Reactivation of Genital Herpes Simplex Virus Type 2 Infection in Asymptomatic Seropositive Persons
Anna Wald, M.D., M.P.H., Judith Zeh, Ph.D., Stacy Selke, M.S., Terri Warren, M.S., Alexander J. Ryncarz, Ph.D., Rhoda Ashley, Ph.D., John N. Krieger, M.D., and Lawrence Corey, M.D.
Background Most persons who have serologic evidence of infectionwith herpes simplex virus (HSV) type 2 (HSV-2) are asymptomatic.Historically, it has been assumed that these persons have lessfrequent viral reactivation than those with symptomatic infection.
Methods We conducted a prospective study to investigate genitalshedding of HSV among 53 subjects who had antibodies to HSV-2but who reported having no history of genital herpes, and wecompared their patterns of viral shedding with those in a similarcohort of 90 subjects with symptomatic HSV-2 infection. Genitalsecretions of the subjects in both groups were sampled dailyand cultured for HSV for a median of 94 days.
Results HSV was isolated from the genital mucosa in 38 of the53 HSV-2–seropositive subjects (72 percent) who reportedno history of genital herpes, and HSV DNA was detected by thepolymerase-chain-reaction assay in cultures prepared from genitalmucosal swabs in 6 additional subjects. The rate of subclinicalshedding of HSV in the subjects with no reported history ofgenital herpes was similar to that in the subjects with sucha history (3.0 percent vs. 2.7 percent). Of the 53 subjectswho had no reported history of genital herpes, 33 (62 percent)subsequently reported having typical herpetic lesions; the durationof their recurrences in these subjects was shorter (median,three days vs. five days; P<0.001) and the frequency lower(median, 3.0 per year vs. 8.2 per year; P<0.001) than inthe 90 subjects with previously diagnosed symptomatic infection.Only 1 of these 53 subjects had no clinical or virologic evidenceof HSV infection.
Conclusions Seropositivity for HSV-2 is associated with viralshedding in the genital tract, even in subjects with no reportedhistory of genital herpes.
Serologic surveys indicate that the prevalence of infectionwith herpes simplex vi-rus (HSV) type 2 (HSV-2) among adultsapproaches 25 percent in the United States and ranges from 4to 18 percent in western Europe.1,2,3,4,5 In most studies, only10 to 25 percent of subjects with HSV-2 infection report a historyof genital lesions.1,2 Historically, it has been assumed thatpersons with asymptomatic HSV infections have less frequentand less severe reactivations than those with symptomatic disease.However, two lines of evidence suggest this may not be true.First, many HSV-2–seropositive subjects who initiallyreport having no history of genital lesions do, after an educationalsession with a clinician, subsequently report having such lesions.6,7Such subjects most likely have unrecognized symptomatic infection.Second, most HSV-2 infections are acquired from a person withno history of genital herpes infection.8,9 These data suggestthat viral shedding in seropositive subjects may be frequent,regardless of the presence or absence of a reported historyof genital herpes.
To investigate viral shedding in HSV-2–seropositive personswho were asymptomatic, we identified HSV-2–seropositivewomen and men who reported no history of genital lesions. Afterthey attended an educational session on the symptoms and signsof genital herpes, the subjects were followed with daily culturesof the genital area to evaluate the frequency and the sitesof viral shedding in the genital tract. The clinical and virologiccharacteristics of the infection in these subjects were comparedwith those in subjects with symptomatic genital HSV-2 infectionswho followed a similar regimen.10
Methods
Study Subjects
We recruited 37 subjects with no reported history of genitalherpes infection from among persons who were identified as beingseropositive for HSV-2 in a random screening for HSV antibodiesamong patients attending a primary care clinic,11,12 but whoreported having no history of genital herpes, and 16 subjectswho were recruited as potential candidates for a study of anexperimental HSV-2 vaccine but who were unexpectedly found tobe positive for HSV-2 antibodies.13 The study was conductedat the University of Washington Family Medicine Clinic and VirologyResearch Clinic in Seattle and was approved by the human-subjectsreview committee of the University of Washington. All subjectsgave written informed consent.
