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A prospective study of herpes simplex virus infection in a defined population in Houston, Texas
A prospective study of herpes simplex virus infection in a defined population in Houston, Texas Karen Adler-Storthz, Ph.D., Gordon R. Dreesman, Ph.D., Raymond H. Kaufman, M.D., Joseph L. Melnick, Ph.D., and Ervin Adam, M.D. Houston, Texas A seroepidemiologic study was conducted to determine the incidence of antibodies to herpes simplex virus in a population of middle-class Caucasian women. In utero exposure to diethylstilbestrol did not influence the frequency of herpes simplex virus infection. The frequency of infection increased with age and number of sex partners and a 50% increase in incidence of herpes simplex virus type 2 infection was noted during the 4-year period of the study. Subclinical herpes simplex virus type 2 infections apparently occurred in some women without preexisting antibodies to herpes simplex virus type 1. (AM J 0BSTET GVNECOL 1985;151 :582-6.)
Key words: Herpes simplex virus, infection, serology, epidemiology
Herpes simplex VIruS type 1 (HSV-l) and type 2 (HSV-2) cause a spectrum of clinical diseases. HSV-2 is responsible for one of the most common venereally transmitted infections and HSV-l has been isolated from a large number of cases of genital HSV infection. ,·8 On the basis of seroepidemiologic studies, the incidence of HSV infection varies from population to population depending on age, race, socioeconomic status, and sexual practices. This study presents serologic data concerning the incidence of HSV infection in a population of middle-class Caucasian women as determined by a solid-phase microradioimmunoassay for detection of type-specific antibody to HSV. The specific aims of the stl'dy were: (1) to determine the prevalence of antibodies to HSV-l and HSV-2 at the time of enrollment, (2) to study the development of antibodies to HSV-l and HSV~2 during a follow-up period, and (3) to compare prospectively the presence of antibodies with history of oral and/or genital HSV infection.
Material and methods Population studied. Women included in the study were participants in the diethylstilbestrol adenosis (DESAD) program in Houston, Texas who agreed to participate in a serologic study of HSV infections. There From the Department of Virology and Epidemiology and the Department of Obstetrics and Gynecology, Baylor College of Medicine, Texas Medical Center. Supported in part by National Research Service Award CA09197 from the National Institutes of Health and by Grants 5-R01-HD10989-01/103 and N01-CN-45092, National Institutes of Health, Department of Health, Education, and Welfare. Received for publication April 23 , 1984; revised September 17, 1984; accepted October 15, 1984. Reprint requests: Ervin Adam, M.D., Department of Obstetrics and Gynecology, Baylor College of Medicine, Texas Medical Center, Houston, TX 77030.
582
were three groups studied: (1) women who were invited to participate in the DESAD study after review of their mothers' records (record review group), (2) women who were referred by other physicians or who initiated their enrollment because they knew about their previous exposure to diethylstilbestrol (walk-ins and referrals), and (3) women who were matched to the record review group by age and by their mothers' ages and who were not exposed to diethylstilbestrol according to the same record source. The mean ages of the groups at enrollment were 22, 21, and 21 years, respectively. All women were middle-class Caucasians. Serum samples and a history of clinically manifest oral and/or genital infection with HSV were obtained during each visit. Assay for antibodies to HSV -1 and HSV -2. Sera were stored at - 20° C. The presence of type-specific antiHSV antibodies was determined by a solid-phase rriicroradioimmunoassay.9.10 The antigens used were the major glycoprotein antigens VP123 for HSV-l and VP119 for HSV-2. All sera were tested at a 1: 10 dilution and iodine 125-labeled goat IgG antihuman IgG was used as the probe. Statistical analysis. The significance of differences between groups was determined by the X2 test. For cells numbered <6, Fisher's Exact Test was used.
Results Table I presents data on the incidence of antibodies to HSV major glycoprotein antigens in both diethylstilbestrol-exposed and unexposed women. The enrollment serum sample was tested for each woman. Of the women exposed to diethylstilbestrol, the walk-in and referral groups had significantly more women (57%) with vaginal epithelial changes than did the rec-
Herpes simplex virus infection
Volume 151 Number 5
Table I. Antibodies to HSV by cohort Exposed to diethylstilbestrol Walk-ins and referrals Antibodies toHSV
Type 1 Type 2 No. of women examined
Unexposed, record reviews
>
50
0
40
II> :J: I-
Zll> ......
::;;:-
Record reviews
0°
3:~
.... Oz
;::::
n
16 5 54
I
%*
n
I %*
30
33
38
9
10
9
88
n
%*
29 14
33
HSV-1
0
HSV-2
30 20
fI'.
i!' 10
~
16
~19
88
20-22
~23
AGE I N YEARS
Fig. 1. Prevalence of antibodies to HSV by age.
