MORE THAN 20% OF ADULTS in the United States have serologically demonstrated herpes simplex virus 2 (HSV-2) infection.1 Most of these infections are clinically unrecognized and undiagnosed.1–4 Even individuals with symptomatic genital ulcerations may not recognize their symptoms as those of genital herpes.5 Herpes simplex virus 2 is a disease of short incubation and, as such, most persons with first episode HSV-2 can identify partners from whom they might have acquired the infection.6–8 In contrast, recurrent HSV-2 is caused by endogenous reactivation of latent virus, an event that is not necessarily related to current sexual behavior or partners.9–10 During the course of a series of studies on the natural history of acquired genital herpes9,11,12 we encountered 41 patients who presented with a clinical history and signs and symptoms of first episode genital herpes and who denied a history of genital ulceration, but who were retrospectively determined by serologic testing to have recurrent disease. This report defines the natural history of these patients with recurrent HSV-2 who presented with first episode signs and symptoms.
In 1974, the University of Washington Virology Division established a research clinic dedicated to the study of genital HSV. We have previously reported the clinical manifestations and course of genital HSV in a cohort of 457 individuals who presented to this clinic with symptoms and signs of first episode genital HSV; all had serologic evidence of recently acquired first episode HSV infection.9 During this period, we also identified 41 persons who clinicians thought had first episode genital herpes but were found on initial serologic testing by Western blot to have a full complement of HSV-2 specific antibodies at study entry. As it requires at least three months to develop such a Western blot profile, this serologic pattern indicates that these individuals had previously acquired subclinical HSV-2 and that their attendance at the clinic was their first recognizable attack.13–17
The patient recruitment and data collection methods have been described previously.9,11,12 Adult volunteers who presented at the University of Washington virology research clinic with what, by history and symptoms, appeared to be their first historical and clinically evident episode of genital herpes were enrolled. At enrollment, we obtained informed consent, performed standardized interviews and genital exams, and collected sera for HSV antibody testing. Patients were then followed at 2- to 3-day intervals until lesion healing occurred. They were requested to return to the clinic at the time of recurrence.
Convalescent sera were drawn 6 weeks after entry and at subsequent 3- to 6-month intervals. Sera were tested by Western blot for HSV-1 and HSV-2 antibodies. Criteria for defining the presence of HSV-2 have been published.13–16 All subjects in this cohort had a full set of bands to HSV-2 in their enrollment sera with no increase in number or intensity in convalescent sera, a hallmark of previously acquired HSV infection. The acute and convalescent sera were run together and were not made available to the clinicians until more than 6 months after enrollment. Viral isolation and typing were performed as previously described.18 All subjects had HSV-2 isolated from genital lesions.
The 41 subjects identified in this cohort were compared with the patients enrolled in the same protocol in whom subsequent serologic testing revealed true primary HSV-2 or with those with prior HSV-1 who acquired first episode HSV-2.9 Statistical analysis was performed using SPSS version 7.5 (SPSS, Inc., Chicago, IL).
The demographic characteristics of the 41 patients with recurrent HSV 2 with first episode symptoms are described in Table 1. Data for 326 primary HSV-2 and 59 nonprimary initial (NPI) HSV-2 cases are provided for comparison.9 The cases of recurrent HSV-2 with first episode symptoms tended to be in older patients who had had more lifetime sexual partners and earlier sexual debuts than those with true primary HSV-2 (Mann Whitney U, p < 0.05). These patients also had a greater lifetime number of sexual partners than individuals with prior HSV-2 who had recently acquired HSV-2 (nonprimary first episode or nonprimary initial HSV-2) (Mann Whitney U, p < 0.05). However, there was no significant difference in the age at presentation or age at sexual debut between the cases of recurrent HSV-2 with first episode symptoms and NPI cases. There was overlap in these parameters in all three groups. The median number of days between the last sexual encounter and presentation was similar in all three groups (4 to 5 days). Therefore, the past and immediate sexual history did not allow any discrimination between the three groups.
Local and systemic signs and symptoms were common among this cohort of patients (Figures 1A and B); 88% reported genital pain, 77% described pruritus, 69% complained of dysuria, and a vaginal or urethral discharge was evident in 53% of subjects. Inguinal adenopathy was documented in 52% of subjects. Fever during the episode was reported by 43%, 15% reported photophobia, and 40% had headache. Fifteen percent had meningismus and 22% had pharyngitis. Overall, 44% of the 41 patients had at least one systemic symptom. This contrasts with 73% of the patients with primary HSV-2 and 54% of the patients with NPI.
When evaluated by clinical signs and symptoms, patients with primary HSV-2 significantly differed from patients with recurrent HSV-2 with first episode symptoms only in the frequency of adenopathy and the overall frequency of constitutional symptoms. Primary HSV-2 patients were more likely to have adenopathy (chi-square, p = 0.01) and at least one systemic symptom (chi-square, p < 0.005). There was no significant difference in the frequency of systemic complaints between those with recurrent HSV-2 with first episode symptoms and those with nonprimary initial HSV-2.
Measurements of median lesion area, duration, and number are shown in Figures 2A, B, and C. Individuals with recurrent HSV-2 with first episode symptoms had significantly fewer lesions than those with primary HSV-2 (Mann Whitney U, p = 0.01) and a significantly shorter lesion duration (Mann Whitney U, p = 0.005). However, there was no significant difference in the median lesion area between the two groups. There were no significant differences in lesion area, number, or duration between patients with recurrent HSV-2 with first episode symptom cases and patients with NPI.
The patients with recurrent HSV-2 with first episode symptoms were followed a median of 433 days from enrollment (range: 60-1418). The first-year recurrence rate was 0.25 herpes outbreaks per month (range: 0-1.08); and the subsequent recurrence rate was 0.24 herpes outbreaks per month (range: 0-0.93) throughout the course of the study. This rate of recurrence was significantly less than the recurrence rates in the patients with primary and NPI HSV-2 (Mann Whitney U, p < 0.05).