All subjects attended an individual standardized educationalsession on genital herpes that included reviewing photographsof herpetic lesions. Photographs of both typical lesions (e.g.,blisters and ulcers) and atypical lesions (e.g., fissures) wereshown, and the common symptoms (e.g., itching and tingling)were discussed. The women were taught to obtain swab specimensof the cervicovaginal, vulvar, and perianal areas for viralcultures, as described previously.10,14 The men were taughtto obtain swabs of the penile skin, perianal area, and the urethralmeatus or a first-morning urine sample for viral culture.15,16,17The subjects were asked to collect samples daily for three months.The subjects kept a diary of symptoms and signs of genital diseaseand were asked to come to the clinic if they noted lesions consistentwith the presence of genital herpes as well as for regular monthlyvisits.
We also studied 90 subjects (44 men and 46 women) with symptomaticgenital herpes who were HSV-2–seropositive and who wereattending the Virology Research Clinic in Seattle or WestoverHeights Clinic in Portland, Oregon. These subjects attendedthe same type of educational session and followed the same dailysampling protocol as the 53 HSV-2–seropositive personswith no reported history of genital herpes. The demographicand clinical characteristics of these 90 subjects were similarto those of the large cohort of subjects with symptomatic genitalherpes whom we have studied in the past two decades.18,19
Laboratory Methods
Serum samples were tested for HSV type 1 (HSV-1) and HSV-2 antibodiesby Western blot analysis.20 Cultures for viral studies wereplaced in transport medium and delivered to the laboratory threetimes per week. Viral isolation was performed as previouslydescribed; all isolates were confirmed and typed with monoclonalantibodies.21,22 HSV DNA was measured by a quantitative real-timefluorescence-based polymerase-chain-reaction (PCR) assay.23
Study End Points
Herpes lesions were defined as blisters, ulcers, or crusts inthe genital or perianal area or on the buttocks. A recurrencewas defined as the presence of a lesion at any of these siteson one or more consecutive days. Episodes of viral sheddingwere defined as the finding of a positive culture on one ormore consecutive days. The rate of viral shedding was calculatedas the number of days with a positive culture divided by thetotal number of days on which cultures were obtained. The analysisof subclinical shedding was based only on findings obtainedon days on which lesions were absent.
Statistical Analysis
The chi-square and Wilcoxon rank-sum tests were used to comparethe characteristics of the 53 subjects who reported having nohistory of genital herpes with those of the 90 subjects withsymptoms. Log-linear models were fitted to examine predictorsof viral shedding. Scale factors were estimated to account forgreater variability than predicted by the Poisson model.24 Pvalues for comparisons of the percentage of days with sheddingbetween the subjects with no reported history of genital herpesand the subjects with such a history were obtained from multivariatelog-linear models and, hence, are adjusted for age and sex.All statistical tests are two-sided.
Results
Characteristics of the Subjects
The median age of the 53 HSV-2–seropositive subjects (42women and 11 men) who reported no history of genital herpeswas 38 years; 89 percent were white. Twenty of these subjectshad antibodies to HSV-2 only, and 33 had antibodies to bothHSV-1 and HSV-2. These subjects supplied swabs for viral cultureon a median of 98 days. The analysis included 5887 days on whichcultures were obtained and more than 17,700 viral cultures fromthese 53 subjects.
Recognition of Genital Herpes
After education and counseling, 26 of the 42 women (62 percent)and 7 of the 11 men (64 percent) who had reported having nohistory of genital herpes reported having typical ulcers, blisters,or crusts in the genital area during follow-up; 19 of these33 subjects reported more than one recurrence of genital herpes.Examples of two symptom diaries are shown in Figure 1. Thirteensubjects never reported lesions but did report localized genitalsymptoms. In 7 of these 13 subjects, HSV-2 was identified inthe genital tract when symptoms were present. Thus, 46 of the53 HSV-2–seropositive subjects (87 percent) who reportedno history of genital herpes reported having either genitallesions or localized genital symptoms during follow-up (Table 1).