*Percent of column.
ord review group (10%, p < 0.001). Of the women exposed to diethylstilbestrol, those with vaginal epithelial changes did not differ significantly from those with no changes with respect to frequency of antibodies to HSV; therefore, these two categories were pooled in the table. There was no significant difference in the frequency of antibodies to HSV-I or HSV-2 between the diethylstilbestrol-exposed groups. In the unexposed group, 33% of the women had antibodies to HSV-l and 16% to HSV-2. These values were not significantly different from those of the diethylstilbestrolexposed groups; therefore, all women were subsequently pooled for antibody studies in relation to age, history of HSV, and number of sex partners. When all women were pooled, 28 (12%) had antibodies to HSV2 and 78 (34%) had antibodies to HSV-l. The prevalence of antibodies to HSV by age is shown in Fig. I. The percentage of women in the ~ 19 age group with antibodies to HSV -1 was higher than, but not significantly different from, those in the other two groups. As expected, the frequency of antibodies to HSV-2 increased with age. There was a significant difference between HSV -2 antibody frequency between the ~19 age group and the :;;.23 age group (5% versus 17%, p = 0.04). Fig. 2 presents the prevalence of antibodies to HSV by number of sex partners. While the percentage of women with antibodies to HSV-l remained fairly constant as the number of sex partners increased, there was an increase in frequency of antibodies to HSV-2. The frequency of antibodies to HSV-2 in women with four or more sex partners was significantly higher than that of women who were virgins (3% versus 22%, p = 0.02) and that of women with one sex partner (8% versus 22%, p = 0.04). The presence of antibodies to HSV-2 in the one virgin was confirmed by microneutralization. Eighty-nine of 213 women (42%) had one or more new sex partners after 1 year in the study and 50 of the 89 (56%) had two or more (Table II). There was an increasing trend of incidence of antibodies to HSV -2 over time in all groups. The women with an
~
583
~ HSV-1
o
> 50 II> :J:
oI - 40
HSV-2
ZVl
~;g 30
;;:g u.. ;:::: Oz
20
~
i!: 10
~
o NUMBER
Fig. 2. Prevalence of antibodies to HSV by number of sex partners.
increase of two or more sex partners had a significantly higher frequency of antibodies to HSV-2 in the second serum sample than those with no change in the number of sex partners (14% versus 30%, p = 0.02). The data in Table III correlate the history of HSV infection with the prevalence of antibodies to HSV at the time of enrollment. Of the women with no HSV history (71 %), 29% had antibodies to at least one of the HSV types and 8% had antibodies to HSV-2. Of 28 women with detectable antibodies to HSV -2, only eight (29%) reported a history of genital infection. Antibodies to HSV were not detected in 41 % of the women who had a history of oral HSV infection. Changes in history of HSV infection with time were correlated with antibodies to HSV in the follow-up specimen (Table IV). Twenty women reported a new history of HSV infection after :;;.12 months in the study. Of the six with new oral infections, five had no change in antibody and one lost detectable antibody to HSV1. Two of 12 women who reported new genital HSV infections had new antibody to HSV-2 only; one, to HSV-l only; and one, to HSV-l and HSV-2. One woman with previous antibodies to HSV -1 developed antibodies to HSV -2. Two women had antibody to HSV-2 in the first and second sera but reported genital infection only at the follow-up visit. The other five reporting new genital infections had no antibody to HSV in either serum sample. Two women reported new oral
584 Adler-Storthz et al.
March 1, 1985
Am J Obstet
Gynecol
Table II. Incidence of antibodies to HSV by increase in number of sex partners during the time period studied in 213 women Antibodies to HSV
Increase in sex partners with time
No increase
HSV-I and HSV-2
HSV-Ionly Serum sample*
I
%t
n
34
36 34
7 8 5 6 5
n
A B A B
38
8 9
33 38
A
12
B
II
34 42
I
%+
HSV-2 only
None
3 9 I 2 3 5
76 73 25 22 30 24
8 I4
15 21 16 30
10
Total pairs of samples
124 39 50
*A = Enrollment sample; B = follow-up sample;;" 12 months after enrollment. tPercent of all with antibodies to HSV-I including those with antibodies to both types of HSV. tPercent of all with antibodies to HSV-2 including those with antibodies to both types of HSV.
Table III. Correlation of history with antibody prevalence History of clinical HSV infection
Oral
None Antibodies
HSV-Ionly HSV-2 only HSV-I and HSV-2 None Total
I
I
Oral and genital
Genital
%
n
34 7 7
21* 4 4
23 6
12
115 163
71 71t
20 49
41 21
n
Total
I
%
n
47
4 34 5 16
%
n
I
25 19 25
%
.
50
n
%
61
27 5 7
II
17
31 7
I 2
141 230
50 I
61
*Percent of column. tPercent of row.
