Rhoda Ashley

The acquisition of herpes simplex virus during pregnancy.

BACKGROUND The acquisition of genital herpes during pregnancy has been associated with spontaneous abortion, prematurity, and congenital and neonatal herpes. The frequency of seroconversion, maternal symptoms of the disease, and the timing of its greatest effect on the outcome of pregnancy have not been systematically studied. METHODS We studied 7046 pregnant women whom serologic tests showed to be at risk for herpes simplex virus (HSV) infection. Serum samples obtained at the first prenatal visit, at approximately 16 and 24 weeks, and during labor were tested for antibodies to HSV types 1 and 2 (HSV-1 and HSV-2) by the Western blot assay, and the results were correlated with the occurrence of antenatal genital infections. RESULTS Ninety-four of the women became seropositive for HSV; 34 of the 94 women (36 percent) had symptoms consistent with herpes infection. Women who were initially seronegative for both HSV-1 and HSV-2 had an estimated chance of seroconversion for either virus of 3.7 percent; those who were initially seropositive only for HSV-1 had an estimated chance of HSV-2 seroconversion of 1.7 percent; and those who were initially HSV-2-seropositive had an estimated chance of zero for acquiring HSV-1 infection. Among the 60 of the 94 pregnancies for which the time of acquisition of HSV infection was known, 30 percent of the infections occurred in the first trimester, 30 percent in the second, and 40 percent in the third. HSV seroconversion completed by the time of labor was not associated with an increase in neonatal morbidity or with any cases of congenital herpes infection. However, among the infants born to nine women who acquired genital HSV infection shortly before labor, neonatal HSV infection occurred in four infants, of whom one died. CONCLUSIONS Two percent or more of susceptible women acquire HSV infection during pregnancy. Acquisition of infection with seroconversion completed before labor does not appear to affect the outcome of pregnancy, but infection acquired near the time of labor is associated with neonatal herpes and perinatal morbidity.

Reactivation of Genital Herpes Simplex Virus Type 2 Infection in Asymptomatic Seropositive Persons

BACKGROUND Most persons who have serologic evidence of infection with herpes simplex virus (HSV) type 2 (HSV-2) are asymptomatic. Historically, it has been assumed that these persons have less frequent viral reactivation than those with symptomatic infection. METHODS We conducted a prospective study to investigate genital shedding of HSV among 53 subjects who had antibodies to HSV-2 but who reported having no history of genital herpes, and we compared their patterns of viral shedding with those in a similar cohort of 90 subjects with symptomatic HSV-2 infection. Genital secretions of the subjects in both groups were sampled daily and cultured for HSV for a median of 94 days. RESULTS HSV was isolated from the genital mucosa in 38 of the 53 HSV-2-seropositive subjects (72 percent) who reported no history of genital herpes, and HSV DNA was detected by the polymerase-chain-reaction assay in cultures prepared from genital mucosal swabs in 6 additional subjects. The rate of subclinical shedding of HSV in the subjects with no reported history of genital herpes was similar to that in the subjects with such a history (3.0 percent vs. 2.7 percent). Of the 53 subjects who had no reported history of genital herpes, 33 (62 percent) subsequently reported having typical herpetic lesions; the duration of 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 in the 90 subjects with previously diagnosed symptomatic infection. Only 1 of these 53 subjects had no clinical or virologic evidence of HSV infection. CONCLUSIONS Seropositivity for HSV-2 is associated with viral shedding in the genital tract, even in subjects with no reported history of genital herpes.

Virologic Characteristics of Subclinical and Symptomatic Genital Herpes Infections

BACKGROUND The frequency, pattern, and anatomical sites of subclinical shedding of herpes simplex virus (HSV) in the genital tract, along with factors that predict such shedding, have not been well characterized. METHODS We studied prospectively the clinical and virologic course of genital herpes in 110 women. The women kept symptom diaries and provided daily samples from the vulva, cervix, and rectum for viral culture. RESULTS During a median follow-up of 105 days, subclinical shedding of virus was identified in 36 of 65 women (55 percent) with HSV type 2 (HSV-2), in 16 of 31 women (52 percent) with HSV type 1 (HSV-1) and HSV-2, and in 4 of 14 women (29 percent) with only HSV-1. Among women with genital HSV-2 infection, subclinical shedding occurred on a mean of 2 percent of the days. The mean duration of viral shedding during subclinical episodes was 1.5 days, as compared with 1.8 days during symptomatic episodes. HSV was isolated from several sites in the genital tract and rectum in 17 percent of subclinical episodes and 22 percent of symptomatic episodes. Half the episodes of subclinical shedding of HSV occurred within seven days of a symptomatic recurrence. The risk of subclinical shedding increased with the frequency of symptomatic recurrences. Subclinical shedding was more frequent among women with more than 12 recurrences per year than among those with no symptomatic recurrences (odds ratio, 3.3; 95 percent confidence interval, 1.4 to 7.9); it was also more frequent among women who had recently acquired genital herpes (odds ratio for women with HSV acquired in the past year as compared with those who had had the infection for a year or more, 1.85; 95 percent confidence interval, 1.1 to 3.1). CONCLUSIONS Among women with a history of genital herpes infection, subclinical shedding of HSV is common and accounts for nearly one third of the total days of reactivation of HSV infection in the genital tract. Women with frequent symptomatic recurrences also have frequent subclinical shedding and may be at high risk for transmitting HSV.