Figure 1. Sample Symptom Diaries Kept by an HSV-2–Seropositive Woman and an HSV-2–Seropositive Man with No Reported History of Genital Herpes.
The woman had antibodies to HSV-1 and HSV-2. During the study, a typical HSV lesion developed on her buttock. During this episode, HSV-2 (2) was isolated initially from the buttock lesion and then from the cervix, vulva, and perianal area. The lesions were located in the genital area (G), buttocks (B), and perianal area (P). The man also had antibodies to HSV-1 and HSV-2. Even after an educational session, the man did not report having typical recurrences. He had an episode of asymptomatic shedding of HSV-2 from the penile skin on days 16 and 17 and mild, nonspecific genital symptoms on days 18 and 19.
Table 1. Correlation between the Recognition of Genital Herpes Lesions and Viral Shedding in 53 HSV-2– Seropositive Subjects with No Reported History of Genital Herpes.
HSV Shedding in the Genital Area
HSV was isolated by viral culture of swabs from the genitalmucosa at least once in 38 of the 53 HSV-2–seropositivesubjects (72 percent) who reported no history of genital herpes.HSV-2 was isolated from 37 subjects, and HSV-1 was isolatedfrom 1 woman who was seropositive for both HSV-1 and HSV-2.Of these 38 subjects, 36 had HSV isolated from geni-tal mucosalswabs obtained on days on which lesions were absent (asymptomaticshedding), whereas 18 subjects had HSV isolated on days on whichlesions were reported. Among the seven subjects who reportedhaving no symptoms or signs of genital herpes during the study,HSV-2 was isolated from four and HSV-1 from one. Among the 13subjects who reported only localized genital symptoms but nolesions, HSV-2 was isolated from 9.
Overall, among the 53 HSV-2–seropositive subjects whoreported having no history of genital herpes at the time ofenrollment, HSV was isolated on 3.8 percent of days on whichcultures were obtained (range, 0 to 17 percent). HSV was isolatedon 168 of the 5591 days (3.0 percent) on which cultures wereobtained in the absence of lesions. Of the 36 subjects who hadsubclinical viral shedding, HSV was isolated on up to 5 percentof days on which lesions were absent in the case of 22 subjectsand on more than 5 percent of days in the case of the remaining14 subjects (Figure 2A).
Figure 2. Frequency of Subclinical Viral Shedding (Panel A) and Any Viral Shedding (Panel B) in HSV-2–Seropositive Subjects with No Reported History of Genital Herpes and in Those with Such a History, as Defined by Isolation of the Virus in Tissue Culture.
The sensitivity of the PCR assay for the detection of HSV isgreater than the sensitivity of culture.23,25 We investigatedwhether mucosal HSV infection could be demonstrated by the PCRassay in 9 of the 15 subjects from whom HSV was not isolatedby standard viral-culture techniques. In six of these nine subjects(four women and two men), HSV DNA was detected by the PCR assayin swabs of genital secretions. The median number of days onwhich HSV DNA was detected in these six subjects was 3.5 (range,2 to 11). The geometric mean number of copies of HSV DNA was8700 per milliliter of PCR specimen (range, 500 per milliliterto 5 million per milliliter). Thus, overall, HSV was detectedin genital secretions by either viral culture or PCR assay in44 of 53 HSV-2–seropositive subjects (83 percent) whoreported having no history of genital herpes (Table 1). Only1 of 53 subjects had no clinical or virologic evidence of HSVinfection.
