27 Herpes Simplex Virus
Infections
DAVID W. KIMBERLIN and KATHLEEN M. GUTIERREZ
CHAPTER OUTLINE Herpes Simplex Virus
Structure
Replication
Latency and Reactivation
Epidemiology and Transmission
Maternal Infection
Factors Influencing Transmission of
­Infection to the Fetus
Incidence of Newborn Infection
Times of Transmission of Infection
Immunologic Response
Neonatal Infection
Pathogenesis and Pathology
Clinical Manifestations
Diagnosis
Clinical Evaluation
Laboratory Assessment
Neonatal herpes simplex virus infection (HSV) was iden-
tified as a distinct disease in the 1930s. The first written
descriptions of neonatal HSV were attributed to Hass, who
described the histopathologic findings of a fatal case, and
to Batignani, who described a newborn child with HSV
keratitis,1,2 During the initial decades that followed, our
understanding of neonatal HSV infections was based on
histopathologic descriptions of the disease, which indicated
a broad spectrum of organ involvement in infants.
An important scientific breakthrough occurred in the
mid-1960s, when Nahmias and Dowdle3 demonstrated
two antigenic types of HSV. The development of viral typing
methods provided the tools required to clarify the epidemiol-
ogy of these infections. HSV infection “above the belt,” pri-
marily of the lip and oropharynx, was found in most cases
to be caused by HSV type 1 (HSV-1). Infections “below the
belt,” particularly genital infections, were usually caused by
HSV type 2 (HSV-2). The finding in the 1960s and 1970s
that genital HSV infections and neonatal HSV infections
were most often caused by HSV-2 suggested a cause and
effect relationship between these two entities. This causal
relationship was strengthened by detection of the virus in
the maternal genital tract at the time of delivery, indicating
that acquisition of the virus occurs by contact with infected
genital secretions during birth.
Knowledge of HSV structure and function, epidemiology,
and natural history, and of the pathogenesis of neonatal
HSV infection, has increased during the past 5 decades.4 The
Treatment
Background
Antiviral Drugs
Other Issues in Acute Management
Long-Term Management of Infected Infants
Prevention
Background
Management of Pregnant Women with
Known Genital Herpes
Management of Infants of Mothers with
Genital Herpes
Conclusion
development of antiviral therapy represented a significant
advance in the management of infected children and has
substantially decreased the morbidity and mortality asso-
ciated with neonatal HSV infections. Neonatal HSV infec-
tion is more amenable to prevention and treatment than
many other viral and bacterial diseases affecting neonates
because it is acquired most often at birth rather than in
utero. Postnatal acquisition of HSV-1 has been documented
from nonmaternal sources, and more cases of genital her-
pes caused by HSV-1 have been identified more recently,
including HSV-1 in the maternal genital tract from changes
in sexual practices that result in increased likelihood of oral-
genital contact. This evolving natural history of genital
herpetic infection has the potential to impact the incidence
and outcomes of neonatal HSV infections. Perspectives on
the changing presentations of neonatal HSV infection, the
obstacles to diagnosis, and the value of antiviral therapy are
addressed in this chapter.
Herpes Simplex Virus
STRUCTURE
Herpes simplex virus types 1 and 2 are members of the
large family of herpesviruses.4 Other human herpesviruses
include cytomegalovirus, varicella-zoster virus, Epstein-
Barr virus, and human herpesviruses 6 (including variants
843
844 SECTION III • Viral Infections
6A and 6B), 7, and 8. Structurally, these viruses are virtu-
ally indistinguishable. The viral DNA genome is packaged
inside an icosahedral capsid that is surrounded by a layer of
proteins called the tegument. A lipid envelope that contains
viral glycoproteins surrounds the capsid and tegument.
These glycoproteins mediate virion attachment and entry
into cells.
The HSV-1 and HSV-2 genomes consist of approximately
150,000 base pairs and encode more than 100 proteins.4
The viral genomes consist of two components, L (long) and
S (short), each of which contains unique sequences that
can invert, generating four isomers. Viral genomic DNA
extracted from virions or infected cells consists of four equal
populations that differ in the relative orientation of these
two unique components. Although the two viruses diverged
millions of years ago, the order of genes in the HSV-1 and
HSV-2 genomes follows the same linear pattern, and most
genes have counterparts in both viruses. The nucleotide
sequence of related genes and the amino acid residues of the
proteins they encode often differ significantly, however.5,6
The two viral types can be distinguished by using restric-
tion enzyme analysis of genomic DNA or, more recently,
by sequencing of selected genes or regions of the genome,
which allows precise epidemiologic investigation of virus
transmission.
REPLICATION
Herpes simplex virus replication is characterized by the
transcription of three gene classes—α, β, and γ—that
encode viral proteins made at immediate-early, early, and
late times after virus entry into the cell.4 Many of these
genes can be removed from the viral genome without block-
ing the capacity of the virus to replicate in cultured cells,
but most have important functions during infection of the
host. The HSV genome can also be manipulated to insert
foreign genes without inhibiting viral replication. Muta-
tions that modify the virulence of HSV-1 and HSV-2 may
provide an opportunity to design genetically engineered
herpesviruses for use as vaccines for genital herpes or as
therapeutic agents in the treatment of brain tumors.7
HSV α genes are expressed at immediate-early times
after infection and are responsible for the initiation of rep-
lication. These genes are transcribed in infected cells in the
absence of viral protein synthesis. Products of the β genes,
or early genes, include the enzymes necessary for viral rep-
lication, such as HSV thymidine kinase, which is targeted
by acyclovir and related antiviral drugs, and other regula-
tory proteins. β genes require functional α gene products
for expression. The onset of expression of β genes coincides
with a decline in the rate of expression of α genes and an
irreversible shutoff of host cellular macromolecular pro-
tein synthesis. Structural proteins, such as proteins that
form the viral capsid, are usually of the γ, or late, gene.
The γ genes are heterogeneous and are differentiated from
β genes by their requirement for viral DNA synthesis for
maximal expression. Most glycoproteins are expressed
predominantly as late genes. In addition to its regulatory
and structural genes, the virus encodes genes that allow
initial evasion of the innate host cell response, including
gene products that block the interferon (IFN) pathway.
HSV-1 and HSV-2 also express proteins that interfere with
adaptive immunity, as exemplified by an immediate-early
protein, ICP47, that mediates the downregulation of major
histocompatibility complex class I molecules, which are
required for recognition of HSV-infected cells by HSV-spe-
cific CD8+ T cells.8,9 Replication of viral DNA occurs in the
nucleus of the cell. Assembly of the virus begins with for-
mation of nucleocapsids in the nucleus, followed by egress
across the nuclear membrane and envelopment at cyto-
plasmic locations. Virus particles are transported to the
plasma membrane, where progeny virions are released.
HSV glycoproteins have been designated as glycoproteins
B, C, D, E, G, H, I, L, and M.4,5 Glycoproteins B, D, and H
(gB, gD, and gH) are required for infectivity and are tar-
gets of neutralizing antibodies against HSV, glycoprotein
C (gC) binds to the C3b component of complement, and
the glycoprotein E (gE) and glycoprotein I (gI) complex
binds to the Fc portion of immunoglobulin G (IgG). The
amino acid sequences of glycoprotein G (gG) produced by
HSV-1 and HSV-2 are sufficiently different to elicit anti-
body responses that are specific for each virus type. The
fact that the antibody response to the two G molecules
exhibits minimal cross-reactivity has provided the basis for
type-specific serologic methods that can be used to detect
recent or past HSV-1 and HSV-2 infections.10-13 The close
antigenic relatedness between HSV-1 and HSV-2 interferes
with the serologic diagnosis of these infections when using
standard, type-common serologic assays, which do not
distinguish between individuals who have had past infec-
tion with HSV-1 only, infection with HSV-2 only, or dual
infection. Commercial type-specific tests based on gG must
be used for diagnosis of HSV-2 infection (Table 27-1).12,14
Clinicians should be knowledgeable regarding the type of
testing performed by the laboratory to interpret results
correctly.
LATENCY AND REACTIVATION
A common characteristic of all members of the human her-
pesvirus family is the ability to establish latency, to persist
in this latent state for various intervals of time, and to reac-
tivate and cause active infection (with or without disease)
and viral transmission at mucosal or other sites. After pri-
mary infection, the HSV genome persists in sensory gan-
glion neurons for the lifetime of the individual. The biologic
phenomenon of latency was first described at the beginning
of the 20th century, when Cushing15 observed in 1905
that patients treated for trigeminal neuralgia by sectioning
a branch of the trigeminal nerve developed herpetic lesions
in areas innervated by the sectioned branch. This specific
association of HSV with the trigeminal ganglion was sug-
gested by Goodpasture.16 Past observations have shown
that microvascular surgery of the trigeminal nerve tract
to alleviate pain associated with tic douloureux resulted
in recurrent lesions in greater than 90% of seropositive
individuals.17,18
Accumulated experience in animal models and from
clinical observations suggests that inoculation of virus at
the portal of entry, usually oral or genital mucosal tissue,
results in infection of sensory nerve endings at that site,
with subsequent transport of the virus to the dorsal root
ganglia.19 Replication at the site of inoculation enhances
access of the virus to ganglia but usually does not produce
 Table 27-1 Quick Reference Guide for Blood Tests to Accurately Detect Type-Specific HSV Antibodies
Biokit HSV-2 Rapid Test Euroimmun
(Also Sold as SureVue Anti-HSV-1 and HerpeSelect HSV-1 HerpeSelect 1 and
HSV-2 Rapid Test by Anti–­HSV-2 ELISA and HerpeSe- 2 Differentiation
Fisher HealthCare) BioPlex HSV Captia ELISA ELISA lect HSV-2 ELISA Immunoblot Liaison HSV-2 AtheNA MultiLyte
Supplier Biokit USA Bio-Rad Trinity Biotech USA Euroimmun US Focus Diagnostics Focus Diagnostics DiaSorin Inverness Medical
Laboratories LLC
FDA approved 1999 2009 2004 2007 2000/2002 2000 2008 2008
Antibodies HSV-2 only HSV-1 or HSV-2 HSV-1 or HSV-2 or HSV-1 or HSV-2 HSV-1 or HSV-2 or both HSV-1 and/or HSV-1 or HSV-1 and/or HSV-2
detected or both HSV-2 HSV-2
both
Best use of POC test to screen or test Screening or Screening or testing Moderate vol- Screening or testing Low volume High volume Screening or testing
test individuals > 3 months testing (high pregnant women ume STD patients or (moderate-to-
post-exposure volume) or STD clinic pregnant women high volume)
patients (moderate (moderate volume)
volume)
Collection Finger stick, whole Blood draw (sent Blood draw (sent to Blood draw (sent Blood draw (sent to Blood draw (sent to Blood draw Blood draw (sent to
method blood or serum in to laboratory) laboratory) to laboratory) ­laboratory) laboratory) (sent to laboratory)
clinic laboratory)
Test time 10 minutes 45 minutes ≈2 hours ≈2 hours ≈2 hours ≈2 hours 35 minutes ≈2 hours
FDA approved Yes Yes Yes Yes
for use
during
pregnancy
Test avail- Limited Limited Widely available Widely available
ability

27 • Herpes Simplex Virus Infections

Website www.bioki www.bio- www.trinity www.euroi www.herpe www.herpe www.diaso www.invernessmed
tusa.com rad.com biotech.com mmunus.com select.com select.com rin.com icalpd.com
For more 800-926-3353 800-224-6723 800-325-3424 800-913-2022 800-328-5669 877-546-8633
­information

From Kimberlin DW, Baley J: Guidance on management of asymptomatic neonates born to women with active genital herpes lesions, Pediatrics 131:e635-e646, 2013.
ELISA, Enzyme-linked immunosorbent assay; HSV, herpes simplex virus; POC, point of care; STD, sexually transmitted disease.

