Simplex Virus Infection
Neonatal herpes simplex infection is a potentially fatal disease.
Neonatal herpes has a broad clinical spectrum and may be categorized
into three patterns: localized infection confined to the skin, eyes,
or mouth; CNS disease; and disseminated disease.
Many infants with CNS and disseminated neonatal herpes do not
develop cutaneous lesions.
Age Neonatal herpes can present
up to 4 weeks of age. Disseminated disease often presents during
the first week of life, while localized infection typically presents
later. CNS infection presents between 14 and 21 days of life.
Prevalence Approximately 1 in 3000
Etiology 75% result from
herpes simplex virus-2 (HSV-2) infection, 25% result from
herpes simplex virus-1 (HSV-1) infection.
Transmission Herpes virus is most
commonly inoculated onto the baby’s mucous membranes during
its passage through the birth canal; however, ascending infection
and transmission in the perinatal period from the mouth or hands
of caregivers may occur.
Herpes virus inoculation occurs mucocutaneously; systemic infection
can ensue with disease limited to the brain or diffuse hematogenous
Pregnant women with recurrent genital herpes are at very low
risk of transmitting HSV to their babies (<5%) because
of anti-HSV antibodies, which pass through the placenta and convey immunity
to the baby. The majority of cases occur in asymptomatic mothers
with primary genital herpes infection making it very difficult to
predict those at risk.
Type of Lesion Skin lesions begin
as 2- to 8-mm macules or papules that progress to single or grouped
vesicles that then rupture leaving an erosion or ulcer, which crusts
over and heals (Fig. 1-15).
Congenital herpes simplex virus,
localized Grouped vesicles on an erythematous base on the scalp
of a newborn.
Color Pink to erythematous.
Distribution Oral lesions are most
frequently located on the tongue, palate, gingiva, lips, and buccal
mucosa. Ocular lesions appear as erosions on the conjuctiva and
cornea. Skin lesions occur at sites of inoculation and infant monitoring
scalp electrodes may produce enough skin trauma to allow invasion by
the herpes virus. At birth in vertex deliveries, the scalp is a
common site for the development of initial herpetic lesions and
conversely, in breech deliveries, the buttocks and perianal area
frequently manifest the first lesions. The vesicles may become generalized
in the disseminated pattern of the disease.
Early in the infection, infants typically present with nonspecific
symptoms such as lethargy, poor feeding, and fever. CNS involvement
is manifested by isolated encephalitis with frequent seizures that
are nonfocal in nature. Eye involvement is seen in 10% to
20% of these patients and is noted characteristically between
age 2 days and age 2 weeks of life. Disseminated infection presents with
irritability, respiratory distress, jaundice, and seizures from
viral infection of the brain, lungs, liver, and adrenal glands.
The diagnosis of neonatal herpes is made by history and clinical
presentation and confirmed by detection of the herpes virus. The
differential diagnosis includes other blistering diseases of the newborn
such as congenital varicella, bullous impetigo, pemphigus vulgaris,
and other causes of neonatal sepsis.
Tzanck Preparation Cells scraped
from the base of vesicular lesions are positive for multinucleated
giant cells in 60% of culture proven HSV.
Histopathology Intraepidermal vesicles
produced by ballooning degeneration. Inclusion bodies (eosinophilic structures
with a surrounding clear halo) are frequently seen in the center
of enlarged, round nuclei of balloon cells.
Direct Immunofluorescence Cells
scraped from the base of vesicular lesions can be tested for the
presence of herpes virus infection using HSV-1 or HSV-2 specific
monoclonal antibodies. Sensitivity and specificity correlate highly
with tissue culture results.
Serology Antibody measurement in
the baby is of little value because the seropositivity rate for
HSV-2 among all women of childbearing age exceeds 20%.
Culture HSV may be cultured within
2 to 5 days from infected samples of skin, throat, conjuctiva, cerebrospinal
fluid, blood, urine, and stool.
Polymerase Chain Reaction Herpes
simplex DNA can be detected in the CSF using the polymerase chain
reaction, an extremely sensitive technique that is frequently used
for CSF evaluation.
Morbidity and mortality of neonatal herpes is strongly associated
with disease classification.
Localized Infection Treated infants
with cutaneous infection have virtually a 100% survival
rate, although some will suffer a cutaneous relapse in the first
year of life. Approximately 10% will manifest herpetic lesions
in the oropharynx. Up to 40% will have persistent ocular
pathology, although this is seen most frequently in children suffering
from severe neurologic residua (see below).