Clinical and Virologic Characteristics in Relation to History and Symptoms
Among the 90 subjects (46 women and 44 men) with a history ofgenital herpes, the frequency of seropositivity for both HSV-1and HSV-2 was lower than that among the subjects with no reportedhistory of genital herpes (40 percent vs. 62 percent, P=0.02).The symptomatic subjects were also younger (median age, 33 vs.38 years; P=0.003). They were predominantly white (92 percent).They supplied swabs for viral culture on a median of 84 days.
The rates of reactivation of HSV infection among the two groupsof subjects are shown in Table 2 and Figure 2. The total rateof viral shedding was significantly higher among subjects witha history of genital herpes than among HSV-2–seropositivesubjects with no reported history of genital herpes (6.4 percentvs. 3.8 percent of days, P=0.001). Of all the days on whichHSV was isolated in each group of subjects, 36 percent weredays on which no lesions were reported among subjects with ahistory of genital herpes, as compared with 79 percent amongthe subjects with no reported history. However, the rates ofsubclinical viral shedding (2.7 percent vs. 3.0 percent) (Figure 2A),the duration of episodes of subclinical shedding (Figure 3A),and the site-specific rates of subclinical shedding weresimilar in the group with a history of genital herpes and thegroup with no reported history.
Figure 3. Duration of Episodes of Subclinical Shedding (Panel A) and Recurrences of Genital Herpes (Panel B) in Subjects with No Reported History of Genital Herpes and in Those with Such a History.
Among the women, the site-specific rates of subclinical viralshedding were 1.6 percent for the cervicovaginal area for thosewith a history of genital herpes and 0.9 percent for those withno reported history of genital herpes; 1.4 percent and 1.2 percent,respectively, for the vulvar area; and 1.5 percent and 1.6 percent,respectively, for the perianal area. Among the men, the site-specificrates were 1.1 percent for the penile skin for those with ahistory of genital herpes and 1.9 percent for those with noreported history and 0.9 percent and 0.7 percent, respectively,for the perianal area.
The recurrence rate was significantly higher among subjectswho had a history of genital herpes than among those with noreported history of genital herpes (median, 8.2 per year vs.3.0 per year; P<0.001) and the recurrences lasted longer(median, five days vs. three days; P<0.001) (Figure 3B).
In an analysis of risk factors for viral shedding, adjustedfor age and sex, the HSV-2–seropositive subjects witha history of genital herpes had a significantly higher riskof viral shedding than those with no reported history (riskratio, 1.84; 95 percent confidence interval, 1.27 to 2.66) (Table 3).The risk of viral shedding was slightly higher among womenthan men and tended to decrease with age. In this analysis,age may be serving as a surrogate for the time since the initialinfection, which was unknown for subjects with no reported historyof genital herpes, because the rates of viral shedding decreaseover time among symptomatic subjects.10,26 In contrast to therisk of any viral shedding, the adjusted risk of subclinicalshedding in the subjects with a history of genital herpes didnot differ significantly from those with no reported historyof genital herpes (risk ratio, 0.95; 95 percent confidence interval,0.59 to 1.53).
Table 3. Predictors of Viral Shedding, as Measured by Viral Culture, in Subjects with HSV-2 Infection.
Discussion
There has been controversy regarding the biologic and clinicalmeaning of asymptomatic HSV-2 infection. At present, the medicaland public health communities largely ignore persons who haveasymptomatic HSV-2 infection because little information is availableregarding the benefit of identifying such persons. We systematicallyevaluated the rates of reactivation of infection among asymptomaticHSV-2–seropositive subjects. We found that 83 percentof subjects who were HSV-2–seropositive but who reportedhaving no history of genital lesions had genital shedding ofHSV during follow-up. Although much of the shedding was subclinical,once identified as seropositive by serologic testing and educatedabout their HSV-2 infection, 62 percent of such subjects reportedhaving typical herpetic lesions. The pattern, sites, and frequencyof subclinical reactivation of infection in these subjects weresimilar to those in subjects with symptomatic infections.
