HERPES SIMPLEX

VIRUS IN THE
NEONATE
Ron Christian Neil T. Rodriguez, MD
Mary Johnston Hospital
Neonatology Hour
Herpes Simplex Virus
• Enveloped, double stranded DNA
viruses
• Consists of HSV-1 and HSV-2
• Among the most prevalent of all viral
infections in humans
• In neonates, occurs in 1 in 2000 to
3000 live births
Pathophysiology
HSV-1 and HSV-2
HSV-1 HSV-2
• Affects face and skin above the waist • Affects the genitalia and skin below
•
the waist
Main cause of maternal genital
herpes • Accounts for ¾ of neonatal herpes
infections
HSV in the Neonate
Intrauterine Intrapartum Postnatal
• Accounts for 5% of HSV • Most common means • Accounts for 10% of
cases in a neonate of HSV infection in the cases of HSV infection
• Acquired neonate (85%) in neonates
transplacentally and • Due to ascending
occurs only in women infections in ruptured
with primary HSV membranes
infection. Incubation
period: 2 to 20 days
• Associated with
placental infarcts and
necrotizing funisitis
HSV in the Neonate
• Three patterns: Skin, eyes and mouth (SEM), Central nervous system (CNS),
Disseminated (Includes signs from the previous 2)
• Maternal infection can be classified as:
• Primary  new infection with either HSV-1 or HSV-2, with no infection from the other
virus type; infants born are at the highest risk (60%)
• First-episode non-primary  has a new infection to 1 virus type (often HSV-2) and has
antibodies due to another virus type (often HSV-1); infants born are at a lower risk (25%)
• Children born to mothers with recurrent infections have the lowest transmission risk
(2%)
HSV Patterns in the Neonate
SEM
• Accounts for 45% of cases
• Skin lesions  discrete
vesicles to large bullous
lesions and denuded skin
• Seen in the vertex and sites
of skin trauma
• Ulcerative mouth lesions
• Keratoconjunctivitis
chorioretinitis
• If untreated  encephalitis
or disseminated disease
CNS (with or without SEM)
• Accounts for 30% of cases
• Seizures (focal or
generalized)
• Lethargy, irritability, tremors
• Poor feeding
• Bulging fontanelle
• Affects infants 16 to 19 days
of age, often without any
skin lesion
• CSF: Mild pleocytosis,
increased protein, low
glucose
Disseminated
• Accounts for 25% of cases
• Worst prognosis with respect
to mortality
• Fever, lethargy, apnea, septic
shock-like picture
• Hemorrhagic pneumonitis,
liver failure, neutropenia,
thrombocytopenia, DIC
• Half of cases also present
with SEM infection and 60-
75% have CNS involvement
HSV Patterns in the Neonate
Diagnosis of HSV in Neonates
• Often delayed
• Early manifestations are subtle and non-specific
• Maternal history is often not helpful
• Relies on ancillaries and imaging
Laboratory Studies
• Surface viral cultures  definitive diagnostic method; involves the skin and mucus
membranes; confirms the presence of absence of the replicating virus; positive
cultures in more than 12 to 24 hours after birth indicates viral replication
• PCR  detects HSV DNA in blood and CSF; useful for diagnosis of HSV
encephalitis; sensitivity 75 to 100% of cases, specificity 71% to 100% of cases; a
negative test does NOT exclude the diagnosis of CNS HSV disease; can be used to
monitor HSV therapy with discontinuation only when PCR is negative
Laboratory Studies
• Immunologic assay  detect HSV antigen in lesions with sensitivity of 80 to 90%
• Liver function test  as HSV characteristically invades liver and causes
hepatocellular damage, measurement of liver function tests are advised
• Serologic tests  helps in diagnosing and differentiating primary vs secondary
maternal disease
• Lumbar puncture  performed in ALL suspected cases; may be normal in early
course of disease but will show a mononuclear cell pleocytosis, normal or
moderately low glucose, and mildly elevated protein; HSV PCR should always be
performed on CSF
Imaging Studies
• CT-scan/MRI  recommended in all infants with suspected HSV CNS disease;
findings include parenchymal brain edema or attenuation, hemorrhage, and
destructive lesions, often in the temporal lobe
• EEG  should be performed in all neonates suspected to have CNS involvement;
may show focal or multifocal epileptiform discharges before abnormal changes
