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Journal of Antimicrobial Chemotherapy (2000) 45, Topic T3, 1–8 Introduction The prevalence of genital herpes simplex virus (HSV) infection is increasing despite the availability of drugs that inhibit its replication. 1 New strategies for reducing genital HSV transmission and infection are needed. 2 This article reviews recent studies that define the characteristics and predictors of asymptomatic shedding, its role in HSV trans- mission and the effect of antiviral therapy on a
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   Journal of Antimicrobial Chemotherapy (2000) 45 , Topic T3 , 1–8 Introduction The prevalence of genital herpes simplex virus (HSV)infection is increasing despite the availability of drugs thatinhibit its replication. 1 New strategies for reducing genitalHSV transmission and infection are needed. 2 This articlereviews recent studies that define the characteristics andpredictors of asymptomatic shedding, its role in HSV trans-mission and the effect of antiviral therapy on asymptomaticshedding. Pathogenesis of HSV infection HSV is labile in the environment and is acquired throughdirect contact with infected tissue or secretions. After bind-ing to and entering cells at the inoculation site through specific receptors, 3,4 HSV replicates with a life cycle of theorder of 1 day and a burst size of at least 100–1000 daughtervirions per infected cell. 5 During primary infection, progenyviruses infect surrounding cells and traverse the neuro-epithelial gap into the distal endings of sensory and auto-nomic axons. Viral proteins are probably also carried toregional lymphoid aggregates by mobile dendritic-lineagecells, where primary immune responses are initiated.After HSV has ascended to nerve cell bodies in the rele-vant ganglia, it is believed to be transmitted to neighbour-ing neurons and to higher-order neurons in the spinal cord. These events have several consequences: (i) based on animal models, the virus may descend acutely the axons of neighbouring neurons back to the periphery, resulting inthe clinical primary infection syndrome; 6 this phenomenonmay account for the multiple crops and wide anatomicaldistribution of lesions during primary genital HSV infec-tion in humans; 7 (ii) ganglionic spread may give rise to anincreased number of latently infected neurons—in animalmodels, the number of such neurons appears to be directlyrelated to the rate of subsequent reactivation; 8 (iii) spreadto the CNS may cause meningeal signs and symptoms. 9 Local peripheral persistence of HSV is detectable insome animal models and in the human cornea, but there isno evidence that the virus persists in the genital epitheliumbetween episodes of shedding. 10 Asymptomatic and symptomatic recurrences of HSVinfection are believed to start in latently infected neurons.During latency, specific and limited viral RNA expressionoccurs, and very few or no viral proteins are made. 5 Duringreactivation, the HSV genome switches to a lytic pattern of gene expression, resulting in the delivery of infectiousvirions from axons to epithelial cells. 11 It is believed thatneurons are not killed in the process of HSV reactivation.Stimuli precipitating HSV reactivation and clinicallesions include both ‘ganglionic’ triggers, such as nerve sec-tion, surgery or fever, 12 and peripheral or ‘skin’ triggers,such as ultraviolet light or trauma. 13,14 Social or emotionalstress is commonly cited by patients as a cause of recurrentHSV episodes, but prospective documentation suggests thatstress may often be the effect, rather than the cause, of recurrences. 15 1 Herpes simplex virus: the importance of asymptomatic shedding D. M. Koelle  a , b ,  d  * and A. Wald  a , c Departments of a Medicine, b Laboratory Medicine and c Epidemiology, University of Washington, Seattle, WA98195; d Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Herpes simplex virus (HSV) is frequently shed after infection of the genital or perianal area. HSVshedding, as determined by culture, occurs on about 3% of days for immunocompetent womenand men, and more for persons with HIV infection or if measured by polymerase chain reaction(PCR). Most horizontal and vertical transmission of HSV occurs during unrecognized or asymp-tomatic shedding, and the majority of HSV-2-infected persons are unaware of their infection.Many persons with ‘asymptomatic’ HSV-2 infection can learn to recognize genital signs andsymptoms as recurrences of HSV-2 infection. However, some shedding episodes remain trulyasymptomatic even after patient education. Antiviral therapy dramatically reduces asympto-matic shedding, and trials to evaluate its effect on HSV transmission are underway. *Correspondence address. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA. Tel:  1-206-341-5207; Fax:  1-341-5203-4411; E-mail: viralimm@uwashington.edu © 2000 The British Society for Antimicrobial Chemotherapy  JAC  D. M. Koelle and A. Wald The ‘skin trigger’ theory of recurrent infection statesthat the presence of the proper local milieu permitting viralreplication controls the formation of lesions to a greaterextent than does neuronal reactivation and virus deliveryto the periphery. 