congenital herpes simplex virus infection

Congenital Herpes Congenital Herpes Simplex Virus Simplex Virus

Infection Infection

Ashley S. Ross, M.D.Ashley S. Ross, M.D.Neonatology FellowNeonatology Fellow

University of Arkansas for Medical SciencesUniversity of Arkansas for Medical Sciences

Arkansas Children’s HospitalArkansas Children’s Hospital

ObjectivesObjectives

1.1. Recognize the clinical presentation Recognize the clinical presentation of congenital (neonatal) herpes of congenital (neonatal) herpes simplex virus (HSV) infectionsimplex virus (HSV) infection

2.2. Discuss current treatment modalities Discuss current treatment modalities for neonatal herpes infectionfor neonatal herpes infection

3.3. Discuss long term sequelae of Discuss long term sequelae of neonatal herpes infectionneonatal herpes infection

Transmission to the Transmission to the NeonateNeonate

1.1. IntrauterineIntrauterine

2.2. Intra-partumIntra-partum

3.3. Post-partumPost-partum

5% of cases5% of cases Ascending infection Ascending infection

cervix or vulvacervix or vulva TransplacentalTransplacental

First 20 weeksFirst 20 weeks Spontaneous abortionSpontaneous abortion StillbirthStillbirth Congenital Congenital

malformationsmalformations HydranencephalyHydranencephaly ChorioretinitisChorioretinitis ControversialControversial





Represents 85% of Represents 85% of casescases

Infected maternal Infected maternal secretions in birth secretions in birth canalcanal

Lesions at delivery, Lesions at delivery, C-section C-section preferred route of preferred route of deliverydelivery





10% of all cases of 10% of all cases of neonatal herpesneonatal herpes

Environmental Environmental sourcessources Oral lesionsOral lesions Herpetic whitlowHerpetic whitlow Other sites, such as Other sites, such as

breastbreast

Neonatal HSVNeonatal HSV

In USA, incidence 1 per 3,000 to In USA, incidence 1 per 3,000 to 20,000 live births20,000 live births

HSV-2 poorer prognosisHSV-2 poorer prognosis 75% of neonatal herpes75% of neonatal herpes HSV-1 infection more common in JapanHSV-1 infection more common in Japan

Incubation 2-14 daysIncubation 2-14 days

Transmission of HSV to Transmission of HSV to the Neonatethe Neonate

Primary infection, symptomatic vs. Primary infection, symptomatic vs. asymptomatic reactivationasymptomatic reactivation Delivered vaginally, with primary infectionDelivered vaginally, with primary infection

33%-50% risk of transmission33%-50% risk of transmission Reactivation risk of transmission 0-5%Reactivation risk of transmission 0-5% Primary vs. recurrent often impossible to distinguishPrimary vs. recurrent often impossible to distinguish >75% of infants with HSV born w/o maternal >75% of infants with HSV born w/o maternal

symptomssymptoms Quantity and quality of maternal antibodiesQuantity and quality of maternal antibodies Duration of ruptured membranes (>4-6 hours)Duration of ruptured membranes (>4-6 hours) Use of fetal scalp monitor during laborUse of fetal scalp monitor during labor

Clinical ManifestationsClinical Manifestations

1.1. Disseminated Disseminated disease disease

2.2. Localized central Localized central nervous systemnervous system

3.3. Skin, eyes, and Skin, eyes, and mouth (SEM) mouth (SEM)

Presentation birth to Presentation birth to 4 weeks4 weeks

Divided equallyDivided equally Overlap between Overlap between

groupsgroups Skin lesions not Skin lesions not

always presentalways present Makes diagnosis Makes diagnosis

difficultdifficult May appear late in May appear late in

disseminated diseasedisseminated disease

Disseminated DiseaseDisseminated Disease

Presentation earliestPresentation earliest 11stst week week

25% of neonatal cases25% of neonatal cases Sepsis syndrome with negative Sepsis syndrome with negative

bacterial culturesbacterial cultures Severe liver dysfunctionSevere liver dysfunction PneumoniaPneumonia

