Transcript Neonatal Herpes Simplex Infection Jesus Peinado M.D. Dept. of Pediatrics: PGY2 July 24, 2008

Neonatal Herpes Simplex
Infection
Jesus Peinado M.D.
Dept. of Pediatrics: PGY2
July 24, 2008
INTRODUCTION
Neonatal HSV infections were first described
in the mid-1930s.
The earliest antiviral agents proved too toxic in
humans to be useful.
Vidarabine was the first systemically
administered antiviral medication.
VIRAL STRUCTURE
Large and enveloped virions
Icosahedral nucleocapsid consisting of 162
capsomeres
Arranged around a linear, double stranded
DNA core
The genome consists of 2 covalently linked
components
VIRAL STRUCTURE
Core: Consists of a single linear molecule
of dsDNa in the form of a torus
Capsid: Surrounding the core w/ a
100 nm diameter and 162 capsomeres
Tegument: Consists of viral enzymes
Envelope: Outer layer composed of
altered host membrane and a dozen
of viral glycoproteins
VIRAL STRUCTURE
VIRAL STRUCTURE
There is considerable cross-reactivity between
HSV-1 and HSV-2 glycoproteins
Unique antigenic determinants exist for each
virus
Eleven glycoproteins have been identified
They mediate attachment, penetration and
provoke immune responses
VIRAL STRUCTURE
gD is the most potent inducer in neutralizing
antibodies
gD is related to viral entry into the cell
gB is related to infectivity
gG provides w/ antigenic specificity w/ the
resulting antibody response allowing
distinction between HSV-1 and HSV-2
BIOLOGY
Latency and neurovirulence directly influence
on human disease
During HSV infection , virions are transported
by by retrograde flow along axons
Vioral multiplication occurs in a small number
of sensory neurons
Viral genome remains in a latent state for the
life of the host
BIOLOGY
Periodic reactivation brought on by events of
physical or emotional stress
The virus is transported back down the axon to
replicate again at or near the point of entry
Reactivation can result in apparent disease
(lesions) or clinically inaparent (subclinical)
infection
Latency is incompletely understood
BIOLOGY
Neurovirulence is the affinity with which HSV
is drawn to and propagated in neuronal tissue
This can result in profound disease with severe
neurologic sequela
Sites for neuurovirulence have been mapped to
the thymidine kinase gene
The gene identified as Y134.5 is required for
replication in the CNS and prevents apoptosis
of infected cells
MATERNAL GENITAL
INFECTIONS
Most common form of genital infection during
gestation
10% of HSV-2 seronegative pregnant women
have an HSV-2 seropositive partner
2/3 of women who acquire genital herpes
during pregnancy have no symptoms
60 to 80% of women who deliver an HSVinfected infant have no evidence of infection
NEONATAL TRANSMISSION
Gravid woman must be shedding virus w/ or
w/out symptoms
In non-pregnant HSV-seropositive women
HSV as detected by PCR is shed w/out
symptoms 1 of every 3 days
Among pregnant women the viral excretion
proximate to delivery from 0.20 to 0.39%
Pregnant women w/ recurrent genital HSV the
incidence is from 0.70 to 1.4%
FACTORS INFLUENCING
TRANSMISSION
Type of maternal infection (primary/recurrent)
Maternal antibody status
Duration of rupture of membranes
Integrity of mucocutaneous barriers
Mode of delivery (C-section/vaginal)
INCIDENCE OF NEONATAL
DISEASE
2/1000 mothers are HSV culture + at delivery
asymptomatic
50-70% affected infants born to women
asymptomatic at the time of delivery
Antepartum cultures are not useful in assessing
risk of neonatal infection
Increased risk w/ primary vs recurrent
infection
Incidence from 1/2000 to 1/5000 live births
and increasing
RISK OF NEONATAL HSV
INFECTION
50% risk: Infants born to women w/ primary
infection near the time of delivery
30% risk: Infants born to mothers with first
episode, non-primary infection (antibody to
type 1, new acquisition type 2 and vice versa)
1 to 3% of infants born to mothers w/ recurrent
infection
Passive immunity protects against infection ,
but has little effect on the severity of disease
RISK FACTORS
Associated w/ primary maternal HSV:
1. Genital symptoms, UTI symptoms not
responsive to therapy
2. Positive HSV cultures from both cervix and
vagina
3. New sexual partner immediately prior to or
during pregnancy
RISK FACTORS
Reasons for increased risk w/ primary
maternal HSV infection
1. Prolonged shedding of virus up to 3 wk vs 2
to 5 days
2. Increased number of viral particles excreted
3. Less passive immunity to HSV, i.e. less
maternal-fetal transfer of HSV neutralizing
antibodies
RISK FACTORS
1.