are detected by CT or MRI
Management of HSV in Neonates
• Antepartum
• Acyclovir or Valacyclovir  for women with primary episode or those with an active
infection near or at the time of delivery; prophylactic treatment beginning at 36 weeks
AOG reduces risk of clinical HSV recurrence at delivery; however, the risk of neonatal
HSV is not totally eliminated
• Cesarean delivery is recommended; vaginal can be done if the are NO visible lesions
Management of HSV in Neonates
Management of HSV in Neonates
Management of HSV in Neonates
• For all infants age 24 hours or less born to mothers with a genital lesion:
• HSV surface cultures and HSV PCR are requested
• Preemptive therapy for exposed infants with acyclovir (60 mkday) for 10 days is
recommended
• For those born to mothers with recurrent infection, close monitoring and symptomatic
treatment is advised
• For those born to mothers with a history of herpes but no active genital lesion at
delivery  observation is warranted; surface cultures nor treatment with parental
acyclovir is needed
Management of HSV in Neonates
• Acyclovir
• IV Acyclovir (60 mkday) is given at 20 mkdose every 8 hours. This is given at a minimum
of 21 days for disseminated and CNS infections, while 14 days for SEM infections
• All patients with CNS infections must have a repeat lumbar puncture near the end of
acyclovir therapy. If CSF HSV PCR is positive  extend IV acyclovir for another week
until PCR result is negative.
• Ganciclovir
• Used if IV acyclovir is not available
• Given at 6 mg/kg for infants < 3 months of age, and 5 mg/kg every 12 hours for infants >
3 months of age
Management of HSV in Neonates
• Ophthalmic drugs containing 1% trifluridine, 0.1% iododeoxyuridine or 0.15%
ganciclovir can be used if there is ocular involvement
• Oral suppressive acyclovir therapy is recommended for 6 months post-treatment
of acute neonatal HSV; it is given at 300 mg/m2/dose, 3 times a day for 6 months
• Breastfeeding can be continued as long as no breast lesions are present on the
mother
Prognosis of HSV in Neonates
• Giving high-dose acyclovir (60 mkday) greatly reduced mortality
• Predictors of mortality:
• Disease severity, virus type, prematurity
• Systemic disease in a premature infants has a near 100% mortality
• CNS disease often results in morbid cases, with only 30% of affected patients
being able to have a normal neurologic development by 12 months of age
• Seizures at or before initiation of antiviral therapy and persistently positive CSF
PCR after 4 weeks of acyclovir is associated with poor neurodevelopmental
outcome
• SEM patients have an excellent outcome, but cutaneous recurrences are common
VARICELLA ZOSTER IN
THE NEONATE
Ron Christian Neil T. Rodriguez, MD
Mary Johnston Hospital
Neonatology Hour
Varicella-Zoster Virus (VZV)
• Member of the herpesvirus family; teratogen that can cross the placenta
• Primary maternal VZV infection can result in fetal or neonatal infection
• Reactivation infections does NOT result to fetal infection
• While VZV can be prevented by immunization, VZV vaccine should NOT be given
to a pregnant woman as the effects to fetal development are unknown
• Postpubertal females immunized with VZV vaccine should avoid pregnancy for at least 1
month after immunization
• 3 forms: Fetal, Congenital (Early Neonatal), Postnatal
Fetal Varicella Syndrome
• Occurs when mother has first exposure to VZV during the first half of pregnancy
• Affects only 5% of women of child-bearing age, with only 1 to 5 cases per 10,000
pregnancies
• Embryopathy and fetopathy in the first 20 weeks is very rare (1 to 2%)
 Fetal Varicella Syndrome -
Pathophysiology

Viremia and
Maternal acquisition transplacental
Replication at
(respiratory droplets or direct passage to the fetus
oropharynx
contact) via hematogenous
route
Fetal Varicella Syndrome
• Effects to fetuses:
• Microcephaly secondary to VZV encephalitis
• Fulminant infection of lungs or liver  fetal demise
• Damage and destruction of the plexi during embryogenesis  denervation of the limbs
and subsequent hypoplasia
• Cutaneous defects secondary to infection of the sensory nerves
• Optic atrophy and chorioretinitis secondary to infection of the developing optic tracts