845
846 SECTION III • Viral Infections
signs of mucocutaneous disease; only a fraction of new
infections with HSV-1 and HSV-2 cause clinically recog-
nizable disease. When viral reactivation occurs at oral or
genital sites, virus then is transported back down axons to
mucocutaneous sites, where viral replication and shedding
of infectious HSV then occurs.
Recognizing that excretion of infectious virus during
reactivation is not usually associated with clinical signs
of recurrent herpes lesions is essential for understanding
the transmission of HSV to newborns. Clinically, silent
viral reactivations are much more common than recur-
rent lesions that are clinically apparent. This distinction
between asymptomatic infection and symptomatic disease
underlies much of the challenge in neonatal HSV preven-
tion because only those relatively fewer situations where
there are clinically apparent lesions can be expected to initi-
ate a response from treating physicians. Reactivation with
or without symptoms occurs in the healthy host in the pres-
ence of HSV-specific humoral and cell-mediated immunity.
Reactivation seems to be spontaneous, although symptom-
atic recurrences have been associated with physical or emo-
tional stress, exposure to ultraviolet light, or tissue damage;
immunosuppression is associated with an increased pre-
dilection for symptomatic HSV disease when reactivation
occurs. Persistence of viral DNA has been documented
in neuronal tissue of animal models and humans.4,20-22
Because the latent virus does not multiply, it is not suscep-
tible during latency to drugs such as acyclovir, which affect
DNA synthesis, and cannot be eradicated from the infected
host. Understanding of the mechanisms by which HSV
establishes a latent state and persists in this form remains
limited.
Epidemiology and Transmission
Transmission of HSV most often occurs as a consequence
of intimate person-to-person contact. Virus must come in
contact with mucosal surfaces or abraded skin for infection
to be initiated.
The usual mode of HSV-1 transmission is through direct
contact of a susceptible individual with infected secretions,
although transfer in respiratory droplets is possible. Acqui-
sition often occurs during childhood. Primary HSV-1 infec-
tion in a young child usually is asymptomatic, but clinical
illness is associated with HSV gingivostomatitis. Primary
infection in young adults has been associated with phar-
yngitis only or with a mononucleosis-like syndrome. Sero-
prevalence studies have shown that acquisition of HSV-1
infection, similar to that of other herpesvirus infections, is
related to socioeconomic factors.23,24 Antibodies, indicative
of past infection, are found early in life more often among
individuals of lower socioeconomic groups, presumably
reflecting the crowded living conditions that provide a
greater opportunity for direct contact with infected indi-
viduals. By the end of the first decade of life, 75% to 90% of
individuals from lower socioeconomic populations develop
antibodies to HSV-1.25-27 In middle and upper-middle socio-
economic groups, 30% to 40% of individuals are seroposi-
tive by the middle of the second decade of life.
A change in seroprevalence rates of HSV-1 has been
recognized in the past few decades, which reflects a delay
in acquisition of infection until later in life. Data from
the National Health and Nutrition Examination Surveys
(NHANES) recently have revealed that in 2005 to 2010
the seroprevalence of HSV-1 was 53.9%.28 From 1999 to
2004 and 2005 to 2010, HSV-1 seroprevalence declined
by nearly 7% (P < .01), with the largest decline being
observed among 14- to 19-year-olds, among whom sero-
prevalence declined by nearly 23%, from 39.0% to 30.1%
(P < .01). In this age group, HSV-1 seroprevalence declined
more than 29% from 1976 to 1980 and 2005 to 2010
(P < .01).28 As a result, an increasing number of adoles-
cents lack HSV-1 antibodies at sexual debut. This is occur-
ring at a time when almost half of teenagers 15 to 19 years
of age and more than four fifths of young adults 20 to 24
years of age have engaged in oral sex.29 Increasing rates of
genital HSV-1 infection already are being seen in several
studies published over the past decade, with 60% to 80%
of cases of genital herpes now being attributed to this virus
type.30-32
Because infection with HSV-2 is usually acquired
through sexual contact, antibodies to this virus are rarely
found until the age of onset of sexual activity.26 A progres-
sive increase in infection rates with HSV-2 in all popula-
tions begins in adolescence. In earlier studies, the precise
seroprevalence of antibodies to HSV-2 had been difficult
to determine because of cross-reactivity with HSV-1 anti-
gens. During the late 1980s, seroepidemiologic studies
performed using type-specific antigen for HSV-2 (glycopro-
tein G-2) identified this virus in approximately 25% to 35%
of middle-class women in several geographic areas of the
United States.11,33-35 Based on national health surveys, the
seroprevalence of HSV-2 in the United States from 1988
to 1994 was 21.9% for individuals 12 years and older,
representing a 30% increase compared with data collected
from 1976 to 1980.35 Among individuals with serologic
evidence of infection, less than 10% had a history of geni-
tal herpes symptoms. A statistically significant decline in
HSV-2 seroprevalence was observed from 1988 to 1994
and 1999 to 2004, but since that time findings suggest
seroprevalence has plateaued.36 HSV-2 seroprevalence
was 15.7% in 2005 to 2010, which was not significantly
different from the estimate in 1999 to 2004.28 Overall,
HSV-2 seroprevalence has increased significantly since
1976 to 1980, primarily because of the large increase
from 1976-1980 to 1988-1994.35 HSV-2 seroprevalence
is highly variable and depends on geographic region, sex,
age, race, and high-risk behaviors.37 The molecular epi-
demiology of HSV infections can be determined by restric-
tion enzyme analysis of viral DNA or polymerase chain
reaction (PCR) assay and sequencing of regions of the
HSV genome obtained from infected individuals. Viruses
have essentially identical genetic profiles when they are
from the same host or are epidemiologically related.38 In
a few circumstances, it has been shown, however, that
superinfection or exogenous reinfection with a new strain
of HSV is possible. Such occurrences are uncommon in a
nonimmunocompromised host with recurrent genital HSV
infection.38-40 Differences in the genetic sequence of viral
DNAs indicating exogenous infections are more common
in immunocompromised individuals who are exposed to
different HSVs, such as patients with acquired immunode-
ficiency syndrome.

MATERNAL INFECTION
Infection with HSV-2, which reactivates and is shed at
genital sites, is common in pregnant women. Using assays
to detect type-specific antibodies to HSV-2, seroepidemio-
logic investigations have shown that approximately one
in five pregnant women has had HSV-2 infection.24,34,41-45
Given the capacity of HSV to establish latency, the pres-
ence of antibodies is a marker of persistent infection of the
host with the virus. The incidence of infection in women
of upper socioeconomic class was 30% or greater in three
large studies.43,45,46 These investigations have shown that
most women with serologic evidence of HSV-2 infection
have no history of symptomatic primary or recurrent dis-
ease. New HSV-2 infections are acquired during pregnancy
with a frequency that is comparable to seroconversion rates
among nonpregnant women, and these infections also usu-
ally occur without clinical signs or symptoms.42-46 Even so,
most genital HSV shedding occurs from reactivation of viral
infection, rather than from primary HSV disease.47-49
HSV-1 is less likely than HSV-2 to reactivate in the genital
tract of nonpregnant women, especially after the first year
after infection.50 HSV-1 reactivations may occur after mid-
pregnancy, however, when women are relatively immuno-
suppressed.51 In contrast, genital HSV-2 continues to recur,
often frequently, for many years.52
Evaluation of pregnant women and their partners has
shown that women can remain susceptible to HSV-2 despite
prolonged sexual contact with a partner who has known
genital herpes.44 In this study, 1 in 10 women were found to
be at unsuspected risk for acquiring HSV-2 infection during
pregnancy as a result of contact with a partner whose HSV-2
infection was asymptomatic. Most maternal infections are
clinically silent during gestation. However, infection dur-
ing gestation may manifest in several clinical syndromes,
the most severe of which is widely disseminated disease.
As first reported by Flewett and coworkers53 in 1969 and
by others54,55 subsequently, disseminated infection during
pregnancy has been documented to involve multiple visceral
sites in addition to cutaneous ones. In a few cases, dissemi-
nation after primary oropharyngeal or genital infection has
led to severe manifestations of disease, including necrotizing
hepatitis with or without thrombocytopenia, leukopenia,
disseminated intravascular coagulopathy, and encephalitis.
Although rare, the mortality rate for these pregnant women
is greater than 50%. Fetal deaths occur in greater than 50%
of cases, although neonatal mortality does not correlate with
the death of the mother. Surviving fetuses have been deliv-
ered by cesarean section during the acute illness or at term,
and may not have evidence of neonatal HSV infection.
Earlier studies described an association of maternal pri-
mary infection before 20 weeks of gestation,56 with spon-
taneous abortion in some women. Although the original
incidence of spontaneous abortion after a symptomatic pri-
mary infection during gestation was thought to be 25%, this
estimate was not substantiated by prospective studies and
was erroneous because of the small number of women fol-
lowed. More precise data obtained from a prospective analy-
sis of susceptible women showed that 2% or greater acquired
infection, but acquisition of infection was not associated
with a risk of spontaneous abortion.57 With the exception
of rare case reports, primary infection that develops later in
27 • Herpes Simplex Virus Infections 847
gestation is not generally associated with premature rupture
of membranes or premature termination of pregnancy.58
Localized genital infection, whether it is associated with
lesions or remains asymptomatic, is the most common form
of HSV infection during pregnancy. Overall, prospective inves-
tigations using cytologic and virologic screening indicate that
genital herpes occurs with a frequency of about 1% in women
tested at any time during gestation.43,57 Most maternal genital
infections are due to recurrent HSV-2 infections when charac-
terized virologically and serologically.49 This potentially could
change as the incidence of HSV-1 genital infection, which is
more likely to be primary than recurrent, increases in the pop-
ulation.29 Because HSV infection of the infant is usually the
consequence of contact with infected maternal genital secre-
tions at the time of delivery, the incidence of viral excretion
at this time point has been of particular interest. The reported
incidence of viral excretion at delivery is 0.01% to 0.39% for all
women, regardless of their history of genital herpes.43,46
Several prospective studies have evaluated the frequency
and nature of viral shedding in pregnant women with a
known history of genital herpes. These women represent
a subset of the population of women with HSV-2 infection
because they had a characteristic genital lesion from which
virus was isolated. In a predominantly white, middle-class
population, symptomatic recurrent infection occurred dur-
ing pregnancy in 84% of pregnant women with a history
of symptomatic disease.59 Viral shedding from the cervix
occurred in only 0.56% of symptomatic infections and
0.66% of asymptomatic infections. These data are similar
to data obtained from other populations.33 The incidence
of cervical shedding in asymptomatic pregnant women has
been reported to range from 0.2% to 7.4%, depending on the
numbers of cultures that were obtained between symptom-
atic episodes. Overall, these data indicate that the frequency
of cervical shedding is low, which may reduce the risk of
transmission of virus to the infant when the maternal infec-
tion is recurrent. The frequency of maternal genital shed-
ding does not seem to vary by trimester during gestation.
Most infants who develop neonatal disease are born to
women who are completely asymptomatic for genital HSV
infection during the pregnancy and at the time of delivery.
These women usually have neither a past history of geni-
tal herpes nor a sexual partner reporting a genital vesicu-
lar rash and account for 60% to 80% of all women whose
infants become infected.60, 61
FACTORS INFLUENCING TRANSMISSION OF
INFECTION TO THE FETUS
The development of serologic assays that distinguish
HSV-1–specific antibodies from HSV-2–specific antibodies
allowed an accurate analysis of risks related to perinatal
transmission of HSV.10-13 The category of maternal genital
infection at the time of delivery influences the frequency
of neonatal acquisition of infection. Maternal infections
are classified as caused by HSV-1 or HSV-2 and as newly
acquired or recurrent.62 These categories of maternal infec-
tion status are based on virologic and serologic laboratory
criteria and are independent of clinical signs.
Women with recurrent infections are those who have pre-
existing antibodies to the virus type that is isolated from the
genital tract, which, until recently, has usually been HSV-2.
848 SECTION III • Viral Infections
Most women classified as having recurrent infection have
no history of symptomatic genital herpes. Infections that
are newly acquired, which have been referred to as first-­
episode infections, are categorized further as either primary or
nonprimary based on type-specific serologic testing. This dif-
ferentiation is made whether clinical signs are present or not.
First-episode primary infections are infections in which the
mother is experiencing a new infection with HSV-1 or HSV-2
and has not already been infected with the other virus type.
These mothers are seronegative for any HSV antibodies (i.e.,
negative for both HSV-1 and HSV-2 antibodies) at the onset
of infection. First-episode nonprimary infections are infections
in which the mother has a new infection with one virus type,
usually HSV-2, but has antibodies to the other virus type,
usually HSV-1, because of an infection that was acquired
previously.
Because transmission has been studied using type-specific
serologic methods, it has become apparent that attempts to
distinguish primary and recurrent disease by clinical crite-
ria are unreliable. Use of both serologic and virologic data to
classify the category of maternal infection is an important
advance because many “new” genital herpes infections in
pregnancy are actually recurrent infections and represent
the first symptomatic episode of a genital HSV infection
acquired at some time in the past. In one study designed
to evaluate acyclovir therapy, pregnant women who were
thought to have recent acquisition of HSV-2 based on symp-
toms all had been infected previously. These women were
experiencing genital symptoms, caused by reactivation of
latent virus, for the first time.55
A hierarchy of risk of transmission has emerged using
virologic and serologic laboratory tools to classify maternal
infection. Infants born to mothers who have a first-episode
primary infection at the time of delivery are at highest risk,
with transmission rates approaching 60%.49,57,60 Infants
born to mothers with first-episode nonprimary infections
are at lower risk, with transmission rates of approximately
25%.49 The lowest risk of neonatal acquisition occurs with
recurrent infection, when the mother has active infection
caused by shedding of virus that she acquired before the
pregnancy or earlier in gestation; the estimated attack rate
for neonatal herpes among these infants is approximately
2%.49 This estimate is reliable because it is based on the
cumulative experience from large, prospective studies of
pregnant women in which viral shedding was evaluated at
delivery, regardless of the mother’s history of genital herpes
or contact with a partner with suspected or documented
genital herpes.
The higher risk of transmission to the infant when the
mother has a new infection can be attributed to differences
in the quantity and duration of viral shedding in the mother
and in the transfer of passive antibodies from the mother
to the infant before delivery. Primary infection is associated
with larger quantities of virus replication in the genital tract
(>106 viral particles/0.2 mL of inoculum) and a period of
viral excretion that may persist for an average of 3 weeks.63
Many women with new infections have no symptoms but
shed virus in high titers. In some mothers, these infections
cause signs of systemic illness, including fever, malaise,
myalgias, dysuria, and headache. Viremia during primary
HSV infection in women is common and is associated with
systemic maternal symptoms.64 In a small percentage of
cases, significant complications, such as urinary retention
and aseptic meningitis, occur in the mother.
In contrast, virus is shed for an average of only 2 to 5 days
and at lower concentrations (approximately 102-103 viral
particles/0.2 mL of inoculum) in women with symptom-
atic recurrent genital infections. Asymptomatic reactiva-
tion is also associated with short periods of viral replication,
often less than 24 to 48 hours. One of the most important
observations about HSV infections that has emerged from
the evaluation of pregnant women is that new HSV-1 and
HSV-2 infections often occur without any of the manifesta-
tions that were originally described as the classic findings in
primary and recurrent genital herpes.
In parallel with the classification of maternal infection,
the mother’s antibody status to HSV at delivery is an addi-
tional factor that influences the likelihood of transmission
and probably affects the clinical course of neonatal herpes.
Transplacental maternal neutralizing antibodies have a
protective, or at least an ameliorative, effect on acquisition
of infection for infants inadvertently exposed to virus.65
Maternal first-episode primary or nonprimary infection
late in gestation may not result in significant passage of
maternal antibodies across the placenta to the fetus. Based
on available evidence, the highest risk of transmission from
mothers with newly acquired genital herpes is observed
when the infant is born before the transfer of passive anti-
bodies to HSV-1 or HSV-2, when the infant is exposed at
delivery, or within the first few days of life.57,66
The duration of ruptured membranes has also been
described as an indicator of risk for acquisition of neonatal
infection. Observations in the early 1970s of a small cohort of
women (n = 22) with symptomatic genital herpes indicated
that prolonged rupture of membranes (>6 hours) increased
the risk of acquisition of virus, perhaps as a consequence of
ascending infection from the cervix.56 This small case series
resulted in the recommendation that women with active
genital lesions at the time of onset of labor be delivered by
cesarean section.67 It was not until 2003, however, that it
was proven in a large, landmark study that cesarean deliv-
ery protects against neonatal HSV infection in infants born to
women from whom HSV was isolated at the time of delivery
(1.2% vs. 7.7%; P = .047).49 In the single baby in this trial to
develop neonatal HSV disease after cesarean delivery, mem-
branes were ruptured in the mother for 19 hours. It is impor-
tant to note, however, that infection of the newborn with
HSV-2 has occurred despite delivery by cesarean section.61,68
Certain forms of medical intervention during labor and
delivery may increase the risk of neonatal herpes if the mother
has active shedding of the virus, although in most instances,
viral shedding is not suspected clinically. Fetal scalp moni-
tors can be a site of viral entry through disrupted skin.49,69,70
The benefits and risks of these devices should be considered
for women with a history of recurrent genital HSV infections.
Because most women with genital infections caused by HSV
are asymptomatic during labor and have no history of geni-
tal herpes, it is usually impossible to make this assessment.
INCIDENCE OF NEWBORN INFECTION
Estimates of the incidence of neonatal herpes have var-
ied from 1 in 3000 to 1 in 20,000 live births.71 Although
fluctuations in the incidence of neonatal HSV disease have