2.
3.
4.
5.
Neonatal risk factors:
Rupture of membranes > 6 hrs
Scalp electrodes or other internal monitoring
Chorioamnionitis
Cervicitis
Vaginal delivery
TIMES OF TRANSMISSION
HSV of the newborn is acquired during one
of three distinct time intervals:
1. Intrauterine (in utero 5%)
2. Peripartum (perinatal 85%)
3. Psotpartum (postnatal 10%)
DISEASE CLASSIFICATION
Disease localized to the skin, eyes and mouth
SEM disease accounting for 45% of cases
Encephalitis w/ or w/out CNS involvement
accounting for 30%
Disseminated infection including CNC, lungs,
etc. accounting for 25%
This classification is predictive of morbidity
and mortality
SEM DISEASE
CUTANEOUS LESIONS
VESICULAR LESIONS HSV
HERPES PNEUMONITIS
INTRAUTERINE INFECTION
Occurs in 1/300,000 deliveries
Cutaneous manifestations: scarring, active
lesions, hypo and hyperpigmentation, aplasia
cutis and an erythematous macular exanthem
Ophthalmologic: microopthalmia, retinal
dysplasia, optic atrophy, chorioretinitis
Neurologic: microcephaly, encephalomalacia,
hydranencephaly, intracranial calcification
DISSEMINATED DISEASE
1/2 to 2/3 of all children w/ neonatal HSV
Encephalitis is a common component
occurring in about 60% to 75%
20% w/ disseminated disease do not develop
vesicular rash
Death relate to severe coagulopathy, liver
dysfunction and pulmonary involvement
CNS DISEASE
1/3 of all neonates w/ HSV infection w/ or
w/out SEM involvement
Manifestations include: seizures (focal and
generalized), lethargy, irritability, tremors,
poor feeding and bulging fontanelle
60 to 70% have associated skin vesicles
Mortality is cause by brain destruction w/
acute neurologic and autonomic dysfunction
HERPES ENCEPHALITIS
HERPES ENCEPHALITIS
SIGNS AND SYMPTOMS
Sings/symptoms
SEM disease
CNS disease
Disseminated
disease
Total
Skin vesicles
83%
63%
58%
68%
Lethargy
19%
49%
47%
38%
Fever
17%
44%
56%
39%
Conjunctivitis
25%
16%
17%
19%
Seizure
2%
57%
22%
27%
DIC
0
0
20%
11%
Pneumonia
0
3%
34%
13%
LABORATORY ASSESSMENT
Type-specific antibody assays have been
approved by FDA
Serologic testing identifies only past infection
Can not identify the site of HSV infection
Serological diagnosis is not of clinical value
Transplacentally acquired IGg confounds the
assessment of neonatal antibody status
Serologic studies play no role in diagnosis
VIRAL CULTURE
Remains the definitive diagnostic method
If skin lesions scraping of the vesicles
Other sites include: CSF, urine, blood, stool or
rectum, oropharynx and conjunctiva
Duodenal aspirates if hepatitis/NEC/GI disease
Of the sites cultured for HSV skin, eye and
conjunctiva provides the greatest yields
PCR AMPLIFICATION
PCR results from CSF of infected neonates
No. (%) of patients with:
PCR result
SEM (n29) CNS (n34) Disseminated (n14)
Positive
7 (24)
26 (76)
13 (93)
Negative
22 (76)
8 (24)
1 (7)
TREATMENT & MANAGEMENT
Mortality in preantiviral era by 1 y of age was
85% disseminated and 50% CNS disease
W/ high dose acyclovir 60mg/kg/day 12mo
mortality for disseminated 29% and 4% for
CNS disease
Lethargy/hepatitis are associated w/ mortality
in disseminated disease
Prematurity/seizures in CNS disease
TREATMENT
Topical agents (trifluridine) are recommended
for use along w/ parenteral acyclovir for ocular
disease
IVIG has no value in the treatment of HSV
Higher doses of acyclovir are associated w/
neutropenia
Adequate hydration reduces risk of
nephrotoxicity
SUMMARY OF CURRENT
TREATMENT
Acyclovir 60mg/kg/day improves morbidity
and mortality
In preterm dosing interval based on CrCl
Disseminated and CNS disease 21 days
SEM 14 days
All patients w/ CNS disease should have a
repeat LP at the end of therapy
CSF w/ + PCR should continue treatment until
PCR negative
PCR results following completion of antiviral
therapy
No. (%) with PCR result
Infant characteristic
Disease classification
CNS disease
Disseminated disease
