1. Neonatal Herpes Simplex Infections MAJ Mark Burnett Pediatric ID Fellow MAR 2003

2. Neonatal Herpes Background A Case Study Types of Infections Risks of Infection Diagnostics Treatment Summary

3. Herpes Infections “Herpes” – from the Greek “to creep, crawl” “Herpetic eruptions” described as early as 100 AD 1960’s – HSV1 and HSV2 differentiated HHV1 – HSV1 HHV2 – HSV2 HHV3 – VZV HHV4 – EBV HHV5 – CMV HHV6 – Causes? HHV7 – HHV8 -

4. A Case Study – A.B. Term infant born to a 22 y/o GBS+ mother with no Pmhx of HSV-2 4 doses of IV PCN given PTD ROM <18 hours PTD, no maternal fevers Forceps delivery APGARS of 9/9 Well until fever to 101.7 at 30 hrs of life Fever work-up initiated

5. A.B. WBC 23K (50S 2B 38L) AST 98 ALT 92 CSF 48 WBC 2650 RBC Pro 93/Glu 53 HSV PCR, Enteroviral PCR, HSV Surface cx – sent Exam unremarkable Amp/Gent/Acyclovir initiated Fevers persisted over next 13 hours, again spiking to 101.5 AST 147 / ALT 93 two days later

6. A.B. – additional info No history of HSV reported in mother, father Mother without febrile illness Niece with a “cold sore” visited prior to delivery, and “held the baby” after he was born LP repeated two days after initial study with normalization of cell count

7. A New Development

8. Questions? What diagnostic tests could we perform, and how reliable are they really? Would it be worthwhile to run tests on mom? Is the niece’s “cold sore” a “red herring” – what are the risks? Bottom line – how worried should we be about HSV, and how would we treat it?

9. Neonatal HSV 1 in 2,500-5,000 deliveries / 500-1500 per yr. Birth to 7 weeks of life HSV2 = 70-75%, HSV1 = 25-30% 3 Main Types Skin, Eye, Mouth (SEM) CNS Disseminated Disease (DISSEM) At Risk: Premature, ROM >6hr, Fetal scalp monitoring Can be acquired congenitally, during the birth process, and in the post-partum period

10. Routes of Transmission 85% via infected maternal genital tract Ascending infection? En route 10% postpartum 5% (or less) – intrauterine/congeni tal infection

11. Congenital HSV Rare, most devastating Only 50 cases described Skin vesicles Chorioretinitis Microcephaly Micro-ophthalmia IUGR

12. Skin, Eye, Mouth (SEM) Approximately ½ of all HSV infections 1 st -2 nd week presentation Limited to skin, eye, mouth/mucous membranes 60-70% of untreated patients progress to CNS/disseminated disease

13. SEM (cont) Long term neurologic sequelae seen in 30% of cases – even if treated Ophthalmology involvement

14. “Presenting Part” (SEM)

15. Scalp Monitors

16. HSV - CNS Disease Encephalitis without visceral involvement, mainly involving the temporal lobes Early to 3 rd week of life presentation Skin lesions may appear late, if at all 35% of all cases, only 2-5% untreated survive normally

17. Radiographic Findings

18. Disseminated Disease Approximately 20% of all infections Hepatitis Pneumonitis DIC Infant may be ill on first day of life Skin lesions appear late, or not at all

19. Signs

20. Postnatal acquisition Most commonly HSV1 Moms with HSV Mask Breastfeeding – O.K. if without lesions The Mohel and the Mezizah

21. Contacts “Personnel with an active herpetic whitlow should not have direct patient care of neonates”. Family transmission has been described

22. Morbidity and Mortality

23. Stretch Break

24. Take Home Message Infection is most common when a mother develops a genital infection late in pregnancy ( her primary HSV1 or HSV2 infection) – then delivers before the development of protective maternal antibodies

25. Herpes Simplex Approximately 5% of the general population has been diagnosed with genital herpes – but approximately 20- 30% of women may be infected with HSV-2 Viral shedding occurs without identifiable lesions on 1-3% of days

26. Maternal Testing? Identify discordant couples to avoid transmission in the third trimester If mom is HSV1/HSV2 negative If mom is HSV2 negative If mom is HSV2 positive – risk is low for a vaginal delivery? Is testing after delivery going to be helpful? Will blood tests of the baby be helpful, or just reflect mom’s status? Psychosocial ramifications?

27. Herpes during Pregnancy As many as 2% of pregnant women are infected with HSV2 during pregnancy 25% of women with a history of genital herpes have an outbreak at some time during their pregnancy, 11-14% at time of delivery 36% at delivery for those with first infection! Virus is recovered from 1% of asymptomatic women at delivery

28. What is the risk? Vaginal delivery when mom has presence of first symptomatic lesions – 50% Vaginal delivery when mom is asymptomatic, but is newly infected – 33% Vaginal delivery when mom has recurrent lesions – 4% Vaginal delivery when mom has a history of herpes lesions in past, none presently – 0.04%

29. OB Management 70’s-80’s – weekly HSV cultures 1988 – patient examined at delivery, Cesarean delivery if: (no data) Identifiable genital lesions Patient describes prodromal symptoms Vaginal delivery for those with hx only Primary infection diagnosed - treat Estimated $2-4 million to prevent each case 20-30% of infants who are diagnosed with neonatal herpes are delivered by Cesarean delivery

30. Diagnostics HSV Cx – positive in 1-2 days (cytopathic effect) DFA – sensitivity/specificity in the 75%-85% range

31. PCR Testing Detects minute amounts of DNA, RNA DISSEM – 93% CNS – 76% SEM – 24% False negative may occur if CSF is obtained “too early” Order through IVF!

32. Diagnostics (cont) Surface cultures Mouth (40-50%) Eyes (25%) Rectum Skin Cultures Stool Urine CSF >100 WBC/Inc. Pro Tzanck – neither sensitive nor specific

33. Treatment - Acyclovir SEM infections 60mg/kg/day divided q8h for 14 days May be lengthened to 21 days in the near future Oral Acyclovir needed later in life? DISSEM and CNS HSV infections 60mg/kg/day divided q8h for 21 days Re-tap if CNS disease exists prior to d/c Watch for neutropenia – 2x week ANCs

34. Questions / Controversies Would maternal “pre-treatment” change the time /clinical presentation of HSV? Should an infant delivered vaginally to a mother with active lesions be treated? Can HSV be resistant to Acyclovir?

35. Take Home Messages Most neonates with HSV infection are born to mothers with asymptomatic genital shedding at delivery, with no history of genital herpetic lesions No one test is 100% sensitive / specific Keep HSV in mind How would you manage our case?