REVIEWS
Genital Herpes Simplex Virus Infections: Clinical Manifestations, Course, and
Complications
LAWRENCE COREY, M.D.; HARRY G. ADAMS, M.D.; ZANE A. BROWN, M.D.; and KING K. HOLMES,
M.D., Ph.D.; Seattle, Washington
The clinical course and complications of 2 6 8 patients with
first episodes and 3 6 2 with recurrent episodes of genital
herpes infection were reviewed. Symptoms of genital
herpes were more severe in women than in men. Primary
first-episode genital herpes was accompanied by systemic
symptoms ( 6 7 % ) , local pain and itching ( 9 8 % ) , dysuria
( 6 3 % ) , and tender adenopathy ( 8 0 % ) . Patients
presented with several bilaterally distributed postular-
ulcerative lesions that lasted a mean of 19.0 days. Herpes
simplex virus was isolated from the urethra, cervix, and
pharynx of 8 2 % , 8 8 % , and 1 3 % of women with first-
episode primary genital herpes, and the urethra and
pharynx of 2 8 % and 7 % of men. Complications included
aseptic meningitis ( 8 % ) , sacral autonomic nervous
system dysfunction ( 2 % ) , development of extragenital
lesions ( 2 0 % ) , and secondary yeast infections ( 1 1 % ) .
Recurrent episodes were characterized by small vesicular
or ulcerative unilaterally distributed lesions that lasted a
mean of 10.1 days. Systemic symptoms were uncommon
and 2 5 % of recurrent episodes were asymptomatic. The
major concerns of patients were the frequency of
recurrences and fear of transmitting infection to partners
or infants.
G E N I T A L HERPES SIMPLEX virus infection is of increas-
ing public health importance. The advent of effective an-
tiviral therapy, the recurrent nature of the infection, its
differing clinical manifestations, and complications such
as aseptic meningitis and neonatal infection, are of great
concern to patients and health care providers (1-5). We
review the clinical manifestations, course, and complica-
tions of first and recurrent episodes of genital herpes sim-
plex virus infections in studies done at the University of
Washington Genital Herpes Simplex Virus Clinic.
Materials and Methods
Since 1974 there has been a special clinic at the Harborview
Medical Center, Seattle, Washington, to study the natural histo-
ry and treatment of genital herpes simplex virus infections. Pa-
tients and their sexual partners were referred to the clinic from
community clinics (20%), private practitioners (55%), stu-
dent health services (5%), and sexually transmitted disease
clinics in Seattle-King County (20%). This report summarizes
the data on 648 patients with herpes simplex virus isolated from
genital lesions, who received either no treatment (44%), place-
bo preparations (33%) [water washable base creams (13%),
polyethylene glycol ointment (14%), or dimethyl sulfoxide so-
lution (6%)]; or treatment that had no influence on the course
of genital herpes (23%) [topical surfactants (15%), 3% vidar-
abine ointment (8%)] (1, 6-10). At the initial clinic visit, all
• From the Departments of Laboratory Medicine. Medicine, Pediatrics, and Ob-
stetrics and Gynecology, University of Washington, the Children's Orthopedic
Hospital Medical Center, and the Seattle Public Health Hospital; Seattle, Wash-
ington.
958 Annals of Internal Medicine 1983:98:958-972.
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patients were first classified as those with no previous history of
genital herpes (first-episode genital herpes) and those with a
previous history of genital herpes (recurrent genital herpes).
All patients with first episodes of genital herpes selected for this
study presented within 7 days of onset of lesions (mean, 4.6
days), and those with recurrent genital herpes all presented
within 48 hours of onset of lesions (mean, 1.4 days). At the
initial clinic visit a standardized interview and genital examina-
tion were done, a sketch of the lesions was made, and cultures
were obtained from all suspect genital lesions and from the cer-
vix in women and the urethra in men. The patients were then
followed at intervals of every other day or more often until
lesions resolved. At each follow-up visit a standardized inter-
view and examination were done, and viral cultures were again
obtained from all lesions and from the cervix. During the acute
episode of the disease, patients with recurrent genital herpes
were followed for an average of eight visits and those with a first
episode for an average of ten visits from the time of consultation
until healing.
LABORATORY METHODS
Cultures for herpes simplex virus were obtained with a calci-
um alginate or dacron swab, placed into viral transport media,
and inoculated into duplicate tubes of diploid fibroblasts. Cul-
tures were examined three times weekly for 3 weeks for evi-
dence of herpes simplex virus cytopathic effect. An aliquot of
the first genital herpes simplex virus isolate from each episode
was frozen at — 70 °C for subsequent subtyping by an indirect
immunoperoxidase technique ( 1 1 ) .
Acute phase serum samples were drawn at the first clinic
visit, and convalescent serum 21 to 28 days later. Sera were
tested for anti-herpes simplex virus antibody by complement
fixation or neutralizing antibody assays (12, 13). In the neutral-
izing antibody assay, antibody subtype was calculated using a
pNi-pN2 value ( 1 4 ) . Herpes simplex virus-2 neutralizing speci-
ficity was considered a pNj-pN2 of less than 0.05, herpes sim-
plex virus-1 neutralizing specificity as a value of greater than
0.5, and indeterminate specificity as a pNj-pN2 value between
0.05 and 0.5 ( 1 4 ) .
STATISTICAL METHODS
For analysis, patients with first-episode genital herpes were
placed in two groups: patients with primary genital herpes
(lacking complement fixation and herpes simplex virus neutral-
izing antibody in their acute phase sera), and those with non-
primary, first-episode genital herpes (possessing a greater than
or equal to 1:8 titer of complement fixation or herpes simplex
virus neutralizing antibody in their acute phase serum sample).
Comparison of demographic characteristics between groups
was done by Wilcoxon rank sum test. Chi-squared analysis or
the Mann Whitney test were used as specified.
Characteristics of the Study Population
T h e m e a n a g e o f patients w i t h s y m p t o m a t i c genital
herpes w a s 27.1 years; 9 6 % were white, 3 2 % were m e n ,
6 4 % were single, and t h e m e a n educational status w a s
15.1 years o f formal education ( T a b l e 1 ) . T h e d e m o -
©1983 American College of Physicians
 Table 1. Characteristics of Patients Seen at the University of Washington Genital Hlerpes Simplex Vii us Clinic, 1 9 7 5 - 1 9 8 0

Meii Worn en
First Episode Recurrent First Episode Recurrent
of Disease Disease of Disease Disease
(77=104) (/i = 218) (77=182) (77=144)

Mean age, yrs 25.9 29.3 24.7 26.9

White, % 94 94 97 93
Single, % 74 65 64 57
Patients relying on oral contraceptives, % 30 19 53 38
Formal education of patients, yrs 15.4 15.9 14.1 14.7
Patients with history of gonorrhea, % 26 35 15 19
Patients with history of nongonococcal urethritis, % 21 36 NA* NA
Patients with history of oral herpes, % 18 24 26 29
Mean number of partners in the 30 days before clinic visit, n 1.6 1.4 1.4 1.1
Patients with one partner 30 days before clinic visit, % 61 69 66 78
Patients with new partner in 30 days before clinic visit, % t 46 24 32 12
Mean number of days from last sexual exposure to onset of disease,
6.4 5.5 5.1
d 6.2
Patients with history of oral sex in 14 days before clinic visit, %
Patient performed oral sex 48 NA 51 NA
Partner performed oral sex 47 NA 55 NA
* N A = not applicable or not ascertained.
t p < 0.01 (chi-squared test), comparing first episode with recurrent disease for both men and wome n.

