Congenital Herpes Simplex Virus Infection

1. Congenital Herpes Simplex Virus Infection Ashley S. Ross, M.D. Neonatology Fellow University of Arkansas for Medical Sciences Arkansas Children’s Hospital

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. Disseminated Disease • Presentation earliest • 1st week • 25% of neonatal cases • Sepsis syndrome with negative bacterial cultures • Severe liver dysfunction • Pneumonia • Overlap with other types

10. Disseminated Disease

11. 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

12. 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

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

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

15. 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

16. CNS Disease • Predictors of poor outcome • At time of treatment • Comatose at initiation of therapy • Premature • Seizures • HSV-2 • Persistently positive CSF HSV PCR

17. 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

18. www.dermatlas.org

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. Treatment • Maternal history of HSV without lesions • Observation of infant • Appropriate evaluation is evidence of infection

26. 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

27. 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

28. 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

29. 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