HERPES SIMPLEX VIRUSES (HSV), members of α-herpesviruses, are common human pathogens. HSV-1 is the main cause of orolabial infections and HSV-2 is most commonly associated with anogenital infections. However, during recent years, an increase in the number of genital herpes infections caused by HSV-1 has been reported in some European countries.1–5 In this respect, we wanted to analyze whether a similar trend is detectable among sexually transmitted disease (STD) clinic patients in southwestern Finland.
Materials and Methods
Patients and Methods
The Department of Venereological Diseases at Turku University Central Hospital has offered venereologic services for decades. Approximately 250,000 persons reside in the metropolitan area that the STD clinic served. Patients seek medical STD attention free of charge without referrals on weekdays. In most cases, the patients visit the Venereological Department during the first symptomatic episode of suspected genital herpes, e.g., blisters or ulcers in the genital region. Virus culture is performed from all patients with this clinical diagnosis only on their first symptomatic visit to confirm the viral etiology of the disease. Virus culture was performed from over 1100 patients from the genital lesions during 1994–2002. There were no changes in laboratory collection of specimens or virus culture techniques during the study period.
The samples for virus cultures were taken of suspected genital herpes lesions by sterile cotton swabs, which were placed in vials containing 2 mL viral transport medium (5% tryptone phosphate broth, 0.5% bovine serum albumin, and antibiotics in phosphate-buffered saline). The samples were stored at +4°C overnight and transported to the virus laboratory, where the inoculation of the samples was performed on the same day.
A rapid virus culture method was used as described earlier.6 Briefly, virus cultures were performed in human diploid foreskin fibroblasts in 24-well cell cluster dishes. After inoculation of the samples (200 μL) in duplicate cells, the plates were incubated overnight at +37°C, washed, and HRPO-labeled monoclonal antibodies against HSV-1 or HSV-2 were added. After 1 hour, incubation cells were washed and a substrate solution of containing 3-amino-9-ethylcarbazole was added. The color reaction was developed by 3% hydrogen peroxidase and virus-infected cells were examined under a light microscope.
Comparison of trends between the periods were made using chi-squared test for prevalence and by t-test for age.
Altogether, 30,499 patients attended the STD clinic during years 1994–2002 (Table 1). A total of 59.2% of the patients were male and 40.8% female. The proportion of female patients increased during the study period from 36.2% in 1994 to 48.8% in 2002. Altogether, 3245 female patients attended the clinic during the first cohort (1994–1996) and 5328 during 2000–2002. The increase of female patients between these 2 cohorts was 1.64-fold. The numbers of male patients were 5619 and 6439, respectively, thus showing only a 1.15-fold increase. There were moderate decreases in the mean ages of the male (29.9–28.8 years) and female (27.4–26.0 years) patients between the 1994–1996 and the 2000–2002 cohorts.
Over 1100 patients with a clinical diagnosis of genital herpes were tested by rapid virus culture. HSV was cultivated from 617 patients. The proportion of HSV-positive cultures from STD clinic attendees with genital herpes varied annually, being lowest (55 [1.5%]) in 2001 and highest (83 [2.9%]) in 1994.
The ages, genders, and proportions of HSV-1 and HSV-2 isolates in the whole study population are presented in Table 2. Of 617 samples, HSV-2 was typed in 79.3% (489 of 617) and HSV-1 in 20.7% (128 of 617). The annual percentages for HSV-2 ranged from 67.3% in 2001 to 84.7% in 1999, and for HSV-1, 32.7% and 15.3%, respectively. The highest proportion of HSV-1-positive samples was found during the last 2 follow-up years (2001–2002). The proportion of HSV-1 infections increased from 18.7% (39 of 209) in 1994–1996 to 25.9% (52 of 201) in 2000–2002.
Most patients with genital herpes and laboratory confirmation were male. However, the proportion of HSV-positive female patients increased significantly in the cohort from the 3 last years (2000–2002) as compared with the cohort from the first 3 years (1994–1996) (P = 0.032, chi-squared test) (Table 2). This was mainly the result of an increase in patients with HSV-1 from the first (1994–1996) cohort to the 2000–2002 cohort (P = 0.0057, chi-squared test). The rise in the amount of detected female HSV-1 cases was 2.5-fold between these cohorts. There was no change in male to female proportions in HSV-2 patient group.