graphic composition of our patients was similar to that of
a recent nationwide survey of patients with genital herpes
(15). The proportion of patients who were white and the
mean educational status were significantly higher than in
patients previously studied in Seattle with Neisseria go-
norrhoeae (16), and our population differed from the
predominantly lower socioeconomic class groups with
genital herpes described in the late 1960s (17, 18).
Genital herpes simplex virus infection was the first sex-
ually transmitted disease most patients had acquired.
Past gonococcal infection was reported by 31 % of men
and 12% of women who presented with their first episode
of genital herpes. The mean number of lifetime sexual
partners before the acquisition of disease was 8.8 for
women and 32.8 for men. For men the number of part-
ners was similar to the number reported by men who
presented to our sexually transmitted disease clinic with
nongonococcal urethritis, but less than half that reported
by men with gonococcal infection (16). Sixty-six percent
of women and 6 1 % of men with first episodes of genital
herpes had only one sexual partner during the 30 days
before the acquisition of disease, and in 39% the source
contact was a new sexual partner. A clinical history of
genital herpes in the source contact was elicited by inter-
view for 47% of the female and 35% of the male index
cases with first-episode genital herpes. Direct interview of
the source contact, however, disclosed a history compati-
ble with previous genital herpes in 66% of male and fe-
male source contacts. The mean time from the last sexual
exposure to the onset of disease was 5.8 days (range, 1 to
45 days).
Viral Type in First and Recurrent Episodes of Genital Herpes
Herpes simplex virus-1 was isolated from genital le-
sions from 21 (7%) of 286 persons with first episodes of
disease and only 6 (2%) of 362 persons with recurrent
genital herpes (p < 0.05). Herpes simplex virus-1 has
been more frequently associated with first than with re-
current episodes of genital herpes in other areas of the
United States, England, and Japan (19-22). Herpes sim-
plex virus-1 has accounted for a widely differing propor-
tion of isolates from first episodes of genital herpes, aver-
aging 7% in Seattle, 50% in Sheffield, England, and 35%
in Japan. Some researchers have speculated that this find-
ing may be related to more frequent oral-genital contact
in such populations. Oral sex was, however, a frequent
sexual activity of patients we studied (Table 1). Al-
though data comparing the incidence of genital herpes in
the United States and other countries are not available,
the reported incidence of most sexually transmitted dis-
eases is higher in the United States today than in Japan
or England. The proportion of patients with clinical geni-
tal herpes attending our King County sexually transmit-
ted disease clinics (4.8%) is double that of attendees of
sexually transmitted disease clinics in England (2.3%)
(23). The higher proportion of genital herpes cases
caused by herpes simplex virus-1 as compared to herpes
simplex virus-2 in the English and Japanese studies may
show a lower risk of genital herpes simplex virus-2 infec-
tion in these populations rather than an increased risk of
genital herpes simplex virus-1 infection due to more fre-
quent oral-genital contact. Factors such as the frequent
use of a condom during intercourse (common in Japan)
may also influence these data.
First Episode
COMPARISON OF PRIMARY A N D N O N P R I M A R Y FIRST
EPISODES
Of 286 patients with first episodes of genital herpes,
209 had primary first-episode genital herpes and 76 non-
primary first episodes of disease. From 1975 to 1977, of
137 consecutive patients who presented to our clinic with
first episodes of genital herpes simplex virus infection,
40% had serologic evidence of previous herpes simplex
virus infection, and 60% had primary first episode genital
herpes. The higher proportion of patients with true pri-
Corey et al. • Genital Herpes Infections 959

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 Table 2. Relation Between Viral Type, Presence of Herpes Simplex Virus Antibody in Acute F'hase Sera, and Seveirity of Disease of First-
Episode Genital Herpes*

Primary Herpes Primary Herpes Non-primary

Simplex Virus-1 Simplex Virus-2 Herpes
Infection Infection Simplex Virus-2
(n = 20) (72 = 189) Infection (n = 76)
Patients with systemic symptoms, %t 58 62 16
Patients with meningitis symptoms, %f 16 26 1
Mean duration local pain, df 12.5 11.8 8.7
Mean number of lesionsf 24.3 15.5 9.5
Mean lesion area, mm2^ 597 517 158
Patients with bilateral lesions, %t 100 82 45
Patients forming new lesions during course of disease, %t 68 75 45
Mean duration viral shedding from genital lesions, df 11.1 11.4 6.8
Mean duration lesions, df 22.7 18.6 15.5
Patients developing extragenital lesions, %t 10 18 8
Patients shedding herpes simplex virus from cervix, % 80 88 65
* Only one patient with complement fixation and neutralizing antibody in acute phase sera had herpes simplex viirus-l isolated from genita 1 lesions.
f p < 0.05 for each comparison between nonprimary and primary herpes simplex virus-2 infection (chi-squared or Student's Mest)

mary genital herpes in our more recent series shows our
particular interest in this form of disease. In the patients
with nonprimary first episodes of genital herpes, neutral-
izing antibody in acute phase sera showed past herpes
simplex virus-1 specificity in 7 1 % (pNi-pN 2 > 0.5). Se-
rologic evidence of past herpes simplex virus-2 infection
in acute phase sera was evident in 8% of patients with
historic first episodes of disease, suggesting previous
asymptomatic acquisition of herpes simplex virus-2 infec-
tion.
Viral Type: Herpes simplex virus-1 was isolated from
genital lesions from 10% of patients with primary first
episodes compared to 1 % with nonprimary first episodes
( p < 0 . 0 2 ) . These data suggest that previous herpes sim-
plex virus-1 infection protects against the acquisition of
genital herpes simplex virus-1 disease. Whether previous
herpes simplex virus-1 infection also protects against the
acquisition of genital herpes simplex virus-2 disease is
unknown. Inoculation of high titers of herpes simplex
virus (even a patient's own strain) onto a susceptible
mucosal surface or into the subcutaneous tissue can re-
sult in lesions, and subsequent recurrences in the same
anatomic areas (24). Persons with previous herpes sim-
plex virus-1 infection should continue to avoid oral-geni-
tal contact with a person with active oral-labial lesions.
Clinical Severity: The frequency of constitutional
symptoms, number of lesions, and the duration of symp-
toms were similar for the 20 patients with primary genital
herpes simplex virus-1 and the 189 patients with primary
genital herpes simplex virus-2 infection (Table 2). How-
ever, patients with nonprimary genital herpes simplex vi-
rus-2 infection had significantly lower frequencies of sys-
temic symptoms, shorter duration of pain, fewer lesions,
less frequent appearance of new lesions during the course
of infection, a shorter duration of viral shedding from
lesions, and shorter healing time than persons with pri-
mary herpes simplex virus-2 infection. Thus, previous
herpes simplex virus-1 infection ameliorates the severity
and duration of first episodes of genital herpes.
CLINICAL M A N I F E S T A T I O N S OF PRIMARY INFECTION
Symptoms: Primary genital herpes simplex virus-2 in-
960 June 1983 • Annals of Internal Medicine • Volume 98 • Number 6
fection was characterized by a high frequency of systemic
symptoms, particularly in women. Fever, headache, mal-
aise, and myalgias were present for 2 or more consecutive
days in 39% of men and 68% of women with primary
herpes simplex virus-2 disease (p < 0.05) (Table 3).
These systemic symptoms appeared early in the course of
the disease, reached a peak within the first 4 days after
onset of lesions, usually at the time of presentation to the
clinic, and gradually receded during the remainder of the
first week of the illness (Figure 1).
Pain, itching, dysuria, vaginal or urethral discharge,
and tender inguinal adenopathy were the predominant
local symptoms. Genital lesions were described as painful
by 95% of men (mean duration, 10.9 days) and 99% of
women (mean duration, 12.2 days). The severity of local
symptoms gradually increased over the first 6 to 7 days of
illness, peaked between days 8 and 10 and gradually re-
ceded over the second week of illness. Tender inguinal
adenopathy appeared during the second and third week
of illness and often was the last manifestation to resolve.
Inguinal nodes were usually enlarged and mildly tender
and nonfluctuant. Tenderness to palpation lasted signifi-
cantly longer in women (14.2 days) than in men (8.6
days) (p < 0.05). Suppurative lymphadenopathy was
not seen in any of the patients in this series. Recently,
however, we have seen one patient who presented with
chancroid-like penile lesions and a firm, non-fluctuant in-
guinal node. Herpes simplex virus was isolated from an
inguinal aspirate of this node.
Duration of Lesions and Viral Shedding: Widely
spaced bilateral lesions on the external genitalia were the
most frequent presenting sign in both men and women.
The mean number of lesions was 15.5, and the mean area
of involvement was 427 mm 2 in men and 550 mm 2 in
women. Lesions were described as starting as small mul-
tiple papules or vesicles that by the time of the first clinic
visit had already coalesced into large pustular or ulcera-
tive areas (Figures 2a and 2b). Seventy-five percent of
patients formed new lesions during the course of infec-
tion (Figure 2c). Ulcerative lesions persisted between 4
and 15 days. Lesions on the penis and mons pubis be-
came crusted before reepithelializing. Lesions on mucosal