Table IV. Changes in antibodies to HSV during the time period studied Antibodies to HSV in second sample New history of HSV infection
Oral
Genital Oral and genital None
No. of women
Antibodies to HSV in enrollment sample
6
HSV-Ionly HSV-2 only HSV-I and HSV-2 None HSV-I only HSV-2 only None None HSV-Ionly None
12 2 19
and genital infections but had no antibodies to HSV in either serum sample. Nineteen women did not report a new history of HSV infection but had serologic evidence of a new HSV infection; 15 of these did not have detectable antibodies to HSV in the enrollment serum sample but had newly detectable antibodies to HSV at the follow-up visit. Five had new antibodies to HSV-l
HSV-I only
1
HSV-2 only
I
HSV-I and HSV-2
I
None
2 2 2 5
7
5 2 4 3
only; seven, to HSV-2 only; and three, to HSV-I and HSV-2. Thus, 10 of these women apparendy experienced a subclinical HSV-2 infection although they had no preexisting antibodies to HSV -1. Four women with preexisting antibodies to HSV -1 developed serologic evidence of subclinical HSV -2 infection. Fig. 3 shows the incidence of HSV infection over a
Herpes simplex virus infection
Volume 151 Number 5
period of 4 years. It is apparent from the slope of the lines, determined by linear regression analysis, that during the second year of the observational period the incidence of HSV -2 infection increased by 6% while that of HSV -1 infection was unchanged. Thereafter the increase was similar.
40 :I:
0 ....
...
V>
This seroepidemiologic study has described the frequency of HSV infection in a well-defined population of middle-class Caucasian women. The frequency of HSV infection has been correlated with diethylstilbestrol exposure, age, number of sex partners, and clinical history. Women exposed to diethylstilbestrol did not differ from the comparison group with respect to frequency of antibodies to HSV. The percentage of diethylstilbestrol-exposed women who develop vaginal epithelial changes reportedly varies from 34% to 65%." When we compared those women with vaginal epithelial changes to those with no changes for the presence of antibodies to HSV, we found no significant differences in frequency of antibodies to either HSV type. Therefore, neither exposure to diethylstilbestrol per se nor the presence of vaginal epithelial changes appeared to influence the frequency of HSV infection in this population. Our findings show that the frequency of HSV -2 infection increased with age while that of HSV -1 infection was fairly constant. Although the age groups in this study were different, other studies have reported similar age-related increases in the frequency of antibodies to HSV -2 as measured by the microneutralization test. 12. 13 Women with multiple sex partners were found to have a higher frequency of antibodies to HSV -2 than those with one sex partner or none. As the number of sex partners increased over time, so did the incidence of antibodies to HSV-2. This parallels the findings of other studies in that the frequency of genital HSV infection increases with increasing numbers of sex partners.13. 14 At the time of enrollment in the study, 12% of the women had antibodies to HSV-2. Vonka et al. 15 have recently reported a 15% frequency of antibodies to HSV -2 in a similar population of women. When the clinical history of HSV infection was correlated with the presence of antibody in the enrollment serum sample, 25% of the women reporting genital HSV infection had antibodies to HSV -1 only. This may be indicative of the increasing incidence of genital HSV -I infections. Five women reporting genital infections were antibody-negative, thus raising the possibilities of an incorrect clinical diagnosis or of a primary infection that may have been missed by our assay.1O Of these five, two
•
HSV-l
•
30
0
0
HSV-2
II)
z~
Comment
•
> V>
585
20
j!: ~
...z
::E :!: 0
-----
..---0-
0--- ---'
_0-
10
u..
0
#-
o
12-24
>25
TIME IN MONTHS AFTER ENROLLMENT
Fig. 3. Incidence of HSV infection by time.
women developed antibodies during the follow-up period, one to HSV -1 and one to HSV -2. This observation is compatible with the finding of late development of antibodies in some infected persons. Our findings suggest that subclinical genital infections with HSV -2 may occur even in the absence of preexisting antibodies to HSV -1. At the follow-up visit, 18 women had newly detectable antibodies to HSV-2; however, only four reported a new history of genital infection. Of the other 14, 10 did not have preexisting antibodies to HSV -1 but evidently experienced a subclinical infection. REFERENCES I. Kaufman RH, Gardner HL, Rawls WE, Dixon RE, Young
2.
3. 4. 5.
6. 7. 8.
9.