We describe 41 patients who presented with symptoms of first episode genital herpes and denied histories of genital HSV, who were later determined by serologic testing to have recurrent HSV-2. These patients had a high frequency of systemic symptoms, had lesion areas similar to those in cases of true first episode genital herpes, and gave a similar history of sexual activity. These individuals were subsequently shown to be older, with a greater number of lifetime sexual partners and a longer period since sexual debut, than patients with true primary HSV-2. In addition, they healed their lesions more rapidly than persons with true primary HSV-2 acquisition. However, these differences in historical features and natural history would be of limited clinical utility to use prospectively on an individual case basis.
This analysis shows the difficulty of determining the time of acquisition of genital herpes by any clinical or historical information. This cohort of 41 patients represents 8% of the volunteers who presented to our research clinic with genital herpes and were judged by our clinicians to have a newly acquired case of the disease. Moreover, these 41 persons represented more than one third of the persons who had nonprimary clinical first episode infections. Serologic testing retrospectively showed that these patients had acquired HSV-2 at least 3 months before presentation, similar to the findings of Bernstein et al.17 These data demonstrate the often overlapping clinical severity of this infection; some recurrences of genital herpes are quite severe and can be associated with systemic symptoms and large lesional areas. Previous studies have demonstrated an average of less than eight lesions in typical cases of recurrent HSV-2, with a mean area of approximately 60 mm and duration of 10 days.19 This is in contrast to the median lesion number of 9, area of 125 mm, and duration of 15 days in these patients with recurrent HSV-2 who presented with first episode symptoms.
The phenomenon of recurrent genital herpes presenting with primary disease symptoms is clinically important. A patient initially presenting with genital herpes often seeks to blame his or her current partner as the source of the disease, resulting in recriminations, extensive medical evaluations, and even legal action. Our data suggest that recurrence may mimic primary disease and that such assigning of blame may be precipitous. We recommend that all patients with first episode infections get serologic and virologic typing. Matching of acute sera and viral type allows the clinician to determine whether genital HSV infection is primary or recurrent and appropriately counsel the patient. Whereas we used Western blot analysis as our serologic screening assay, the full complement of antibodies present in the profile of these patients suggest to us that recombinant gG2-based assay will also detect such persons. Patients with serologically demonstrated recurrent genital HSV who present with first episode symptoms should be told that they subclinically acquired HSV sometime in their past and that the current reactivation may be unrelated to their current sexual partner.
1. Fleming DT, McQuillan G, Johnson RE, et al. Herpes simplex virus type 2 in the United States 1976 to 1994. N Engl J Med 1997; 337:1105–1111.
2. Breinig MK, Kingsley LA, Armstrong JA, Freeman DJ, Ho M. Epidemiology of genital herpes in Pittsburgh: serologic, sexual, and racial correlates of apparent and inapparent herpes simplex infections. J Infect Dis 1990; 162:299–305.
3. Cowan FM, Johnson AM, Ashley R, Corey L, Mindel A. Relationship between antibodies to herpes simplex virus (HSV) and symptoms of HSV infection. J Infect Dis 1996; 174:470–475.
4. Koutsky LA, Ashley RL, Holmes KK, et al. The frequency of unrecognized type 2 herpes simplex virus infection among women. Sex Transm Dis 1990; 17:90–94.
5. Langenberg A, Benedetti J, Jenkins J, Ashley R, Winter C, Corey L. Development of clinically recognizable genital lesions among women previously identified as having “asymptomatic” herpes simplex virus type 2 infection. Ann Intern Med 1989; 110:882–887.
6. Mertz GJ, Schmidt O, Jourden JL, et al. Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm Dis 1985; 12:33–39.
7. 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.
8. Rooney JJ, Felser JM, Ostrove JM, Straus SE. Acquisition of genital herpes from an asymptomatic sexual partner. N Engl J Med 1986; 314:1561–1564.
9. Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994; 121:847–854.
10. Roizman B, Sears AE. Herpes viruses and their replication. In: Fields Virology. 3rd ed. Fields BN, Knipe DM, Mowley PM, et al., eds. Philadelphia: Lippincott-Raven Publishers, 1996:2231–2295.
11. Koelle DM, Benedetti J, Langenberg A, Corey L. Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes. Ann Intern Med 1992; 116:433–437.
12. Benedetti JK, Zeh J, Selke S, Corey L. Frequency and reactivation of nongenital lesions among patients with genital herpes simplex virus. Am J Med 1995; 98:237–242.
13. Ashley RL. Laboratory techniques in the diagnosis of herpes simplex infection. Genitourin Med 1993; 69:174–183.
14. Ashley R, Cent A, Maggs V, Nahmias A, Corey L. Inability of enzyme immunoassays to discriminate between infections with herpes simplex virus types 1 and 2. Ann Intern Med 1991; 115:520–526.
15. Ashley RL, Corey L. Effect of acyclovir treatment of primary genital herpes on the antibody response to herpes simplex virus. J Clin Invest 1984; 73:681–688.
16. Ashley RL, Dalessio J, Burchett S, et al. Herpes simplex virus-2 (HSV-2) type-specific antibody correlates of protection in infants exposed to HSV-2 at birth. J Clin Invest 1992; 90:511–514.
17. Bernstein DI, Lovett MA, Bryson YJ. Serologic analysis of first-episode non-primary genital herpes simplex infections. Am J Med 1984; 77:1055–1060.
18. Lafferty WE, Krofft S, Remington M, et al. Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence Population. J Clin Microbiol 1987; 25:323–326.
19. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983; 98:958–972.