The mean ages of the HSV-positive patients in the 9 study years are presented separately in Figure 1. The mean age of the HSV-1-positive patients in the 2000–2002 cohort was lower than that of the patients in the 1994–1996 cohort (P = 0.0017).
The mean ages of the patients grouped by gender and HSV type during 1994–1996 and 2000–2002 are shown in Figure 2. Patients with HSV-1 infection were younger than patients with HSV-2 infection. A significant decrease from 29.3 to 24.1 years (P = 0.023 t-test) in the mean age of the male patients with HSV-1 in the 1994–96 cohort compared with the 2000–2002 cohort was detected. No significant change in the mean age of HSV-1-infected women was seen.
No significant changes were seen in the mean ages of the patients with HSV-2 infection. The ages of the patients with HSV-2 display a wide range and consequently large standard deviation, whereas the variation in the ages of patients with HSV-1 is small in the last (2000–2002) cohort.
HSV-2 is the dominant agent of genital herpes infections. The proportion of HSV-1 in genital infections varies, but an increase in genital HSV-1 infections has been recognized in Europe as mentioned, and in the United States,7 especially in young women. Accordingly, our study shows a clear increase in the amount of genital infections caused by HSV-1 in a Finnish STD population during the latest 3-year follow-up period of our study.
The overall annual numbers of genital herpes patients in our STD clinic were relatively constant. An increase in the amount of female patients, especially young females, in our STD clinic has been found during the 9-years study period. A clear increase in female HSV-1 cases was seen between the first and third years cohort, indicating that HSV-1 is indeed more commonly associated with genital herpes infections among females than previously. No fundamental changes in medical services have taken place in our city. The increase in the amount of HSV-1 cases may be in part the result of the clear increase in the number of the partners of female attendees in our STD clinic during the study period (personal observation).
Overall, a decrease in the age of HSV-1-positive patients attending our clinic was detected. According to recent data, primary orolabial HSV infection is acquired later than earlier,8,9 which gives rise to a young population susceptible to a genital HSV infection as their primary HSV infection. In a recent study comparing 8 European countries, the lowest HSV-1 seropositivity (52.4%) was measured in Finland.10 In the same study, it was shown that of these countries, the median age of acquisition of HSV-1 was highest, over 25 years, in Finland. In accordance, the prevalence of HSV-1 antibodies in children has been shown to be low in our region.11 Pre-existing HSV antibodies are known to diminish the severity of the acquired genital herpes infection, even preventing transmission.12–14
In particular, the age of male patients with HSV-1 genital infections decreased and was 24 years in the last cohort. One explanation might be that the number of sexual partners of female clients had increased and the use of condoms had decreased as discovered in the patient interviews.
The cause for a change in HSV-1/HSV-2 ratio in genital herpes has been discussed to be partly to be the result of changed sexual behavior. Oral sex may partly explain the increase in HSV-1 genital herpes infections.15,16 Consequently, early age of first intercourse has been associated with genital HSV-1 infection.17
The natural history of genital HSV-1 infection is thought to be more favorable than of HSV-2 infection. Genital HSV-1 has less frequent clinical recurrences and less frequent subclinical shedding, but the clinical course of primary genital HSV-1 infection is similar to the course of primary genital HSV-2 infection.18–21 Sex education should emphasize the risk of subclinical HSV infection and the risk of virus acquisition in oral sex.22
In conclusion, our study in a Finnish STD population shows an increase in HSV-1 infections in young females and a decrease of mean age of male patients with HSV-1. The data collected most recently clearly indicate that genital herpes is a HSV-1 disease of young adults, whereas genital herpes caused by HSV-2 is seen with a wide range of age. Although our study consists of clients of a STD clinic, the findings most obviously reflect the ongoing changes in viral pattern and sexual habits in young people in our country in general.
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