been observed,46,71 the current estimated rate of occur-
rence is approximately 1 in 3200 deliveries.49 Although a
progressive increase in the number of cases of neonatal HSV
infection has been noted in some areas of the country,72
neonatal HSV infections still occur far less frequently than
do genital HSV infections in the adult childbearing popu-
lation. Overall, the United States, with approximately 4.0
million deliveries per year, has an estimated 1500 cases of
neonatal HSV infection annually.
In studies where maternal serologic status during preg-
nancy and virologic status at the time of delivery are
evaluated prospectively, the rate of transmission leading
to neonatal HSV infection ranges from 12 to 54 newborn
infections per 100,000 births (1/8300 and 1/1850 births,
respectively). Higher rates of transmission are seen in
infants born to seronegative mothers and mothers infected
with HSV-1.49 Based on seroprevalence studies, the high-
est risk of HSV transmission would be expected to occur
in infants born to non-Hispanic white mothers, whose
HSV seroprevalence is the lowest.24 Some countries do
not report a significant number of cases of neonatal HSV
infection despite a similar high prevalence of antibodies to
HSV-2 in women. In the United Kingdom, genital herpes
infection is relatively common, but very few cases of neona-
tal HSV infection are recognized. Neonatal HSV infection in
the Netherlands occurs in only 2.4 of 100,000 newborns.73
Although underreporting of cases may explain some differ-
ences between countries, unidentified factors may account
for these differences. The interpretation of incidence data
must also include the potential for postnatal acquisition of
HSV infection. Not all cases of neonatal infection are the
consequence of intrapartum contact with infected mater-
nal genital secretions, which alters the overall estimate of
delivery-associated infection. The prevalence of neonatal
HSV infection relative to serious bacterial infections in hos-
pitalized neonates was evaluated more recently in a retro-
spective study and found to be 0.2% compared with 0.4%
and 4.5% for infants with bacterial meningitis and serious
bacterial infections, respectively.74
TIMES OF TRANSMISSION OF INFECTION
Herpes simplex virus infection of the newborn can be
acquired in utero, intrapartum, or postnatally. The mother
is the source of infection for the first two of these three
routes of transmission of infection. With regard to post-
natal acquisition of HSV infection, the mother can be a
source of infection from a nongenital site, or other contacts
or environmental sources of virus can lead to infection of
the infant. A maternal source is suspected when maternal
herpetic lesions are discovered during or shortly after the
birth of the infant, or when the infant’s illness is caused by
HSV-2. Although intrapartum transmission accounts for
approximately 85% of cases of neonatal HSV, in utero and
postnatal infection must be recognized for public health and
prognostic purposes.
In utero transmission is very rare, causing approximately
5% of all cases of neonatal HSV disease.75-78 Although it was
originally presumed that in utero acquisition of infection
resulted in a totally normal infant or premature termina-
tion of gestation,56 it has become apparent that intrauterine
acquisition of infection can lead to severe clinical disease and
27 • Herpes Simplex Virus Infections 849
sequelae. When using stringent diagnostic criteria, more
than 70 infants with symptomatic congenital disease have
been described in the literature.75 These criteria include
identification of infected infants with lesions present at birth
or within the first 24 hours of life; virologic confirmation of
HSV at that time; and exclusion of other infectious agents
whose pathogenesis mimics the clinical findings of HSV
infections, such as congenital cytomegalovirus infection,
rubella, syphilis, or toxoplasmosis. Virologic diagnosis is a
necessary criterion because no standard method for reli-
able detection of IgM antibodies is available, and infected
infants often fail to produce IgM antibodies detectable by
research methods.66,79 Intrauterine HSV disease occurs in
approximately 1 in 300,000 deliveries.75 Although rare,
in utero disease is unlikely to be missed due to the extent
of involvement of affected babies. Infants acquiring HSV
in utero typically have a triad of clinical findings consist-
ing of cutaneous manifestations (scarring, active lesions,
hypopigmentation and hyperpigmentation, aplasia cutis,
and/or an erythematous macular exanthem), ophthal-
mologic findings (microopthalmia, retinal dysplasia, optic
atrophy, and/or chorioretinitis), and neurologic involve-
ment (microcephaly, encephalomalacia, hydranencephaly,
and/or intracranial calcification).76,77,80,81
In utero infection can result from transplacental or
ascending infection. The placenta can show evidence of
necrosis and inclusions in the trophoblasts, which suggests
a transplacental route of infection.82 The situation can
result in an infant who has hydranencephaly at the time
of birth, or it may be associated with spontaneous abortion
and intrauterine HSV viremia. Virus has been isolated from
the products of conception under such circumstances. His-
topathologic evidence of chorioamnionitis suggests ascend-
ing infection as an alternative route for in utero infection.83
Risk factors associated with intrauterine transmission are
unknown. Primary and recurrent maternal infections can
result in infection of the fetus in utero. HSV DNA has been
detected in the amniotic fluid of two women experiencing a
first-episode nonprimary infection and in one woman dur-
ing a symptomatic recurrent infection. All three infants
were healthy at birth and showed no clinical or serologic
evidence of HSV infection during follow-up.84
The second and most common route of infection is intra-
partum contact of the fetus with infected maternal genital
secretions. Intrapartum transmission can occur when a
baby passes through a birth canal when HSV is present.
Approximately 85% of cases of neonatal HSV are acquired
in the intrapartum period. Intrapartum transmission is
more likely to occur when the neonate is being delivered to a
mother with newly acquired infection (25%-60% likelihood
of transmission if virus is present in the genital tract) but
can also occur with recurrent maternal infection (approxi-
mately a 2% likelihood of transmission if virus is present in
the genital tract).
Postnatal acquisition is the third route of transmission,
accounting for approximately 10% of cases of neonatal HSV
disease. Postnatal acquisition of neonatal HSV is virtually
always due to HSV-1 because the source of transmission is
nongenital. However, with the increasing incidence of geni-
tal HSV-1 disease in sexually active adults, simply detecting
HSV-1 in a neonate does not define the timing of transmis-
sion as postnatal. The most recent data on the proportion of
850 SECTION III • Viral Infections
neonatal HSV that is caused by HSV-1 are from the 1980s,
when the National Institute of Allergy and Infectious Dis-
eases (NIAID) Collaborative Antiviral Study Group (CASG)
reported that approximately 25% to 35% of cases of neona-
tal herpes are caused by this virus type.61,85
The documentation of postnatal transmission of HSV-1
has focused attention on nongenital sources of virus.86-90
Postpartum transmission from mother to child has been
reported as a consequence of nursing on an infected
breast.91 Transmission from fathers and grandparents has
also been documented.90 When the infant’s mother has not
had HSV infection, the infant may be inoculated with the
virus from a nonmaternal contact in the absence of any
possible protection from maternally derived passive anti-
bodies. Because of the high prevalence of HSV-1 infection
in the general population, many individuals have intermit-
tent episodes of asymptomatic excretion of the virus from
the oropharynx and can provide a source of infection for
the newborn. The occurrence of herpes labialis, commonly
referred to as fever blisters or cold sores, has ranged from
16% to 46% in various groups of adults.92
Population studies conducted in two hospitals indicated
that 15% to 34% of hospital personnel had a history of non-
genital herpetic lesions.92,93 In both hospitals surveyed, at
least 1 in 100 individuals documented a recurrent cold sore
each week. As is true of genital herpes, many individuals
have HSV-1 infection with no clinical symptoms at the time
of acquisition or during episodes of reactivation and shed-
ding of infectious virus in oropharyngeal secretions. Pro-
spective virologic monitoring of hospital staff increased the
frequency with which infection was detected by twofold;
however, no cases of neonatal HSV infection were docu-
mented in these nurseries.
The risk of nosocomial infection in the hospital envi-
ronment is a concern. Identification by restriction endo-
nuclease or sequence analysis of virus recovered from an
index case and a nursery contact leaves little doubt about
the possibility of spread of virus in a high-risk nursery
population.87,89 The possible vectors for nosocomial trans-
mission have not been defined. The risk of transmission
to infants by health care professionals who have herpes
labialis or who are asymptomatic oral shedders of virus
is low. Compromising patient care by excluding health
care professionals with cold sores who are essential for the
operation of the hospital nursery must be weighed against
the potential risk of newborn infants becoming infected.
Health care professionals with cold sores who have contact
with infants should cover and not touch their lesions and
should comply with hand hygiene policies. Transmission
of HSV infection from health care professionals with geni-
tal lesions is not likely as long as they comply with hand
hygiene policies. Health care professionals with an active
herpetic whitlow should not have responsibility for direct
care of neonates or immunocompromised patients and
should wear gloves and use hand hygiene during direct
care of other patients.
Because most mothers have antibodies to HSV, and these
antibodies are transferred to their infants, postnatal expo-
sures to the virus in the neonatal period usually do not
result in neonatal disease. If the mother is seronegative,
nosocomial exposure may pose a more significant risk to
the neonate, however.
Immunologic Response
The neonatal host response to HSV is impaired compared
with older children and adults.66,79,94-98 There is no evi-
dence for differences in virulence of particular HSV strains.
The severity of the manifestations of HSV-1 and HSV-2
infections in the newborn can be attributed to immuno-
logic factors. Relevant issues are protection by transplacen-
tal antibodies, the innate immune response of the exposed
infant, and the acquisition of adaptive immunity by the
infected newborn.
Passive antibodies to HSV influence the acquisition of
infection and its severity and clinical signs.45,60,66,79 Trans-
placentally acquired antibodies from the mother are not
totally protective against neonatal infection, but transpla-
centally acquired neutralizing antibodies correlate with a
lower attack rate in exposed newborns.60,65,66 Although
the absence of any detectable antibodies has been associated
with dissemination and systemic disease in the neonate, the
presence of antibodies at the time that clinical signs appear
does not predict the subsequent outcome.61,79
Most infected newborns eventually produce HSV IgM
antibodies, but the interval to detection is prolonged, requir-
ing at least 2 to 4 weeks.66 These antibodies increase rapidly
during the first 2 to 3 months but may be detectable for 1
year after infection. The quantity of neutralizing antibodies
and antibodies that mediate antibody-dependent cellular
cytotoxicity in infants with disseminated disease is lower
than in infants with more limited disease.66,97 Humoral
antibody responses to specific viral proteins, especially gly-
coproteins, have been evaluated by assays for antibodies to
gG and by immunoblot.10,79 Immunoblot studies indicate
that the severity of infection correlates directly with the
number of antibody bands to defined polypeptides. Children
with a more limited infection, such as infection of the skin,
eye, or mouth (SEM disease), have fewer antibody bands
compared with children with disseminated disease.
A vigorous antibody response to the ICP4 α gene prod-
uct, which is responsible for initiating viral replication, has
been correlated with poor long-term neurologic outcome,
suggesting that these antibodies reflect the extent of viral
replication. A regression analysis that compared neurologic
impairment with the quantity of antibodies to ICP4 identi-
fied the child at risk for severe neurologic impairment.79
Adaptive cellular immunity is a crucial component of
the host response to primary herpetic infection. Newborns
with HSV infections have a delayed T-lymphocyte prolif-
erative response compared with older individuals.66,94,95
Most infants have no detectable T-lymphocyte responses to
HSV when evaluated 2 to 4 weeks after the onset of clinical
symptoms.66 The delayed T-lymphocyte response to viral
antigens in infants whose initial disease is localized to the
SEM may be an important determinant of the frequent pro-
gression to more severe disease in infants.66,94 The impor-
tance of IFN-γ may be related to its effect on the induction
of innate immune mechanisms, such as natural killer–cell
responses.96 Other mechanisms of the innate immune
system of the newborn that may be deficient in control-
ling HSV include other nonspecific cytokine responses and
complement-mediated effects. T lymphocytes from infected
infants have decreased IFN-γ production during the first