A Prospective Study of New Infections with Herpes Simplex Virus Type 1 and Type 2

BACKGROUND AND METHODS Herpes simplex virus (HSV) infections are endemic, but the clinical characteristics of newly acquired HSV type 1 (HSV-1) and HSV type 2 (HSV-2) infections in adults have not been rigorously defined. We monitored 2393 sexually active HSV-2-seronegative persons for clinical and serologic evidence of new HSV infection. Of the participants, 1508 were seropositive for HSV-1 and 885 were seronegative. Charts were reviewed in a blinded manner for classification of those with genitourinary or oropharyngeal symptoms. Charts were also reviewed for all 174 persons with HSV seroconversion. RESULTS The rates of new HSV-1 and HSV-2 infections were 1.6 and 5.1 cases per 100 person-years, respectively. Of the 155 new HSV-2 infections, 57 (37 percent) were symptomatic, 47 of which (82 percent) were correctly diagnosed at presentation. Among the 74 patients given a clinical diagnosis of genital HSV-2 during the study, 60 were given a correct diagnosis and 14 were given an incorrect diagnosis of genital herpes, for a ratio of true positive results to false positive results of 4:1. Among the 98 persons with asymptomatic HSV-2 seroconversion, 15 percent had genital lesions at some time during follow-up. Women were more likely than men to acquire HSV-2 (P<0.01) and to have symptomatic infection. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of asymptomatic seroconversion, as compared with symptomatic seroconversion, by a factor of 2.6 (P<0.001). Of the 19 new HSV-1 infections, 12 were symptomatic. The rates of symptomatic genital HSV-1 infection and oropharyngeal HSV-1 infection were the same (0.5 case per 100 person-years). CONCLUSIONS Nearly 40 percent of newly acquired HSV-2 infections and nearly two thirds of new HSV-1 infections are symptomatic. Among sexually active adults, new genital HSV-1 infections are as common as new oropharyngeal HSV-1 infections.

Risk Factors for the Sexual Transmission of Genital Herpes

OBJECTIVE To determine the risk of sexual transmission of genital herpes simplex virus (HSV) in heterosexual couples. DESIGN Prospective study of couples who were participants in a clinical trial. Each source partner had symptomatic, recurrent genital HSV, and each susceptible partner was without serologic or clinical evidence of genital herpes. Couples were followed for a median of 334 days. SETTING Two university-based research clinics. PATIENTS One hundred forty-four heterosexual couples were studied out of an initial enrollment of 214 couples. MAIN OUTCOME MEASURES Development of culture-proven HSV infection or type-specific antibodies in the susceptible partner. MAIN RESULTS Transmission occurred in 14 (9.7%) couples, including 11 (16.9%) of 65 couples with male and 3 (3.8%) of 79 with female source partners (P = 0.05). The annual rate of acquisition was higher (31.8%) in susceptible female partners who lacked antibodies to either HSV type 1 or 2 at entry compared with females with HSV type 1 antibodies at entry (9.1%). Couples avoiding transmission of HSV reported fewer days with genital lesions in source partners. Detailed histories were available at the time of transmission in 13 couples. In nine couples, transmission occurred when the source partner was reported to be asymptomatic and in four, it resulted from sexual contact at the time of prodrome (1 case) or within hours before lesions were first noticed by the source partner (3 cases). CONCLUSIONS Despite clear recognition of genital herpes in source partners, there was substantial risk for transmission; in 70% of patients, transmission appeared to result from sexual contact during periods of asymptomatic viral shedding. The risk for acquisition of HSV was higher in women than men, and previous HSV type 1 infection appeared to reduce the risk for acquisition of HSV type 2 infection among women.

Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor.

Abstract Background and Methods. To define the risk factors associated with neonatal acquisition of herpes simplex virus (HSV) infection, we prospectively obtained HSV cultures from the cervix and external genitalia of 15,923 pregnant women in early labor who were without symptoms or signs of genital HSV infection. Follow-up of the women with positive cultures for HSV and their HSV-exposed infants included serologic tests and serial cultures for HSV. Results. HSV was isolated from 56 of the women (0.35 percent), 18 of whom (35 percent) had serologic evidence of a recently acquired, subclinical first episode of genital HSV infection, and 34 of whom (65 percent) had reactivation of HSV. Neonatal HSV developed in 6 of 18 infants (33 percent) born to the women with a first episode of genital HSV, and in 1 of 34 infants (3 percent) born to the women with reactivation of HSV (P<0.01); neonatal HSV also occurred in three of the infants born to the 15,867 women with negative cultures. Neonatal HSV-2 occurred in 1...

Genital ulceration as a risk factor for human immunodeficiency virus infection

Among 115 heterosexual men who presented with genital ulcers to a sexually transmitted disease clinic in Nairobi, Kenya, the prevalence of serum antibody to HIV was 16.5%. A past history of genital ulcers was reported by 12 (63%) of 19 men with antibody to HIV versus 30 (31%) of 96 without antibody (P = 0.008). HIV infection was also positively associated with lack of circumcision, but was not associated with the etiology of the current genital ulcer. Logistic regression analysis (adjusted for age, number of recent sex partners, recent prostitute contact, circumcision, tribal ethnic identity, past history of urethritis, and current diagnoses) confirmed only the association between prior history of genital ulcer disease and HIV infection; (P = 0.04, odds ratio 2.35, 95% confidence limits, 1.01-5.47). The incidence of genital ulcers, particularly chancroid, is much higher in parts of Africa than in Europe or North America. This may contribute to the increased risk of heterosexual transmission of HIV in Africa. Aggressive control of chancroid and syphilis may offer one very feasible approach to reducing transmission of HIV in this region.