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 or moist cutaneous surfaces reepithelialized without
crusting. Suppurative secondary infection of lesions was
not seen in this population and residual scarring from
lesions was uncommon. Vaginal mucosal lesions were
seen in only 4% of women with primary genital herpes.
The mean time from the onset of lesions to complete
reepithelialization of all lesions was 16.5 days in men
compared to 19.7 days in women (p<0.05).
The mean duration of viral shedding from the onset of
lesions until the last positive viral culture was 11.4 days,
similar in men and women. The mean time from the on-
set of lesions to the appearance of the crust stage correlat-
ed with the duration of viral shedding. Figure 1 . The clinical course of primary genital herpes simplex vi-
Herpes Simplex Virus Cervicitis: Herpes simplex virus rus infection.
was isolated from the cervix at the time of illness from
88% of women with primary herpes simplex virus-2 in-
fection of the external genitalia, 80% of women with pri- Both symptomatic and asymptomatic excretion of her-
mary genital herpes simplex virus-1 infection, and 65% pes simplex virus from the cervix occur commonly dur-
with nonprimary first episodes of genital herpes simplex ing first episodes of genital herpes. Acute herpetic cervici-
virus-2 infection. In contrast, herpes simplex virus was tis may be the sole manifestation of first episode genital
isolated from the cervix in only 12% of women who pre- herpes simplex virus infection (25). For example, herpes
sented with recurrent genital lesions. The cervix had an simplex virus has been isolated from 8% of women pre-
abnormal appearance in 89% of the women from whom senting to our sexually transmitted disease clinic with
herpes simplex virus was isolated during first episodes of mucopurulent cervicitis without evidence of external gen-
genital herpes. The commonest cervical abnormality was ital lesions (PAAVONEN J, HOLMES KK. Unpublished
diffuse friability, although extensive ulcerative lesions of data). In first episodes of genital herpes, herpetic ulcers
the exocervix or severe necrotic cervicitis were often of the cervix involve both the endocervical and the strati-
found (Figures 2d and 3a). Gram stains of cervical exu- fied squamous cells of the exocervix. Ectocervical cells
date showed abundant polymorphonuclear leukocytes. are more apt to show intranuclear inclusions and giant
cell formations, and are more likely to produce herpes
Table 3. Clinical Symptoms and Marlifestations of Primary Geni- simplex virus infection in vitro than endocervical cells
tal Herpes Simplex Virus-2 Infection in Men and W<)men
(26). In contrast, cervical infection with TV. gonorrhoeae
Men Women or Chlamydia trachomatis only involve the columnar cell
(72 = 63) (n = 126) epithelium of the endocervix or of the zone of ectopy.
Patients with systemic symptoms, %»• 39 68 Herpes simplex virus has been isolated from the cervix,
Patients with meningitis symptoms, %* 11 36 often in the absence of genital symptoms, from 1.6% to
Patients with local pain, % 95 99 8% of women attending sexually transmitted disease clin-
Mean duration of local pain ics and 0.25% to 1.5% of patients seen in private gyne-
(range), d 10.9(1-40) 12.2(1-37) cology practices (17, 27, 28). Shedding of herpes simplex
Patients with dysuria, %* 44 83 virus from the vulva in the absence of symptoms or visi-
Mean duration of dysuria (range),
df 7.2 (2-20) 11.9(1-26) ble lesions has also been reported and may be even more
Patients with urethral or abnormal frequent than asymptomatic cervical shedding (29). The
vaginal discharge, %* 27 85 duration of such asymptomatic viral shedding has been
Mean duration of discharge, df 5.6 12.9 short (mean, 3.2 days; range, 1 to 5 days). In addition,
Patients with tender adenopathy, % 80 81
Mean duration of adenopathy, df 8.6 14.2 the titer of virus isolated during these periods of asymp-
Mean number of lesions (range) 15.7 (3-50) 15.4(1-60) tomatic shedding is lower (101 to 103 tissue culture infec-
Patients with bilateral lesions, % 2 77 82 tive doses) than titers isolated from persons with sympto-
Mean area of lesions (range), mm 427 (6-1671) 550 (8-3908) matic cervicitis (10 4 to 106 tissue culture infective doses)
Patients forming new lesions (30-32).
during infection, % 76 74
Mean number days of new lesion Herpes Simplex Virus Pharyngitis: Herpes simplex vi-
formation (range), d 7.2(1-18) 8.1 (1-20) rus was isolated from the pharynx from 21 (11%) of 189
Mean duration viral shedding patients with primary herpes simplex virus-2 infection, 4
from genital lesions, d 10.5 11.8 of 20 patients with primary genital herpes simplex virus-1
Patients with herpes simplex virus
isolated from urethra, %* 28 82 infection, 1 % of patients with nonprimary first-episode
Patients with herpes simplex virus genital herpes, and 1% of those with recurrent genital
isolated from cervix, % NA 88 herpes. Forty patients (19%) complained of sore throat
Mean duration viral shedding during the acute episode of primary genital herpes; 36
from cervix, d NA 11.4 had herpes simplex virus-2 and 4 had herpes simplex vi-
Mean duration of lesions, df 16.5 19.7
rus-1 isolated from the genitalia. Viral cultures were ob-
*p < 0.05 (chi-squared test),
t p < 0.05 (Student's Mest). tained from the throat in 26 of these patients. Herpes
Corey eta/. • Genital Herpes Infections 961

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 Figure 2 . Clinical manifestations of primary genital herpes, a. Coalescent painful ulcerative lesions, b. Bilateral serpiginous ulcerative lesions
of the labia minora and majora in a woman with extensive primary genital herpes simplex virus-2 infection, c. Development of new penile
vesicles on day 8 of illness. Original lesions are crusted. New lesions are not contiguous with original vesicles, d. Culposcopic photograph of
two large ulcerative lesions of the exocervix in a woman who presented with primary herpes simplex virus-2 cervicitis. External vulvar lesions
did not develop.

simplex virus was isolated from the pharynx from 18 and
from none of 20 patients who did not have a sore throat.
Clinical signs of herpes simplex virus pharyngitis ranged
from mild erythema to severe diffuse ulcerative or exuda-
tive pharyngitis of the posterior pharynx (Figure 3b).
Occasionally lesions extended into the anterior gingival
area. Fever, malaise, myalgia, headache, and tender ante-
rior cervical adenopathy were usually present, and many
patients had recently been diagnosed as having strepto-
coccal pharyngitis.
Glezen and associates (33) reported that primary her-
pes simplex virus-1 infection was a frequent cause of
pharyngitis in college students. Herpes simplex virus-2
pharyngitis is also common among patients with primary
genital herpes. Severe exudative herpes simplex virus
pharyngitis leading to laryngeal obstruction has been re-
ported (34). Whether oral-labial herpes simplex virus-2
9 6 2 June 1983 • Annals of Internal Medicine • Volume 98 • Number 6
infection recurs as frequently as oral-labial herpes sim-
plex virus-1 infection or as frequently as genital herpes
simplex virus-2 infection is unknown.
Herpes Simplex Virus Urethritis: Among our patients
with primary genital herpes, dysuria was reported by
83% of women and 44% of men (p < 0.05). Urethral
cultures for herpes simplex virus were done in 63 men
and 57 women with primary herpes simplex virus-2 infec-
tion. Herpes simplex virus was isolated from 28% of
these men and 82% of women (Table 3) (p < 0.01).
Ninety percent of men with primary herpes simplex
virus-2 infection who had urethral discharge had dysuria,
and had herpes simplex virus isolated from their urethra.
The urethral discharge was usually clear and mucoid.
The subjective severity of dysuria was out of proportion
to the amount of discharge found on genital examination,
and was significantly worse than dysuria associated with