month of life. This defect can be predicted to limit the clonal
expansion of helper and cytotoxic T lymphocytes specific
for herpes viral antigens, allowing more extensive and pro-
longed viral replication. Antibody-dependent cell-mediated
cytotoxicity has been shown to be an important component
of adaptive immunity to viral infection.97 Lymphocytes,
monocytes, macrophages, or polymorphonuclear leuko-
cytes and antibodies and complement lyse HSV-infected
cells in vitro.99 However, newborns appear to have fewer
effector lymphocytes than older individuals do. The imma-
turity of neonatal monocytes and macrophage function
against HSV infection has been demonstrated in vitro and
in animal models.100,101 Additional information regarding
the immune response to HSV is provided in Chapter 4.
Neonatal Infection
PATHOGENESIS AND PATHOLOGY
After direct exposure, replication of HSV is presumed to
occur at the portal of entry, which is probably the mucous
membranes of the mouth or eye, or at sites where the skin
integrity has been compromised. Factors that determine
whether the infection causes symptoms at the site of inoc-
ulation or disseminates to other organs are poorly under-
stood. Sites of replication during the incubation period have
not been well defined, but the virus evades the host response
during this early stage, probably by mechanisms such as
interfering with expression of the IFN response genes and
blocking cell-mediated immune recognition of viral pep-
tides by preventing major histocompatibility complex class
I molecules from reaching the surface of infected cells.
Intraneuronal transmission of viral particles may pro-
vide a privileged site that is relatively inaccessible to cir-
culating humoral and cell-mediated defense mechanisms,
facilitating the pathogenesis of encephalitis. Transplacen-
tal maternal antibodies may be less effective under such
circumstances. Disseminated infection seems to be the
consequence of viremia. HSV DNA has been detected in
peripheral blood mononuclear cells, even in infants who
have localized infection.102 Extensive cell-to-cell spread
could help explain primary HSV pneumonia after aspira-
tion of infected secretions.
After the virus has adsorbed to cell membranes and pen-
etration has occurred, viral replication proceeds, leading to
release of progeny virus and cell death. The synthesis of cel-
lular DNA and protein ceases as large quantities of HSV are
produced. Many infants with disseminated HSV infection
have high viral loads and higher concentrations of inflam-
matory cytokines compared with infants with central
nervous system (CNS) infection alone or SEM disease.103
Uncontrolled host immune responses may contribute to
the development of multiorgan dysfunction. Cell death in
critical organs of the newborn, such as the brain, results
in devastating consequences, as reflected by the long-term
morbidity of herpes encephalitis. Cellular swelling, hemor-
rhagic necrosis, development of intranuclear inclusions,
and cytolysis all result from the replication process and
ensuing inflammatory response. Small, punctate, yellow-
to-gray areas of focal necrosis are the most prominent gross
lesions in infected organs. When infected tissue is examined
27 • Herpes Simplex Virus Infections 851
by microscopy, there is extensive evidence of hemorrhagic
necrosis, clumping of nuclear chromatin, dissolution of
the nucleolus, cell fusion with formation of multinucleate
giant cells, and, ultimately, a lymphocytic inflammatory
response.104 Irreversible organ damage results from isch-
emia and direct viral destruction of cells. A major advance
in our understanding of the pathogenesis of sequelae of
neonatal HSV CNS disease is the finding that subclinical
reactivation of virus within the CNS occurs after successful
treatment of the acute disease and that this contributes to
the long-term neurologic sequelae of this manifestation of
neonatal HSV disease.105
CLINICAL MANIFESTATIONS
Pediatricians should consider the diagnosis of neonatal her-
pes in infants who have clinical signs consistent with the
disease, regardless of the maternal history of genital her-
pes. Only a minority (20%-40%) of mothers whose infants
develop neonatal herpes have had symptomatic genital
herpes or sexual contact with a partner who has recognized
HSV infection during or before the pregnancy.
The clinical presentation of infants with neonatal HSV
infection depends on the initial site of infection and the
extent of viral replication. In contrast to human cytomega-
lovirus, neonatal infections caused by HSV-1 and HSV-2 are
almost invariably symptomatic. Case reports of asymptom-
atic infection in the newborn exist but are uncommon, and
long-term follow-up of these children to document absence
of subtle disease or sequelae is not sufficient to determine if
neonatal infection actually occurred.
Classification of newborns with HSV infection is used for
prognostic and therapeutic considerations.106 Historically,
infants with neonatal HSV infection were classified as hav-
ing localized or disseminated disease, with the former group
being subdivided into infants with SEM disease versus infants
with CNS infection. This classification system understated
the significant differences in outcome within each category,
however.107 In a revised classification scheme, infants who
are infected intrapartum or postnatally are divided into three
groups: disease localized to the skin, eyes, or mouth (SEM dis-
ease); encephalitis, with or without SEM involvement (CNS
disease); and disseminated infection that involves multiple
organs, including the CNS, lung, liver, adrenals, and SEM (dis-
seminated disease). This classification system is predictive of
both morbidity and mortality.85,106,108-110 Patients with dis-
seminated or SEM disease generally present to medical atten-
tion at 10 to 12 days of life, whereas patients with CNS disease
on average present somewhat later at 16 to 19 days of life.85
Knowledge of the patterns of clinical disease caused by
HSV-1 and HSV-2 in the newborn is based on prospectively
acquired data obtained through the NIAID CASG. These
analyses have used uniform case record forms from one
study interval to the next. Approximately 25% of babies
with neonatal HSV infection are classified as having dis-
seminated disease, whereas 30% have CNS disease and
45% have SEM disease.61,111
Intrauterine Infection
Intrauterine infection is very rare, constituting only about
5% of cases of neonatal HSV infection.75 When infec-
tion occurs in utero, severe disease follows acquisition of
852 SECTION III • Viral Infections
infection at virtually any time during gestation. In the most
severely affected group of infants, evidence of infection is
apparent at birth or within the first 24 hours of life and is
characterized by a triad of findings: skin vesicles or scarring,
eye damage, and severe manifestations of microcephaly or
hydranencephaly. CNS damage is caused by intrauterine
encephalitis. Infants do not have evidence of embryopa-
thy, such as cardiac malformations. Often, chorioretinitis
combined with other eye findings, such as keratoconjunc-
tivitis or microphthalmia, is a component of the clinical
presentation.
Serial ultrasound examination of the mothers of infants
infected in utero has demonstrated the presence of hydran-
encephaly, but cases are seldom diagnosed before delivery.
Chorioretinitis alone should alert the pediatrician to the
possibility of this diagnosis, although it is a sign for other,
more commonly encountered congenital infections as well.
A few infants have been described who have signs of HSV
infection at birth after prolonged rupture of membranes.
These infants may have no other findings of invasive mul-
tiorgan involvement—no chorioretinitis, encephalitis, or
evidence of other diseased organs—and can be expected to
respond to antiviral therapy. Antiviral therapy cannot be
expected to improve long-term outcomes for infants who
are born with very severe CNS involvement or hydranen-
cephaly. Intrauterine HSV infection has been reported as a
cause of hydrops fetalis.112
Disseminated Disease
Infants with disseminated neonatal HSV disease have the
highest mortality rate of the three intrapartum and post-
natal disease classifications. Many of these infants are born
to mothers who are experiencing a first-episode primary or
nonprimary HSV-1 or HSV-2 infection and may lack any
passively acquired antibodies against the infecting virus
type.10,60,113 Patients with disseminated disease gener-
ally present to medical attention at 10 to 12 days of life.85
The short incubation period of disseminated herpes reflects
an acute viremia, which allows transport of the virus to
all organs; the principal organs involved are the adrenals
and the liver, resulting in fulminant hepatitis in some
cases.106,114-117 Viremia is associated with infection of circu-
lating mononuclear cells in these infants.102,114,116,118,119
Disseminated infection can affect multiple organs,
including the CNS, larynx, trachea, lungs, esophagus,
stomach, lower gastrointestinal tract, spleen, kidneys, pan-
creas, and heart. Initial signs and symptoms are irritability,
seizures, respiratory distress, jaundice, coagulopathy, and
shock. The characteristic vesicular exanthem oftentimes is
not present when the symptoms begin. Untreated infants
may develop cutaneous lesions resulting from viremia, but
greater than 40% of children with disseminated infection
do not develop skin vesicles during the course of their ill-
ness.61,85,114 Disseminated infections caused by HSV-1 and
HSV-2 are indistinguishable by clinical criteria.
The diagnosis of disseminated neonatal herpes is exceed-
ingly difficult because the clinical signs are often vague and
nonspecific, mimicking signs of neonatal bacterial sepsis
(e.g., group B streptococcal or Escherichia coli sepsis) or neo-
natal enteroviral sepsis syndrome.
Evaluation of the extent of dissemination is imperative to
provide appropriate supportive interventions early in the
clinical course. Infants should be assessed for hypoxemia,
acidosis, hyponatremia, transaminitis, direct hyperbilirubi-
nemia, neutropenia, thrombocytopenia, and bleeding dia-
thesis. Chest radiographs also should be obtained. Depending
on signs and whether the infant is stable enough, abdomi-
nal radiography, electroencephalography, and computed
tomography (CT) or magnetic resonance imaging (MRI)
of the head should be obtained to determine further the
extent of disease. The radiographic picture of HSV lung dis-
ease is characterized by a diffuse, interstitial pattern, which
progresses to a hemorrhagic pneumonitis and, rarely, a
significant pleural effusion.120 Frequently, necrotizing
enterocolitis with pneumatosis intestinalis can be detected
when gastrointestinal disease is present. Meningoenceph-
alitis seems to be a common component of disseminated
infection, occurring in about 60% to 75% of children. Usual
examinations of cerebrospinal fluid (CSF), including PCR
for HSV DNA and viral culture, should be performed along
with noninvasive neurodiagnostic tests to assess the extent
of brain disease.
The mortality rate for disseminated HSV in the absence of
therapy exceeds 80%, and many survivors are impaired. The
most common causes of death of infants with disseminated
disease are intravascular coagulopathy or HSV pneumoni-
tis. Premature infants seem to be at particularly high risk
for disseminated disease with pneumonitis and have a high
mortality rate, even with appropriate antiviral therapy.121
Central Nervous System Disease
Almost one third of all infants with neonatal HSV infec-
tion have only encephalitis as the initial manifestation of
disease.122,123 These infants have clinical manifestations
distinct from infants who have CNS infection associated
with disseminated HSV, and the pathogenesis of these two
forms of brain infection is probably different. The virus is
likely to reach brain parenchyma by a hematogenous route
in infants with disseminated infection, resulting in mul-
tiple areas of cortical hemorrhagic necrosis. In contrast,
neonates who present with only CNS disease are likely to
develop brain infection because of retrograde axonal trans-
port of the virus to the CNS. Patients with CNS disease on
average present at 16 to 19 days of life.85 Clinical mani-
festations of encephalitis include seizures (focal or gener-
alized), fever, lethargy, irritability, tremors, poor feeding,
temperature instability, bulging fontanelle, and pyramidal
tract signs. Similar signs are observed when disseminated
herpesvirus is associated with encephalitis. Approximately
one third of infants with CNS disease do not have skin vesi-
cles when signs of illness begin. Some infants have a history
or residual signs of lesions of the SEM that were not recog-
nized as herpetic.
Anticipated findings on CSF examination include a
mononuclear cell pleocytosis, moderately low glucose
concentrations, and elevated protein. A few infants with
CNS infection, proven by brain biopsy done immediately
after the onset of seizures, have no abnormalities of CSF,
but most infants have some degree of pleocytosis and mild
reduction of the glucose level. The hemorrhagic nature of
the encephalitis may result in an apparent “bloody tap,”
although this is seen less frequently in the current era com-
pared with the 1970s, when awareness of neonatal HSV
infection was lower and earlier assessment less likely to