13,16 Irrespective of how peripheral recur-rent infection is initiated, HSV then replicates and maypotentially be transmitted. After symptomatic recurrentdisease, local innate and acquired host immune responsesterminate replication. 17 Little, if anything, is known withregard to the local or systemic immune correlates of asymp-tomatic shedding of HSV. Clinical definitions Asymptomatic shedding is generally defined as the detec-tion of HSV in the absence of genital lesions. Symptomsmay be present, but they are not recognized by the patientor clinician as related to herpes. Subclinical reactivationand subclinical shedding are synonymous with asympto-matic shedding, 9,18 the former emphasizing the concepts of ganglionic latency and a discrete neuronal reactivationevent. In unrecognized genital herpes, lesions are tempor-ally and spatially correlated with detection of HSV, butalthough they are within the spectrum of known HSV syn-dromes, 9 they are not recognized as such by the patient andclinician. The relationship between unrecognized,symptomatic and asymptomatic infection Underdiagnosis of genital herpes Most HSV-2-seropositive persons deny a history of genitalherpes. 9 Knowledge of the signs and symptoms of genitalherpes is variable, among both clinicians and patients. Clinicians may diagnose correctly a greater proportion of people with genital herpes by having a low threshold forperforming culture or other virus detection tests for genitalor perianal symptoms, or from subtle changes noted onphysical examination. Adjuncts to physical examinationmay affect the symptomatic status of an HSV shedding event.For example, colposcopy may reveal tiny cervical ulcera-tions in culture-positive asymptomatic women, which wouldnot be visible during routine examination. 19 Overall, per-formance of type-specific serology for HSV-2 infection isthe most cost-effective way of documenting genital herpes,recognizing that in some geographical areas, up to 50% of genital herpes is due to HSV-1. 9 Patient education To address the role of patient education in the recognitionof recurrent genital herpes infection, three studies haveinvestigated the frequency of symptomatic, but unrecog-nized, genital herpes among HSV-2-seropositive personswithout a documented history of genital herpes. Langen-berg et al. 20 studied 62 HSV-2-seropositive women whodenied a history of genital herpes. The subjects received adescription of typical genital HSV signs and symptoms, areview of transmission and reactivation, and viewed pic-tures of HSV lesions. Forty-eight (77%) of the women sub-sequently presented with recurrent HSV lesions. Subjectsin a second study 21 of HSV-2-seropositive women without ahistory of genital herpes were recruited predominantlyfrom a family medicine clinic. Subjects received an educa-tional counselling session, including teaching illustrationsof typical and atypical lesions, performed daily home cul-tures and kept a symptom diary. Overall, 61% of the sub- jects reported a clinical history consistent with genital HSVinfection, and 74% had documented viral shedding. Similarfindings were reported by Frenkel et al. 22 among pregnantwomen. Taken together, these studies show that mostHSV-2-seropositive persons have signs and symptomsassociated with some HSV shedding events.Even after education, some episodes of HSV sheddingremain truly asymptomatic. This was documented, for ex-ample, in a study performed by Wald et al  . 18 Subjects with ahistory of recurrent genital herpes received intensive edu-cation regarding the signs and symptoms of genital herpes.Most cultures were performed at home, but some were performed in the clinic, where an experienced researchclinician took a detailed history and performed a completeexamination. Several episodes of asymptomatic sheddingwere detected at study visits. It is important to recognizethat essentially all HSV-2-infected people periodically shedvirus. Individuals can be categorized as: (i) having sympto-matic shedding events that they recognize as herpetic (a minority); (ii) having unrecognized symptomatic disease(a majority); or (iii) having neither class of symptomaticdisease (probably a small minority). Most persons with un-recognized disease can be ‘converted’ to symptomatic disease after education about lesions and symptoms. Im-portantly, individuals in all three groups have periods of true asymptomatic shedding events, and the data availablesuggest that the frequency of asymptomatic shedding issimilar between these groups. 23 Patient counselling regard-ing therapy should, therefore, be similar for most HSV-2-infected persons, regardless of symptoms. The role of asymptomatic shedding in thetransmission of HSV infection In prospective studies of partners discordant for HSV-2infection, most transmission events were not associatedwith a clinically recognized HSV recurrence (or prodrome)in the source partner. 23 Earlier cross-sectional studies pro-duced similar results. 24 Many anecdotes address this scenario, including acquisition of genital herpes from part-ners unaware of their infection status. 25 Even when adviceis given to abstain from sex during recurrences and whenbarrier methods of contraception are used, horizontal trans- 2  Asymptomatic shedding of herpes simplex virus mission may still occur, although compliance with suchadvice has not been carefully monitored. 