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 TV. gonorrhoeae or nongonococcal urethritis. Gram stain
of the urethral discharge usually showed between 5 and
15 polymorphonuclear leukocytes per oil immersion field.
Herpes simplex virus urethritis may also occur as the
sole symptomatic manifestation of genital herpes. In a
recent study of women with the urethral syndrome (dys-
uria-frequency syndrome), herpes simplex virus was iso-
lated from the urethra or cervix in 5% (35). Herpes sim-
plex virus has been isolated from the urine of both men
and women with dysuria or hematuria, and cystoscopic
examination has shown mucosal ulcerations in some of
these patients (36). It is likely that herpes simplex virus
cystitis occasionally occurs as a result of ascending infec-
tion from the urethra into the bladder.

COMPLICATIONS OF PRIMARY INFECTION

Women more frequently had complications of genital
herpes simplex virus infections than men (Table 4); com-
plications were related to local extension of infection or
spread of virus to extragenital sites. Fungal superinfec-
tion was also encountered.
Aseptic Meningitis: Symptoms of stiff neck, headache,
and photophobia, with or without fever, were found on
two consecutive examinations in 36% of women and
13% of men with primary genital herpes simplex virus-2
infection (p < 0.001). Eight patients, one man and seven
women, with primary genital herpes simplex virus-2 in-
fections were ill enough to require hospitalization; all had
fever, severe headache, malaise, photophobia, nuchal ri-
gidity, positive Kernig's or Brudzinski's signs, and all
had a lymphocytic pleocytosis in cerebrospinal fluid. The
mean time from onset of lesions to hospitalization was
9.3 days, ranging from 6 to 12 days. With bed rest, anal-
gesics, and intravenous fluids, all symptoms and signs
gradually resolved without residual neurologic sequelae,
and meningitis did not recur with subsequent recurrences
of genital herpes.
Herpes simplex virus has been isolated from the cere- Figure 3. Herpes simplex virus cervicitis and pharyngitis, a. Necrot-
brospinal fluid from 0.5% to 3.0% of patients presenting ic cervicitis due to herpes simplex virus-2. b. Exudative pharyngitis
in a patient with primary genital herpes. Herpes simplex virus-2
to the hospital with aseptic meningitis (37, 38). In adults was isolated f r o m the pharynx and genital lesions. Restriction endo-
and infants, herpes simplex virus-2 has been more com- nuclease analyses of viral DNA showed the strains to be identical.
monly isolated from cerebrospinal fluid than herpes sim-
plex virus-1 (39, 40). Patients with primary genital pes simplex virus-2 from the buffy coats of adults with
herpes frequently have lymphocytic pleocytosis in their herpes simplex virus-2 meningitis, and hypothesized that
cerebrospinal fluid, suggesting that most patients with hematogenous spread to the central nervous system or
headache, fever, and mild photophobia with their first meninges accounted for its pathogenesis. In animal mod-
episode of genital herpes have mild herpes simplex virus els central nervous system involvement appears to result
meningitis (41). Examination of cerebrospinal fluid in from direct spread of herpes simplex virus from mucosal
patients with herpes simplex virus-2 meningitis may show sites via peripheral nerves (43). Neurotropic spread in
a slightly elevated opening pressure, leukocyte counts animals is often associated with clinical paralysis or death
ranging from 5 to greater than 1000/mm 3 (median, 300 due to encephalitis, manifestations of disease that have
to 400) with a predominance of lymphocytes. The cere- been rarely reported in aseptic meningitis associated with
brospinal fluid glucose value is usually more than 50% of genital herpes in humans. The pathogenesis of herpes
the blood sugar, although hypoglycorrhachia has been simplex virus meningitis is unclear. We have been unable
reported (42). Neurologic residua are rare after herpes to isolate herpes simplex virus from buffy coat cultures of
simplex virus-2 aseptic meningitis. Whether antiviral 30 consecutive patients with systemic symptoms of head-
therapy will shorten the course of established aseptic ache and photophobia. Whether hematogenous, neuro-
meningitis or prevent the development of disease is not tropic, or a combination of both these methods are means
known. by which the virus reaches the central nervous system
Craig and Nahmias (4) reported the isolation of her- requires further study. Encephalitis did not occur in any
Corey et at. • Genital Herpes Infections 963