occur. Although initial protein concentrations may be nor-
mal or only slightly elevated, infants with localized brain
disease usually show progressive increases in protein. The
importance of CSF examination in all infants is underscored
by the finding that even subtle abnormalities have been
associated with significant developmental sequelae.106
Electroencephalography and MRI or CT can be very use-
ful in defining the presence and extent of CNS abnormalities
and should be obtained before discharge of all infants with
this diagnosis.124,125 Abnormalities may also be detected
by ultrasound examination.125 Typical abnormalities seen
by neuroimaging include localized or multifocal areas of
abnormal parenchymal attenuation, atrophy, edema, and
hemorrhage involving the temporal, frontal, parietal, and
subcortical regions of the brain (Fig. 27-1).126 Predominant
brainstem involvement is rare but reported.127
Localized CNS disease is fatal in approximately 50% of
infants who are not treated. With rare exceptions, survivors
who are not treated are left with neurologic impairment.106
With parenteral antiviral therapy, mortality is decreased
to approximately 5%,108 and 30% of survivors who also
receive 6 months of oral acyclovir suppressive therapy have
some degree of neurologic impairment,105 often in associa-
tion with microcephaly, hydranencephaly, porencephalic
cysts, spasticity, blindness, chorioretinitis, or learning dis-
abilities. Quantitative PCR methods show a greater amount
of HSV-2 DNA in CSF from patients with more extensive
neurologic impairment.128 Although many infants have
obvious severe sequelae within a few weeks after onset of
HSV encephalitis,109,129 recent data document that without
follow-up suppressive oral therapy progressive, subclinical
neurologic damage occurs after parenteral treatment of the
acute infection.105
Figure 27-1 Herpes simplex encephalitis. Computed tomography
scan of an infant with herpes simplex virus type 2 infection and severe
sequelae.
27 • Herpes Simplex Virus Infections 853
Despite the presumed differences in pathogenesis, neuro-
logic manifestations of disease in children with CNS disease
are virtually identical to the findings for brain infection in
disseminated disease. For infants with CNS disease, approxi-
mately two thirds develop evidence of a vesicular rash char-
acteristic of HSV infection. A newborn with pleocytosis and
elevated protein in the CSF but without the characteristic
rash of neonatal HSV can easily be misdiagnosed as having
another viral or bacterial infection unless HSV infection is
considered.
Skin, Eye, or Mouth Disease
Infection localized to the SEM or some combination of these
sites seems benign at the onset but is associated with a high
risk of progression to serious disease. When infection is
localized to the skin, the presence of discrete vesicles remains
the hallmark of disease (Fig. 27-2). Vesicles occur in greater
than 80% of children with SEM disease. The skin vesicles
usually erupt from an erythematous base and typically are
1 to 2 mm in diameter. The formation of new lesions adja-
cent to the original vesicles is typical, creating a cluster that
may coalesce into larger, irregular vesicles. In some cases,
the lesions progress to bullae larger than 1 cm in diameter.
Clusters of vesicles may appear initially on the presenting
part of the body, presumably because of prolonged contact
with infectious secretions during birth, or at sites of trauma
(e.g., scalp monitor sites). However, it also is common for
the first herpetic lesions in infants with localized cutaneous
disease to be on the trunk, extremities, and other sites.
Patients with SEM disease generally present to medical
attention at 10 to 12 days of life.85 Although discrete vesi-
cles are usually encountered, crops and clusters of vesicles
have been described, particularly before antiviral treatment
was available or when the cause of the first lesions was not
recognized. In these cases, the rash can progress to involve
other cutaneous sites, presumably by viremia and hema-
togenous spread. The scattered vesicles can resemble vari-
cella. Although progression is expected without treatment,
a few infants have had infection of the skin limited to one or
two vesicles, with no further evidence of cutaneous disease.
These infants may be identified after the newborn period
and should have a careful evaluation because many are
likely to have had neurologic disease that was not detected.
A zosteriform eruption is another manifestation of herpetic
skin disease reported in infants.130
Figure 27-2 Cutaneous herpes simplex virus infection. Initial vesicular
lesion in a premature infant with herpes simplex type 2 infection.
854 SECTION III • Viral Infections
Table 27-2 Morbidity and Mortality Among Patients After 12 Months by Viral Type, 1981-1997
SEM
Outcome HSV-1 HSV-2
Normal 24 (100%) 19 (95%)
Mild impairment 0 (0%) 0 (0%)
Moderate impairment 0 (0%) 1 (5%)
Severe impairment 0 (0%) 0 (0%)
Death 0 (0%) 0 (0%)
Unknown Total of 20
Data from Douglas J, Schmidt O, Corey L: Acquisition of neonatal HSV-1 infection from a paternal source contact, J Pediatr 103:908-910, 1983.
CNS, Central nervous system; SEM, skin, eyes, or mouth.
Infections involving the eye may manifest as keratocon-
junctivitis. Ocular infection may be the only site of involve-
ment in a newborn. When localized eye infection is observed
in infants who also have microphthalmos and retinal dys-
plasia, intrauterine acquisition should be suspected, and
a thorough neurologic evaluation should be done. Before
antiviral therapy was available, persistent ocular disease
resulted in chorioretinitis caused by HSV-1 or HSV-2.131
Keratoconjunctivitis can progress to chorioretinitis, cata-
racts, and retinal detachment despite therapy. Cataracts
have been detected as a long-term consequence in infants
with HSV infections acquired intrapartum.
Localized infection of the oropharynx involving the
mouth or tongue occurs, but newborns do not develop the
classic herpetic gingivostomatitis caused by primary HSV-1
infection in older children. Overall, approximately 10% of
patients have evidence of HSV infection of the oropharynx
by viral culture. Many of these children did not undergo
a thorough oral examination to determine whether the
detection of infectious virus in oropharyngeal secretions
was associated with lesions.
Long-term neurologic impairment has been encountered
in children whose disease seemed to be localized to the SEM
during the newborn period.61,106,109 Significant findings
included spastic quadriplegia, microcephaly, and blindness.
However, these outcomes were described before routine use
of CSF PCR analysis for HSV DNA and likely occurred in
babies who were PCR positive and now would be classified
as having CNS disease.132
Most newborns who have skin lesions experience cutane-
ous recurrences for months or years. Table 27-2 shows mor-
bidity and mortality 12 months after infection by HSV viral
type and disease classification in patients enrolled in two
studies conducted by the NIAID CASG from 1981 to 1997.
Although HSV-2 outcomes appear to be more severe than
HSV-1 outcomes, the differences between viral types do not
reach statistical significance in regression analysis (P = .10).85
Subclinical Infection
A few cases of apparent subclinical infection with HSV
proven by culture isolation of virus in the absence of symp-
toms have been described.133 It has been difficult to docu-
ment such cases in the course of prospective evaluations
of several hundred infants from many centers around the
United States. Conversely, infants who were exposed to
active maternal infection at the time of delivery and who did
DISEASE CLASSIFICATION
CNS DISSEMINATED
HSV-1 HSV-2 HSV-1 HSV-2
4 (57%) 7 (17.5%) 3 (23%) 14 (41%)
0 (0%) 7 (17.5%) 0 (0%) 1 (3%)
1 (14%) 7 (17.5%) 0 (0%) 0 (0%)
2 (29%) 13 (32.5%) 1 (8%) 3 (9%)
0 (0%) 6 (15%) 9 (69%) 16 (47%)
Total of 16 Total of 12
not develop symptoms have been followed for the first year
of life and did not have immunologic evidence of subclini-
cal infection.60 HSV-1 or HSV-2 may be recovered from the
infant’s oropharyngeal secretions transiently, without repre-
senting true infection. Because of the propensity of the new-
born to develop severe or life-threatening disease, laboratory
evidence of neonatal HSV infection requires careful follow-
up for clinical signs and administration of antiviral therapy.
Diagnosis
CLINICAL EVALUATION
The clinical diagnosis of neonatal HSV infection is difficult
because the appearance of skin vesicles cannot be relied on
as an initial component of disease presentation. Neonatal
enteroviral sepsis syndrome is a major differential diag-
nostic possibility in infants with signs suggesting neona-
tal HSV. Bacterial infections of newborns, such as group
B streptococcal and E. coli sepsis, also can mimic neonatal
HSV infection. Skin lesions may resemble lesions seen with
bullous or crusted impetigo. Some infants infected by HSV
have been described who had concomitant bacterial infec-
tions, including group B streptococci, Staphylococcus aureus,
Listeria monocytogenes, and gram-negative bacteria. A posi-
tive culture for one of these pathogens does not rule out
HSV infection if the clinical suspicion for neonatal herpes
infection is present.
Many other disorders of the newborn can be indistin-
guishable from neonatal HSV infections, including acute
respiratory distress syndrome, intraventricular hemorrhage,
necrotizing enterocolitis, and various ocular or cutaneous
diseases. When vesicles are present, alternative causes of
neonatal exanthems should be excluded (Box 27-1). Cutane-
ous disorders such as erythema toxicum, neonatal melanosis,
acrodermatitis enteropathica, and incontinentia pigmenti
often confuse physicians who suspect neonatal HSV infec-
tions. HSV lesions can be distinguished rapidly from lesions
caused by these diseases using direct immunofluorescence
stain of lesion scrapings or other methods for rapid detection
of viral proteins and confirmation by viral culture.
Neonatal HSV CNS disease is a difficult clinical diagnosis
to make, particularly because many such neonates do not
have a vesicular rash at the time of clinical presentation.
Infection of the CNS is suspected in a child who has evidence
 27 • Herpes Simplex Virus Infections 855

