Treatment of Neonates Exposed to and Infected with HSV Michael T. Brady, MD Pediatric Professor The Ohio State University Associate Medical Director Nationwide Children s Hostile
Faculty Disclosure Michael T. Brady, M.D. In the past 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in this presentation.
Epidemiology of Neonatal HSV Perinatal infections are primarily horizontal (motherto-infant) HSV-2 75%; HSV-1-25% (HSV-1 is increasing) Only 30% of women who give birth to an infant with HSV have a history of current or prior HSV genital infections. Risk of transmission to newborn from mother with active HSV at the time of delivery: First episode/primary genital infection-60% First episode/non-primary infection-25% Recurrent genital infection-1-3%
HSV in Pregnancy Approximately 1% of women are HSV culturepositive at term (recurrent >> primary); most are without symptoms or lesions 90% of pregnant women with genital HSV do not know they are infected 67% of mothers with HSV-infected neonates deny ever having any symptoms of genital herpes prior to delivery
HSV During Pregnancy Symptomatic Genital Infection Can be either a primary, non-primary first episode (prior non-genital HSV) or a recurrent infection Symptoms include: Painful tender vesicles; dysuria Fever, headache, lymphadenopathy (not noted with recurrent infection) Primary disease involves vulva, vagina, cervix and urethra Recurrent disease typically involves only the vulva In most cases, infection is asymptomatic or mild and infection is not recognized as HSV
Primary Genital Herpes Simplex Infection During Pregnancy HSV-2 - -75% HSV-1 - - 25 (proportion is increasing) Disseminated infection (viremia) including HSV meningitis (benign) occurs but is rare Infections before 20 weeks gestation are associated with increased risk of spontaneous abortion
Perinatal Herpes Simplex Transmission Intrauterine (rare: 5%) Transplacental (viremia; primary infection) Ascending ( ROM) Intrapartum/Natal (most common 85%) Post-natal (horizontal) ( 10%) Family members/friends Nosocomial
Perinatal Herpes Simplex Source of HSV Source Maternal genital tract (HSV-1 25%; HSV-2 75%) Percent 80-85 Maternal non-genital (HSV-1) 5 Non-Maternal (HSV-1) (other family/nosocomial, etc.) 5-15
Pathogenesis of Neonatal HSV Infection Maternal Genital Herpes Simplex Virus Infection Intrauterine Infection (5%) (transplacental or ascending) Postnatal (horizontal) Infection (10%) Intrapartum transmission (85%) Viremia = Disseminated Disease 25% Localized (Skin, Eye, and/or Mouth) 45% Neuronal Spread = Localized Encephalitis 30% Hutto C, et al. J Pediatr. 1987:110:97-101.
Perinatal Herpes Simplex Risk for Transmission Characteristic Risk Maternal infection Primary (60%)>>Recurrent (2%) Maternal genital lesions Symptomatic >Asymptomatic Gestational age Premature>Full-term Method of delivery Duration of ROM Instrumentation Vaginal >C-section >6 hours>> <4 hours Scalp elelectrode/instrument delivery >> none
HSV Shedding at Delivery Maternal Infection Primary Secondary Vital titer (viral particles) >10 6 /0.2 ml 10 2-10 3 /0.2 ml Duration of shedding 14-21 days 2-5 days Cervical involvement Common Rare HSV Antibody Absent Variable
Neonatal Herpes Simplex Clinical Manifestations Local (skin, eye and/or mouth = SEM) (45%) Central nervous system (30%) Disseminated (25%)
Neonatal Herpes Simplex Mean onset of symptoms: SEM mean -11 days postpartum ( range: 3-20 days) Disseminated: mean 11 days postpartum (range: 3-20 days) CNS: mean 17 days postpartum (range: 7-35 days) 70% of untreated SEM CNS/disseminated Recurrences after treatment are not uncommon: skin recurrences >>>CNS recurrences
Presentation of SEM Disease Vesicles are seen in 83% Presents around 3-20 days of life Lesions may appear anywhere including oropharyngeal lesions Often on the scalp, particularly those born vaginally Thorough examination of the entire body is essential Localized SEM, but at risk of progression to serious disease Conjunctivitis in 25% Fever in 17%
Neonatal Herpes Simplex Skin Lesions May be single or multiple Present as crops or clusters of vesicles with surrounding erythema Vesicles are small (1-6 mm) and do not break easily (bullous impetigo lesions are friable) Frequently at site of presentation or trauma (e.g. scalp electrode, forceps, etc.)