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 Table 4. Complications of Primary Genii:al Infection with Herpes retention, or impotence (47). The high incidence of auto-
Simplex Virus-2 nomic nervous system dysfunction in homosexual men
with herpes simplex virus proctitis suggests that anorec-
Men Women
(/i = 63)
tal herpes simplex virus infection may predispose to this
(72 = 126)
complication. Numbness and tingling of the buttocks or
Patients with stiff neck, headache, and perineal area preceded urinary retention and constipa-
photophobia, %*f 13 36 tion. In men, impotence was associated with a decreased
Patients hospitalized with aseptic bulbocavernosus reflex. Cerebrospinal fluid pleocytosis
meningitis, % 2 6
Patients with autonomic nervous may be found. In all of our patients these symptoms re-
system dysfunction, % 0 2 solved slowly over a period of days to weeks. Rarely,
Patients with herpes simplex virus transverse myelitis associated with the development of a
pharyngitis, % 7 13 rapidly progressive symmetrical paralysis of the lower ex-
Patients with development of extra-
genital lesions, % t 10 26
tremities has been reported (48).
(72 = 60) (n = 101) Extragenital Lesions: Extragenital mucocutaneous le-
Lip 1 4 sions developed in 26% of women and 10% of men with
Buttocks, groin 2 11 primary herpes simplex virus-2 infection (p < 0.05).
Breast 1 2
Finger 1 8 These lesions were most frequently located on the but-
Eye 1 1 tocks, groin, or thighs, but 8% of patients developed le-
Patients with pelvic inflammatory sions on their fingers, and herpes simplex virus conjuncti-
disease syndrome, % NA 1.6 vitis occurred in 2 patients (Table 4). Twenty-six of the
Patients with yeast balanitis or 30 patients who developed extragenital lesions during the
vaginitis, % t 3 14
course of infection did so during the second week of dis-
* AH three symptoms found on two consecutive examinations. ease.
t p < 0.01 (chi-squared test).
The distribution of lesions on the fingers (but not the
feet), in areas adjacent to genital lesions, and their devel-
of our patients with genital herpes; herpes simplex virus-2 opment late in the course of disease, suggest that most
has been isolated only rarely in adults with herpes sim- extragenital lesions arise by autoinoculation rather than
plex virus encephalitis shown by biopsy (44). None of by viremia (49-51). The increased risk of extragenital
our 362 patients with recurrent genital herpes developed lesions in women compared to men probably results from
clinical signs of central nervous system or meningeal in- exposure of the buttocks, thighs, and fingers to infected
volvement. Although recurrent aseptic meningitis has cervical secretions.
been associated with recurrences of genital herpes, herpes Upper Genitourinary Tract Infections: In one woman
simplex virus-2 has not to our knowledge been repeatedly with primary genital herpes simplex virus infection, low-
isolated from the cerebrospinal fluid of patients with re- er abdominal pain, and uterine and adnexal tenderness
current episodes of meningitis. were seen on physical examination. The relation between
Other Neurologic Complications: Two women, both genital herpes simplex virus infection and pelvic inflam-
with vulvar and perianal external genital herpes, devel- matory disease is not known. We have isolated herpes
oped sacral anesthesia, urinary retention, and constipa- simplex virus from the endometrium in one woman with
tion during primary genital herpes simplex virus-2 infec- concomitant herpes simplex virus cervicitis, and herpes
tion. Physical examination showed decreased fine touch simplex virus endometritis has been reported in one
perception in the sacral region, poor perineal reflexes and woman with an intrauterine device who developed fatal
decreased rectal sphincter tone, and bladder distention. disseminated primary genital infection (52). Whether
Slowed nerve conductions and fibrillation potentials were these cases resulted from hematogenous spread of herpes
shown by electromyographic examination. Both patients simplex virus or ascending infection is unclear. We have
required intermittent urinary catheterization as their neu- done a laparoscopic examination on one woman with pri-
rologic abnormalities gradually resolved over 4 to 8 mary genital herpes not included in the current series.
weeks. This woman had severe bilateral adnexal pain and thick-
Autonomic nervous system dysfunction has been re- ening on physical examination; laparoscopic examination
ported in association with both herpes simplex virus and showed vesicular lesions over the fimbria of the fallopian
varicella zoster virus infections (45, 46). The pathogene- tube and on the uterus. Herpes simplex virus was isolated
sis of autonomic nervous system dysfunctions is not com- from the cervix, but not from a sample of exudate ob-
pletely understood. We have seen manifestations suggest- tained during the laparoscopic examination. It is unclear
ing autonomic nervous system dysfunction in 2 of 126 whether the association between pelvic inflammatory dis-
women with primary genital herpes, none of 63 hetero- ease and primary genital herpes is due to extension of
sexual men with primary genital herpes, none of 78 heter- herpes simplex virus into the upper genital tract or to the
osexual men or women with nonprimary first-episode presence of other concomitant sexually transmitted infec-
genital herpes, and none of 362 heterosexual men and tions.
women with recurrent genital herpes. In contrast, among Symptomatic herpes simplex virus infection of adnexal
23 homosexual men with herpes simplex virus proctitis, genital structures in men has only been rarely reported.
12 had evidence of poor rectal sphincter tone, urinary During intercurrent periods of disease, we have obtained
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 cultures from 47 samples of semen and expressed prostat- Table 5. Prevalence and Duration in Days of Clinical Symptoms
ic secretions from 35 men. Herpes simplex virus was not and Signs of Recurrent Genital Herpes
isolated from any of these samples. Recent studies of epi- Men Women
didymitis and prostatitis have not implicated herpes sim- (72 = 2 1 8 ) (n =144)
plex virus as an important cause of these entitites (53,
54). Centifano and associates (55) isolated herpes sim- Patients with prodromal symp-
plex virus from seminal fluid from 15% of asymptomatic toms, % 53 43
Mean duration of prodrome before
men; however, we and others have isolated herpes sim- onset of lesions (range), d 1.5 (0-6) 1.2 (0-3)
plex virus only infrequently from semen or prostatic se- Patients with pain, %* 67 88
cretions (56). Mean duration of pain (range), df 3.9(1-14) 5.9(1-13)
Disseminated Herpes Simplex Virus Infection: Other Patients with itching, % 85 87
complications of primary genital herpes simplex virus in- Mean duration of itching (range),
d 4.6(1-16) 5.2(1-15)
fections include cutaneous or visceral dissemination, and Patients with dysuria, %* 9 27
thrombocytopenia (57, 58). Monoarticular arthritis has Mean duration of dysuria (range),
been reported in association with disseminated herpes <*t 1.7(1-3) 4.1 (1-8)
simplex virus-1 infection (59). Immunosuppressed pa- Patients with urethral or vaginal
discharge, %* 4 45
tients, especially those with T-cell abnormalities such as Mean duration of discharge
thymic aplasia, Wiskott-Aldrich syndrome, or those re- (range), df 1.7(1-5) 5.3 (1-14)
ceiving immunosuppressive medication, may develop cu- Patients with tender lymph nodes,
taneous or visceral dissemination of herpes simplex virus % 23 31
(60, 61). Anecdotal experience has suggested that pri- Mean duration of tender nodes
(range),d 9.2(1-25) 6.9(1-15)
mary genital herpes in pregnancy may predispose to cuta- Mean number of lesions at onset of
neous and visceral dissemination (62, 63). Because of the illness (range) 7.5 (1-25) 4.8(1-15)
severe morbidity and high mortality of these infections, Mean lesion area (range), mm2 62.7 (2-270) 53.5 (4-208)
patients with disseminated herpes simplex virus infection Patients with bilateral lesions, %% 15 4
are candidates for antiviral chemotherapy. Patients forming new lesions after
presenting for care, %% 43 28
Fungal Superinfection: We did routine wet mount ex- Mean duration to crusting (range),
amination of vaginal fluid in 10% potassium hydroxide d 4.1 (2-10) 4.7 (2-13)
at the first clinical consultation and at the second to third Mean duration to healing (range),
d 10.6 (5-25) 9.3 (4-29)
week visit. Vaginal superinfection with Candida species Mean duration of viral shedding
was shown in 14% of women with primary genital herpes from lesions (range), d 4.2(1-20) 3.9 (2-14)
in whom the initial potassium hydroxide examination Patients shedding virus from
was negative. Three percent of men developed clinical cervix, % NA 12
evidence of yeast balanitis. Characteristically, fungal su- Duration viral shedding from
cervix (range), d NA 3.2(1-16)
perinfection in women was seen during the second week
of disease, when external genital lesions and mucopuru- *p<0.01 (chi-squared test).
tp<0.01 (Student's t test).
lent cervicitis due to herpes simplex virus were resvolv- Jp<0.05 (chi-squared test).
ing. Vaginal discharge, vulvar erythema, and itching in-
creased, often associated with the appearance of small develop constitutional symptoms, have fewer complica-
vulvar fissures, and pseudohyphae were seen on potassi- tions, and have a shorter duration of disease than persons
um hydroxide examination of vaginal discharges. with true primary genital herpes. Immune mechanisms
Our use of only the potassium hydroxide examination that may account for the milder course of nonprimary
may have underestimated the rate of yeast superinfection first episodes include the presence of preexisting neutral-
in this patient population. Yeast vaginitis occurred much izing antibody to herpes simplex virus that has been
more frequently in women with primary genital herpes shown to inactivate extracellular virus and interrupt the
than in those with recurrent disease. Whether this com- spread of herpes simplex virus infection in tissue culture
plication is related to cervicitis, altered vaginal flora, and in animal models, and the earlier appearance of cel-
changes in local immune responses, or other factors is lular immune responsiveness to herpes simplex virus anti-
unknown. gens (3, 8, 64). Although the duration of viral shedding
from external genital lesions is similar for men and wom-
SUMMARY: FIRST EPISODES OF GENITAL HERPES en with primary genital herpes, the duration of symptoms
First-episode genital herpes is a disease of both system- is longer, and, more important, complications occur
ic and local manifestations. Over 50% of patients with more frequently in women. The greater severity of pri-
primary genital herpes suffer constitutional symptoms; mary disease in women may be related to cervical in-
33% have headache, stiff neck, and mild photophobia, volvement and the greater total surface area of infection.
and almost all have several anatomic sites of involve-
ment, such as the cervix, urethra, pharynx, extragenital Recurrent Infection
cutaneous regions, and central nervous system. Herpes CLINICAL MANIFESTATIONS
progenitalis is clearly a misnomer in first-episode genital The clinical manifestations of recurrent genital infec-
herpes. Patients with nonprimary first episodes less often tion in 144 women and 218 men are shown in Table 5.
Corey eta/. • Genital Herpes Infections 965