CNS Infection Untreated cases have
a mortality rate of 50% and treated cases have a mortality
rate of 15% to 30%. HSV-2 causes significantly
worse encephalitis as compared to HSV-1. Many of these cases sustain
permanent neurologic impairment.
Disseminated These neonates frequently
progress to cardiovascular compromise, coagulopathy, and, in the absence
of therapy, some 80% of cases result in death. With antiviral
therapy, the mortality rate is reduced to approximately 25%.
In light of the varied clinical manifestations of neonatal herpetic
infections and the severe consequences of untreated disease, immediate
institution of antiviral chemotherapy has been recommended for any
infant presenting with signs of severe, unidentified infection in
the first month of life, even in the absence of any characteristic
Antiviral therapy of IV acyclovir 60 mg/kg divided into
three equal doses and administered every 8 hours for 14 days if
limited disease, 21 days if disseminated or involving CNS. If ocular involvement
is present, addition of topical 1% trifluridine drops can
be instituted. Infants with CNS or disseminated disease that have
been treated successfully may require long-term suppressive antiviral
therapy to prevent subclinical CNS recurrences.
The majority of infants exposed to varicella zoster virus (VZV)
infection during pregnancy are asymptomatic and normal. There are
two exceptions: congenital VZV syndrome and neonatal varicella.
Congenital VZV Syndrome Occurs
if a mother is infected in the first 20 weeks of pregnancy and transplacental
infection of fetus occurs before maternal immunity can protect the
infant. This acquired infection leads to severe fetal sequelae and
mortality in up to 30%.
Neonatal Varicella Occurs if the
mother is infected VZV within three weeks of delivery. Since the
infant is born before maternal antibodies have been generated, the
infant has no immunity and will have a severe infection in the first
12 days of life with pneumonitis, hepatitis, meningoencephalitis,
and up to a 20% mortality.
Incidence Both congenital VZV and
neonatal VZV are very rare.
Transmission Varicella causes maternal
viremia, which can cause transplacental infection; ascending infection from
the birth canal and transmission in the perinatal period also may
Type Cicatricial scars, skin loss,
Distribution Sometimes in a dermatomal
General Findings Low-birth-weight,
eye defects, encephalomyelitis, hypoplastic limbs, microcephaly,
Type Monomorphic progression from
macule, papules, vesicles to crust (Fig. 1-16).
Congenital varicella zoster
virus infection T5 dermatomal erythematous plaque on the right
side of a newborn’s body. (Slide courtesy of Karen Wiss.)
General Findings Pneumonitis,
hepatitis, and meningoencephalitis.
Congenital HSV, other TORCH (toxoplasmosis, other [syphilis],
rubella, CMV, HSV) infections, sepsis.
Direct immunofluorescence (DFA), polymerase chain reaction, or
skin biopsy of cutaneous lesions can demonstrate VZV. Cultures of
tissue or CSF have not been shown to reliably grow VZV in infants
with congenital VJV syndrome. IgG and IgM antibodies to VZV can
be demonstrated in the mother’s sera to determine either
previous immunity or active infection to confirm the findings and
VZV-specific IgG antibodies in the baby that persist older than
7 months of life (by which point any maternal antibodies should
Based on history or maternal infection, clinical appearance of
the newborn, and laboratory findings.
Infants in utero of mothers with VZV are generally protected
by the transplacental acquired antibodies generated during maternal
VZV infection. Thus, most infants are unaffected and born normal.
These infants may develop unusual manifestations of attenuated immunity
later in life such as herpes zoster at an early age. Such children
are immunocompetent, but had in utero primary VZV infection (chicken
pox) and an attenuated immune response since maternal antibodies
were present to help fight the infection. Infants born to mothers
who develop varicella 5 days prior to delivery to 2-day postpartum
are at highest risk for a fatal course because of insufficient time
for maternal antibody acquisition.
Congenital VZV syndrome has up to a 30% mortality rate
but long-term outcome can be good for surviving patients.
Herpes zoster (shingles) in a pregnant woman is generally thought
to have minimal risk for sequelae for the fetus.