Lesion at site of scalp monitor treated with Neosporin for 3d
17 day old; lesion present since day 6 of life
Lesion on lip & tongue after sucking on HSV infected breast
Presentation of CNS Disease Presents around 7-35 days (mean 17 days) of life Associated with lethargy, seizures, temperature instability, poor feeding, irritability, tremors, bulging fontanelle 60-70% have vesicles at one point in course; frequently absent at first symptoms Can involve multiple parts of brain In contrast to temporal lobe predilection in herpes encephalitis in older children and adults
Neonatal Herpes Simplex Encephalitis CSF pleocytosis common but not universal; usually mononuclear cells CSF protein usually elevated CSF detection of HSV Viral culture ( 5% positive) HSV DNA detection by PCR (>90%); occasionally first LP will be negative while PCR on repeat will become positive
39d old infant who presented to OSH at 29d of life with fever and irritability; CSF 57,250 RBC, 75 WBC, 84% M/L. Treated with ampicillin/cefotaxime. Transferred to CH on 33d of life. CSF 350 RBC, 130 WBC, 98% M/L, protein 685; HSV PCR (+)
Presentation of Disseminated HSV Presents at 3-20 days of life (mean 11 days) 80% develop skin lesions; some later in course 20% may never develop any vesicles CNS affected in 60-75% Symptoms suggestive of severe bacterial sepsis with respiratory symptoms, liver failure, DIC and shock Hepatomegaly and jaundice Pneumonia with progressive respiratory
Neonatal Herpes Simplex Disseminated: Clinical Presentations Vesicular lesions on skin at Presentation (58%) Conjunctivitis (17%) Lethargy (47%) Fever (56%) Seizures (22%) DIC (34%) Pneumonia (47%)
Diagnosis of Neonatal HSV Surface cultures (even in absence of lesions) Swabs of mouth, nasopharynx, conjunctivae, rectum Swab of lesions-pcr and/or viral culture CSF for PCR (± culture) Whole blood for PCR (in addition to standard work-up, above)* No data exist to support use of serial blood PCR assay to monitor response to therapy Blood for alanine aminotransferase (ALT)* DFA staining of vesicle scrapings (optional) * New in 2012 Red Book (Report of the Committee on Infectious Diseases)
Neonatal Herpes Simplex - Diagnosis Rapid fluorescent antibody skin vesicles - >80% sensitivity, other sites (NP, conjunctiva much lower) Viral culture (sensitivity based on duration of lesion) Aspirate fluid from vesicles or scrap base of lesion cotton swab; not Calcium alginate Viral transport media: ice or -70 o Growth 1-7 days PCR CSF - ~98% sensitive overall, initial result occasionally false-negative Lesions, buffy coat, blood, urine-more sensitive than culture, especially older lesions; usually much more rapid results.
Management of Neonates Perinatally Exposed to HSV
Classification of Maternal HSV Genital Infection Documented First Episode Primary Infection Documented First Episode Non- Primary Infection Assume First Episode (Primary or Non- Primary) Infection Recurrent Infection PCR/Culture from Genital Lesion Positive, either virus Positive for HSV-1 Positive for HSV-2 Positive for HSV-1 OR HSV-2 Negative OR not available Positive for HSV-1 Positive for HSV-2 Maternal HSV-1 and HSV-2 IgG Ab Status Both negative Positive for HSV-2 AND negative for HSV-1 Positive for HSV-1 AND negative for HSV-2 Not available Negative for HSV-1 and/or HSV-2, OR not available Positive for HSV-1 Positive for HSV-2 When genital lesion is strongly suspicious for HSV, clinical judgment should supersede the virologic test results. If in retrospect the genital lesion was not likely to be caused by HSV and the PCR/culture is negative, departure from the algorithm may be warranted.
Risk of Transmission Type of Maternal Infection Women delivered (n=58,288) Adapted from: JAMA 2003;289:203-209 Cultured within 48 hrs (n=39,949) (69%) Subclinical shedding (n=128) (0.3%) Serologies available (n=121) (95%) First episode genital HSV (n=23) (19%) Recurrent genital HSV (n=98) (81%) 1º HSV-1 (n=3) (13%) 1º HSV-2 (n=4) (17%) Non-1º HSV-1 (n=1) (4%) Non-1º HSV-2 (n=15) (65%) HSV-1 (n=8) (8%) HSV-2 (n=90) (92%) Infant with HSV (n=3) Infant with HSV (n=1) Infant with HSV (n=0) Infant with HSV (n=4) Infant with HSV (n=2) Infant with HSV (n=0) 57% 25% 2%
Neonates Delivered to Women with History of Genital Herpes but no active lesions Observe for signs of infection (e.g., vesicular lesions of the skin, respiratory distress, seizures, or signs of sepsis) Should not obtain surface cultures for HSV at 12-24 hours of life Should not receive empiric parenteral acyclovir Educate parents about the signs and symptoms of neonatal HSV infection during the first 6 weeks of life Red Book: 2012 Report of the Committee on Infectious Diseases
