R eview Cenita! herpes Genital herpes M. Rogi Butina SUMM ARY Genital herpes is one of the most common sexually transmitted diseases in the world. It results from the infection with herpes simplex virus, commonly with herpes simplex virus type 2, occasionally with type 1. The infection is life-long, and after the initial episode, recurrences can appear any tirne. The virus is able to elicit a number of pathological conditions; however the recurrent clinical outbreaks of genital herpes most often cause not only physical but also psychosocial problems. We present a brief overview of current concepts regarding the epidemiology, pathology, clinical manifestations and treatment options. Introduction Herpes simplex virus (HSV) infection is today suppo- sed to be the most common cause of geni.tal ulcerations in industrialized countries . As such it causes physical and probably even more important psychosocial mor- bidity, besides it is coinvolved in a number of other pathological conditions. It can result from the infection with HSV type 1 and HSV type 2, both usually result from contact with infec- ted secretions on geni.tal or oral mucosal surfaces. The two virnses belong to the Herpesviridae family, more precisely to the group of alphaherpesvituses. Both are approximately 150- 220 nm in diameter and have a similar strncture: the inner core w ith a double stranded DNA genome in a protective capside consisting of seven different proteins. Around the capside is the tegument, which is in turn surrounded by the lipid membrane where the herpesvirns glycoproteins are embedded. (Figure 1) The genomes of HSV 1 and HSV 2 are dissimilar enough to be distinguished as two species (1). On the other si.de most of their antigens are very much alike, and among the glycoproteins on the surface only one (glycoprotein G) bas been found to be sufficiently chara- cteristic to be used as the antigen for the type specific serology. Glycoprotein G 1 (HSV 1) consists of appro- ximately 150 aminoacids, whereas G2 (HSV 2) bas 600 aminoacids. · Humans are the only known hosts' rese1voir for HSV. Infection and clinical manifestations of geni.tal herpes can occur with botl1 types, HSV 2 stili being more fre- quently the cause. The reason for this is not yet clear, currently it is thought that it may be due to the diffe- Acta Dermatoven APA Vol 9, 2000, No 1 3 Cenita! he1pes rences in the propensity of each virus to reactivate in either the trigeminal or sacral ganglia (2). However, in the recent CDC reports (3) HSV 1 is etiologically implicatecl in 5- 30 % initial episocles of genital herpes, ancl among HSV 1 positive inclivicluals 15 % are supposecl to have genital involvement from this virus (4). Epidemiology Serosurveys for type specific antibodies have shown a significant increase in prevalence of HSV 2 in the last clecade (5,6,7). The last National health ancl nutrition examination survey in USA stucly (7) reports a 21, 9 % seroprevalence in USA (white persons: 15 % men, 20 % women, ancl in black persons 35 % men, 55 % women were seropositive). Ashley ancl all. (8) report that HSV 2 seroprevalence reaches up to 50 % among women attending sexually transmittecl cliseases (STDs) clinics, ancl is between 60 - 90 % in female sex workers worlcl wide. Most epidemiological stuclies of HSV 2 reportecl the highest inciclence in the third decacle of life, but recently a strong increase in seroconversion rates among teenagers was observed (7). Epidemiologically the presence of antibodies against HSV type 2 seems to be an important serological marker of sexual lifestyle (higher risk) in populations (9). In Slovenia the seroprevalence study on HSV 1 ancl HSV 2 is still going on, but the preliminary results show much lower infection rates compared to the above men- tioned reports. Pathology and clinical manifestations Clinical manifestations of genital herpes are various and clepend mostly on the type of the virus, previous exposure to herpes simplex virus, immunologic condition ancl gender of the patient. Herpetic lesions can either be initial genital herpes or a recurrent one. The initial genital herpes can be a trne primary genital herpes, that is the first episode of the disease without an evidence of prior herpes simplex infection (negative history ancl serology). It can also be a non-primary initial genital herpes where, during tl1e tirne of the first clinically apparent episode, the serological signs of prior infection are present. During the initial infection, the squamous epithelial cells of the epidermis are infectecl, they become swollen and lysecl, multinucleatecl cells may also be observed. As a result vesicles form (ballooning), containing edematous cells ancl cell groups, and are accompanied by an inflammato1y mononuclear infiltrate in tl1e clermis. 