Neonatal Herpes Simplex Infection

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Neonatal Herpes Simplex Infection

• Jesus Peinado M.D.
• Dept. of Pediatrics PGY2
• July 24, 2008

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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.

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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

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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
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VIRAL STRUCTURE
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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

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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

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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

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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

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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

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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 HSV-infected
  infant have no evidence of infection

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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

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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)

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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

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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

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RISK FACTORS

• Associated w/ primary maternal HSV
• Genital symptoms, UTI symptoms not responsive to
  therapy
• Positive HSV cultures from both cervix and vagina
• New sexual partner immediately prior to or during
  pregnancy

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RISK FACTORS

• Reasons for increased risk w/ primary maternal
  HSV infection
• Prolonged shedding of virus up to 3 wk vs 2 to 5
  days
• Increased number of viral particles excreted
• Less passive immunity to HSV, i.e. less
  maternal-fetal transfer of HSV neutralizing
  antibodies

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RISK FACTORS

• Neonatal risk factors
• Rupture of membranes 6 hrs
• Scalp electrodes or other internal monitoring
• Chorioamnionitis
• Cervicitis
• Vaginal delivery

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TIMES OF TRANSMISSION

• HSV of the newborn is acquired during one of
  three distinct time intervals
• Intrauterine (in utero 5)
• Peripartum (perinatal 85)
• Psotpartum (postnatal 10)

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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

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SEM DISEASE
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CUTANEOUS LESIONS
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VESICULAR LESIONS HSV
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HERPES PNEUMONITIS
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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

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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

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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

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HERPES ENCEPHALITIS
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HERPES ENCEPHALITIS
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SIGNS AND SYMPTOMS
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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

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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

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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)

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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

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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

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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

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PCR results following completion of antiviral
therapy

• No.
  () with PCR result
• Infant characteristic
• Negative
  Positive P
• Disease classification
• CNS disease 4
  (36.4) 14 (73.7)
• Disseminated disease 0 (0.0)
  5 (26.3)
• SEM disease 7
  (63.6) 0 (0.0)
• CSF indices
• Normal 6
  (54.5) 1 (5.3)
• Abnormal 3
  (27.3) 17 (89.4)
• Morbidity/mortality 12 mo
• Normal 6
  (54.5) 1 (5.3)
• Mild
  0 (0.0) 0 (0.0)
• Moderate 1
  (9.1) 3 (15.8)
• Severe
  2 (18.2) 10 (52.6)
• Dead
  0 (0.0) 5 (26.3)
• Unknown 2
  (18.2) 0 (0.0)

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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

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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

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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

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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)

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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

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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

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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

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DIAGNOSTIC TESTS

• Cultures from skin lesions, mouth, nasopharynx,
  conjunctiva, urine, stool/ano-rectum 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

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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

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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

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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

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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
  200611363-5