Recurrence Rates in Genital Herpes after Symptomatic First-Episode Infection

Genital herpes continues to be epidemic throughout most sexually active populations [1-4]. A recent serosurvey indicated that 21.7% of the U.S. population have HSV-2 antibodies, which represents a 31% increase in prevalence in the last decade [5, 6]. The seroprevalence of HSV-2 averages 30% in most family practice and obstetrics clinics and 30% to 50% among sexually transmitted disease clinic attendees. Seroprevalence is consistently higher in women than in men [7, 8]. The natural history of HSV infection includes acute or subclinical first-episode mucocutaneous infection, establishment of neuronal latency, and intermittent virus reactivation with or without associated recurrent symptoms [9, 10]. Although this sequence of events has been recognized for more than five decades, little is known about the long-term natural history of genital herpes. In the late 1970s, supported by the National Institutes of Health, we began a prospective study of a large cohort of persons with recently acquired symptomatic genital HSV infection in order to define more precisely the natural history of genital herpes. Clinical, demographic, and recurrence data were collected for 457 patients who presented with virologically, serologically, and clinically confirmed first-episode genital infection. More than half of these patients did not receive antiviral therapy during their primary episode, providing a population not likely to be replicated in the future. We summarize the natural history of symptomatic recurrences in the complete population and in the subset of untreated patients. Methods In 1974, a research clinic dedicated to the study of genital herpes infection was established at Harborview Medical Center, a King Countyfunded hospital affiliated with the University of Washington. Patients were referred by their private physicians or by the sexually transmitted disease clinic at Harborview, or responded to advertisements for participation in clinical studies of HSV infection. Only patients willing to participate in prospective studies with long-term follow-up or in therapeutic trials were enrolled. Between 1974 and 1988, we registered 457 patients with serologically and virologically proven first-episode infection who were followed for at least 60 days from the onset of infection. At the initial clinic visit, genital lesions were cultured and described by anatomic site, stage, and area. Patients were then generally followed at 2- to 3-day intervals until their lesions had healed. The median number of visits and genital examinations during the initial disease episode was 5 (range, 3 to 14 visits). After resolution of the first clinical episode, patients were instructed to return to the clinic during each recurrence or for routine visits at least every 2 to 3 months. Patients who were unable to return for each recurrence were instructed to maintain a diary of onset and resolution dates for each recurrence. These data were collected at the following clinic visit. In general, we insisted that patients return for recurrences until they were able to recognize the signs and symptoms of genital herpes reactivation and to fill out patient diaries about onset and healing of reactivations. We defined a recurrence of genital herpes as the presence of genital ulcerations. We defined duration of a recurrence as the number of days from the first appearance of genital lesions to the reepithelialization of all lesions. If new lesions appeared before complete healing of other lesions, all were considered part of the same episode. We report only recognized symptomatic (lesional) recurrences and do not address subclinical shedding of HSV in the genital tract. Serum specimens from both the acute and convalescent phases were obtained from all patients and tested for HSV-specific antibodies by Western blot; all patients showed seroconversion to HSV-1 or HSV-2 [11, 12]. Some had antibodies to HSV-1 in their acute-phase specimen and antibodies to both HSV-1 and HSV-2 in their convalescent-phase specimens. Patients were categorized as having primary first-episode disease if their acute-phase serum specimen showed absence of antibodies to HSV by Western blot. Based on Western blot profiles of convalescent-phase specimens and the subtype of the HSV isolates from lesions, patients were categorized as having primary HSV-1 or primary HSV-2 infection. Patients who had HSV-1 antibodies in acute-phase specimens and antibodies to HSV-2 in convalescent-phase specimens were classified as having nonprimary first-episode HSV-2 disease [11, 13]. Patients with detectable antibodies to the homologous viral type isolated in initial specimens were classified as having recurrent disease [13]. Forty-two patients had serologic evidence of HSV-2 antibodies in acute- and convalescent-phase serum specimens, and 19 patients with HSV-1 antibodies in both their acute- and convalescent-phase specimens were classified as having reactivation infection and were not included in this study even though they claimed to be experiencing their first episode. We also excluded 64 patients seen between 1974 and 1985 whose serum specimens were analyzed by microneutralization but whose enrollment specimens could not be retrospectively retrieved for confirmation by Western blot [14]. In this study, we compared baseline patient characteristics and severity of primary infection with the subsequent recurrence experience of the patient. Patient characteristics included sex, race, age, and measures of past sexual activity, such as number of partners and history of sexually transmitted diseases. Clinical characteristics included pain, itch, discharge, fever, headache, photophobia, and stiff neck. Because many patients were participants in our early randomized trials of acyclovir, treatment status was also recorded [15-17]. Statistical Methods Monthly recurrence rates for each patient were estimated by dividing the number of recorded recurrences by the number of months the patient was followed. Comparisons of recurrence rates were made using the Wilcoxon rank-sum test or, for comparisons between more than two groups, the Kruskal-Wallis test. The Kaplan-Meier estimate was used to compute time to first recurrence, and appropriate comparisons were made using the Cox model [18]. Recursive partitioning was used as an exploratory technique to identify potential subsets of patients at higher risk for subsequent recurrence. Classification and regression trees were used for recursive partitioning of recurrence rates and a modification of this technique by LeBlanc and Crowley was used to establish time to first recurrence [19, 20]. These techniques identify the variable (and cutpoint, for continuous variables) most closely related to the recurrence pattern. Within each of these two splits, or nodes, of the data, the data are split again. This process is repeated within each node until no further splits appear to be important in predicting recurrences. This partitioning of the data can be represented as a tree that shows the splits of the variables into disjoint patient subsets. Because our previous placebo-controlled treatment trials failed to detect an effect of antiviral therapy on subsequent recurrences, most of our analyses are reported for the entire patient population. However, because treatment is known to affect the duration of primary symptoms, analyses to assess the potential effect of symptoms on subsequent recurrences were also done in the subset of untreated patients. Results Viral Type and Clinical Classification of Persons with First-Episode Genital Herpes Of the 457 patients presenting with first-episode genital herpes, 399 (87%) had primary genital HSV infection; 73 (16% of the total cohort) were infected with HSV-1 and 326 (71% of the total cohort) were infected with HSV-2. Fifty-eight (13%) patients were classified as having nonprimary HSV-2 infection. The median age of the patients was 24 years; 92% were single and 91% were white. Demographic characteristics were similar among those presenting with primary HSV-1, primary HSV-2, and nonprimary HSV-2 infection and were identical to those reported previously [10, 15-17, 21]. Frequencies of the major clinical signs and symptoms of the initial episode of genital herpes are shown in Figure 1. Patients with true primary genital herpes infection, regardless of infecting viral type, tended to have more severe disease than did patients with previous HSV-1 infection. This was most evident with respect to constitutional symptoms: Seventy-nine percent of those with primary HSV-1 or HSV-2 infection reported at least one constitutional symptom (fever, headache, photophobia, or stiff neck) during their first episode, compared with only 43% of those with nonprimary infection. Seventy-seven percent of those with primary episodes had inguinal adenopathy compared with 52% of those with nonprimary genital herpes (P = 0.001). Frequencies of symptoms and signs were similar between those with primary genital HSV-1 and primary genital HSV-2 infections, except in the case of nuchal rigidity, which was reported by 42% of patients with primary HSV-2 infection and 12% of those with primary HSV-1 infection (P = 0.005). Figure 1. Frequency of clinical signs and symptoms of first-episode genital herpes by viral type and evidence of previous herpes simplex virus type 1 (HSV-1) exposure. P Overall Recurrence Rates after Resolution of the Initial Episode Follow-up was defined as the time from enrollment to the date of the last clinic visit or to the date that a patient initiated long-term suppressive oral acyclovir therapy. The median follow-up was 418 days (range, 61 to 4897 days) and was similar in all subsets of patients whether segregated according to viral type, sex, or severity of clinical episode. The median numbers of clinic visits per patient in the first 90, 91 to 180, 181 to 365, and 366 to 720 days of follow-up were 10, 2, 2, and 1, respectively. The large numbers o