RL. Clinical features of herpes genitalis. Cancer Res 1973;33:1446. Kaufman RH, Adam E, Mirkovic RR, MelnickJL, Young RL. Treatment of genital herpes simplex virus infection with photodynamic inactivation. AM J OBSTET GYNECOL 1978; 132:861. Kawana T, Kawagoe K, Takizawa K, Chen JT, Kawasuchi T, Sakamoto S. Clinical and virologic studies on female genital herpes. Obstet Gynecol 1982;60:456. Peutherer J, Smith I, Robertson D. Genital infection with herpes simplex virus type I. J Infect 1982;4:33. Ozaki Y, Ishiguro T, Ohashi M, Kimura E. Relationship between antigenic type of virus and antibody response in female patients with herpes genitalis. J Med Virol 1980; 5:249. Ishiguro T, Ozaki Y, Matsunami M, Funakoshi S. Clinical and virological features of herpes genitalis in Japanese women. Acta Obstet Gynecol Scand 1982;61:173. Fife K, Schmidt 0, Remington M, Corey L. Primary and recurrent concomitant genital infection with herpes simplex virus types 1 and 2. J Infect Dis 1983;147:163. Kit S, Trkula D, Qavi H, et al. Sequential genital infections by herpes simplex virus types 1 and 2: restriction endonuclease analyses of viruses from recurrent infections. Sex Transm Dis 1983;10:67. Matson D, Adler-Storthz K, Adam E, Dreesman G. A micro solid-phase radioimmunoassay for detection of herpesvirus type-specific antibody: parameters involved in standardization. J Virol Methods 1983;6:71.
Adler-Storthz et al.
March 1, 1985 Am J Obstet Gynecol
10. Adler-Storthz K, Matson D, Adam E, Dreesman G. A micro solid-phase radioimmunoassay for detection of herpesvirus type-specific antibody: specificity and sensitivity. J Virol Methods 1983;6:85. 11. O'Brien PC, Noller KL, Robboy SJ, et al. Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis Project. Obstet Gynecol 1979;53:300. 12. Adam E, Kaufman RH, MelnickJL, Levy AH, Rawls WE. Seroepidemiologic studies of herpesvirus type 2 and carcinoma of the cervix. III. Houston, Texas. Am J EpidemioI1972;96:427.
13. Adam E, Rawls WE, Melnick JL. The association of herpesvirus type 2 infection and cervical cancer. Prev Med 1974;3: 122. 14. Josey WE, Nahmias AJ, Naib ZM. The epidemiology of type 2 (genital) herpes simplex virus infection. Obstet Gynecol Surv 1972;27(suppl):295. 15. Vonka V, Kanka J, Hirsch I, et al. Prospective study on the relationship between cervical neoplasia and herpes simrlex type-2 virus. II. Herpes simplex type-2 antibody presence in sera taken at enrollment. Int J Cancer 1984;33:44.
The effect of prostaglandin E2 on the initial immune response to herpes simplex virus infection David A. Baker, M.D., and Joanne Thomas Stony Brook, New York Numerous clinical situations, demonstrated to be associated with reactivation of herpes simplex virus infections, have also been shown to produce increases in local levels of prostaglandins. The current study was initiated to determine if prostaglandins playa role in the immune response and control of herpes simplex virus infections. Lymphocytes from volunteers were stimulated with concanavalin A, herpes simplex virus 1, or herpes simplex virus 2 in the presence of prostaglandin E2 or ibuprofen, and the lymphocytes served as their own controls. The data suggest a statistically significant suppression in nonspecific T cell mitogen stimulation (concanavalin A), as well as specific herpes simplex virus 1 and 2 stimulations as measured by tritiated thymidine uptake by lymphocytes when stimulated in the presence of prostaglandin E2 • Ibuprofen did not alter the proliferative response to concanavalin A, herpes simplex virus 1, or herpes simplex virus 2 stimulation. This report examines the involvement of prostaglandins in herpesvirus infection such as the suppression of T cell function, allowing for a clinical recurrence. The usefulness of nonsteroidal antiinflammatory agents in the therapy of herpes simplex virus infections is also discussed. (AM J OBSTET GVNECOL 1985;151 :586-90.)
Key words: Prostaglandin E2 , herpesvirus infection, immune response The immune response to herpes simplex virus infections is complex and may differ in the primary and recurrent stages of the disease. Studies have suggested that the cell-mediated immune response is important in controlling and limiting herpes simplex virus. I A significant increase in recurrent disease with significant mortality and morbidity seems to occur when patients are treated with immunosuppresive agents! From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Health Sciences Center, State University of New York at Stony Brook. Supported in part by Biomedical Research Support Grant No. 2S07RR0573609 and by The Upjohn Co., Kalamazoo, Michigan. Presented in part at the Thirtieth Annual Meeting of the Society for Gynecologic Investigation, Washington, D. C., March 17-20, 1983. Received for publication October 27, 1983; revised July 16, 1984; accepted October 2, 1984. Reprint requests: David A. Baker, M.D., Department of Obstetrics and Gynecology, State University of New York at Stony Brook, Stony Brook, NY 11794.