23 Most verticaltransmission of HSV to the neonate also occurs duringasymptomatic shedding. This is rare and most often occurswhen genital herpes is newly acquired by the mother in latepregnancy. Transmission may occur before primary infec-tion becomes symptomatic; often, the primary infection inthe mother is asymptomatic. 26,27 Rates of asymptomatic shedding of HSV Our research group and others have undertaken detailedstudies of the rates, anatomical sites and predictors of asymptomatic shedding and its role in the transmission of HSV. Prospective studies have used both intermittent anddaily sampling, more recently at multiple anatomical sitesand using both culture and highly sensitive quantitativePCR to detect HSV.Almost all women with symptomatic recurrent genitalHSV-2 infection also experience asymptomatic shedding of the virus. When PCR and culture were compared in 20women studied daily at multiple anatomical sites, sheddingwas detected in 19/20 women (95%) by PCR comparedwith 15/20 (75%) by culture. 28 The detection of asympto-matic shedding is dependent upon the system used, thenumber of anatomical sites and the duration of sampling. Duration of sampling Among women who had cultures of the genital and perianalareas performed for  100 days, 100% had at least 1 day of asymptomatic shedding, while only 5.6% of women demon-strated asymptomatic shedding when studied for  25 days. 29  Anatomical site Asymptomatic HSV-2 shedding among women withsymptomatic recurrent disease from whom cervical/vaginal,vulvar and perianal/rectal specimens are analysed by cul-ture, has been shown to occur during 2–8% of days in several studies. 18,28,30,31 This range is a reasonable estimateto use in counselling immunocompetent subjects with estab-lished, symptomatic disease. Larger studies have shownthat asymptomatic shedding occurs more often from theperianal area than from the vulva or cervix, 31 althoughsome studies have documented roughly equal rates fromeach area. 18 Asymptomatic shedding is typically of shorterduration than shedding associated with lesions. Three-quarters of asymptomatic shedding events lasted for only asingle day, compared with 57% of symptomatic sheddingevents in a daily culture study. 31 Method of detection PCR is generally a more sensitive tool for HSV detectionthan culture. Substitution of PCR for culture in sheddingstudies results in similar findings and trends in asympto-matic shedding, although the absolute magnitude of shed-ding tends to be higher. In a study that used daily specimencollection, genital or perianal shedding was detected on27.9% of days (range, 0–77.3% of days) among 20 womenwith recent onset, symptomatic genital HSV-2 infection.Specimens for the detection of HSV by PCR can be dividedinto culture-positive and culture-negative specimens. Amongthe total group of specimens collected on days when genitallesions were and were not detectable, the culture-positivespecimens had approximately 100-fold higher mean levelsof HSV DNA than did culture-negative specimens. How-ever, some specimens that were highly positive by PCRwere negative by culture, and some specimens with verylow amounts of HSV DNA (10–100 copies) were positiveby culture. Considering the days showing positive HSV cul-tures only, it is interesting to note that the amount of HSVDNA recovered was approximately the same regardless of the presence of lesions. 28 The presence of culturable virusand relatively high amounts ( c. 10 4 copies) of HSV DNA inthe absence of lesions during asymptomatic shedding isconsistent with the possibility that the host inflammatoryresponse may contribute to lesion formation during sympto-matic HSV disease.  Impact of patient education As mentioned above, most women with HSV-2 infectionare not aware of their infection, although some can be edu-cated to recognize recurrent symptomatic infection. Dailycultures from 30 women unaware of their HSV-2 infectionshowed an overall HSV-2 shedding rate of 3.1% and anasymptomatic shedding rate of approximately 2.1% of days, with the majority having had at least one asymp-tomatic shedding event. While symptomatic shedding rateswere lower in this group of women than in women with clin-ically diagnosed recurrent genital HSV-2 infection, evenafter intensive education, there was little overall differencein asymptomatic shedding rates between the groups. 21 HSV-2 seroconversion Primary genital HSV-2 infection is typically more severeand more prolonged than recurrent infection. 9 However,primary genital HSV-2 infection can also be asymptomaticor unrecognized. Cross-sectional studies found that only9–25% of HSV-2-seropositive persons had any history of genital herpes, either as a single, initial episode or as recur-rent disease. 1,9,32 Prospective studies have documentedasymptomatic seroconversion to HSV-2 even in exten-sively counselled patients. 