SEM disease
CSF indices
Normal
Abnormal
Morbidity/mortality >12 mo
Normal
Mild
Moderate
Severe
Dead
Unknown
Negative
Positive
4 (36.4)
0 (0.0)
7 (63.6)
14 (73.7)
5 (26.3)
0 (0.0)
6 (54.5)
3 (27.3)
1 (5.3)
17 (89.4)
6 (54.5)
0 (0.0)
1 (9.1)
2 (18.2)
0 (0.0)
2 (18.2)
1 (5.3)
0 (0.0)
3 (15.8)
10 (52.6)
5 (26.3)
0 (0.0)
P
< 0.001
<0.001
ANTIBODY THERAPY
Utilization of passive immunotherapy as
adjuvant to active antiviral interventions
Human and humanized monoclonal Ab against
gB or gD are benefical in animal models
Studies w/ humans have documented
protective effects
VACCINE DEVELOPMENT
HSV-2 gD adjuvanted w/ alum combined w/
3-deacylated monmophosphoryl lipid A has
demostrated promising results
75% efficacy in preventing HSV-1 HSV-2
genital disease
40% efficacy in preventing HSV-2 infection
RECOMMENDATIONS
Pregnant women w/ primary or first episode:
Acyclovir therapy at 36 wk 400mg tid
Primary HSV in 3rd trimester: C-section should
be offered where lesions can occur within 6 wk
of anticipated delivery and seroconversion has
not occurred yet
Recurrent HSV: Acyclovir at 36 wk 400 mg
tid
RECOMMENDATIONS
Women in labor: HSV lesions C-section
may reduce the risk if performed 4-6 hrs ROM
Many recommend C-section even if ROM >6
hrs
If term and active lesions  C-section
If preterm  Acyclovir 15mg/kg/day
If no lesions only history  VD
If genital lesions No invasive procedures
(scalp sampling or monitors or early ROM)
INFANTS BORN BY NSVD
CULTURES
Asymptomatic infants exposed to HSV
Mother had HSV but no lesions at delivery
Should be taken from urine, stool, rectum,
mouth, eyes and nasopharynx
If therapy is initiated a CSF sample should be
obtained prior to treatment
Duration of therapy is 14 to 21 days
INFANTS BORN BY NSVD
Acyclovir therapy is not recommended for the
asymptomatic infant
Symptomatic infants PCR testing of CSF and
blood
The index of suspicion should be maintained
for 6 wk
HSV infection may occur as late as 4-6 wk
after delivery
INFECTION CONTROL
MESASURES
Contact precautions
Hand washing before and after care of infants
Mother w/ lesions on hands hand hygiene and
gloves
BF is allowed if no lesions on the breast and if
active lesions are covered
Mother w/ herpes labialis or stomatitis should
wear disposable masks
DIAGNOSTIC TESTS
Cultures from skin lesions, mouth,
nasopharynx, conjunctiva, urine, stool/anorectum and CSF.
Positive cultures at more than 48 hrs are
consistent w/ viral replication as opposed to
colonization
Serologic tests should not be relied on
PCR testing for CSF HSV DNA is the
diagnostic method of choice for HSV
encephalitis
TREATMENT AND FOLLOW UP
Acyclovir is the treatment of choice
SEM 14 days of treatments
CNS and disseminated disease 21 days
Oral acyclovir contraindicated in neonates for
HSV treatment
Ocular involvement requires trifluridine
FUTURE RESEARCH ISSUES
The optimal management of pregnant women
w/ genital HSV as this relates to antenatal
acyclovir
The management of women w/ known or
primary HSV who present w/ PROM
The pharmacokinetics of acyclovir in VLBW
The significance of acyclovir-resistant HSV
from neonates w/ prolonged exposure
FUTURE RESEARCH ISSUES
The role of new agents such as famciclovir and
valacyclovir where oral therapy is desired
The impact of long-term suppressive therapy
on neurological outcomes and immune
responses
Development/standardization of PCR on
different body fluids
Role of combination antiviral therapy w/
acyclovir plus monoclonal HSV antibodies
Development of vaccines against HSV
REFERENCES
Neonatal Herpes Simplex Infection, Kimberlin
David; Clinical Microbiology reviews, Jan
2004 p 1-13.
AAP 2005, Herpes Simplex, p 309-318. In
L.K. Pickering (ed.) 2005 Red Book.
Current management of HSV infection in
pregnant women and their newborn infants,
Canadian Paediatric Society, Paediatrics and
Child health 2006;11:363-5