Those pregnant women who have been exposed to varicella should
have a VZV-IgG level measured if they do not have a history of varicella
infection or vaccination. For those with negative histories or serologies,
varicella zoster immune globulin (VZIG) is indicated at any point
during pregnancy. Administration of acyclovir should be given at
the first clinical sign of VZV infection. For VZV infections between
5 days before and 2-day postpartum, mothers should be given acyclovir
and an attempt to delay the delivery may be made. The neonates should
be given VZIG and systemic acyclovir immediately upon delivery and
should be isolated and observed for 2 weeks.
The “blueberry muffin baby” is so-named because
of the baby’s clinical presentation, with disseminated
red–blue papules and nodules representing islands of extramedullary
hematopoiesis. The blueberry muffin baby can be seen with in utero
infections with toxoplasmosis, varicella, cytomegalovirus (CMV),
human immunodeficiency virus (HIV), and rubella.
Etiology Maternal infection during
pregnancy and transplacental infection with toxoplasmosis, varicella, CMV,
HIV, or rubella.
Type Purpuric macules, papules,
and nodules (Fig. 1-17).
Blueberry muffin baby Scattered
red–blue papules and nodules on the face of a newborn.
The lesions represent sites of extramedullary hematopoiesis.
Color Bluish-red to purple.
Size 2 to 8 mm in diameter.
Palpation Infiltrated, larger lesions
are palpable 1 to 2 mm above the skin’s surface.
hepatosplenomegaly, hydrocephaly, microcephaly, cataracts, pneumonitis, chorioretinitis,
CMV Jaundice, hepatosplenomegaly,
anemia, thrombocytopenia, respiratory distress, convulsions, and chorioretinitis.
HIV Hepatosplenomegaly, other opportunistic
Rubella Cataracts, deafness, growth
retardation, hepatosplenomegaly, cardiac defects, and meningoencephalitis.
The differential diagnosis of a blueberry muffin baby is typically
the infectious causes of extramedullary dermal hematopoiesis: toxoplasmosis,
varicella, CMV, HIV, and rubella. The diagnosis is typically made
by maternal history and detection of one of the above-named infectious
Dermatopathology Blueberry muffin
lesions show aggregates of large nucleated and nonnucleated erythrocytes.
DNA Detection of parasite DNA in
amniotic fluid or fetal blood.
Serology Infant antitoxoplasma
IgM higher than maternal IgM is diagnostic of congenital infection.
Wright’s or Giemsa Stain CSF
or lymph node, spleen, or liver demonstrating Toxoplasma gondii.
Skull Films Diffuse, punctate,
comma-shaped, intracranial calcifications.
Culture Urine, liver, CSF, gastric
washing, and pharynx will show characteristic large cells with intranuclear
and cytoplasmic inclusions.
Head CT scan Intracranial calcifications
may be present.
Serology Elevated antirubella IgM
in infant or persistent antirubella IgG in infants older than 6
months. Fourfold or greater increase in acute and convalescent sera
is also diagnostic.
Culture Virus can be isolated from
nasopharynx, urine, CSF, skin, stool, or eyes.
Toxoplasmosis Infected infants
may be stillborn, premature, or full term. At birth, they may present
with malaise, fever, rash, lymphadenopathy, hepatosplenomegaly,
convulsions, and chorioretinitis, though most are asymptomatic.
Overall prognosis is poor, especially with infants that have liver
and bone marrow involvement.
CMV Affected infants may have sensorineural
hearing loss, mental retardation, learning disabilities, and seizures.
Poor prognosis, especially with intracranial calcifications or hydrocephalus.
Rubella Rubella acquired during
the first trimester may lead to low-birth-weight, microcephaly,
mental retardation, cataracts, deafness, and heart abnormalities.
Rubella acquired during second or third trimester can lead to hepatosplenomegaly,
pneumonitis, myocarditis, encephalitis, osteomyelitis, or retinopathy.
Toxoplasmosis 30+ days of sulfadiazine
(150–200 mg/kg/d divided qid) plus pyrimethamine
(1–2 mg/kg/d divided bid). Infants with
chorioretinitis or high CSF protein levels may need systemic steroids.
CMV Ganciclovir can be used to
treat retinitis and organ involvement.
Rubella Immune globulin administered
to exposed pregnant mother within 22 hours of onset can prevent/reduce
fetal infection. Neonatal rubella requires ophthalmologic and supportive
care. However, infected infants can shed the virus for up to a year.
