Congenital herpes simplex virus infection
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Congenital Herpes Simplex Virus Infection. Ashley S. Ross, M.D. Neonatology Fellow University of Arkansas for Medical Sciences Arkansas Children’s Hospital. Objectives. Recognize the clinical presentation of congenital (neonatal) herpes simplex virus (HSV) infection

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Congenital Herpes Simplex Virus Infection

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Congenital herpes simplex virus infection

Congenital Herpes Simplex Virus Infection

Ashley S. Ross, M.D.

Neonatology Fellow

University of Arkansas for Medical Sciences

Arkansas Children’s Hospital


Objectives

Objectives

  • Recognize the clinical presentation of congenital (neonatal) herpes simplex virus (HSV) infection

  • Discuss current treatment modalities for neonatal herpes infection

  • Discuss long term sequelae of neonatal herpes infection


Transmission to the neonate

Intrauterine

Intra-partum

Post-partum

5% of cases

Ascending infection

cervix or vulva

Transplacental

First 20 weeks

Spontaneous abortion

Stillbirth

Congenital malformations

Hydranencephaly

Chorioretinitis

Controversial

Transmission to the Neonate


Transmission to the neonate1

Intrauterine

Intra-partum

Post-partum

Represents 85% of cases

Infected maternal secretions in birth canal

Lesions at delivery, C-section preferred route of delivery

Transmission to the Neonate


Transmission to the neonate2

Intrauterine

Intra-partum

Post-partum

10% of all cases of neonatal herpes

Environmental sources

Oral lesions

Herpetic whitlow

Other sites, such as breast

Transmission to the Neonate


Neonatal hsv

Neonatal HSV

  • In USA, incidence 1 per 3,000 to 20,000 live births

  • HSV-2 poorer prognosis

    • 75% of neonatal herpes

    • HSV-1 infection more common in Japan

  • Incubation 2-14 days


Transmission of hsv to the neonate

Transmission of HSV to the Neonate

  • Primary infection, symptomatic vs. asymptomatic reactivation

    • Delivered vaginally, with primary infection

      • 33%-50% risk of transmission

    • Reactivation risk of transmission 0-5%

    • Primary vs. recurrent often impossible to distinguish

    • >75% of infants with HSV born w/o maternal symptoms

  • Quantity and quality of maternal antibodies

  • Duration of ruptured membranes (>4-6 hours)

  • Use of fetal scalp monitor during labor


Clinical manifestations

Disseminated disease

Localized central nervous system

Skin, eyes, and mouth (SEM)

Presentation birth to 4 weeks

Divided equally

Overlap between groups

Skin lesions not always present

Makes diagnosis difficult

May appear late in disseminated disease

Clinical Manifestations


Disseminated disease

Disseminated Disease

  • Presentation earliest

    • 1st week

  • 25% of neonatal cases

  • Sepsis syndrome with negative bacterial cultures

    • Severe liver dysfunction

    • Pneumonia

  • Overlap with other types


Disseminated disease1

Disseminated Disease


Disseminated disease2

Disseminated Disease

  • Encephalitis in 75% of disseminated infections

    • Blood-borne route as opposed to neuronal spread

    • MRI with panencephalitis possible

  • High morbidity and mortality

    • 50% permanent neurological sequelae

    • 85% mortality if untreated

    • If treated, 30% mortality

      • Still 15% with permanent neurological impairment


Cns disease

35% of neonatal disease

Presents later (2nd to 3rd week)

Seizures

Lethargy

Tremors

Poor feeding

Temperature instability

Mortality 50% when untreated

2/3 will have permanent neurological sequelae

Temporal focus initially

Focality on MRI or EEG

Panencephalitis can develop

CNS Disease


Cns disease1

CNS Disease

Coren ME, et al.J Neurol Neurosurg Psychiatry. 1999 Aug;67(2):243-5.


Cns disease2

CNS Disease

Burke JW, et al. AJNR Am J Neuroradiol. 1996 Apr;17(4):773-6.