In this study, as in prior studies,6,7 knowledge of their seropositivityfor HSV-2 combined with education regarding the clinical manifestationsof genital herpes resulted in the recognition of typical lesionsamong most subjects with "silent" HSV-2 infections. The subjects'lack of recognition of recurrent genital herpes may be explainedby the lower frequency and shorter duration of lesions amongsubjects with silent infections, as compared with those withclinically evident genital herpes.10 Although perception clearlyhas an important role in the diagnosis of this disease, thereported frequency or duration of episodes noted by the subjectswas unlikely to have been underestimated, given the intensivefollow-up and frequent visits required by our protocol. Subjectswith symptomatic infection typical of those enrolled in treatmenttrials are at the more severe end of the clinical spectrum ofHSV-2 infection.27,28,29
Whether host or viral factors are responsible for the differencein clinical and virologic manifestations of infection betweensubjects with frequent reactivation of HSV and those with infrequentreactivation is not known. However, the rates of subclinicalviral shedding were similar among the subjects with previouslyunrecognized genital herpes and those with recognized infection.HSV is often transmitted during episodes of subclinical shedding8,30;with regard to infectivity, HSV-2–seropositive personswho initially reported having no lesions differed little fromHSV-2–seropositive persons who recognized the lesions.Our findings concerning the potential for the transmission ofHSV to sexual partners are therefore not comforting to eitherpatients or providers.
Asymptomatic shedding of HSV has been investigated predominantlyamong women. Because women may shed virus "internally" (i.e.,from the cervix and vagina), the idea that some reactivationsof infection may go unnoticed appears plausible. In contrast,the anatomy of the genital tract in men and the fact that thegenital epithelium is predominantly skin and not mucosa havemade less plausible the concept of asymptomatic shedding frommen's genital skin. This issue was illustrated in a study ofphysicians' attitudes toward asymptomatic shedding of HSV,31in which both male and female physicians tended to dismiss thepossibility of asymptomatic shedding in men as anatomicallyimplausible. We found that this reasoning is erroneous; therates of subclinical shedding among men approximated those amongwomen.
Although our study included more than 17,700 viral culturesfrom HSV-2–seropositive persons with no history of genitalherpes, all cultures were obtained from a total of 53 such subjects.Since studies such as ours are difficult and time consumingfor the subjects, only subjects who were particularly concernedabout HSV-2 infection and who were able to comply with the proceduresparticipated. However, since most of the asymptomatic subjectsin this study were initially recruited in a general medicalclinic and did not present with genitourinary symptoms, it seemsunlikely that the cohort was biased toward those with more severesubclinical HSV infections.
Prevention of the spread of HSV to neonates and sexual partnerswill require the identification and control of infection inpersons with subclinical HSV infection. Although accurate, type-specificserologic tests have been available in research laboratoriesfor more than a decade, commercially available assays have beendeveloped and marketed only fairly recently.32,33,34,35,36 Thus,it is just becoming possible to identify the large reservoirof persons with infrequent, short episodes of HSV-2 reactivation.Our data suggest that such persons often may not require antiviralchemotherapy for clinical symptoms and signs of infection becausetheir episodes are short and infrequent. However, they do requireeducation and counseling regarding their risk of transmittingthe infection to others.
Supported by a grant (AI-30731) from the National Institutesof Health.
Source Information
From the Departments of Medicine (A.W., L.C.), Epidemiology (A.W.), Statistics (J.Z.), Laboratory Medicine (S.S., A.J.R., R.A., L.C.), and Urology (J.N.K.), University of Washington, Seattle; Westover Heights Clinic, Portland, Oreg. (T.W.); and the Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle (L.C.). Presented in part at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, September 15–18, 1996.
Address reprint requests to Dr. Wald at the University of Washington Virology Research Clinic, 1001 Broadway, Suite 320, Seattle, WA 98122, or at annawald{at}u.washington.edu.
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