*Department of Microbiology, Rabin Medical Center, Beilinson Campus, Petah Tikva, and the †Infectious Diseases Unit, Wolfson Hospital, Holon, Israel
Reprint requests: Michael Dan, MD, the E. Wolfson Hospital, Holon 58100, Israel. E-mail: firstname.lastname@example.org
Received January 7, 2003,
revised April 4, 2003, and accepted April 7, 2003.
Background and Goal: The changing epidemiology of genital herpes with the increasing importance of herpes simplex virus (HSV) type 1 prompted a study on the relative prevalence of HSV-1 and HSV-2 among cases of genital herpes in the Tel Aviv area, Israel.
Study Design: A retrospective laboratory-based study of positive genital and nongenital herpes cultures performed at the Beilinson Medical Center between 1993 and 2002. Data regarding the number of isolates of each type and the age and sex of patients with genital lesions were retrieved from the database. Cultures were performed using Vero cells, and positive results were confirmed and typed by immunofluorescence
Results: A total of 285 positive genital cultures and 659 positive nongenital cultures were recorded. HSV-1 was identified in 189 (66.3%) of the positive genital specimens and in 656 (99.55%) of the nongenital specimens. HSV-1 was isolated in 174 of 262 (66.4%) female subjects and 15 of 23 (65.2%) male subjects. The proportion of HSV-1 genital isolates was 72.7% in patients 15 to 24 years of age, 62% in those 25 to 44 years, and 46% in those aged 45 years or older. Overall, the annual isolation rate of genital HSV-1 has not changed markedly over the years.
Conclusion: Herpes simplex virus type 1 has clearly been the predominant HSV type isolated from genital specimens in the Tel Aviv area over the last decade.
HERPES SIMPLEX VIRUS (HSV) types 1 and 2 are closely related α-herpesviruses with a gram-positive cocci content of 68% and 69%, respectively, and a substantial overall DNA and protein homology. 1 The dominant associations between HSV-1 and orolabial herpes and between HSV-2 and genital herpes have been well known for some time. According to a report from Seattle, HSV-2 accounted for more than 90% of the genital herpes cases in the early 1980s. 2 However, at the same time a different trend has emerged in other parts of the world. In a Japanese study performed in a small group of women in the mid-1970s, HSV-1 was detected in 53.8% (7/13) of patients with positive genital cultures. 3 In a number of British studies from the same period, 40% to 79% of the genital isolates were identified as HSV-1. 4–6 More recently, the increasingly important role of HSV-1 in the etiology of genital herpes was demonstrated in North America and Europe. In Kentucky, 44.8% of the female patients with the condition developed HSV-1 by 1999 7; in Nova Scotia, 54% of the genital isolates in 1998 to 2001 were HSV-1. 8 In a university student health service in Wisconsin, the proportion of HSV-1 genital isolates increased from 29% in 1993 to 78% in 2001. 9 A Swedish study reported identification of HSV-1 in 43% and 64% of positive genital cultures in patients with first clinical episode of genital herpes and in those with primary infection, respectively, from 1995 to 1999. 10 In Bergen, Norway, 51% of women with a first episode of genital herpes in 1996 to 1998 developed HSV-1. 11
Most of the studies that have investigated the proportion of HSV-1 and HSV-2 in cases of genital herpes have been conducted in highly developed countries, and it was suggested that the shift toward HSV-1 infection might be due the declining rates of HSV-1 acquisition during childhood. 11 Very little information on this issue is available from other, less industrialized countries. 12 The objective of the current study was to examine the relative contribution of the two HSV types to genital herpes in Israel.
The results of all genital and nongenital herpes cultures performed at the department of microbiology of the Beilinson Hospital between 1993 and 2002 were examined. The number of positive cultures, the number of isolates of each type, and the age and sex of patients with genital lesions were retrieved from the laboratory database. Lesions were sampled with Dacron swabs and placed in 2 ml of virus transport medium (Venturi Transystem transport swab; Copan Diagnostics, Inc, Corona, CA). The specimens were inoculated on a monolayer of Vero cells and incubated at 35°C with 5% carbon dioxide. Cultures were examined daily for cytopathic effects during seven days, and were usually observed after 2 to 3 days of incubation. All isolates were confirmed and typed using monoclonal antibodies against HSV-1 and HSV-2 (PathoDx, Diagnostic Products Corporation, Los Angeles, CA). Each isolate represents a single patient.
During the study period, 659 positive nongenital cultures and 285 positive genital cultures were recorded. HSV-1 was identified in 656 (99.55%) of the positive nongenital specimens and in 189 (66.3%) of the positive genital specimens. Almost half (46.7%) of the patients with positive nongenital cultures were aged 15 years or older; all three cases of HSV-2 isolates were neonates (in no case was HSV-1 isolated from a neonate). Patients with positive genital cultures included 262 (91.9%) women and 23 (8.1%) men. HSV-1 was isolated in 174 of 262 (66.4%) female subjects and 15 of 23 (65.2%) male subjects. The distribution of HSV-1 and HSV-2 isolates among different age groups is shown in Table 1. The proportion of HSV-1 isolates declined with increasing patient age (P = 0.05, chi-square test). The repartition of the two HSV types over the study period is shown in Figure 1. The proportion of HSV-1 isolates oscillated annually between 47.6% and 75%, with no particular trend.
