-1 oral> HSV-2 oral> HSV-2 genital. c) HSV-2 oral>HSV-2 genital> HSV-1 genital> HSV-1 oral. d) HSV-2 genital>HSV-2 oral> HSV-1 genital> HSV-1 oral. e) HSV-1 oral>HSV-2 genital> HSV-1 genital> HSV-2 oral. 7. Qual a complicao mais comum do herpes simples? a) Quadros urticariformes. b) Parafimose secundria. c) Infeco secundria. d) Eritema polimorfo acral. e) Paralisia de Bell. 8. Qual das opes abaixo no considerada uma forma de primoinfeco maligna? a) Eczema herptico. b) Herpes anorretal. c) Herpes neonatal. d) Dermatite herpetiforme. e) Meningoencefalite herptica. 9. A doena de Alzheimer pode estar associada ao HSV em um certo nmero de casos. Admite-se que a presena do vrus no sistema nervoso central pode ser um co-fator importante na gnese de substncias envolvidas nessa molstia. Assinale a opo que inclui a cepa do HSV e a substncia envolvida na patogenia da doena de Alzheimer. a) HSV-2 e mucopolissacardeos. b) HSV-1 e apolipoprotena E. c) HSV-1 e glicosaminoglicanas. d) HSV-2 e cido homogentsico. e) HSV-1 e cido hialurnico. 10. A erupo variceliforme de Kaposi j foi descrita no curso de diversas molstias, exceto a) eczema atpico. b) pnfigo foliceo. c) doena de Darier. d) doena de Hailey-Hailey. e) doena de Grover. 11. O herpes simples visceral pode acometer os rgos abaixo relacionados, exceto a) suprarenais. b) crebro. c) fgado. d) medula ssea. e) esfago.
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12. Doenas e teraputicas de alta morbidade esto intimamente associadas a quadros malignos e agressivos de herpes simples, exceto a) pnfigo vulgar. b) mieloma mltiplo. c) uso de citostticos. d) leucemia e linfomas. e) cetoacidose diabtica. 13. O herpes neonatal complicao grave e de difcil preveno. Quanto existncia de histria pregressa de herpes genital por parte da gestante e ao percentual de mortalidade do concepto no caso de herpes neonatal, a opo correta a) 30% e 70%. b) 70% e 30%. c) 40% e 60%. d) 60% e 40%. e) 50% e 50%. 14. O efeito citoptico tpico da infeco herptica a) coilocitose. b) corpo citomeglico. c) clulas vacuoladas. d) clulas de Sternberg. e) clulas balonizadas. 15. A excreo dos derivados de nucleosdeos utilizados no tratamento do herpes simples primordialmente a) heptica. b) renal. c) biliar. d) fecal. e) ocular. 16. O mecanismo de ao da acicloguanosina, droga utilizada no tratamento do herpes simples, baseia-se em a) inibio da DNA polimerase, aps a fosforilao da droga. b) ativao da RNA integrase, aps a fosforilao da droga. c) inibio da DNA integrase, aps a oxidao da droga. d) inibio da RNA polimerase, aps a fosforilao da droga. e) ativao da RNA polimerase, aps a oxidao a droga. 17. A resistncia do HSV ao aciclovir e seus derivados pode ocorrer pela mutao em que enzimas virais? a) Timidina cinase e RNA fosfatase. b) RNA integrase e DNA polimerase. c) Timidina cinase e DNA integrase. d) DNA polimerase e timidina cinase. e) RNA fosfatase e DNA polimerase.
18. A resistncia ao aciclovir um evento biolgico de pouco impacto, diferente da resistncia aos antibiticos. Isso decorre do fato de restringir-se a alguns grupos especficos de pacientes, exceto a) transplantados em uso de imunossupressores. b) pacientes HIV positivos. c) portadores de deficincias imunolgicas congnitas. d) portadores de linfopenia idioptica de clulas CD4+. e) usurios de corticoterapia em altas doses 19. A primeira opo teraputica em indivduos imunossuprimidos com cepas de HSV resistentes ao aciclovir a) ster L-valina do aciclovir. b) tromantadina + vidarabina. c) ac.fosfonofrmico trissdico. d) idoxuridina. e) valaciclovir + famciclovir. 20. As vacinas anti-herpticas de segunda gerao so estruturadas a partir de qual estrutura viral? a) Vrus inteiro inativado. b) Vrus inteiro atenuado. c) Glicoprotenas de superfcie. d) Capsdeo viral + adjuvantes. e) Frao imunognica do DNA.
Gabarito Dermatoses 2000;75(2):129-42
1. c 2. a 3. e 4. e 5. e 6. c 7. b 8. d 9. e 10. a
11. c 12. a 13. d 14. e 15. d 16. d 17. c 18. b 19. d 20. a

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Educao Mdica Continuada / Continuing Medical Education

Herpes simples * Herpes simplex *

An bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.

Figura 2: Herpes simples genital

Figura 3: Herpes orolabial recorrente

Figure 3: Recurrent orolabial herpes0

An bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.

An bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.

An bras Dermatol, Rio de Janeiro, 75(3):261-275, maio/jun. 2000.

Questes e Resultado das Questes / Questions and Answers to Questions

An bras Dermatol, Rio de Janeiro, 75(3):276-277, maio/jun. 2000.

Gabarito Dermatoses 2000;75(2):129-42

An bras Dermatol, Rio de Janeiro, 75(3):276-277, maio/jun. 2000.

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