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 Figure 4 . Comparison of the mean duration of symptoms and signs in patients with first episode primary, first episode non-primary, and
recurrent genital herpes (n = 6 2 7 ) . SD = standard deviation.
Constitutional symptoms were infrequent with episodes
of recurrent genital herpes appearing in 5% and 12% of
men and women, respectively. The mean duration of lo-
cal symptoms, the mean duration of viral shedding, the
mean time to crusting of lesions, and the time to com-
plete healing of lesions were all significantly shorter in
patients with recurrent genital herpes than those with
first-episode primary or first-episode nonprimary infec-
tions (Figure 4 ) .
The symptoms of recurrent genital herpes were more
severe in women than in men. Lesions were described as
painful by 88% of women and 67% of men. Most women
described the pain as moderate to severe whereas most
men described the pain as mild. The mean duration of
pain was 5.9 days in women and 3.9 days in men
(p < 0.05). Dysuria, described as external by most wom-
en and internal by most men, was reported by 27% of
women and 9% of men. Herpes simplex virus was isolat-
ed from the urethra from only 4% of men with recurrent
genital herpes.
Nearly 50% of the patients with recurrent genital her-
pes had a prodrome consisting of a mild "tingling" hy-
peresthesia or dysesthesia that began from 1 to 2 days to
a few hours before the appearance of the vesicles. In some
patients, the prodrome included pain that radiated into
the buttocks and hips (sacral dermatomal neuralgia). In
many patients these symptoms were often the most both-
ersome part of the recurrent episode.
The mean lesion was area approximately 10% that
seen with primary genital herpes. The number of lesions
differed greatly, but in contrast to the single large vesicu-
lar lesions typical of recurrent oral-labial herpes, recur-
rent genital herpes usually produced several small vesicu-
lar lesions that coalesced into larger ulcers (Figure 5).
Lesions generally increased in size over the first 3 days of
the episode, reached a plateau during days 4 to 8, and
then rapidly resolved (Figure 6). New lesions developed
during the course of infection in 4 3 % of men and 28% of
women (p < 0.05). The mean duration of lesions was
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10.6 days in men and 9.3 days in women.
We isolated herpes simplex virus type-1 from genital
lesions in only five patients with recurrent episodes of
genital herpes. Among women who presented with recur-
rent genital vulvar lesions, herpes simplex virus was con-
comitantly isolated from the cervix from only 12%. Her-
pes simplex virus ulcerations were seen on the exocervix
only infrequently, although culposcopic examination was
not routinely done. Extragenital lesions were seen at the
time of recurrent genital herpes in 3 % of men and 5% of
women.
R E C U R R E N T INFECTION IN I M M U N O C O M P R O M I S E D
PATIENTS
Although much of the literature describing herpes sim-
plex virus infection in immunosuppressed patients has
concentrated on recurrent herpes simplex virus-1 infec-
tions, the increasing prevalence of genital herpes and the
increasing use of immunosuppressive agents have result-
ed in an increasing awareness of genital herpes in this
patient population (65). In immunocompromised pa-
tients, recurrent genital herpes may cause large numbers
of coalescent vesicles and ulcers from which the virus can
be isolated for prolonged periods of time (median, 13 to
15 days) (66). Recurrent genital herpes may also lead to
disseminated infection. Ramsey and associates (67) re-
ported the isolation of herpes simplex virus-2 from lung
parenchyma of 1 of 15 adult bone marrow transplant
recipients who developed herpes simplex virus pneumoni-
tis. Early antiviral chemotherapy is useful in decreasing
the morbidity of these episodes in immunosuppressed pa-
tients (66, 68). In some settings the use of prophylactic
acyclovir may decrease the incidence of recurrent genital
herpes (68, 69).
R A T E OF R E C U R R E N C E
The risk and rate of recurrence of genital herpes ap-
pears to be influenced by herpes simplex virus type, host
immune response to genital infection, and a previous his-
 tory of past genital herpes. We have prospectively fol-
lowed 175 of the 209 patients with first episodes of genital
herpes including 18 of 20 with primary genital herpes
simplex virus-1 infection. Subsequent recurrent episodes
were reported by 55% of patients after primary genital
herpes simplex virus-1 infection compared to 88% of pa-
tients after primary genital herpes simplex virus-2 infec-
tion (p < 0.05). The mean rate of recurrence was 0.09
recurrences per month after primary genital herpes sim-
plex virus-1 infection compared to 0.3 and 0.4 in patients
with primary (p < 0.01) and nonprimary (p < 0.01)
genital herpes simplex virus-2 infections. Among patients
with primary herpes simplex virus-2 infections, men ap-
peared to have slightly more frequent recurrences (0.429
per month of follow-up) than women (0.314 per month
of follow-up). However, the slightly lower frequency of
complete follow-up in our male populations, 63% fol-
lowed for 12 months compared to 83% follow-up in our
female population, may overestimate the mean recur-
rence rate in men.
Long-term studies are not available to determine
whether the rate of recurrence of genital herpes simplex
virus infection changes over time. Preliminary analysis of
the recurrence rate among a small cohort of men with
recurrent genital herpes followed in our clinic suggests
that the mean rate of observed recurrence was about 50%

Figure 6. Mean lesion area by day of disease in patients with recur-

rent genital herpes.

less in men with a past history of genital herpes of more

Figure 5. Penile vesicles in a man with recurrent genital herpes.
than 4-years duration, as compared with those with a
past history of only 6-months to 2-years duration. How-
ever, a recent survey of a large cohort of patients with
recurrent genital herpes showed no difference in the me-
dian recurrence rate for patients having the disease more
than 5 years versus those who had it for less than 5 years
(15).
Although host factors that affect the subsequent rate of
recurrence after primary infection are not defined, the
development of high titers of complement-independent
neutralizing antibody after primary infection is associat-
ed with a higher risk of subsequent recurrences. In addi-
tion, the median time to the next recurrence is longer in
patients with first episodes (median, 123 days) compared
to recurrent episodes (median, 55 days) of genital herpes
(3). These data suggest that severity of the episode may
influence the time to next recurrence. The severity of in-
fection and the frequency of seroconversion with the two
herpes simplex virus types are similar. As such, neither
severity nor serum antibody response appears to account
for the difference in rate of recurrence between genital
herpes simplex virus-1 and genital herpes simplex virus-2
infections.
The lower rate of recurrence of genital herpes simplex
virus-1 infection, as compared to genital herpes simplex
virus-2 infection, helps explain why most isolates of her-
pes simplex virus from genital sites are herpes simplex
Corey etaf. • Genital Herpes Infections 967