Of the sites routinely cultured for HSV during a recent

Box 27-1 Differential Diagnosis for Vesicular
study,85 skin or eye/conjunctival cultures consistently pro-
Eruptions in the Neonate vided the greatest yields regardless of disease classification,
Infectious Etiologies with greater than or equal to 90% of cultures being positive.
Overall, 58 (94%) of 62 patients had a positive skin or eye
HSV
culture, 33 (48%) of 69 patients had a positive mouth/oro-
Staphylococcus aureus
Pseudomonas
pharyngeal culture, and 17 (40%) of 42 patients with CNS
Haemophilus influenzae type b involvement (CNS disease or disseminated disease with CNS
Treponema pallidum involvement) had a positive CSF or brain biopsy culture.85
Candida Viral DNA detection by PCR assay is the gold standard
Aspergillus diagnostic method for CNS involvement.132,134-136 PCR was
VZV used in the retrospective analysis of materials collected from
CMV 24 infants enrolled in the NIAID CASG antiviral studies.132
Listeria monocytogenes HSV was detected by PCR assay of CSF in 71% of infants
Group B streptococci before antiviral therapy was initiated. At least one speci-
Noninfectious Conditions men was positive in 76% of infants, and all samples that
Erythema toxicum
were positive by viral culture were positive by PCR. Simi-
Pustular melanosis lar findings were reported by Swedish investigators when
Miliaria stored CSF specimens obtained from infants with neonatal
Letterer-Siwe disease HSV infection were tested for HSV by PCR. HSV DNA was
Urticaria pigmentosa detected from CSF in the acute phase of illness from 78%
Bullous mastocytosis of patients with CNS disease.137 Older patients with herpes
Pemphigus vulgaris simplex encephalitis can have initial HSV PCR results that
Dermatitis herpetiformis are negative early in the course of illness; CSF obtained 4 to 7
Herpes gestationis days after the initial CSF samples was subsequently positive
Incontinentia pigmenti
for HSV DNA in a few patients.138 Most studies of PCR for the
Neonatal lupus
Epidermolysis bullosa
diagnosis of HSV CNS infections indicate the test is sensitive
Epidermolytic hyperkeratosis in approximately 75% to 100% of cases in small cohorts of
Acropustulosis infants.132,135-137 Specificity of the test ranges from 71% to
Neonatal bullous dermatitis 100%. The broad range of values for sensitivity and specific-
Langerhans cell histiocytosis ity of HSV PCR probably results from different study meth-
Bednar aphthae ods and disease classifications.111 In difficult cases in which
repeated CSF PCRs are negative, histologic examination and
Modified from Kohl S: Neonatal herpes simplex virus infection, Clin Perinatol viral culture of a brain tissue biopsy specimen is the most
24:129-150, 1997. definitive method of confirming the diagnosis of HSV CNS
disease. Viral cultures of CSF from a patient with neonatal
HSV CNS disease are positive in 25% to 40% of cases.
of acute neurologic deterioration, often but not always Application of PCR testing to blood specimens from
associated with the onset of seizure, and in the absence of infants with suspected HSV disease appears promising.*
intraventricular hemorrhage and metabolic causes. Using Data are insufficient at the current time to allow use of serial
PCR assay to detect viral DNA in CSF has become the gold blood PCR measurements to establish response to antiviral
standard diagnostic methodology for confirming neonatal therapy or guide decisions about the duration of therapy.
HSV CNS involvement, replacing the need for diagnosis by Cytologic methods, such as Papanicolaou, Giemsa, or
brain biopsy.134 Infants with localized CNS disease usually Tzanck staining, have a sensitivity of only approximately 60%
have increases in CSF cell counts and protein concentra- to 70%. A negative result must not be interpreted as excluding
tions and negative bacterial cultures of CSF. Noninvasive the diagnosis of HSV, and a positive result should not be the
neurodiagnostic studies such as MRI and CT can be used to sole diagnostic determinant of HSV infection in the newborn.
define sites of involvement. Intranuclear inclusions and multinucleated giant cells may
be consistent with, but not diagnostic of, HSV infection.
For diagnosis of neonatal HSV infection, the following
LABORATORY ASSESSMENT
specimens should be obtained141: (1) swab specimens from
The appropriate use of laboratory methods is essential if a the mouth, nasopharynx, conjunctivae, and anus (“surface
timely diagnosis of HSV infection is to be achieved. Virus cultures”) for HSV culture and, if desired, for HSV PCR assay
isolation remains the gold standard diagnostic method from (all surface swab specimens can be obtained with a single
non-CNS sites. HSV grows readily in cell culture. Special swab, ending with the anal swab, and placed in one viral
transport media are available that allow transport to local transport media tube); (2) specimens of skin vesicles and
or regional laboratories for culture. Cytopathogenic effects CSF for HSV culture and PCR assay; (3) whole-blood sample
typical of HSV infection usually are observed 1 to 3 days for HSV PCR assay; and (4) whole-blood sample for mea-
after inoculation. Methods of culture confirmation include suring alanine aminotransferase. The performance of PCR
fluorescent antibody staining, enzyme immunoassays, and assay on skin and mucosal specimens from neonates has not
monolayer culture with typing. Cultures that remain nega-
tive by day 5 likely will continue to remain negative. * References 102, 128, 135, 137, 139, 140.
856 SECTION III • Viral Infections
been studied; if used, surface PCR assay should be performed
in addition to, and not instead of, the gold standard surface
culture. Positive cultures obtained from any of the surface
sites more than 12 to 24 hours after birth indicate viral repli-
cation and therefore are suggestive of infant infection rather
than merely contamination after intrapartum exposure. As
with any PCR assay, false-negative and false-positive results
can occur. Whole-blood PCR assay may be of benefit in diag-
nosis of neonatal HSV disease, but its use should not sup-
plant the standard workup of such patients, which includes
surface cultures and CSF PCR assay; no data exist to support
use of serial blood PCR assay to monitor response to ther-
apy. Rapid diagnostic techniques also are available, such
as direct fluorescent antibody staining of vesicle scrapings
or enzyme immunoassay detection of HSV antigens. These
techniques are as specific but slightly less sensitive than cul-
ture. Typing HSV strains differentiates between HSV-1 and
HSV-2 isolates. Histologic examination of lesions for pres-
ence of multinucleated giant cells and eosinophilic intranu-
clear inclusions typical of HSV (e.g., with Tzanck test) has
low sensitivity and should not be performed.
Interpretation of negative or positive HSV cultures and
PCR results must depend on clinical findings. A negative
PCR result for HSV in CSF in the setting of clinical, labora-
tory, or radiologic findings consistent with CNS infection
does not rule out HSV infection. It is important to continue
to use standard clinical and laboratory diagnostic methods
for the evaluation of infants with possible neonatal HSV.
In contrast to some other neonatal infections, serologic
diagnosis of HSV infection has little clinical value. The inter-
pretation of serologic assays is complicated by the fact that
transplacentally acquired maternal IgG cannot be differenti-
ated from endogenously produced antibodies, making it dif-
ficult to assess the neonate’s antibody status during acute
infection. Serial type-specific antibody testing may be useful
for retrospective diagnosis if a mother without a prior history
of HSV infection has a primary infection late in gestation and
transfers little or no antibody to the fetus. However, thera-
peutic decisions cannot await a diagnostic approach based
on comparing acute-phase and convalescent-phase antibody
titers. IgM production is delayed or does not occur in infected
infants because of inherent immaturity in the immune
response to systemic viral infections in the newborn, and
commercially available assays for IgM antibodies to HSV have
limited reliability. The results of specific laboratory tests for
HSV should be used in conjunction with clinical findings and
general laboratory tests, such as platelet counts, CSF analysis,
and liver function tests, to establish a disease classification.
Treatment
BACKGROUND
The cumulative experience of the past 4 decades shows
that intrapartum-acquired HSV infections are amenable to
treatment with antiviral agents, with parenteral acyclovir
being the standard of care.122 Because most infants acquire
infection at the time of delivery or shortly thereafter, anti-
viral therapy has the potential to decrease mortality and
improve long-term outcome. The benefits that antiviral
therapy can provide are influenced substantially by earlier
diagnosis, when possible. Without treatment, approxi-
mately 70% of infants presenting with disease localized to
the SEM develop involvement of the CNS or disseminated
infection. Treatment initiated after disease progression is
not optimal because many of these children die or are left
with significant neurologic impairment.
ANTIVIRAL DRUGS
Historically, four nucleoside analogues have been used
to treat neonatal herpes: idoxuridine, cytosine arabino-
side, vidarabine, and acyclovir. Of these, the first three are
nonspecific inhibitors of cellular and viral replication. The
fourth, acyclovir, is monophosphorylated by HSV-specific
thymidine kinases and then converted to its diphosphate
and triphosphate forms by cellular enzymes. Acyclovir acts
as a competitive inhibitor of HSV DNA polymerase and ter-
minates DNA chain elongation.142 Idoxuridine and cyto-
sine arabinoside have no value as systemic therapy for any
viral infection because of toxicity and equivocal efficacy.
Vidarabine was the first drug shown to be efficacious, with
decreased mortality and improved morbidity in neonatal
HSV infections.110
In the preantiviral era, 85% of patients with disseminated
neonatal HSV disease died by 1 year of age, as did 50% of
patients with CNS neonatal HSV disease (Table 27-3).110
Evaluations of two different doses of vidarabine and of a
lower dose of acyclovir (30 mg/kg/day for 10 days) docu-
mented that both of these antiviral drugs reduce mortality
to comparable degrees,109,110,143 with mortality rates at 1
year from disseminated disease decreasing to 54% and from
CNS disease decreasing to 14% (see Table 27-3).109 Despite
its lack of therapeutic superiority, the lower dose of acyclo-
vir quickly supplanted vidarabine as the treatment of choice
for neonatal HSV disease because of its favorable safety pro-
file and its ease of administration. Unlike acyclovir, vidara-
bine had to be administered over prolonged infusion times
and in large volumes of fluid. With use of a higher dose of
acyclovir (60 mg/kg/day for 21 days), 12-month mortality
is further reduced to 29% for disseminated neonatal HSV
disease and to 4% for CNS HSV disease (Fig. 27-3A and
B, respectively).108 Differences in mortality at 24 months
among patients treated with the higher dose of acyclovir
and the lower dose of acyclovir are statistically significant
after stratification for disease category (CNS vs. dissemi-
nated) (P = .0035; odds ratio, 3.3 with 95% confidence
interval of 1.5 to 7.3).108 Lethargy and severe hepatitis are
associated with mortality among patients with dissemi-
nated disease, as are prematurity and seizures in patients
with CNS disease.85
Improvements in morbidity rates with antiviral therapies
have not been as dramatic as with mortality. In the prean-
tiviral era, 50% of survivors of disseminated neonatal HSV
infections were developing normally at 12 months of age
(see Table 27-3).110 With use of the higher dose of acyclo-
vir for 21 days, this percentage has increased to 83% (Fig.
27-4).108 In the case of CNS neonatal HSV disease, 33% of
patients in the preantiviral era were developing normally at
12 months of age (see Table 27-3), whereas 31% of higher-
dose acyclovir recipients develop normally at 12 months
today (see Fig. 27-4).108,110 Seizures at or before the time of
initiation of antiviral therapy are associated with increased
 27 • Herpes Simplex Virus Infections 857

Table 27-3 Mortality and Morbidity Outcomes Among 295 Infants With Neonatal HSV Infection, Evaluated by the National
Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group Between 1974 and 1997
EXTENT OF DISEASE TREATMENT
Placebo110 Vidarabine109 Acyclovir109 30 mg/kg/day Acyclovir108 60 mg/kg/day
DISSEMINATED DISEASE n = 13 n = 28 n = 18 n = 34
Dead 11 (85%) 14 (50%) 11 (61%) 10 (29%)
Alive 2 (15%) 14 (50%) 7 (39%) 24 (71%)
   Normal 1 (50%) 7 (50%) 3 (43%) 15 (63%)
   Abnormal 1 (50%) 5 (36%) 2 (29%) 3 (13%)
   Unknown 0 (0%) 2 (14%) 2 (29%) 6 (25%)
CENTRAL NERVOUS SYSTEM INFECTION n=6 n = 36 n = 35 n = 23
Dead 3 (50%) 5 (14%) 5 (14%) 1 (4%)
Alive 3 (50%) 31 (86%) 30 (86%) 22 (96%)
   Normal 1 (33%) 13 (42%) 8 (27%) 4 (18%)
   Abnormal 2 (67%) 17 (55%) 20 (67%) 9 (41%)
   Unknown 0 (0%) 1 (3%) 2 (7%) 9 (41%)
SKIN, EYE, OR MOUTH INFECTION n=8 n = 31 n = 54 n=9
Dead 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Alive 8 (100%) 31 (100%) 54 (100%) 9 (100%)
   Normal 5 (62%) 22 (71%) 45 (83%) 2 (22%)
   Abnormal 3 (38%) 3 (10%) 1 (2%) 0 (0%)
   Unknown 0 (0%) 6 (19%) 8 (15%) 7 (78%)

Modified from Kimberlin DW: Advances in the treatment of neonatal herpes simplex infections, Rev Med Virol 11:157-163, 2001.
HSV, Herpes simplex virus.

