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Neonatal Herpes Simplex Infection

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1 Neonatal Herpes Simplex Infection
Jesus Peinado M.D. Dept. of Pediatrics: PGY2 July 24, 2008

2 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.

3 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

4 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 Core. The core consists of a single linear molecule of dsDNA in the form of a torus. Capsid. Surrounding the core is an icosahedral capsid with a 100 nm diameter constructed of 162 capsomeres. Tegument. Between the capsid and envelope is an amorphous, sometimes asymmetrical, feature named the tegument. It consists of viral enzymes, some of which are needed to take control of the cell's chemical processes and subvert them to virion production, some of which defend against the host cell's immediate responses, and others for which the function is not yet understood. Envelope. The envelope is the outer layer of the virion and is composed of altered host membrane and a dozen unique viral glycoproteins. They appear in electron micrographs as short spikes embedded in the envelope Envelope: Outer layer composed of altered host membrane and a dozen of viral glycoproteins


6 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

7 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

8 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

9 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

10 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

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

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%

Type of maternal infection (primary/recurrent) Maternal antibody status Duration of rupture of membranes Integrity of mucocutaneous barriers Mode of delivery (C-section/vaginal)

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

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

16 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

17 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

18 RISK FACTORS Neonatal risk factors: Rupture of membranes > 6 hrs
Scalp electrodes or other internal monitoring Chorioamnionitis Cervicitis Vaginal delivery

19 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%)

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





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

26 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

27 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



30 SIGNS AND SYMPTOMS Skin vesicles Lethargy 83% 19% 63% 49% 58% 47% 68%
Sings/symptoms SEM disease CNS disease Disseminated disease Total Skin vesicles Lethargy 83% 19% 63% 49% 58% 47% 68% 38% Fever Conjunctivitis Seizure 17% 25% 2% 44% 16% 57% 56% 22% 39% 27% DIC Pneumonia 3% 20% 34% 11% 13%

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

32 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

33 PCR results from CSF of infected neonates
PCR AMPLIFICATION PCR results from CSF of infected neonates No. (%) of patients with: PCR result SEM (n29) CNS (n34) Disseminated (n14) Positive (24) (76) (93) Negative (76) (24) (7)

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

35 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

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

37 PCR results following completion of antiviral therapy
No. (%) with PCR result Infant characteristic Negative Positive P Disease classification CNS disease (36.4) (73.7) < 0.001 Disseminated disease (0.0) (26.3) SEM disease (63.6) (0.0) CSF indices Normal (54.5) (5.3) Abnormal (27.3) (89.4) Morbidity/mortality >12 mo Normal (54.5) (5.3) <0.001 Mild (0.0) (0.0) Moderate (9.1) (15.8) Severe (18.2) (52.6) Dead (0.0) (26.3) Unknown (18.2) (0.0)

38 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

39 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

40 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

41 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)

42 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

43 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

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

45 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

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

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

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

49 REFERENCES Neonatal Herpes Simplex Infection, Kimberlin David; Clinical Microbiology reviews, Jan 2004 p 1-13. AAP 2005, Herpes Simplex, p 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 2006;11:363-5

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