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 virus-2. It is unclear, however, whether the difference in
recurrence rates between herpes simplex virus-1 and her-
pes simplex virus-2 genital infections is due to a lower
frequency of the establishment of sacral ganglionic laten-
cy with herpes simplex virus-1, or to differences in the
rate of reactivation of herpes simplex virus-1 versus her-
pes simplex virus-2 once latency has been established.
Recently, latent infection of the sacral nerve root ganglia
was shown in only 27% of mice after intravaginal inocu-
lation with herpes simplex virus-1 compared to 87% of
mice inoculated intravaginally with herpes simplex virus-
2 (70). In guinea pigs with experimental vaginal infec-
tion, the inoculum of virus and virus strain appear to be
related both to the number of latently infected ganglia
and subsequent antibody response (71). Inoculum size,
severity of primary infection, and strain to strain differ-
ences in herpes simplex virus-2 isolates may influence the
rate of recurrence in humans after herpes simplex virus-2
infection.
S U M M A R Y : R E C U R R E N T G E N I T A L HERPES
The clinical symptoms and manifestations of recurrent
genital herpes are less severe and of shorter duration than
those of primary or nonprimary first episodes of genital
herpes. There is, however, considerable variability in the
intensity and duration of symptoms, number of lesions,
and duration of viral shedding and of lesions among per-
sons, and between episodes in the same person. New vesi-
cle formation is common during recurrences. The major
morbidity of recurrent genital herpes is the frequency of
recurrence and the fear of transmission of disease to an
infant or sexual partner. Patients with genital herpes
should be instructed about the nature of prodromal
symptoms and how to detect lesions if local symptoms of
disease are present. We instruct patients to avoid sexual
intercourse when prodromal symptoms or lesions occur
and resume sexual activity only after lesions completely
reepithelialize, because herpes simplex virus can be isolat-
ed from lesions even at the crust stage of disease. Educa-
tion of the patient as to the manifestations and mode of
transmission of disease has, in our experience, been of
greater use than rigid guidelines as to when to resume
sexual activity after the onset of an episode.
Genital Herpes Simplex Virus Infections in Pregnancy
One of the major concerns of patients with genital her-
pes is the effect of disease on pregnancy and on the infant.
The incidence of genital herpes simplex virus recurrences
during pregnancy as well as the incidence of neonatal
herpes simplex virus infection appears to be influenced by
the socioeconomic status, age, and past sexual activity of
the patient population studied (2, 5). In an urban patient
population, serologic evidence suggesting past herpes
simplex virus-2 infection was found in 35.7% of obstetri-
cal patients (72). Herpes simplex virus has been isolated
from about 1 % of obstetric patients from lower socioeco-
nomic class (73). Estimates of the incidence of neonatal
herpes have ranged from 1 in 3000 to 1 in 20 000 live
births (39). Neonatal herpes simplex virus infection is
not a reportable disease in the United States. The overall
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estimated frequency of neonatal herpes simplex virus in-
fection in the United States is thought to be approximate-
ly 1 in 7500 live births, or about 500 cases yearly.
CLINICAL COURSE
The severity, duration of viral shedding, and mortality
rate of herpes simplex virus-2 infection in pregnant mice
are significantly greater than in nonpregnant mice, and
progesterone and prostaglandins have been shown to en-
hance the spread of herpes simplex virus in tissue culture
(74, 75). Although the risk of dissemination of herpes
simplex virus infection may be increased in pregnant
women, only anecdotal evidence for this observation ex-
ists (62, 63). In our experience, most of the clinical man-
ifestations of recurrent genital herpes, including the fre-
quency of cervicitis, pain, constitutional symptoms, and
duration of lesions are similar in pregnant and nonpreg-
nant women (29). However, it is not known whether the
frequency of symptomatic or asymptomatic vulvar or
cervical viral shedding is increased in pregnancy or
changed during the course of pregnancy.
EFFECTS O N P R E G N A N C Y O U T C O M E
Studies in the 1960s in lower socioeconomic popula-
tions suggested that genital herpes simplex virus infection
is associated with an increased frequency of spontaneous
abortion and premature delivery (76). Among women
with herpes simplex virus cervical infection found by Pap
smear, Nahmias and associates (76) reported spontane-
ous abortion in 5 of 9 women thought to have primary
genital herpes, 7 of 28 women thought to have recurrent
genital herpes, ana 696 of 6536 women in the general
hospital population. The rate of spontaneous abortion
may be higher with primary genital herpes than recurrent
genital herpes because of the higher frequency, longer
duration, and higher titer of herpes simplex virus in cer-
vical secretions, and subsequent higher risk of ascending
chorioamnionitis. The potential for hematogenous spread
and less prompt immune response in women with pri-
mary infection may also account for these differences.
Although a 25% rate of spontaneous abortion was seen
in the women with recurrent genital herpes studied by
Nahmias and associates, these patients may not represent
all women with recurrent genital herpes during pregnan-
cy, because all had herpes simplex virus infection of the
cervix. Recurrent vulvar genital herpes is usually not as-
sociated with concomitant cervicitis. Similarly, some
studies have shown that the spontaneous abortion rate in
some groups of normal women may be as high as 40%
(77). It is uncertain whether middle-class women with
recurrent vulvar herpes who infrequently have herpes
simplex virus cervicitis have an increased risk of early
spontaneous abortion.
Similarly, the relationship between recurrent genital
herpes and premature delivery requires clarification.
Nahmias and associates reported premature delivery by
13% of women who had herpes simplex virus cervicitis
during weeks 20 to 24 of gestation, 24% women with
herpes simplex virus cervicitis during weeks 24 to 28,
22% between weeks 28 to 32, and 30% between weeks 32
 to 36. The rate of premature delivery was 35% in women
thought to have clinical evidence of primary infection as
compared to only 14% in those thought to have recur-
rent genital herpes. The rate of premature delivery for the
general hospital population was 17.6%. Two recent stud-
ies in middle-class white women with recurrent genital
herpes simplex virus infection showed no increased risk
of premature delivery in these women (29, 78). Future
studies are needed comparing the relative risk of prema-
ture delivery in pregnant women with recurrent herpes
simplex virus cervicitis and those with only recurrent vul-
var lesions.
TRANSMISSION OF INFECTION TO THE INFANT
The major source of neonatal herpes simplex virus in-
fection is via contact with the infected genital tract at the
time of delivery (5). The risk of neonatal herpes simplex
virus infection and subsequent clinical illness after vagi-
nal delivery through a birth canal infected with herpes
simplex virus has not been precisely ascertained. Primary
genital herpes appears to cause a greater frequency of
transmission of disease to the infant than does recurrent
genital herpes. The risk of neonatal infection may be as
high as 50% with vaginal delivery during primary genital
herpes in the mother, whereas the risk appears to be
about 5% with vaginal delivery during recurrent herpes
simplex virus cervicitis (39).
Transmission of herpes simplex virus from mother to
infant may occur during symptomatic or asymptomatic
maternal infection. In recent studies, over 70% of infants
with neonatal herpes simplex virus infection had mothers
without symptoms or signs of infection at delivery (79).
In our own institution we have, however, found a history
of previous genital herpes in the mother or her sexual
partners in 13 of the last 20 parents of infants with neo-
natal herpes simplex virus-2 infection, although 11 of
these 13 mothers were asymptomatic at the time of deliv-
ery. In addition to contact with infected maternal genital
secretions, other factors such as virus titer in maternal
secretions, duration of rupture of membranes, local envi-
ronmental and immune factors, use of fetal monitoring
devices, cellular immune responsiveness of the neonate,
and titer of maternal antibody in serum or amniotic fluid
may be important determinants of whether infants devel-
op infection (80, 81).
MANAGEMENT OF PREGNANT WOMEN WITH GENITAL
HERPES
The management of the pregnant woman with genital
herpes simplex virus infection must be based on the clini-
cal course of disease in the mother as well as the avail-
ability of virologic and laboratory support. The acquisi-
tion of primary infection in pregnancy carries the risk of
transplacental transmission of virus to the infant. One
question commonly raised by women with first episodes
of genital herpes during pregnancy who do not abort is
the use of amniocentesis to ascertain if intrauterine fetal
infection is present. Although studies evaluating the pre-
dictive value of amniotic fluid cultures in this clinical
situation are not available, current evidence suggests that
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false-positive results as well as false-negative results can
be obtained from this procedure. Uninfected, apparently
normal infants have been delivered, despite the antepar-
tum isolation of herpes simplex virus from amniotic fluid
(82). Resolution of infection despite the presence of an
infected infant or damaged placenta may also result in
false-negative amniotic fluid cultures in a congenitally in-
fected infant. In addition, antiviral substances in amniot-
ic fluid may make isolation of virus difficult (83). Thus,
amniocentesis does not appear to be a reliable test for