586
Within a clinical setting in an intact host, certain situations provoke reactivation of latent herpes. In women the most frequent correlation is with the onset of menstruation, but other situations such as fever, exposure to sunlight, emotional stress, and surgical resection have all been associated with an increased incidence of reactivation of latent herpes within the body.' All of these specific clinical situations have also been associated with increased local levels of prostaglandins. In exploring the role of prostaglandins in herpesvirus infection, it must be noted that these agents have been shown to increase viral multiplication and cell-to-cell spread of herpes simplex virus in specific in vitro models. 4.5 Moreover, Blyth et al. 6 have produced a model in mice using herpes simplex virus 1 where reactivation of the virus was demonstrated after local inoculation of prostaglandin. The specific study was undertaken to determine what role prostaglandins play in the immune response and
Key words: Herpes simplex virus, infection, serology, epidemiology
Herpes simplex VIruS type 1 (HSV-l) and type 2 (HSV-2) cause a spectrum of clinical diseases. HSV-2 is responsible for one of the most common venereally transmitted infections and HSV-l has been isolated from a large number of cases of genital HSV infection. ,·8 On the basis of seroepidemiologic studies, the incidence of HSV infection varies from population to population depending on age, race, socioeconomic status, and sexual practices. This study presents serologic data concerning the incidence of HSV infection in a population of middle-class Caucasian women as determined by a solid-phase microradioimmunoassay for detection of type-specific antibody to HSV. The specific aims of the stl'dy were: (1) to determine the prevalence of antibodies to HSV-l and HSV-2 at the time of enrollment, (2) to study the development of antibodies to HSV-l and HSV~2 during a follow-up period, and (3) to compare prospectively the presence of antibodies with history of oral and/or genital HSV infection.
Material and methods Population studied. Women included in the study were participants in the diethylstilbestrol adenosis (DESAD) program in Houston, Texas who agreed to participate in a serologic study of HSV infections. There From the Department of Virology and Epidemiology and the Department of Obstetrics and Gynecology, Baylor College of Medicine, Texas Medical Center. Supported in part by National Research Service Award CA09197 from the National Institutes of Health and by Grants 5-R01-HD10989-01/103 and N01-CN-45092, National Institutes of Health, Department of Health, Education, and Welfare. Received for publication April 23 , 1984; revised September 17, 1984; accepted October 15, 1984. Reprint requests: Ervin Adam, M.D., Department of Obstetrics and Gynecology, Baylor College of Medicine, Texas Medical Center, Houston, TX 77030.
582
were three groups studied: (1) women who were invited to participate in the DESAD study after review of their mothers' records (record review group), (2) women who were referred by other physicians or who initiated their enrollment because they knew about their previous exposure to diethylstilbestrol (walk-ins and referrals), and (3) women who were matched to the record review group by age and by their mothers' ages and who were not exposed to diethylstilbestrol according to the same record source. The mean ages of the groups at enrollment were 22, 21, and 21 years, respectively. All women were middle-class Caucasians. Serum samples and a history of clinically manifest oral and/or genital infection with HSV were obtained during each visit. Assay for antibodies to HSV -1 and HSV -2. Sera were stored at - 20° C. The presence of type-specific antiHSV antibodies was determined by a solid-phase rriicroradioimmunoassay.9.10 The antigens used were the major glycoprotein antigens VP123 for HSV-l and VP119 for HSV-2. All sera were tested at a 1: 10 dilution and iodine 125-labeled goat IgG antihuman IgG was used as the probe. Statistical analysis. The significance of differences between groups was determined by the X2 test. For cells numbered <6, Fisher's Exact Test was used.
Results Table I presents data on the incidence of antibodies to HSV major glycoprotein antigens in both diethylstilbestrol-exposed and unexposed women. The enrollment serum sample was tested for each woman. Of the women exposed to diethylstilbestrol, the walk-in and referral groups had significantly more women (57%) with vaginal epithelial changes than did the rec-
Herpes simplex virus infection
Volume 151 Number 5
Table I. Antibodies to HSV by cohort Exposed to diethylstilbestrol Walk-ins and referrals Antibodies toHSV
Type 1 Type 2 No. of women examined
Unexposed, record reviews
>
50
0
40
II> :J: I-
Zll> ......
::;;:-
Record reviews
0°
3:~
.... Oz
;::::
n
16 5 54
I
%*
n
I %*
30
33
38
9
10
9
88
n
%*
29 14
33
HSV-1
0
HSV-2
30 20
fI'.
i!' 10
~
16
~19
88
20-22
~23
AGE I N YEARS
Fig. 1. Prevalence of antibodies to HSV by age.