Human Herpesvirus 6 in Lung Tissue from Patients with Pneumonitis after Bone Marrow Transplantation

BACKGROUND Human herpesvirus 6 (HHV-6) is a recently described herpesvirus that is epidemiologically and biologically similar to cytomegalovirus. It is the cause of exanthem subitum (roseola) in children. METHODS To evaluate the possible role of HHV-6 infection in pneumonitis in immunocompromised patients, we used quantitative HHV-6 polymerase chain reactions to study lung-biopsy specimens from 15 patients with pneumonitis after bone marrow transplantation and lung tissue from 15 immunocompetent subjects without pneumonitis and 6 fetuses. RESULTS HHV-6 DNA was detected in lung tissue from all 15 patients, from 14 seropositive control subjects, and from none of the 7 seronegative control subjects. Six patients had levels of HHV-6 DNA in lung tissue that were 10 to 500 times higher than those in any of the other patients or control subjects. Increased levels of HHV-6 DNA correlated with a decreased risk of death from pneumonitis (P = 0.015), an increased severity of graft-versus-host disease (P = 0.023), and the presence of idiopathic pneumonitis (P = 0.037). Levels of HHV-6 DNA correlated directly with the changes in HHV-6 antibody titers in the interval between the pretransplantation period and the open-lung biopsy (P = 0.002). Low levels of HHV-6 antibody at the time of the open-lung biopsy were also associated with the diagnosis of idiopathic pneumonitis (P = 0.002). CONCLUSIONS The concentrations of HHV-6 genome in lung tissue and their relation to changes in serologic titers support an association between HHV-6 infection and idiopathic pneumonitis in immunocompromised hosts.

Antibody to herpes simplex virus type 2 as serological marker of sexual lifestyle in populations

Abstract Objectives: To examine the epidemiology of antibody to herpes simplex virus type 2 and to assess its suitability as a serological marker of sexual behaviour in populations with high and low prevalences. Design: Cross sectional survey. Setting: Department of genitourinary medicine and blood donation centre in central London. Subjects: Representative sample of 869 patients attending department between November 1990 and December 1991, and 1494 consecutive blood donors attending for donation between February and April 1992. Method: Participants had a blood sample taken for antibody testing with a novel type specific assay and completed a questionnaire. Results - Prevalence of antibody differed significantly between the two groups (188/833 (22.7%) clinic attenders; 102/1347 (7.6%) blood donors). In both populations antibody was strongly associated with sex, sexual orientation, years of sexual activity, number of lifetime sexual partners, and past infection with sexually transmitted diseases after other factors were controlled for. Only 130 (45%) of all those with antibody had symptoms suggestive of genital herpes, and 79 (27.4%) had had genital herpes diagnosed. Of those without antibody to herpes simplex viruses type 1 and 2, 8.0% reported genital blisters or sores and 1.1% had had genital herpes diagnosed by a doctor. Conclusions: The strong relation between herpes simplex virus type 2 and sexual lifestyle suggests that the presence of antibody to the virus may be suitable for use as an objective, serological marker of patterns of sexual behaviour in different populations. These data show that only a minority of those infected with herpes simplex virus type 2 have a diagnosis of genital herpes or express clinical symptoms, making serological determinants of infection essential for epidemiological studies.