predicting the presence or absence of a congenitally in-
fected infant. Most pregnant women with recurrent vul-
var herpes deliver normal infants, and routine amniocen-
tesis is not recommended in these women or in those who
have had recurrent episodes of genital herpes in the early
stages of pregnancy.
Criteria for laboratory screening and surveillance for
recurrent herpes simplex virus infections in pregnancy as
well as delivery procedures for women with recurrent
genital herpes simplex virus infections are the most fre-
quently encountered questions from physicians managing
pregnant women with genital herpes. It is obvious that
the high prevalence rate of antibody to herpes simplex
virus-2 in pregnant populations (ranging from 10% to
50%) and the low incidence of neonatal disease (estimat-
ed at 1 in 7500 live births) suggests that only a small
percentage of women who have been infected with herpes
simplex virus-2 deliver infants who acquire the disease.
Cesarean section is, therefore, not routinely warranted
for all women with either clinical, virologic, or serologic
evidence of genital herpes. Because intrapartum trans-
mission of infection accounts for most cases, only women
who shed herpes simplex virus at or near the time of
delivery need be considered for abdominal delivery. Be-
cause asymptomatic intrapartum shedding of virus from
the cervix or vulvar area appears to be an important
source of neonatal infection, laboratory and clinical
methods to detect the presence of cervical and external
genital herpes simplex virus infection should be used near
term in pregnant women with a history of recurrent geni-
tal herpes. Women who have had sexual partners with
genital herpes or who have herpes simplex virus-2 anti-
body are also candidates for virologic screening proce-
dures. Although viral isolation is the most sensitive labo-
ratory method for detection of herpes simplex virus, use
of more rapid viral diagnostic techniques, such as immu-
nofluorescence and cytologic monitoring can be of use.
Most authorities recommend starting virologic or cyto-
logic monitoring between weeks 32 and 36 of gestation
(84). Thereafter, cultures or smears of cervical and ex-
ternal genital secretions should be obtained at least week-
ly.
Patients with a history of recurrent genital herpes
should be encouraged to come to the delivery room as
soon as possible after the onset of labor or rupture of
membranes. At this time, careful examination of the ex-
ternal genitalia and the cervix should be done. If avail-
able, a smear of the cervical secretions is recommended
for cytologic examination. In a woman with previous
genital herpes who has been followed with weekly cul-
Corey et at. • Genital Herpes Infections 969
 tures for herpes simplex virus and has no clinical evi-
dence of lesions or recent evidence of asymptomatic viral
shedding, vaginal delivery can be safely done. A negative
cytologic or immunofluorescent examination for herpes
simplex virus antigen at the onset of labor gives further
reassurance. Any evidence of asymptomatic viral shed-
ding from the cervix or external genitalia, or clinical evi-
dence of herpes lesions involving the genital tract at the
onset of labor are indications for abdominal delivery.
Controversy exists as to denning "near the time of la-
bor." For example, if a genital lesion or cervical virus
culture was positive at 34 weeks and the woman enters
labor at 38 weeks, should delivery be abdominal or vagi-
nal? For these women, frequent sampling techniques and
communication between the virology laboratory and the
clinician can reduce the frequency of cesarean section. It
is our current policy that if an episode of asymptomatic
cervical viral shedding or genital lesions has been found
after 34 weeks of gestation, sampling is done more often
(two to three times weekly). If two sequential viral cul-
tures incubated for 3 to 4 days are negative and no genital
lesions are present at the time of delivery, we recommend
vaginal rather than abdominal delivery. If any evidence
of a clinical lesion is present at the time of delivery, we
recommend abdominal delivery.
Another concern is the relation between the duration
of ruptured membranes and potential for transmission to
the infant. Delivery of infants by cesarean section, even
from women with intact membranes, has occasionally re-
sulted in neonatal herpes (84). Prolonged contact with
infected secretions may increase the risk of neonatal in-
fection. Many authors recommend that if membranes
have been ruptured for over 4 to 6 hours, cesarean sec-
tion should no longer be considered. However, as noted
earlier, only 15% to 25% of women with recurrent exter-
nal genital lesions have concomitant herpes simplex virus
cervicitis. The infants of mothers with recurrent external
genital herpes may not come in prolonged contact with
infected genital secretions until the late stages of labor.
Thus, in women with recurrent genital herpes who have
active external genital lesions at the time of labor, we still
recommend abdominal delivery, irrespective of the dura-
tion of rupture of membranes unless cervical involvement
has been shown near term by clinical or laboratory exam-
ination. In women with recurrent genital herpes, manipu-
lations that result in breaks or abrasions of fetal skin such
as fetal scalp electrodes, blood sampling, or vacuum ex-
traction should be avoided or used only after careful con-
sideration of their obstetrical indications.
HOSPITAL ISOLATION OF T H E I N F A N T
Infants delivered by cesarean section before the rup-
ture of membranes or by vaginal delivery after virologic
and cytologic monitoring techniques show no evidence of
recent maternal herpes simplex virus infection are at min-
imal risk of developing herpes simplex virus infection.
Nonetheless, most hospitals recommend segregating such
infants from others. If this is not feasible, we recommend
putting the infant in an isolette, making hospital person-
nel aware of the necessity to use wound and skin precau-
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tions, and proper handwashing techniques.
Infants whose mothers were considered infectious at
delivery, should be placed in isolation (85). In these in-
fants, viral cultures, liver function studies, and cerebro-
spinal fluid examinations should be obtained during the
first week of life and the infant watched closely for the
first month of life. Any symptoms of neonatal disease
such as poor feeding, fever, hypothermia, skin lesions, or
central nervous system signs such as seizures or abnor-
mal cerebrospinal fluid examination should lead to an
expeditious study for evidence of neonatal herpes simplex
virus infection (86).
Contact between infant and mother should also be
handled on an individual basis. For women who acquire
primary genital herpes near term, the high risk of late
extragenital lesions, and the high titers and prolonged
duration of viral shedding suggest that separation of
mother and infant is warranted. For mothers with recur-
rent genital herpes, careful protection of the infant from
exposure to infected genital secretions is adequate. When
handling the infant in the hospital, the mother should
wear a gown and observe proper handwashing tech-
niques. We allow rooming in with mothers who have
been taught protective measures and are cognizant of the
importance of handwashing after touching potentially in-
fectious lesions and before touching the infant. Oral-labi-
al herpes may be a greater risk to the infant for acquisi-
tion of herpes simplex virus infections than genital herpes
simplex virus (87). Nursery personnel and other adults
with oral-labial lesions caused by herpes simplex virus
should be excluded from contact with the newborn in-
fant.
Summary
Genital herpes simplex virus infection is a disease of
growing public health importance. There are major gaps
in understanding the pathogenesis and natural history of
this infection. Available data suggest that in some groups
a decrease in the age-specific prevalence of oral-labial
herpes simplex virus and an increase in the age-specific
prevalence of genital herpes simplex virus infections may
be occuring simultaneously. In the United States sympto-
matic genital herpes is a prominent disease of middle-
class white men and women between the ages of 18 and
44 years. This infection is frequently seen by physicians
in private practice.
Genital herpes is a disease with diverse clinical mani-
festations. Seroepidemiologic studies suggest that asymp-
tomatic infection is common. The infection to disease
ratio as well as determinants associated with the
development of clinical as compared to asymptomatic in-
fection are largely unknown. First episodes of clinically
manifest genital herpes involve several anatomic sites,
last about 3 weeks, and have a relatively high frequency
of neurologic and extragenital manifestations. Recurrent
episodes of genital herpes are, in contrast, of much milder
duration and intensity. The major morbidity of recurrent
genital herpes is its frequency of recurrence, chronicity,
and effect on the patient's personal relationships. For
women, the long-term burden of having an increased risk
 of subsequent cervical abnormalities and potential trans-
mission of disease to an infant are of major concern.
Recent studies suggest that the use of new antiviral
agents such as acyclovir may significantly influence mor-
bidity ( 1 , 66, 68). However, in evaluating therapy one
must distinguish between the effect of shortening the
course of the disease and influencing the recurrence rate
over time. Further knowledge of the long-term natural
history of the disease and factors responsible for recur-
rent disease are needed if we are to devise new ap-
proaches to the therapy and appropriate strategies for
prevention of this physically and psychosocial^ devastat-
ing disease.
ACKNOWLEDGMENTS: Grant support: in part by grants AI-14495, AI-
20381, and A M 2192.
• Requests for reprints should be addressed to Lawrence Corey, M.D.; Divi-
sion of Virology, Children's Orthopedic Hospital Medical Center, P.O. Box
C5371, 4800 Sand Point Way, Seattle, WA 98105.
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