Cns disease3

CNS Disease

  • CNS disease:

    • HSV CSF culture rarely positive

    • Need HSV polymerase chain reaction (PCR)

    • Elevated CSF protein

      • Evidence of RBC’s

    • Cutaneous lesion usually absent


Cns disease4

CNS Disease

  • Predictors of poor outcome

    • At time of treatment

      • Comatose at initiation of therapy

      • Premature

      • Seizures

    • HSV-2

    • Persistently positive CSF HSV PCR


Sem disease

SEM Disease

  • 40% of neonatal HSV cases Presents at 10-11 days of age

  • Discrete vesicles and conjunctivitis

  • Untreated disease

    • 75% will progress to CNS or disseminated disease

    • 30-40% develop neurological impairment

      • Spastic quadriplegia, microcephaly, blindness

      • Usually becomes apparent at 6-12 months

  • Treat as aggressively as disseminate/CNS


Congenital herpes simplex virus infection

www.dermatlas.org


Diagnosis

Diagnosis

  • Average time from onset of symptoms to treatment is 6 days!

    • Time has not shortened

  • Early treatment, improved mortality/morbidity

  • Absent skin lesions does NOT exclude diagnosis

  • Absent maternal history does NOT exclude diagnosis


Diagnosis1

Diagnosis

  • Readily grows in cell culture

  • Cytopathogenic effects seen in 1-3 days

  • Special media

    • For delayed inoculation

  • Cultures negative at 15 days likely negative

  • Obtain cultures after 48 hours


Diagnosis2

Viral cultures can be obtained from

Unroofed lesions

Urine

Nasopharynx or mouth

Rectum

Blood

Readily grows in cell culture

Cytopathogenic effects seen in 1-3 days

Special media

For delayed inoculation

Cultures negative at 15 days likely negative

Obtain cultures after 48 hours

Surface contamination

CSF for HSV PCR

Attempt to seek evidence of disseminated disease with:

Liver function tests

CBC

CSF analysis

Chest x-ray

IV acyclovir should be administered at time of lab evaluation

Do not wait for lab results!!!!!

Diagnosis


Diagnosis3

Diagnosis

  • CSF cultures not useful (need PCR)

  • Serology not useful acutely

  • Direct fluorescent antibody (DFA) and Enzyme Immunoassay (ELISA)

    • Typing of culture aspirates

  • Supportive diagnosis

    • EEG

    • MRI


Neonatal hsv treatment

Neonatal HSV: Treatment

  • Treat all infections with IV acyclovir

  • Acyclovir of 60 mg/kg/day IV divided Q8 hours

    • 14 days for SEM disease

    • 21 days for disseminated or CNS disease

  • Repeat CSF analysis prior to end of therapy

  • Consider tertiary referral, neonatologist/infectious disease referral

  • Monitor renal function and neutropenia

    • Keep well hydrated

    • Twice weekly labs


Treatment

Treatment

  • Lumbar puncture at end of therapy for HSV PCR

    • Continue treatment until CSF sterile

  • Many will have recurrence

    • May need long-term suppressive treatment

    • May need intermittent acyclovir therapy

    • Recurrent SEM under investigation

  • Ocular involvement

    • Pediatric ophthalmologist

    • Topical treatment with IV acyclovir


Treatment1

Treatment

  • Maternal history of HSV without lesions

    • Observation of infant

    • Appropriate evaluation is evidence of infection


Treatment2

Primary infection and exposed infant

At least 50% risk of infection

Controversy over approach

Surface cultures 24-48 hours after delivery

Empiric therapy vs. treating only positive surface cultures

Signs of infection/rash, immediate treatment and cultures

Recurrent infection and exposed infant

Surface cultures

Observation

Vesicular lesions

Jaundice

Respiratory distress

Seizures

Careful observation if cultures negative

Treat positive cultures

Treatment

Any symptomatic infant is treated


Neonatal hsv prevention

Neonatal HSV: Prevention

  • All mothers screened prenatally and at deliver

  • Delivery by C-section

    • Clinically apparent lesions

      • No invasive fetal monitoring

      • Risk of infection 50%-5%

      • Within 4-6 hours of ROM

    • Maternal history of HSV without lesions

      • May deliver vaginally


Conclusion

Conclusion

  • >75% of infants are born to mom’s without a history of lesions

  • A lack of skin lesions does not eliminate the diagnosis of HSV

  • Think about HSV early and start therapy even if you only have a suspicion of HSV

  • Remember your surface cultures

  • Remember liver function test


References

References

  • American Academy of Pediatrics. Herpes simplex. In: Pickering LK, ed. 2003 Red Book: Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2003:344–353

  • Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, the NIAID Collaborative Antiviral Study Group. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108:223–229

  • Waggoner-Fountain LA, Grossman LB. Herpes Simplex Virus. Pediatrics in Review. 2004;25:86-93


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