• Early shingles in life after birth
Fetal Varicella Syndrome - Manifestations
• Skin lesions (60-70%)  cicatricial scars and skin loss
• CNS defects or disease (60%)  microcephaly, seizures, encephalitis, cortical and
spinal cord atrophy, mental retardation, cerebral calcifications
• Ocular abnormalities (60%)  microphthalmia, chorioretinitis, cataracts, optic
atrophy, nystagmus, Horner syndrome
• Limb abnormalities (50%)
• Prematurity and IUGR (35%)
Fetal Varicella Syndrome - Manifestations
Fetal Varicella Syndrome – Diagnosis
• Mostly obtained by maternal history and use of laboratory studies and is
dependent on the fulfillment of these criteria:
• Appearance of meternal varicella during pregnancy
• Presence of congenital skin lesions
• Proof of intrauterine VZV infection  viral DNA detection via PCR, presence of VZV-
specific IgM, persistence of VZVZ IgG beyond 7 months of age, or appearance of
shingles in early infancy
• Prenatal diagnosis: Ultrasonography at 17 to 21 weeks AOG and VZV PCR of the
amniotic fluid
Fetal Varicella Syndrome - Management
• Maternal:
• Treated with Varicella-Zoster immunoglobulin (VariZIG) if past history is negative or
uncertain, and is exposed during the first or second trimester
• VariZIG is preferably givenin within 72 hours but may extend up to 10 days; if VariZIG is
not available IVIG can be used
• Acyclovir or valacyclovir therapy can be given if with chickenpox
• Infant
• Supportive management due to profound neurologic impairment
• Acyclovir can help prevent the progression of eye disease or shingles, which is common
in the first 2 years of life
• Isolation of mother and infant is NOT necessary
Fetal Varicella Syndrome - Prognosis
• 30% of cases die in the first months of life secondary to intractable GER, severe
recurrent aspiration pneumonia, and respiratory failure
• Survivors usually present with profound mental retardation and major neurologic
disabilities
Congenital Varicella Infection
• Occurs when a pregnant woman has chickenpox during the last 3 weeks of
pregnancy or within the first few days postpartum
• Disease begins in the neonate just before delivery or during the first 10 to 12 days
of life
• More common than FVS, yet still rare in occurrence, accounting for only 0.7 per
100,000 live births per year
 Congenital Varicella Infection -
Pathophysiology
Maternal contact during near term
Transplacental viremia,
ascending infection or
Appearance of
respiratory
characteristic lesions in
droplet/direct contact
the mother
with the lesion after
birth
Congenital Varicella Infection -
Pathophysiology
• If onset of maternal disease is between 5 days before delivery or 2 days
postpartum  high attack rate (up to 50%), mortality (up to 30%)
• Infants present with classic skin lesions, pneumonia, hepatitis, menigoencephalitis
and/or sever coagulopathy from liver failure and thrombocytopenia
• Milder cases occur if onset of maternal rash happens 5 days before delivery
• Premature infants, especially those < 28 weeks are extremely susceptible
Congenital Varicella Infection -
Manifestations
• Skin  Centripetal rash (begins at trunk and spreads to face and scalp, sparing the
extremities)  macules  vesicles and encrustations
• More common in the diaper area and skin folds
• Lung involvement  appears 2 to 4 days after onset of rash; symptoms include
fever, cyanosis, rales, and hemoptysis; CXR shows diffuse nodular-miliary pattern
• Focal necrosis in the liver, adrenals, intestines, kidneys and thymus
Congenital Varicella Infection - Diagnosis
• PCR is the most sensitive and specific method for detection of VZV DNA, and thus,
the diagnostic method of choice
• Viral cultures and direct fluorescent antibody assays are less sensitive than PCR
and are not usually recommended
• Serum testing for VZV antibody can help detect acute infection in difficult cases
but this is often not reliable
Congenital Varicella Infection -
Managment
• Varicella-Zoster Immunoglobulin (VariZIG)  given to infants whose mothers
develop rash within 5 days before or 2 days after delivery
• Given 125 U or 62.5 U if <2 kg) as soon as possible and not more than 10 days.