risk of morbidity, both in patients with CNS disease and in
patients with disseminated infection.85 Unlike disseminated
or CNS neonatal HSV disease, morbidity after SEM disease
has dramatically improved during the antiviral era. Before
use of antiviral therapies, 38% of SEM patients experienced
developmental difficulties at 12 months of age (see Table
27-3).110 With vidarabine and lower-dose acyclovir, these
percentages were reduced to 12% and 2%, respectively.109
In the high-dose acyclovir study, no SEM patients developed
neurologic sequelae at 12 months of life (see Fig. 27-4).108
The improvements in mortality and morbidity achieved
with use of higher-dose acyclovir support use of acyclovir
at 60 mg/kg/day delivered intravenously in three divided
daily doses, as is currently recommended.108,141 The dosing
interval of intravenous acyclovir may need to be increased
in premature infants, based upon their creatinine clear-
ance.144 Duration of therapy is 21 days for patients with
disseminated or CNS neonatal HSV disease and 14 days
for patients with HSV infection limited to the SEM.145 All
patients with CNS HSV involvement should have a repeat
lumbar puncture at the end of intravenous acyclovir ther-
apy to determine that the specimen is PCR negative in a
reliable laboratory and to document the end-of-therapy CSF
indices.85 Those persons who remain PCR positive should
continue to receive intravenous antiviral therapy until PCR
negativity is achieved.85,132
The primary apparent toxicity associated with the use
of intravenous acyclovir administered at 60 mg/kg/day is
neutropenia, with approximately one fifth of patients devel-
oping an absolute neutrophil count (ANC) of less than or
equal to 1000/μL.108 Although the neutropenia resolves
either during continuation of intravenous acyclovir or after
its cessation, it is prudent to monitor neutrophil counts
at least twice weekly throughout the course of intrave-
nous acyclovir therapy, with consideration being given to
decreasing the dose of acyclovir or administering granulo-
cyte colony-stimulating factor (G-CSF) if the ANC remains
less than 500/μL for a prolonged period of time.108
Determining which infants admitted to the hospital with
presumed sepsis should be treated empirically with acyclovir
remains a topic of debate.146,147 In all cases of presumptive
therapy, specimens should be obtained before initiation of
antiviral treatment for laboratory testing to guide the deci-
sion of whether to continue treatment. During the course of
therapy, careful monitoring is important to assess the ther-
apeutic response. Even in the absence of clinical evidence
of encephalitis, evaluation of the CNS should be done for
prognostic purposes when starting antiviral therapy. Serial
evaluations of hepatic and hematologic parameters may
indicate changes caused by the viral infection or by drug
toxicity. Intravenous acyclovir is tolerated well by infants.
Adequate hydration is necessary to minimize the risk of
nephrotoxicity, and dosage adjustments are necessary if
renal clearance is impaired. As for all drugs, the possibility
of acute toxicity should be considered in any child receiving
parenteral antiviral therapy and should be assessed by seri-
ally evaluating bone marrow, renal, and hepatic functions.
Acyclovir resistance has been reported in neonatal HSV
disease, but only rarely and in the form of case reports.
One infant with acute HSV infection of the larynx in the
newborn period developed antiviral resistance during the
course of therapy; in this case, the initial isolate was not
inhibited by acyclovir, although the source of this infection
could not be explained.148 Acyclovir resistance has also
been reported in a premature infant with cutaneous and
CNS disease caused by an initially acyclovir-susceptible
858 SECTION III • Viral Infections

1.0
0.9
0.8

Proportion surviving
0.7
0.6
0.5
0.4
0.3 30 mg/kg/day (n = 18)*
45 mg/kg/day (n = 7)
0.2
60 mg/kg/day (n = 34)
0.1
*Historical cohort
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
A Months

1.0
0.9
0.8
Proportion surviving

0.7
0.6
0.5
0.4
0.3 30 mg/kg/day (n = 35)*
45 mg/kg/day (n = 5)
0.2
Figure 27-3 Mortality rates for patients with dis- 60 mg/kg/day (n = 23)
seminated disease (A) and central nervous system 0.1
disease (B) depending on dose of acyclovir. (Data *Historical cohort
from Kimberlin DW, Lin CY, Jacobs RF, et al: Safety 0
and efficacy of high-dose intravenous acyclovir in 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
the management of neonatal herpes simplex virus
infections, Pediatrics 108:230-238, 2001.) B Months

Severe Moderate Mild Normal primary HSV-2 infection developed an acyclovir-resistant

N=6 N=2 N = 28 N = 13 N = 5 N = 18 mutant during acyclovir therapy for disseminated HSV
100 infection and eventually died. The use of steroids to treat
90 blood pressure instability may have hampered this infant’s
80 immune response to infection further.150 Emergence of
70
Percentage

60 viral resistance to acyclovir also has been described in

50 patients requiring prolonged or repeated treatment with
40 this drug. One infant who was given long-term oral acy-
30 clovir for suppression of recurrences during the first 6
20 months of life had a resistant HSV isolated from a lesion
10
0 after therapy was discontinued, but subsequent isolates
30 60 30 60 30 60 were susceptible.151 However, isolates of HSV recovered
SEM CNS Disseminated from infants who received intravenous acyclovir for cuta-
Figure 27-4 Morbidity among patients with known outcomes after 12 neous disease in the newborn period and had subsequent
months of life. CNS, Central nervous system; SEM, skin, eyes, or mouth. recurrent cutaneous lesions typically remain sensitive to
(Modified from Kimberlin DW, Lin CY, Jacobs RF, et al: Safety and efficacy acyclovir,152 and antiviral resistance generally does not
of high-dose intravenous acyclovir in the management of neonatal herpes explain the failure of infants with the disseminated or CNS
simplex virus infections, Pediatrics 108:230-238, 2001.)
form of the disease to respond well to antiviral therapy.
Rather, clinical deterioration despite appropriate therapy
HSV. The infant developed recurrent disseminated HSV and supportive care can almost always be attributed to
infection 8 days after a 21-day course of acyclovir. The virus-induced destruction of cells compromising infected
virus isolated at the onset of recurrent symptoms was organs, such as liver or brain, or irreversible changes,
found to lack thymidine kinase activity on the basis of a such as disseminated intravascular coagulopathy.
frameshift mutation in the thymidine kinase gene.149 The NIAID CASG recently completed a multicenter, ran-
Another infant born to a mother with severe systemic domized, placebo-controlled, double-blind study of 6 months

of oral acyclovir suppressive therapy after parenteral treat-
ment of acute disease.105 Subjects were stratified by CNS
versus SEM disease and were randomized to either oral acy-
clovir at 300 mg/m2/dose administered three times per day
or to a matching placebo. If a subject had two cutaneous
recurrences, the blinded suppression drug was stopped and
open-label suppression was provided. Subjects randomized
to receive acyclovir had significantly higher (better) mean
Bayley Mental Scores at 1 year (88.24 vs. 68.12; P = .046).
Distribution of neurologic outcomes was: 69% normal, 6%
mild impairment, 6% moderate impairment, and 19% severe
impairment for subjects randomized to acyclovir suppression
versus 33%, 8%, 25%, and 33%, respectively, for subjects
randomized to placebo. Of note, this distribution of outcomes
was virtually identical to that from a small uncontrolled case
series (N = 16) of oral acyclovir suppression after neonatal
HSV CNS disease in which patients received five times the
dose for four times the duration (69% having normal out-
comes in both studies).153 In the CASG study, the 12-month
Bayley Mental Scores were incrementally higher because
subjects were on active suppression for longer periods of
time. For subjects in the SEM study, no differences in Bayley
Mental Scores were noted. Combining the 74 subjects with
either CNS or SEM disease, time to a second cutaneous HSV
recurrence was statistically significantly longer for the group
randomized to acyclovir suppression. Time to first ANC less
than or equal to 500 cells/mm3 was not statistically different
for those subjects randomized to acyclovir versus placebo,
although a trend for neutropenia in those who received acy-
clovir was noted (P = .09). In total, 25% and 20% of subjects
on the CNS study and SEM study, respectively, who were
randomized to acyclovir developed an ANC of less than or
equal to 500 cells/mm3, compared with 5% and 7% of pla-
cebo recipients in the respective trials. Neutropenia resolved
in all affected subjects both with and without cessation of
suppressive therapy, and none had associated complica-
tions.105 These results have led to routine use of oral acyclovir
suppressive therapy for the 6 months after treatment of acute
neonatal HSV disease to improve neurodevelopmental
outcomes in infants with HSV CNS disease and to prevent
skin recurrences in infants with any disease classification of
neonatal HSV.141
OTHER ISSUES IN ACUTE MANAGEMENT
Neonates with HSV infection should be hospitalized and man-
aged with contact precautions if mucocutaneous lesions are
present. Many infants with this infection have life-threatening
problems, including disseminated intravascular coagulation,
shock, and respiratory failure, and they require supportive
care that is available only at tertiary medical centers.
There is no indication that administration of immu-
noglobulin or hyperimmunoglobulin is of value for the
treatment of neonatal HSV infection. Although a series of
studies have suggested that the quantity of transplacen-
tal neutralizing antibodies affects the attack rate among
exposed infants and may influence the initial disease
manifestations, the presence of antibodies may or may not
influence the subsequent course of infection.60,61,65,66,97
The administration of standard preparations of intrave-
nous immunoglobulin does not enhance the titers of func-
tional antibodies against HSV in infants with low birth
weight.154
27 • Herpes Simplex Virus Infections 859
No other forms of adjunctive therapy are useful for
treating neonatal HSV infections. Various experimental
modalities, including interferon, immunomodulators, and
immunization, have been attempted, but none has pro-
duced demonstrable effects.
LONG-TERM MANAGEMENT OF INFECTED
INFANTS
With the advent of antiviral therapy, an increasing num-
ber of newborns with HSV infection are surviving and
require careful long-term follow-up. The most common
complications of neonatal HSV infection include neuro-
logic and ocular sequelae that may be detected only on
long-term follow-up. It is necessary that these children
receive serial long-term evaluation from qualified pediatric
specialists in these areas, which should include neurode-
velopmental, ophthalmologic, and hearing assessments.
Recurrent skin vesicles are present in many children, includ-
ing children who did not have obvious mucocutaneous dis-
ease during the acute phase of the clinical illness. Skin vesicles
provide a potential source for transmission of infection to other
children or adults who have direct contact with these infants.
The increasing use of daycare for children, including children
surviving neonatal HSV infections, stimulates many ques-
tions from daycare providers about these children. There is
some risk that children with recurrent HSV skin lesions would
transmit the virus to other children in this environment. The
most reasonable recommendation in this situation is to cover
the lesions to prevent direct contact. HSV-1 is much more
likely to be present in the daycare environment in the form of
asymptomatic infection or gingivostomatitis. In both cases,
virus is present in the mouth and pharynx, and the frequent
exchange of saliva and other respiratory droplets that occurs
among children in this setting makes this route of transmis-
sion more likely. Education of daycare workers and the gen-
eral public about herpesvirus infections, their implications,
and the frequency with which they occur in the population as
a whole can calm fears and correct common misconceptions.
Parents of children with neonatal HSV infection often
have significant feelings of guilt. Parents often require
support from psychologists, psychiatrists, or counselors.
The family physician or pediatrician can provide a valu-
able supportive role to the family in this situation. Most
parents and many physicians are unaware of the high
prevalence of HSV-2 infection and the increasing inci-
dence of HSV-1 genital infection in the United States and
of the lifelong persistence and subclinical nature of these
infections. Concern about the risk of fetal and neonatal
infection during subsequent pregnancies is often a major
issue that can be addressed effectively based on the low
risks as proven from large, prospective studies.
Prevention
BACKGROUND
Despite the progress that has been made in antiviral treat-
ment of neonatal HSV infection, the ideal approach is to pre-
vent the exposure of infants to active maternal infection at
the time of delivery. Genital infections caused by HSV often
are clinically silent when they are acquired as new infections
860 SECTION III • Viral Infections
Table 27-4 Projected Risk of Transmission of Herpes
Simplex Virus Type 2 (HSV-2) From Mothers to Infants at
Delivery in a Cohort of 100,000 Pregnant Women
25% with past HSV-2 infection 75% susceptible to HSV-2 infection
25,000 women 75,000 women
1.5% reactivation at delivery 0.02% seroconversion/week
375 women with reactivation 30 women with infection <2 weeks
before delivery
<5% risk of transmission 50% risk of transmission
19 infected infants 15 infected infants
Data from Arvin AM: The epidemiology of perinatal herpes simplex infec-
tions. In Stanberry L, editor: Genital and neonatal herpes, New York, 1996,
John Wiley & Sons, pp 179-192.
and when the virus reactivates. With the high prevalence of
HSV-2 infection in the U.S. population and the increasing
practice of oral-genital sexual contact, women are at risk
for acquiring new genital infections during pregnancy. The
problem of asymptomatic genital HSV infection means that
the transmission of HSV from mothers to infants cannot be
eliminated even with the best obstetric management.
Sequential genital cultures during the last weeks of ges-
tation in women with a history of genital herpes do not
predict the infant’s risk of exposure at delivery59 because
of the usually brief duration of asymptomatic shedding
and the time required for the culture to become positive.
Because of the attention of the lay press to the devastating
outcome of neonatal HSV infections, many women who
know that they have genital herpes experience severe anx-
iety about the potential risks to the fetus and the newborn.
As a consequence, these women may have an unneces-
sarily high frequency of cesarean deliveries. The risk of
neonatal HSV infection in the newborn is approximately
equivalent for women who have no prior history of genital
herpes or a partner with known infection (Table 27-4).
Although development of a vaccine has received sub-
stantial industry and government support, a recent large
clinical trial of the vaccine product that was farthest along
in development failed to show protection.31 Although
development efforts continue, it will be many years, if
ever, before a vaccine for genital herpes is available.
MANAGEMENT OF PREGNANT WOMEN WITH
KNOWN GENITAL HERPES
Women who have a history of recurrent genital herpes
should be reassured that the risk of fetal or neonatal infec-
tion is very low. Intrauterine HSV infections are very rare,
with an estimated overall risk of 1 in 300,000 pregnancies.77
Information about the risk of exposure to asymptomatic viral
reactivation at delivery derived from six large-scale prospec-
tive studies is sufficient to conclude that the incidence of
asymptomatic reactivation in these women is about 2% and
that the attack rate for their exposed infants is approximately
2% or less. Because laboratory methods cannot be used to
detect asymptomatic infection in a timely manner, the cur-
rent approach to management is to perform a careful vaginal
examination at presentation and to elect cesarean delivery if
the mother has signs or symptoms of recurrent genital herpes
at the onset of labor. Given the low probability of neonatal
infection, it is appropriate to deliver infants of women who
have a history of recurrent genital herpes but who have no
active clinical disease at delivery by the vaginal route.67 An
analysis of the occurrence of HSV infections in infants in
California showed no change from 1985 to 1995, despite a
documented decrease in deliveries by cesarean section and an
increase in the proportion of women with a previous diagnosis
of genital herpes whose infants were delivered vaginally.155
A culture for HSV obtained at the time of delivery may be
useful in establishing whether the virus was present at deliv-
ery to facilitate recognition of neonatal infection if it occurs.
The value of this approach has not been established, however.
Alternative diagnostic approaches, such as those based on PCR
assay to detect virus, may ultimately expedite identification of
women at risk for delivering infected infants.156,157 Evidence
indicates that detection of viral presence in genital samples by
PCR assay is more sensitive than culture methods. The signifi-
cance of a positive PCR result in predicting risk of transmission
of HSV to the infant is unknown, however.158 Viral DNA can
persist for a longer interval than infectious virus.
The utility of suppressive therapy of genital herpes in
women with a known history of recurrent infection remains
a question for clinical investigation because of risk-benefit
considerations. Some studies indicate that prophylactic
acyclovir (400 mg three times daily) reduces the number of
genital lesions from HSV. Despite prophylaxis, a few women
continue to have virus detectable by PCR assay.158 Use of
prophylactic valacyclovir also reduced clinical HSV recur-
rences but did not decrease shedding of HSV within 7 days
of delivery compared with placebo.159 Even with suppres-
sive therapy, the potential for neonatal HSV infection is not
eliminated entirely, and cases of neonatal HSV after delivery
to women on antiviral suppression have been reported.160
Based on limited scientific evidence, the American College of
Obstetricians and Gynecologists recommends that women
with active recurrent genital herpes should be offered sup-
pressive viral therapy at or beyond 36 weeks of gestation
until delivery.67 Universal antenatal type-specific HSV
screening to prevent neonatal HSV is not recommended.161
MANAGEMENT OF INFANTS OF MOTHERS WITH
GENITAL HERPES
Infants of mothers with histories of genital herpes delivered
vaginally or by cesarean section and whose mothers have
no evidence of active genital herpetic infection are at low
risk for acquiring neonatal HSV infection. These infants
need no special evaluation during the newborn period.
Infants delivered to women with clinically apparent
genital herpetic lesions are at known risk for acquisition
of neonatal HSV. However, the magnitude of the risk is
influenced by the category of maternal infection, with
women with first episode primary or nonprimary genital
infection being at 30 to 50 times the likelihood of having
their babies acquire neonatal HSV than women with recur-
rent genital infection. The American Academy of Pedi-
atrics (AAP) recently released a clinical report that seeks
to provide guidance on the management of these babies,
using serologic and virologic testing to ascertain the level
of risk and then providing recommendations on manage-
ment of the infants accordingly.14 The algorithms from this
clinical report are reproduced in Figures 27-5 and 27-6.
 27 • Herpes Simplex Virus Infections 861