A prenatal spirochetal infection with characteristic early and
late signs and symptoms. Clinical manifestations of early congenital
syphilis (first several months of life) include anemia, fever, wasting,
hepatosplenomegaly, lymphadenopathy, rhinitis (snuffles), mucocutaneous
lesions (including rhagades: radial fissures and furrows around
the mouth), and pseudoparalysis. Symptoms of late congenital syphilis,
which appears after 2 years of age, include interstitial keratitis, Hutchinson
teeth (notched central incisors), and eighth nerve deafness; these
three compose the Hutchinson triad. Frontal bossing, mulberry molars,
saddle nose deformity, Clutton joints (painless knee swelling),
and anterior bowing of the shins are also features of late congenital
Synonym Prenatal syphilis.
Age Within first months of life
and after the age of 2.
Incidence Incidence had dropped
to insignificant levels in 1959, but since then has been increasing.
Etiology Spirochete Treponema pallidum
crosses the placenta to infect the fetus.
Neonates with syphilis are often born without signs of disease
at time of birth. Clinical manifestations in first month of life
are common. Skin findings include macules, papules, papulosquamous, and
vesicobullous lesions. Widespread desquamation can occur (Fig. 1-18).
Mucocutaneous involvement of mouth and lips is common. Systemically,
there is lymphadenopathy, hepatosplenomegaly, and pseudoparalysis.
Neonatal syphilis Copper-colored
macules and diffuse desquamation on the plantar surface of a newborn
with secondary syphilis.
Early Congenital Syphilis Signs
and symptoms appearing in first 2 months of life.
Noted in one-third to one-half of affected infants. Skin lesions
Type Macules, papules, or papulosquamous
lesions on body. Patches on mucous membranes, raised verrucous plaques
on anogenital, or oral membranes.
Color Bright pink to erythematous;
fades to copper-colored or brownish.
Size and Shape Large, round, or
Distribution Generalized or localized
to any area.
Sites of Predilection Face, dorsal
surface of trunk and legs, diaper area, palms, and soles.
Hepatomegaly, lymphadenopathy (especially epitrochlear), splenomegaly,
jaundice, anemia, thrombocytopenia, osteochondritis, and meningitis. “Barber-pole
umbilical cord” spiral red, white, and black discoloration
of necrotizing umbilical cord.
Late Congenital Syphilis Signs
and symptoms appearing after 2 years of age.
Hypersensitivity type reaction or scars and deformities related
to infection. Skin lesions no longer infectious.
Hutchinson’s triad: (1) interstitial keratitis, (2)
Hutchinson teeth, (3) eighth nerve deafness; dental changes (mulberry
molars or bony gums that progress to necrotic ulcers), Higoumenakia
sign (unilateral, thickened inner one-third of clavicle), arthritis,
Parrot lines (radial scars after rhagades heal), and eye changes
(choroiditis, retinitis, and optic atrophy).
The diagnosis of congenital syphilis can be made based on clinical
suspicion and confirmed by positive dark-field microscopy or fluorescent
antibody tests of the umbilical cord, placenta or skin lesions,
by radiologic bony changes, and positive serology for syphilis.
A serologic titer in the newborn at least fourfold higher than the
mother is diagnostic of congenital syphilis.
Dark-Field Microscopy of the umbilical
cord, skin lesions, or mucous membranes for T. pallidum.
Radiologic Studies for bone abnormalities:
widening of the epiphyseal line with increased density of the shafts.
Placental Changes include focal
villositis, endovascular and perivascular proliferation in villous
vessels, and relative immaturity of villi.
Relative to time during pregnancy of maternal spirochetemia and
subsequent fetal inoculation. Up to 4 months of gestation, spontaneous
abortion is common. Infection after 4 months of gestation may result
in stillborn or fatally ill neonate. Prognosis with contracted disease
is dependent on early and proper diagnosis and adequate treatment.
Treatment without CNS involvement:
1. Aqueous crystalline penicillin G: (100000– 150000
units/kg) IM or (50000 units/kg IV q 8–12 hour)
× 14 days.
2. Procaine penicillin G: (50000 units/kg IM q 24 hour
× 10–14 days).
3. Benzathine penicillin G: (50000 units/kg IM × 1 dose).
Treatment with CNS involvement:
1. Crystalline penicillin G: (30000–50000
units/kg) divided bid–tid × 3 weeks.
2. Procaine penicillin G: (50000 units/kg) qid × 3 weeks.