23,33,34 To address the frequency of symptoms associated withHSV seroconversion, a large group of HSV-2-seronegativepatients was recently studied prospectively for  1 year.Subjects were educated regarding typical signs and symp-toms of genital HSV infection at the start of the study, and 3  D. M. Koelle and A. Wald asked to report to the clinic if any such events occurred.HSV infection was documented by culture and repeatserology at the end of the study period. Overall, 37% of theHSV-2 acquisition events were symptomatic. Men showedmore asymptomatic seroconversion than did women, whilewomen were at a higher overall risk for HSV-2 acquisition.Most of the people with symptomatic seroconversionreported to the clinic at the time of their initial infection.While approximately 75% had typical lesions, some did nothave genital lesions and had genital pain or urethral dis-charge only. Other syndromes included aseptic meningitisand fever with radicular pain. Cases of asymptomatic seroconversion followed by typical symptomatic recurrentdisease were also observed. 33 Predictors of asymptomatic shedding inimmunocompetent women Virus type The lower symptomatic recurrence rate for anogenitalHSV-1 infection in comparison with HSV-2 is also applica-ble to asymptomatic shedding, 35 reflecting a type-specificdifference in pathogenesis. The overall rate of cervical orexternal genital shedding is 1.2% for HSV-1 and 4.3% forHSV-2 during the first year after primary infection. 30 Inpatients with established recurrent disease (median 462days since the first clinical episode), the rate of shedding forHSV-1 was 0.7%, compared with 2.0% for HSV-2. 31 Duration of infection The rate of recurrence and the rate of shedding of HSV-2from genital and perianal areas both decrease over time. 36 It is not known if this is related to the acquisition of immunological control or to a neuronal factor. Among 227women with primary genital HSV-2 infection, the rate of shedding from the cervix or vulva decreased from 3.1% of days during the first year, to 2.3% during the second yearand 2.1% during the third year ( P  0.005). 30 In a multi-variate analysis of predictors of asymptomatic shedding,women studied  1 year after the acquisition of genital herpes had an adjusted odds ratio of 1.9 (95% confidenceinterval, 1.1–3.1) for asymptomatic shedding comparedwith women who had had genital herpes for  1 year. 31 However, asymptomatic shedding persists even in patientswith long-standing disease. 28 Frequency of recurrences In a multivariate analysis, 31 the rate of asymptomatic shed-ding of HSV from the anogenital area was also shown to berelated to the frequency of recurrences of genital herpes.The relationship persisted regardless of whether recur-rences were symptomatic or culture-confirmed and wasmost dramatic for women with  12 recurrences per year.The host or virus factors that lead to an increased total burden of HSV shedding in apparently immunocompetentpersons are unknown. Asymptomatic shedding in immunocompetentmen Anecdotal case reports have recently been supplementedwith prospective observational studies. 25 In homosexualmen, the most common site of shedding was the perianalarea followed by the penile skin and, rarely, the urethra andsemen. 9 In heterosexual men, the penile skin was the mostcommon site of asymptomatic shedding. The subclinicalshedding rate for men with a history of genital herpes was2.0% of days using daily home cultures. As in women,lesions and symptoms were absent on one-third of the dayswith positive cultures. In a small group of HSV-2-seroposi-tive men without a history of genital herpes, subclinicalshedding was detected on 3.9% of days. 37 Similar resultswere noted in a smaller study of HIV-negative homosexualmen. 38 HSV infection of men and women appears to besimilar with regard to the overall rate of asymptomaticshedding and the presence of shedding in persons without aclinical history of genital herpes. Host immune status and asymptomatic shedding The viral or host factors controlling the development of lesions and symptoms when HSV reactivates are unknown.Immunity to HSV-1 does not confer protection againstasymptomatic shedding of HSV-2. Two studies of womenhave failed to show an association between HSV-1 sero-status and the rate of asymptomatic recurrent anogenitalshedding of HSV-2. 30,31 Recent data showing that previousHSV-1 infection does not prevent HSV-2 acquisition hasled to a reassessment of the overall concept of protectivetype-common immunity to HSV. 26,34 In a large prospectivestudy, the presence of previous HSV-1 infection did notprotect against HSV-2 seroconversion. An immunologicalinfluence on the recognition of disease during initial HSV-2 infection could be discerned, as asymptomatic sero-conversion to HSV-2 was more common in people withpre-existing HSV-1 infection. 33 Men infected with HIV-1 form the largest group of immunodeficient subjects studied to date. The overall ratesof asymptomatic shedding of HSV-2 from the anogenitaltract in HIV-infected men in two recent daily home culturestudies were 7.3% 39 and 5.1%. 40 Approximately two-thirdsof overall shedding was asymptomatic, and both total andasymptomatic shedding in this group was higher than in agroup of HIV-negative homosexual men who were studiedin parallel. The most common area of shedding was theperianal area, where some proportion of shedding may be 4
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