Overlap with other typesOverlap with other types


Encephalitis in 75% of disseminated Encephalitis in 75% of disseminated infectionsinfections Blood-borne route as opposed to neuronal Blood-borne route as opposed to neuronal

spreadspread MRI with panencephalitis possibleMRI with panencephalitis possible

High morbidity and mortalityHigh morbidity and mortality 50% permanent neurological sequelae50% permanent neurological sequelae 85% mortality if untreated85% mortality if untreated If treated, 30% mortalityIf treated, 30% mortality

Still 15% with permanent neurological impairmentStill 15% with permanent neurological impairment

CNS DiseaseCNS Disease

35% of neonatal 35% of neonatal diseasedisease

Presents later (2Presents later (2ndnd to 3to 3rdrd week) week) SeizuresSeizures LethargyLethargy TremorsTremors Poor feedingPoor feeding Temperature Temperature

instabilityinstability

Mortality 50% when Mortality 50% when untreateduntreated

2/3 will have 2/3 will have permanent permanent neurological sequelaeneurological sequelae

Temporal focus Temporal focus initiallyinitially Focality on MRI or Focality on MRI or

EEGEEG Panencephalitis can Panencephalitis can

developdevelop


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


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


CNS disease:CNS disease: HSV CSF culture rarely positiveHSV CSF culture rarely positive Need HSV polymerase chain reaction Need HSV polymerase chain reaction

(PCR)(PCR) Elevated CSF proteinElevated CSF protein

Evidence of RBC’sEvidence of RBC’s Cutaneous lesion usually absentCutaneous lesion usually absent


Predictors of poor outcomePredictors of poor outcome At time of treatmentAt time of treatment

Comatose at initiation of therapyComatose at initiation of therapy PrematurePremature SeizuresSeizures

HSV-2HSV-2 Persistently positive CSF HSV PCRPersistently positive CSF HSV PCR

SEM DiseaseSEM Disease 40% of neonatal HSV cases Presents at 40% of neonatal HSV cases Presents at

10-11 days of age10-11 days of age Discrete vesicles and conjunctivitisDiscrete vesicles and conjunctivitis Untreated diseaseUntreated disease

75% will progress to CNS or disseminated 75% will progress to CNS or disseminated diseasedisease

30-40% develop neurological impairment30-40% develop neurological impairment Spastic quadriplegia, microcephaly, blindnessSpastic quadriplegia, microcephaly, blindness Usually becomes apparent at 6-12 monthsUsually becomes apparent at 6-12 months

Treat as aggressively as Treat as aggressively as disseminate/CNSdisseminate/CNS

www.dermatlas.org

DiagnosisDiagnosis

Average time from onset of symptoms Average time from onset of symptoms to treatment is 6 days!to treatment is 6 days! Time has not shortenedTime has not shortened

Early treatment, improved Early treatment, improved mortality/morbiditymortality/morbidity

Absent skin lesions does NOT exclude Absent skin lesions does NOT exclude diagnosisdiagnosis

Absent maternal history does NOT Absent maternal history does NOT exclude diagnosisexclude diagnosis

DiagnosisDiagnosis

Readily grows in cell cultureReadily grows in cell culture Cytopathogenic effects seen in 1-3 Cytopathogenic effects seen in 1-3

daysdays Special mediaSpecial media

For delayed inoculationFor delayed inoculation Cultures negative at 15 days likely Cultures negative at 15 days likely

negativenegative Obtain cultures after 48 hoursObtain cultures after 48 hours

DiagnosisDiagnosis Viral cultures can be obtained Viral cultures can be obtained

fromfrom Unroofed lesionsUnroofed lesions UrineUrine Nasopharynx or mouthNasopharynx or mouth RectumRectum BloodBlood

Readily grows in cell cultureReadily grows in cell culture Cytopathogenic effects seen Cytopathogenic effects seen

in 1-3 daysin 1-3 days Special mediaSpecial media

For delayed inoculationFor delayed inoculation Cultures negative at 15 days Cultures negative at 15 days

likely negativelikely negative Obtain cultures after 48 hoursObtain cultures after 48 hours

Surface contaminationSurface contamination

CSF for HSV PCRCSF for HSV PCR Attempt to seek Attempt to seek

evidence of evidence of disseminated disease disseminated disease with:with: Liver function testsLiver function tests CBCCBC CSF analysisCSF analysis Chest x-rayChest x-ray

IV acyclovir should be IV acyclovir should be administered at time of administered at time of lab evaluationlab evaluation Do not wait for lab Do not wait for lab

results!!!!!results!!!!!