• IVIG can be given at 400 mg/kg if VariZIG is not available
• Immunoglobulin treatment can prolong incubation, thus respiratory isolation and
close monitoring for 28 days must be done
• Infants born to mothers who develop rash more than 5 days prior to delivery do
NOT need VariZIG, EXCEPT if they are premature (<28 weeks of gestation)
Congenital Varicella Infection -
Managment
• Acyclovir  given at 15 mkdose every 8 hours for 7 days as both postexposure
prophylaxis and treatment
• Antibiotics can be given if secondary bacterial skin infections occur
• Breastfeeding nor pumping of breastmilk is not contraindicated as long as there
are no lesions on the breast
Congenital Varicella Infection - Prognosis
• If mother has onset of disease within 5 days before delivery or 2 days after, infant
has no antibodies, is exposed, and will be at risk for severe disease
• Sepsis and multiple organ failure can occur in 30% of cases
• Most common sequelae leading to mortality: pneumonia, fulminant hepatitis, DIC
Postnatal Chickenpox
• Occurs after the 12th day of life, with no transplacental infection from the mother
• Relatively rare due to presence of varicella vaccine, occurring only in 0.7 per
100,000 live births
• Infection occurs via droplet transmission, and is often mild due to passive
immunity from maternal antibodies
• Preterm infants are still more susceptible than term infants
Postnatal Chickenpox – Risk Factors
• Seronegative mothers
• Preterm delivery (<28 weeks)
• Birthweight < 1.5 kg
• Postnatal age > 2 months
• Immunocompromised neonates
Postnatal Chickenpox – Manifestations
• Typical rash presents as centripetal
spread, with all stages of the rash
possibly appearing at the same time:
• Red macules  Clear vesicles 
Crusting lesions
• Complications are rare but may
include secondary infections and
varicella pneumonia
Postnatal Chickenpox – Diagnosis and
Management
• Diagnosis is mostly clinical and similar to congenital varicella
• Acyclovir therapy is often controversial for these cases as the disease is often mild; only
recommended for infants with breakthrough lesions or prophylactically beginning 7 days after
exposure.
• For nosocomial chickenpox in the NICU:
• VariZIG  given to all exposed infants who are < 28 weeks gestational age or weighs < 1 kg;
recommended to be given to premature infants (28 weeks – 36 weeks) whose mothers are
seronegative
• If mother is seropositive, infants are protected by antibodies obtained transplacentally
• Isolation for 8 to 21 days after rash onset is recommended, with those who receive VariZIG or IVIG
isolated for 28 days
• Breastmilk is considered protective. As such, so long as there is no lesion in the breast,
breastfeeding is NOT contraindicated
Postnatal Chickenpox – Diagnosis and
Management
• This form of VZV is mild and prognosis is excellent
• Term neonates who develop postnatal chickenpox have the same risk of
complications as that of older children
• Premature infants are at increased risk of acquiring the disease nosocomially
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