*Percent of column.
ord review group (10%, p < 0.001). Of the women exposed to diethylstilbestrol, those with vaginal epithelial changes did not differ significantly from those with no changes with respect to frequency of antibodies to HSV; therefore, these two categories were pooled in the table. There was no significant difference in the frequency of antibodies to HSV-I or HSV-2 between the diethylstilbestrol-exposed groups. In the unexposed group, 33% of the women had antibodies to HSV-l and 16% to HSV-2. These values were not significantly different from those of the diethylstilbestrolexposed groups; therefore, all women were subsequently pooled for antibody studies in relation to age, history of HSV, and number of sex partners. When all women were pooled, 28 (12%) had antibodies to HSV2 and 78 (34%) had antibodies to HSV-l. The prevalence of antibodies to HSV by age is shown in Fig. I. The percentage of women in the ~ 19 age group with antibodies to HSV -1 was higher than, but not significantly different from, those in the other two groups. As expected, the frequency of antibodies to HSV-2 increased with age. There was a significant difference between HSV -2 antibody frequency between the ~19 age group and the :;;.23 age group (5% versus 17%, p = 0.04). Fig. 2 presents the prevalence of antibodies to HSV by number of sex partners. While the percentage of women with antibodies to HSV-l remained fairly constant as the number of sex partners increased, there was an increase in frequency of antibodies to HSV-2. The frequency of antibodies to HSV-2 in women with four or more sex partners was significantly higher than that of women who were virgins (3% versus 22%, p = 0.02) and that of women with one sex partner (8% versus 22%, p = 0.04). The presence of antibodies to HSV-2 in the one virgin was confirmed by microneutralization. Eighty-nine of 213 women (42%) had one or more new sex partners after 1 year in the study and 50 of the 89 (56%) had two or more (Table II). There was an increasing trend of incidence of antibodies to HSV -2 over time in all groups. The women with an
~
583
~ HSV-1
o
> 50 II> :J:
oI - 40
HSV-2
ZVl
~;g 30
;;:g u.. ;:::: Oz
20
~
i!: 10
~
o NUMBER
Fig. 2. Prevalence of antibodies to HSV by number of sex partners.
increase of two or more sex partners had a significantly higher frequency of antibodies to HSV-2 in the second serum sample than those with no change in the number of sex partners (14% versus 30%, p = 0.02). The data in Table III correlate the history of HSV infection with the prevalence of antibodies to HSV at the time of enrollment. Of the women with no HSV history (71 %), 29% had antibodies to at least one of the HSV types and 8% had antibodies to HSV-2. Of 28 women with detectable antibodies to HSV -2, only eight (29%) reported a history of genital infection. Antibodies to HSV were not detected in 41 % of the women who had a history of oral HSV infection. Changes in history of HSV infection with time were correlated with antibodies to HSV in the follow-up specimen (Table IV). Twenty women reported a new history of HSV infection after :;;.12 months in the study. Of the six with new oral infections, five had no change in antibody and one lost detectable antibody to HSV1. Two of 12 women who reported new genital HSV infections had new antibody to HSV-2 only; one, to HSV-l only; and one, to HSV-l and HSV-2. One woman with previous antibodies to HSV -1 developed antibodies to HSV -2. Two women had antibody to HSV-2 in the first and second sera but reported genital infection only at the follow-up visit. The other five reporting new genital infections had no antibody to HSV in either serum sample. Two women reported new oral
584 Adler-Storthz et al.
March 1, 1985
Am J Obstet
Gynecol
Table II. Incidence of antibodies to HSV by increase in number of sex partners during the time period studied in 213 women Antibodies to HSV
Increase in sex partners with time
No increase
HSV-I and HSV-2
HSV-Ionly Serum sample*
I
%t
n
34
36 34
7 8 5 6 5
n
A B A B
38
8 9
33 38
A
12
B
II
34 42
I
%+
HSV-2 only
None
3 9 I 2 3 5
76 73 25 22 30 24
8 I4
15 21 16 30
10
Total pairs of samples
124 39 50
*A = Enrollment sample; B = follow-up sample;;" 12 months after enrollment. tPercent of all with antibodies to HSV-I including those with antibodies to both types of HSV. tPercent of all with antibodies to HSV-2 including those with antibodies to both types of HSV.
Table III. Correlation of history with antibody prevalence History of clinical HSV infection
Oral
None Antibodies
HSV-Ionly HSV-2 only HSV-I and HSV-2 None Total
I
I
Oral and genital
Genital
%
n
34 7 7
21* 4 4
23 6
12
115 163
71 71t
20 49
41 21
n
Total
I
%
n
47
4 34 5 16
%
n
I
25 19 25
%
.
50
n
%
61
27 5 7
II
17
31 7
I 2
141 230
50 I
61
*Percent of column. tPercent of row.