4 In the vesicle fluicl interferons and cytokines can be cletected. After the vesicle ruptures HSV is shecl for approximately 10 clays from the remaining ulcer. (Figure 2). The ulcer becomes crusted; epithelization occurs in . 21 clays (2). True primary genital herpes usually presents 2 - 14 days after the infection with HSV with patches of inflammation, redclened mucosa, vesicles anc! erosions spread over the major part of genitalia. Together with local disturbances (c!ysuria, urethral anc! vagina! discharge, regional lymphac!enopathy) patients often c!evelop systemic symptoms (fever, myalgia, fatigue, ancl photophobia). The c!isease has usually milcler course in the inclivic!uals who hacl had prior HSV 1 infection ancl lat er develop geni tal HSV 1 or HSV 2 infection (1 O). In general the symptoms are more pronouncecl in women. The c!ifferential cliagnosis of initial genital herpes, especially when they are connectec! with systemic sym- ptoms includes various causes of genital ulceration: syphilis, chancroid, e1ythema exsuc!ativum multiforme, Beh1.=et syndrome etc. Complications following the initial episocle appear more oft:en in women, the most frequent being extragenital cutaneous lesions, yeast super- infections, involvement of central ancl peripheral ner- vous system, erythema exsudativum multiforme. Arounc! 50 % of the patients presenting with initial episode of genital herpes are actually experiencing a non-primary outbreak. The alreac!y present immune response most probably attenuates tl1e severity of those episocles , ancl lesions are less wic!esp/eacl, systemic symptoms ancl/or complications oft:en missing. After the infection of the skin the virus enters the cutaneous endings ancl ascends within the peripheral sensory nerves until it reaches spina! or trigeminal ganglia. In these neurons HSV either replicate furthers (procluctive infection) or enters a state oflatency. During the latent s tate only a small part of the genome replicate (latency associatecl transcripts-LATs), though the part that codes the synthesis of vira! proteins is never replicated. In the time of reactivation virus starts a complete replication again, it is actively transported to axons and then to nerve enclings from where it attacks the epidermal cells again. As a rule processes of re- activation and transport cause no c!amage to the neu- rons. Stimuli that most often incluce the reactivation are ultraviolet light, trauma, and menstruation, physical and · emotional stress or various acute and chronic disorders. Their systemic messengers include adrenaline and other stress hormones, whereas the local mediators are pro- staglanc!ins (PG), especially PG E 2 and PG F 2 (11). Recurrent genital herpes refers to the second and all the following clinical episodes. It is quite often asymptomatic or non-recognisecl (6). It is harclly overlooked in its typical clinical presentation: ery- Review Acta Dermatoven APA Vol 9, 2000, No 1 Review 1 2 3 1 Acta Dermatoven APA Vol 9, 2000, No 1 Genital herpes thematous patches with grouped vesicles, their content is in the beginning clear, later it often becomes purulent; soon (after 1 - 2 days) the vesicles erode leaving small round ulcerations (far 2 - 3 days) which heal with a crust (in 5 - 6 days). In that form it is ordinarily more painful and lasts longer in women. Around 50 % of patients notice prodromal symptoms of burning/ itching, paraesthesias, rarely also sacral neuralgia. (Figure 3). It is however estimated that approximately one third of infected patients undergo asymptomatic infections and another third display atypical presentations: from non-painful ulceration to edema, small crusts, fissures, small erythematous patches or only a transient irritation. With recurrent genital herpes complications are relatively rare, mostly they present as neuralgias, lym- phangitis, erythema exsudativum multiforme and some- times urethral strictures. Recurrences of genital herpes are almost regular in the first two years after the initial outbreak. The estimated median rate of recurrences is 5 outbreaks per year, but actually there is marked variability among patients. They are more frequent with HSV 2 infection (80 - 90 % of individuals) than with HSV 1 infection (50 - 60 %) (12, 13) and many more patients are experiencing asym- ptomatic or subclinical vira! shedding. Transmission Transmission of HSV may occur both during