DiagnosisDiagnosis

CSF cultures not useful (need PCR)CSF cultures not useful (need PCR) Serology not useful acutelySerology not useful acutely Direct fluorescent antibody (DFA) Direct fluorescent antibody (DFA)

and Enzyme Immunoassay (ELISA)and Enzyme Immunoassay (ELISA) Typing of culture aspiratesTyping of culture aspirates

Supportive diagnosisSupportive diagnosis EEGEEG MRIMRI

Neonatal HSV: Neonatal HSV: TreatmentTreatment

Treat all infections with IV acyclovirTreat all infections with IV acyclovir Acyclovir of 60 mg/kg/day IV divided Q8 Acyclovir of 60 mg/kg/day IV divided Q8

hourshours 14 days for SEM disease 14 days for SEM disease 21 days for disseminated or CNS disease21 days for disseminated or CNS disease

Repeat CSF analysis prior to end of therapyRepeat CSF analysis prior to end of therapy Consider tertiary referral, Consider tertiary referral,

neonatologist/infectious disease referralneonatologist/infectious disease referral Monitor renal function and neutropeniaMonitor renal function and neutropenia

Keep well hydratedKeep well hydrated Twice weekly labsTwice weekly labs

TreatmentTreatment Lumbar puncture at end of therapy for Lumbar puncture at end of therapy for

HSV PCRHSV PCR Continue treatment until CSF sterileContinue treatment until CSF sterile

Many will have recurrenceMany will have recurrence May need long-term suppressive treatmentMay need long-term suppressive treatment May need intermittent acyclovir therapyMay need intermittent acyclovir therapy Recurrent SEM under investigationRecurrent SEM under investigation

Ocular involvementOcular involvement Pediatric ophthalmologistPediatric ophthalmologist Topical treatment with IV acyclovirTopical treatment with IV acyclovir

TreatmentTreatment

Maternal history of HSV without Maternal history of HSV without lesionslesions Observation of infantObservation of infant Appropriate evaluation is evidence of Appropriate evaluation is evidence of

infectioninfection

TreatmentTreatment

Primary infection and Primary infection and exposed infantexposed infant At least 50% risk of At least 50% risk of

infectioninfection Controversy over Controversy over

approachapproach Surface cultures 24-48 Surface cultures 24-48

hours after deliveryhours after delivery Empiric therapy vs. Empiric therapy vs.

treating only positive treating only positive surface culturessurface cultures

Signs of infection/rash, Signs of infection/rash, immediate treatment immediate treatment and culturesand cultures

Recurrent infection Recurrent infection and exposed infantand exposed infant Surface culturesSurface cultures ObservationObservation

Vesicular lesionsVesicular lesions JaundiceJaundice Respiratory distressRespiratory distress SeizuresSeizures

Careful observation if Careful observation if cultures negativecultures negative

Treat positive culturesTreat positive cultures

Any symptomatic infant is Any symptomatic infant is treatedtreated

Neonatal HSV: Neonatal HSV: PreventionPrevention

All mothers screened prenatally and All mothers screened prenatally and at deliverat deliver

Delivery by C-sectionDelivery by C-section Clinically apparent lesionsClinically apparent lesions

No invasive fetal monitoringNo invasive fetal monitoring Risk of infection 50%-5%Risk of infection 50%-5% Within 4-6 hours of ROMWithin 4-6 hours of ROM

Maternal history of HSV without lesionsMaternal history of HSV without lesions May deliver vaginallyMay deliver vaginally

ConclusionConclusion >75% of infants are born to mom’s >75% of infants are born to mom’s

without a history of lesionswithout a history of lesions A lack of skin lesions does not eliminate A lack of skin lesions does not eliminate

the diagnosis of HSVthe diagnosis of HSV Think about HSV early and start therapy Think about HSV early and start therapy

even if you only have a suspicion of HSVeven if you only have a suspicion of HSV Remember your surface culturesRemember your surface cultures Remember liver function testRemember liver function test

ReferencesReferences 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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