Table IV. Changes in antibodies to HSV during the time period studied Antibodies to HSV in second sample New history of HSV infection
Oral
Genital Oral and genital None
No. of women
Antibodies to HSV in enrollment sample
6
HSV-Ionly HSV-2 only HSV-I and HSV-2 None HSV-I only HSV-2 only None None HSV-Ionly None
12 2 19
and genital infections but had no antibodies to HSV in either serum sample. Nineteen women did not report a new history of HSV infection but had serologic evidence of a new HSV infection; 15 of these did not have detectable antibodies to HSV in the enrollment serum sample but had newly detectable antibodies to HSV at the follow-up visit. Five had new antibodies to HSV-l
HSV-I only
1
HSV-2 only
I
HSV-I and HSV-2
I
None
2 2 2 5
7
5 2 4 3
only; seven, to HSV-2 only; and three, to HSV-I and HSV-2. Thus, 10 of these women apparendy experienced a subclinical HSV-2 infection although they had no preexisting antibodies to HSV -1. Four women with preexisting antibodies to HSV -1 developed serologic evidence of subclinical HSV -2 infection. Fig. 3 shows the incidence of HSV infection over a
Herpes simplex virus infection
Volume 151 Number 5
period of 4 years. It is apparent from the slope of the lines, determined by linear regression analysis, that during the second year of the observational period the incidence of HSV -2 infection increased by 6% while that of HSV -1 infection was unchanged. Thereafter the increase was similar.
40 :I:
0 ....
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This seroepidemiologic study has described the frequency of HSV infection in a well-defined population of middle-class Caucasian women. The frequency of HSV infection has been correlated with diethylstilbestrol exposure, age, number of sex partners, and clinical history. Women exposed to diethylstilbestrol did not differ from the comparison group with respect to frequency of antibodies to HSV. The percentage of diethylstilbestrol-exposed women who develop vaginal epithelial changes reportedly varies from 34% to 65%." When we compared those women with vaginal epithelial changes to those with no changes for the presence of antibodies to HSV, we found no significant differences in frequency of antibodies to either HSV type. Therefore, neither exposure to diethylstilbestrol per se nor the presence of vaginal epithelial changes appeared to influence the frequency of HSV infection in this population. Our findings show that the frequency of HSV -2 infection increased with age while that of HSV -1 infection was fairly constant. Although the age groups in this study were different, other studies have reported similar age-related increases in the frequency of antibodies to HSV -2 as measured by the microneutralization test. 12. 13 Women with multiple sex partners were found to have a higher frequency of antibodies to HSV -2 than those with one sex partner or none. As the number of sex partners increased over time, so did the incidence of antibodies to HSV-2. This parallels the findings of other studies in that the frequency of genital HSV infection increases with increasing numbers of sex partners.13. 14 At the time of enrollment in the study, 12% of the women had antibodies to HSV-2. Vonka et al. 15 have recently reported a 15% frequency of antibodies to HSV -2 in a similar population of women. When the clinical history of HSV infection was correlated with the presence of antibody in the enrollment serum sample, 25% of the women reporting genital HSV infection had antibodies to HSV -1 only. This may be indicative of the increasing incidence of genital HSV -I infections. Five women reporting genital infections were antibody-negative, thus raising the possibilities of an incorrect clinical diagnosis or of a primary infection that may have been missed by our assay.1O Of these five, two
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women developed antibodies during the follow-up period, one to HSV -1 and one to HSV -2. This observation is compatible with the finding of late development of antibodies in some infected persons. Our findings suggest that subclinical genital infections with HSV -2 may occur even in the absence of preexisting antibodies to HSV -1. At the follow-up visit, 18 women had newly detectable antibodies to HSV-2; however, only four reported a new history of genital infection. Of the other 14, 10 did not have preexisting antibodies to HSV -1 but evidently experienced a subclinical infection. REFERENCES I. Kaufman RH, Gardner HL, Rawls WE, Dixon RE, Young
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RL. Clinical features of herpes genitalis. Cancer Res 1973;33:1446. Kaufman RH, Adam E, Mirkovic RR, MelnickJL, Young RL. Treatment of genital herpes simplex virus infection with photodynamic inactivation. AM J OBSTET GYNECOL 1978; 132:861. Kawana T, Kawagoe K, Takizawa K, Chen JT, Kawasuchi T, Sakamoto S. Clinical and virologic studies on female genital herpes. Obstet Gynecol 1982;60:456. Peutherer J, Smith I, Robertson D. Genital infection with herpes simplex virus type I. J Infect 1982;4:33. Ozaki Y, Ishiguro T, Ohashi M, Kimura E. Relationship between antigenic type of virus and antibody response in female patients with herpes genitalis. J Med Virol 1980; 5:249. Ishiguro T, Ozaki Y, Matsunami M, Funakoshi S. Clinical and virological features of herpes genitalis in Japanese women. Acta Obstet Gynecol Scand 1982;61:173. Fife K, Schmidt 0, Remington M, Corey L. Primary and recurrent concomitant genital infection with herpes simplex virus types 1 and 2. J Infect Dis 1983;147:163. Kit S, Trkula D, Qavi H, et al. Sequential genital infections by herpes simplex virus types 1 and 2: restriction endonuclease analyses of viruses from recurrent infections. Sex Transm Dis 1983;10:67. Matson D, Adler-Storthz K, Adam E, Dreesman G. A micro solid-phase radioimmunoassay for detection of herpesvirus type-specific antibody: parameters involved in standardization. J Virol Methods 1983;6:71.