clini- cally evident outbreaks and asymptomatic virus she- dding. Even though the risk is significantly higher with active herpetic lesions, asymptomatic vira! shedding is probably the primary mode of transmission (13). It occurs by close personal contact (mostly sexual contact) and it appears to be most efficient from men to women. Studies of serologically discordant heterosexual couples report transmission rate between 10 - 12 % per year (14,15). Figure 1. Electrone micrograph of Herpes simplex virus: (1) capsid, (2) tegun:,ent, (3) lipid membrane with glycoproteins Figure 2. lnitial (primary) genital herpes in a male Figure 3. Recurrent genital herpes in a male J Cenita/ herpes Immunity The role of immune response in genital herpes is not quite understood yet, but it seems that both parts (i) the 11011-specific response /natura! killer cells, activated macrophages, production of interferon/ and (ii) the specific immune reactions / anti HSV IgM and IgG antibodies, CD4 cells activity/ are important. Lately, also the knowledge of ways by which HSV evades the immune system defense is growing. The viruses down regulate MHC class I antigen expression on the surface of infectecl cells and consequently render CD 8 cells inactive against those cells . They can also inactivate complement ancl immunoglobulins by binding to them via certain HSV glycoproteins. Any further impairment of immune system (immu- nosuppressive therapy in organ transplantation, HIV infection etc.) increases the probability of (i) clinically eviclent disease (ii) extensive local changes (iii) dissemination of lesions and (iv) further complications (1). Diagnostic procedures There are many diagnostic proceclures available, most of them being highly specific ancl sensitive if we respect their limitations. Various tests performecl in the Institute of Microbiology ancl Immunology, Medica! Facully Ljubljana, are listed and specifiecl in the paper of Marin et al. (16). The interpretation of laboratory results frequently remains inconclusive and makes the decision concer- ning the treatment difficult. (17) Treatment Elimination of herpesviruses from neuron is not possible yet; therefore the presently recommendecl treatment is aimed at controlling the disease with chemotherapy. For the initial genital h erpes episode sys temic treatment with antiviral clrugs is advisable . In Slovenia we can choose between acyclovir (VirolexR tbl. a 200 mg): 5 x 1 tbl /clay, 7 -10 days , and valacyclovir (ValtrexR tbl. a 500mg) 2 x 1 tbl. /clay, 7 - 10 clays. Famcyclovir, which is not available in our country at the moment, is a prodrug of pencyclovir and the recommended schedule is 250 mg 3 times a day, 7 -10 days. The above mentioned treatments are supposed to alleviate the systemic symptoms, shorten the duration of herpetic lesions and of vira! shedding, but they do not effect the establishment of latency or the frequency of future recurrences. 6 For the recurrent episodes three possible regimens of therapy are recommended (at present): a) Topical treatment: either witb indifferent substances (for example with zine oxide) or with topically appli- cable antivirals. b) Episodic management with systemic antivirals: reco- mmended drugs being again acyclovir 200 mg 5 times / day, valacyclovir 500 mg twice a day, famcyclovir 250 mg 3 times / day. Ali regimens shoulcl be performed for 5 clays (18). Regarcling the initiation of the treatment it has been shown that the most efficient regimen is the so-callecl patient initiated management, where the patient is trained to recognize prodromal symptoms and early signs and starts the therapy immediately. The episodic treatment reduces the tirne of herpetic lesions and subclinical vira! shedding but cloes not affect the latency. c) Continuous suppressive therapy: it is recommenclecl for the patients who have ve1y severe or/ and frequent recurrences (more than six a year) or are immuno- logically incompetent ancl to those who are psychically and socially very clisturbecl by the disease. In severa! sL1.1dies it has been reported that suppre- ssive treatment (acyclovir 400 mg / 12 h, valacyclovir 500 mg once a clay, famcyclovir 250 mg /12h) signifi- cantly reduce not only clinical outbreaks but also asym- ptomatic vira! sheclcling and as such it may importantly diminish the transmission (19,20,21). At present the application of vaccines (therapeutic or preventive) is stili in an experimental stage. Some of the vaccines in the past have been cliscardecl because of the possibly carcinogenic effect ancl in the seventies Nasemann (22) even proposecl that