The current study has documented the predominant role of HSV-1 in the etiology of genital herpes in the Tel Aviv area during the 1993 to 2002 period. However, HSV-2 was rarely isolated from nongenital lesions. The only previous attempt to document the involvement of the two herpes types in genital lesions in Israel dates back to the 1970s. Out of 26 genital isolates, 24 (92%) were HSV-2 and 2 (8%) were HSV-1. 13 The high and rising proportion of HSV-1 genital lesions has been attributed to an increasing frequency of orogenital sex and perhaps to a declining incidence of HSV-1 infection in childhood. HSV-1 infection rates in children declined in the industrialized world during the 1950s and 1960s as a result of improved personal hygiene standards. Serologic surveys from the United Kingdom indicated that infection with HSV-1 was almost universal by the onset of adulthood during the 1940s, but had decreased to only 40% of adults by the 1960s. 14 In a survey of a small group of Israeli adolescents in 1998 to 1999, the prevalence of anti–HSV-1 antibodies was 45.7% in persons aged 11 to 14 years (35 tested), 53.8% in persons 15 to 17 years (39 tested), and 60.2% among 18- to 21-year-olds (171 tested). 15 Consequently, many Israeli youth enter the age of sexual activity with no HSV-1 antibodies, and constitute a reservoir of potential candidates for genital HSV-1 infection.
Orogenital sex has been gaining popularity, particularly among teenagers, because it cannot result in unwanted pregnancy and is believed not to transmit sexually transmitted diseases. 16 Lowhagen et al. 10 found a significant correlation between being infected with HSV-1 and having orogenital sex and a partner with a history of labial herpes. In another study, receptive oral sex in the preceding 2 months significantly increased the odds that the initial infections were HSV-1 rather than HSV-2. 17 However, if orogenital sex does play an important role in the sexual transmission of HSV, one should expect an increase in the isolation rate of HSV-2 from orolabial lesions. There is no clear evidence for such a trend. 18 However, in a recent report from Germany, 19 3 out of 18 persons with a positive HSV polymerase chain reaction result from a specimen taken at the orolabial site were found to shed HSV-2, suggesting that orolabial HSV-2 infection might be mostly asymptomatic.
Several studies have demonstrated an inverse relationship between the isolation rate of HSV-1 from genital lesions and the age of patients. 8–11 This trend was also observed in the current study, with the proportion of HSV-1 being significantly higher in persons aged 15 to 24 years than in those 45 years or older. Because recurrent clinical episodes and subclinical viral shedding are far less common in patients with genital HSV-1 than in those with HSV-2 infection, the proportion of HSV-1 isolates in primary lesions is significantly higher than that in recurrent episodes. 11,17 This issue was not examined in the current study because information regarding the stage of the sampled lesions was not available; nevertheless, it is likely that most of the isolates were derived from initial cases. Lafferty et al. 17 found that the proportion of HSV-1 among initial genital herpes infections was higher among men who have sex with men (46.9%) than among heterosexual men (14.6%). The retrospective design of our study did not allow us to obtain information regarding the sexual orientation and sexual practices of the patients who were tested. The overrepresentation of the female sex in the study population is most likely a result of the increased concern to diagnose the condition in women because of the potential obstetrical repercussions of an untreated infection.
The rising proportion of genital herpes due to HSV-1 may have some positive consequences. As mentioned previously, persons with genital HSV-1 infection have far fewer symptomatic recurrences and much less subclinical shedding than those with HSV-2 (approximately 0.02 and 0.33 per month, respectively), 20,21 so that genital HSV-1 infection is a lesser concern clinically and socially than HSV-2. Also, because of the same reasons, it was assumed that HSV-1 might be associated with fewer neonatal complications than HSV-2. However, a recent study 22 showed that the rate of transmission of HSV from mother to infant was higher when HSV-1 was isolated at delivery (31.1%) compared with HSV-2 (2.7%). Because of the higher sensitivity of HSV-1 to acyclovir and a lower rate of acute and long-term neurologic sequelae, the overall outcome of neonatal HSV-1 infections seems to be better than that of cases caused by HSV-2. 23
The concept that HSV-1 causes infection “above the waist” (orolabial herpes) and that HSV-2 causes infection “below the waist: (genital herpes) is no longer relevant. HSV-1 is, at present, the leading cause of genital herpes in many parts of the world. Consequently, seroprevalence studies that use HSV-2 type-specific assays significantly underestimate the incidence and prevalence of genital HSV infection
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