Adler-Storthz et al.
March 1, 1985 Am J Obstet Gynecol
10. Adler-Storthz K, Matson D, Adam E, Dreesman G. A micro solid-phase radioimmunoassay for detection of herpesvirus type-specific antibody: specificity and sensitivity. J Virol Methods 1983;6:85. 11. O'Brien PC, Noller KL, Robboy SJ, et al. Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis Project. Obstet Gynecol 1979;53:300. 12. Adam E, Kaufman RH, MelnickJL, Levy AH, Rawls WE. Seroepidemiologic studies of herpesvirus type 2 and carcinoma of the cervix. III. Houston, Texas. Am J EpidemioI1972;96:427.
13. Adam E, Rawls WE, Melnick JL. The association of herpesvirus type 2 infection and cervical cancer. Prev Med 1974;3: 122. 14. Josey WE, Nahmias AJ, Naib ZM. The epidemiology of type 2 (genital) herpes simplex virus infection. Obstet Gynecol Surv 1972;27(suppl):295. 15. Vonka V, Kanka J, Hirsch I, et al. Prospective study on the relationship between cervical neoplasia and herpes simrlex type-2 virus. II. Herpes simplex type-2 antibody presence in sera taken at enrollment. Int J Cancer 1984;33:44.
The effect of prostaglandin E2 on the initial immune response to herpes simplex virus infection David A. Baker, M.D., and Joanne Thomas Stony Brook, New York Numerous clinical situations, demonstrated to be associated with reactivation of herpes simplex virus infections, have also been shown to produce increases in local levels of prostaglandins. The current study was initiated to determine if prostaglandins playa role in the immune response and control of herpes simplex virus infections. Lymphocytes from volunteers were stimulated with concanavalin A, herpes simplex virus 1, or herpes simplex virus 2 in the presence of prostaglandin E2 or ibuprofen, and the lymphocytes served as their own controls. The data suggest a statistically significant suppression in nonspecific T cell mitogen stimulation (concanavalin A), as well as specific herpes simplex virus 1 and 2 stimulations as measured by tritiated thymidine uptake by lymphocytes when stimulated in the presence of prostaglandin E2 • Ibuprofen did not alter the proliferative response to concanavalin A, herpes simplex virus 1, or herpes simplex virus 2 stimulation. This report examines the involvement of prostaglandins in herpesvirus infection such as the suppression of T cell function, allowing for a clinical recurrence. The usefulness of nonsteroidal antiinflammatory agents in the therapy of herpes simplex virus infections is also discussed. (AM J OBSTET GVNECOL 1985;151 :586-90.)
Key words: Prostaglandin E2 , herpesvirus infection, immune response The immune response to herpes simplex virus infections is complex and may differ in the primary and recurrent stages of the disease. Studies have suggested that the cell-mediated immune response is important in controlling and limiting herpes simplex virus. I A significant increase in recurrent disease with significant mortality and morbidity seems to occur when patients are treated with immunosuppresive agents! From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Health Sciences Center, State University of New York at Stony Brook. Supported in part by Biomedical Research Support Grant No. 2S07RR0573609 and by The Upjohn Co., Kalamazoo, Michigan. Presented in part at the Thirtieth Annual Meeting of the Society for Gynecologic Investigation, Washington, D. C., March 17-20, 1983. Received for publication October 27, 1983; revised July 16, 1984; accepted October 2, 1984. Reprint requests: David A. Baker, M.D., Department of Obstetrics and Gynecology, State University of New York at Stony Brook, Stony Brook, NY 11794.
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Within a clinical setting in an intact host, certain situations provoke reactivation of latent herpes. In women the most frequent correlation is with the onset of menstruation, but other situations such as fever, exposure to sunlight, emotional stress, and surgical resection have all been associated with an increased incidence of reactivation of latent herpes within the body.' All of these specific clinical situations have also been associated with increased local levels of prostaglandins. In exploring the role of prostaglandins in herpesvirus infection, it must be noted that these agents have been shown to increase viral multiplication and cell-to-cell spread of herpes simplex virus in specific in vitro models. 4.5 Moreover, Blyth et al. 6 have produced a model in mice using herpes simplex virus 1 where reactivation of the virus was demonstrated after local inoculation of prostaglandin. The specific study was undertaken to determine what role prostaglandins play in the immune response and