future herpes vaccines be manufacturecl only from primarily non- oncogenic strains . In Europe heat killed whole virus vaccines have been wiclely available in the last three clecacles, but only few controlled studies have been reportecl (23,24) From more recent reports the most promising seem to be the genetically engineered proclucts and recombinant HSV glycoprotein vaccines (25,26). Conclusion The HSV infections are relatively frequently ob- served in the STD clinics. The initial infection and especially the recurrences are annoying for the patient, but are not life endangering , except for the severely immunocompromisecl persons. Its direct role in carci- nogeneity is being cleniecl cluring the last clecacle, nonetheless it is one of the STDs, which as a bulk are an important cofactor in promotion of carcinoma of genitals. Review Acta Dermatoven APA Vol 9, 2000, No 1 8 Cenita/ herpes l. Rouse BT, editor. Herpes simplex virus. Berlin Heidelberg New York: Springer Verlag; 1992. 2. Cunningham AL, Flexman JP, Dwyer D, Holland D, editors. Clinician's manual on genital herpes. London: Science press; 1997. 3. Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR 1998; 47:18-65. 4. Schomogyi M, Wald A, Corey L. Herpes simplex virus-Z infection: An emerging disease? Infect Dis North Am 1998; 12: 47-61. 5. Nahmias AJ, Lee FK, Beckman-Nahmias S. Sero-epidemiological and sociological patterns ofherpes simplex infection in the world. Scand J Infect Dis 1990; 69: 19-36. 6. Siegel D, Golden E, Washington E, Morse SA, Fullilove MT, Catania JA, Marin B, Hulley SB. Prevalence and correlates ofHerpes simplex infections. The population-based AIDS in multiethnic neighborhoods study. JAMA 1992; 268: 1702-8. 7. Fleming DT, McQuillan GM,Johnson RE et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N EnglJ med 1997; 337: 1105-11. 8. Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type specific serology. Ciin Microbiol R 1999; 12: 1-8. 9. Cowan FM, Johnson AM, Sahley R, Corey L, Mindel A. Antibody to herpes simplex virus type 2 as serological marker of sexual lifestyle in populations. BMJ 1994; 309: 1325-9. 10. Kinghorn Gr. Limiting the spread of genital herpes. Scand J Infect Dis 1996; 100: 20-5. 11. Pereira FA. Herpes simplex: evolving concepts. J Am Acad Dermatol 1996; 26: 698-709. 12. BenedettiJ, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first episode infection. Ann Int Med 1994; 121: 847-54. 13. Corey L. The current trend in genital herpes: progress in prevention. Sex Transm Dis 1994; 21: S38-S44. 14. Bryson Y, Dillon M, Bernstein DI, Radolf J, Zakowski P, Garratty E. Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study. J Infect Dis 1993; 167: 942-6. 15. Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med 1992; 116: 197-202. 16. Marin J. Laboratorijska diagnostika herpetičnih obolenj. ACTA dermatoven APA 2000; in print. 17. Barton SE. The practical application of serological testing for HSV infection. Herpes 1998; 5: 39- 41. 18. Reichman RC, Badger GJ, Mertz GJ. Treatment of recurrent genital herpes simplex infections with acyclovir: a controlled tria!. JAMA 1984; 251: 2103-7. 19. Tyring SK, Douglas JM, Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol 1998; 134: 185-91. 20. Goldberg LH, KaufmanR, Kurtz G et al. Long term supression of recurrent herpes with acyclovir: a 5-year benchmark. Acyclovir Study Group. Arch Dermatol 1993; 129: 582-7. 21. WaldA, ZehJ, Barnum G, Davis LG, CoreyL. Supression ofsubclinical shedding ofherpes simplex virus type 2 with acyclovir. Ann Intern Med 1996; 124: 8-15. 22. Nasemann T. Herpes simplex type 2 vaccine: the favorable european experience. Int J Dermatol 1976; 15: 587-8. 23. Calista D, Baldari U. Trattamento profilattico delle infezioni erpetiche recidivanti mediante immunostimolazione specifica con Lupidon Go H. G Ital Dermatol Venereol 1997; 132: 27-32. 24. Mastrolorenzo A, Tiradritti L, Salimbeni L, Zuccati G. multicentre clinical tria! with herpes simplex virus vaccine in recurrent herpes infection. Internati ona! Journal of STD&AIDS 1995; &: 431-435. Acta Dermatoven APA Vol 9, 2000, No 1 Genital herpes AUTHOR'S ADDRESS Acta Dermatoven APA Vol 9, 2000, No 1 25. Parr D, Savarese B, Burke RL, Margolis D, Meier J, Markoff Letal. Ability of recombinant herpes simplex virus type 2 glycoprotein D vaccine to induce antibody titers comparable to those following genital herpes. Ciin Res 1990; 39:216A 26. Baltimore D. Intracellular immunization. Nature 1988; 395-6. Mirjam Rogl Butina MD, dermatovenereologist, Dpt. Dermatovenereology, Clinical Centre, Zaloška 2, 1525 Ljubljana, Slovenia 9