Asymptomatic neonate after vaginal or cesarean delivery to mother with visible genital
lesions that are characteristic of HSV

Obstetric provider obtains swab of lesion for HSV PCR and culture
Type all positives

Maternal history of genital HSV preceding pregnancy?

No Yes

Send maternal type specific serology for At ~24 hours of age* obtain from the neonate:
HSV-1 and HSV-2 antibodies, if test assays • HSV surface† cultures (and PCRs if desired)
are available at the delivery hospital • HSV blood PCR‡
If infant remains asymptomatic, do not start acyclovir

At ~24 hours of age* obtain from the neonate:

• HSV surface† cultures (and PCRs if desired)
• HSV blood PCR‡
• CSF cell count, chemistries, and HSV PCR Neonatal surface Neonatal surface
• Serum ALT cultures negative, AND cultures positive, OR
Start IV acyclovir at 60 mg/kg/day in three divided doses blood and surface blood or surface PCRs
PCRs negative positive

Determine maternal HSV infection classification

Educate family on signs Obtain CSF for cell
and symptoms of count, chemistries, and
neonatal HSV disease HSV PCR. Send serum
and follow closely§ ALT. Start IV acyclovir
at 60 mg/kg/day in three
First episode primary or divided doses
Recurrent infection
First episode nonprimary

Go to Figure 27-6.

Neonatal virology studies

negative (PCRs negative; Neonatal PCRs or viral
viral cultures negative at cultures positive
48-72 hours)

Go to Figure 27-6.
Stop acyclovir. Educate Go to Figure 27-6.
family for signs and
symptoms of neonatal
HSV disease and follow
closely§

This algorithm should be applied only in facilities where access to PCR and type-specific serologic testing is readily available and turnaround time for test
results is appropriately short. In situations where this is not possible, the approach detailed in the algorithm will have limited, and perhaps no, applicability.
*Evaluation and treatment is indicated before 24 hours of age if the infant develops signs and symptoms of neonatal HSV disease. In addition, immediate
evaluation and treatment may be considered if:
• There is prolonged rupture of membranes (>4-6 hours)
• The infant is premature (<37 weeks' gestation)
†Conjunctivae, mouth, nasopharynx, and rectum, and scalp electrode site, if present
‡HSV blood PCR is not used for assignment of disease classification
§Discharge after 48 hours of negative HSV cultures (and negative PCRs) is acceptable if other discharge criteria have been met, there is ready access to
medical care, and a person who is able to comply fully with instructions for home observation will be present. If any of these conditions is not met, the
infant should be observed in the hospital until HSV cultures are finalized as negative or are negative for 96 hours after being set up in cell culture,
whichever is shorter.

Figure 27-5 Algorithm for the evaluation of asymptomatic neonates after vaginal or cesarean delivery to women with active genital herpes lesions. ALT,
Alanine aminotransferase; CSF, cerebrospinal fluid; HSV, herpes simplex virus; IV, intravenous; PCR, polymerase chain reaction. (Modified from Kimberlin
DW, Baley J: Guidance on management of asymptomatic neonates born to women with active genital herpes lesions, Pediatrics 131:e635-e646, 2013.)
862 SECTION III • Viral Infections

Patient remains asymptomatic, CSF indices not indicative of infection,

CSF and blood PCR negative, and normal serum ALT*

No Yes

Treatment of infection and proven disease Preemptive therapy of infection but no

Treat with intravenous acyclovir at 60 mg/kg/day proven disease
in three divided daily doses for 14 days (SEM) or Treat with intravenous acyclovir at 60 mg/kg/day
21 days (CNS or disseminated) in three divided daily doses for 10 days
Additional evaluation may be indicated

*Serum ALT values in neonates may be elevated due to noninfectious

Repeat CSF HSV PCR near end of 21-day
causes (delivery-related perfusion, etc.). For this algorithm, ALT values
course of treatment† more than two times the upper limit of normal may be considered
suggestive of neonatal disseminated HSV disease for HSV-exposed
neonates
†If evidence of CNS disease at beginning of therapy

Positive Negative

Continue intravenous D/C intravenous

acyclovir for 7 days acyclovir after 21-day
more treatment course

Figure 27-6 Algorithm for the treatment of asymptomatic neonates after vaginal or cesarean delivery to women with active genital herpes lesions.
ALT, Alanine aminotransferase; CSF, cerebrospinal fluid; D/C, discontinue; HSV, herpes simplex virus; PCR, polymerase chain reaction; SEM, skin, eyes,
or mouth. (Modified from Kimberlin DW, Baley J: Guidance on management of asymptomatic neonates born to women with active genital herpes lesions,
Pediatrics 131:e635-e646, 2013.)

This report seeks to move beyond the recommendations Conclusion

that preceded its publication in 2013 that “some experts”
do one thing and “other experts” do something else. Parts
of the report use expert consensus in some of its recom-
mendations, such as preemptive therapy with parenteral
acyclovir in neonates delivered to women with first-epi-
sode primary and nonprimary infections because of their
substantial risk of neonatal HSV disease, even though
such an approach has not been, and never will be, clini-
cally investigated. However, these expert consensus rec-
ommendations are grounded in the risk assessments
derived from categorizing the mother’s infection as first-
episode primary, first-episode nonprimary, and recurrent.
The clinical report was written by the AAP Committee on
Infectious Diseases and Committee on Fetus and Newborn
and was supported by the American College of Obstetri-
cians and Gynecologists.
An issue of frequent concern is whether the mother
with an active genital HSV infection at delivery should
be isolated from her infant after delivery. Women with
recurrent orolabial HSV infection and cutaneous HSV
infections at other sites (e.g., breast lesions) are at simi­lar
risk for transmission of virus to their newborns. Because
transmission occurs by direct contact with the virus,
appropriate precautions by the mother, including careful
hand washing before touching the infant, should prevent
any need to separate mother and child. In some cases,
it is possible to have the exposed infant room-in with
the mother as a means of isolating the infant from other
newborns. Breastfeeding is contraindicated if the mother
has vesicular lesions involving the breast.
Neonatal HSV infection is a life-threatening disease in the
newborn. With an increasing prevalence of HSV-1 geni-
tal herpes, a continuing high prevalence of HSV-2 genital
herpes, and the recognition that many infections are com-
pletely asymptomatic in the mother, pediatricians, neo-
natologists, obstetricians, and family practitioners must
continue to remain vigilant to infants whose symptoms
may be compatible with HSV infections.
Acknowledgments
The databases on clinical presentations, diagnosis, and anti-
viral treatment of neonatal HSV infections have been gener-
ated through the efforts of the NIAID Collaborative Antiviral
Study Group for more than 35 years, with support from the
National Institute of Allergy and Infectious Diseases. The
Institute also has supported prognostic studies of HSV infec-
tion in pregnancy and newborns in the United States.
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 28 Human Parvovirus
STUART P. ADLER and WILLIAM C. KOCH

CHAPTER OUTLINE
ERRNVPHGLFRVRUJ
Microbiology Overview
General Aspects of Pathogenesis Fetal Death
Epidemiology and Transmission Asymptomatic Fetal Infection
Overview Birth Defects
Global Distribution Other Fetal Manifestations
Seasonality and Periodicity Fetal Hydrops
Seroprevalence by Age Fetal Outcome in Relation to Maternal
Seroprevalence by Gender Manifestations
Seroprevalence by Race Long-term Outcomes
Incidence Pathogenesis of Infection in the Fetus
Risk Factors for Acquisition Fetal Immune Responses to Parvovirus B19
Hospital Transmission Pathogenesis of Parvovirus B19 Hydrops
Routes of Viral Spread Pathology in the Fetus
Risk of Parvovirus B19 Acquisition for Anatomic and Histologic Features
Women of Childbearing Age Placenta
Clinical Manifestations (Other Than Intra- Heart
uterine Infection) Other Organs
Erythema Infectiosum Diagnostic Evaluation and Manage-
Transient Aplastic Crisis ment of the Woman and Fetus Exposed
Arthropathy to or Infected by Parvovirus B19 During
Infection in Immunocompromised Hosts Pregnancy
Other Dermatologic Syndromes Overview
Central Nervous System Infection and Prevalence of Erythema Infectiosum
­Neurologic Disorders History of Exposure
Renal Disease Clinical Features Suggesting Signs and
Myocardial Disease Symptoms of Parvovirus B19 Infection
in the Pregnant Woman
General Aspects of Diagnosis
Laboratory Diagnosis in the
Laboratory Diagnostic Methods Pregnant Woman
Epidemiology of Parvovirus B19 Fetal Monitoring
­Infections and Risk of Acquisition
in Pregnant Women Fetal Therapy
Prevalence and Incidence in the Differential Diagnosis
United States Prognosis
Prevalence and Incidence in Other Countries Prevention
Clinical Manifestations of Parvovirus B19 General Measures
Infections in Pregnant Women Vaccine Development
Intrauterine Transmission Rates, Clinical
Manifestations, and Fetal Outcomes

The parvoviruses are a family of single-stranded DNA
viruses that have a wide cellular tropism and broad host
range, causing infection in invertebrate species and verte-
brates, from insects to mammals. Although many parvovi-
ruses are important veterinary pathogens, there are only
two human pathogens in the family: human parvovirus
B19 and the more recently described human bocavirus.1,2
Human bocavirus seems to be primarily a respiratory
pathogen of young children and is not discussed further
here. Human parvovirus B19 is most commonly referred
866
to as parvovirus B19 or simply B19. B19 is the prototype
of the genus Erythrovirus in the Parvoviridae family, and
a new genus and name have been proposed for this virus,
Erythrovirus B19,3 based on its cellular tropism for ery-
throid lineage cells and to distinguish it from the other
mammalian parvoviruses. Compared with most other com-
mon human viruses, B19 is a relatively new pathogen, but
since its initial description, B19 has come to be associated
with a variety of seemingly diverse clinical syndromes in
many different patient populations (Table 28-1). Although