Management of asymptomatic neonates born to women with active genital herpes lesions AAP COID/COFN Pediatrics 2013;131(2):e635-e646 Asymptomatic neonate following vaginal or cesarean delivery to mother with visible genital lesions that are characteristic of HSV Obstetric provider obtains swab of lesion for HSV PCR and culture Type all positives Maternal history of genital HSV preceding pregnancy? no Send maternal type specific serology, if test assays are available at the delivery hospital At ~24 hours of age* obtain from the neonate: HSV surface cultures (and PCRs if desired) HSV blood PCR CSF cell count, chemistries, and HSV PCR Serum ALT Start IV acyclovir at 60mg/kg/day in three divided doses Determine Maternal HSV Infection Classification At ~ 24 hours of age* obtain from the neonate: HSV surface cultures (and PCRs if desired) HSV blood PCR If infant remains asymptomatic, do not start acyclovir Neonatal surface cultures negative, AND blood and surface PCRs negative yes Neonatal surface cultures positive, OR blood or surface PCRs positive First Episode Primary or First Episode Non-Primary Recurrent Infection Go to Treatment Algorithm * Immediate evaluation and treatment may be considered if: prolonged rupture of membranes (> 4-6 hours) prematurity ( 37 weeks gestation) Neonatal virology studies negative (PCRs negative; viral cultures negative at 48-72 hours Stop acyclovir. Educate family for signs and symptoms of neonatal HSV disease and follow closely Neonatal PCRs or viral cultures positive Go to Treatment Algorithm Educate family on signs and symptoms of neonatal HSV disease and follow closely Obtain CSF cell count, chemistries and HSV PCR. Send serum ALT. Start IV acyclovir at 60mg/kg/day in three divided doses Go to Treatment Algorithm
Neonates Delivered to Women with Active Genital HSV Lesions Obtain HSV cultures at 12-24 hours of life If mother has first-episode genital infection, some experts recommend empiric parenteral acyclovir treatment Can begin after HSV cultures are obtained at 12-24 hours of life Can begin at birth (still obtain HSV cultures prior to starting antiviral therapy) Most experts would not empirically treat neonates born to women with active recurrent genital HSV lesions with acyclovir First-episode clinical infections are not always primary infections Red Book: 2012 Report of the Committee on Infectious Diseases, pp. 398-408
HSV Culture Follow-up If the neonate s HSV cultures obtained at 12-24 hours of life subsequently grow, HSV infection is confirmed and the baby should then be evaluated for HSV disease (including LP, ALT) No evidence of HSV disease: empiric treatment x 10d Evidence of HSV disease: treatment x 14-21 days Red Book: 2012 Report of the Committee on Infectious Diseases, pp. 398-408
AAP COID/COFN Pediatrics 2013;131(2):e635-e646 No Treatment Algorithm Patient remains asymptomatic, CSF indices not indicative of infection, CSF and blood PCR negative, and normal serum ALT* Yes Treatment of Infection and Proven Disease Treat with intravenous acyclovir at 60 mg/kg/day in three divided daily doses for 14 days (SEM) or 21 days (CNS or disseminated) Additional evaluation may be indicated Preemptive Therapy of Infection but No Proven Disease Treat with intravenous acyclovir at 60 mg/kg/day in three divided daily doses for 10 days Repeat CSF HSV PCR near end of 21 day course of treatment Positive Continue intravenous acyclovir for 7 days more Negative D/C intravenous acyclovir after 21 day treatment course For this algorithm, ALT values more than two-times the upper limit of normal may be considered suggestive of neonatal disseminated HSV disease for HSV-exposed neonates If evidence of CNS disease at beginning of therapy
Neonatal Herpes Simplex Treatment Intravenous acyclovir is therapy of choice Acyclovir dose of 60 mg/kg/day is more effective than 30 mg/kg/day 14 days for SEM disease 21 days for CNS/disseminated disease For conjunctivitis topical 1% trifluridine 1 gtt affected eye q 2 hrs Follow with ophthalmology
Neonatal Herpes Simplex Prognosis with Treatment (Acyclovir) Survival Normal Local SEM 100% 100% CNS 84% 32% Disseminated 71% 82%
Percentage Neonatal Morbidity Among Survivors With Known Outcomes After 12 Months 100 90 80 70 60 50 40 30 20 10 0 n=46 n=2 n=28 n=13 n=5 n=18 30 60 30 60 30 60 mg/kg/d mg/kg/d mg/kg/d mg/kg/d mg/kg/d mg/kg/d Severe Moderate Mild Normal SEM Disease CNS Disease Disseminated Disease Kimberlin D. Sem Pediatr Infect Dis 2005;16:271
Study of 74 infants (45 CNS, 29 SEM) between 8/97 and 4/08 randomized to receive PO acyclovir vs placebo for 6 months after completion of IV acyclovir therapy Kimberlin D et al. New England Journal of Medicine 2011;365:1284-92
Percentage Neonatal Morbidity Among Survivors: With and Without Past-Therapy Suppression 100 90 80 70 60 50 40 30 20 10 0 n=28 n=13 n=11 n=13 30 60 60 60 mg/kg/d mg/kg/d mg/kg/d + mg/kg/d + placebo suppression CNS Disease CASG 101 N Engl J Med 2011;365:1284-92 CNS Disease CASG 103 Severe Moderate Mild Normal
Percentage N Engl J Med 2011;365(14):1284-92 Bayley Mental Score at 12 Months 100 90 80 70 60 50 40 30 20 10 0 n=28 n=13 n=11 n=13 30 60 60 60 mg/kg/d mg/kg/d mg/kg/d + mg/kg/d + placebo suppression CNS Disease CASG 101 P>0.13 CNS Disease CASG 103 P=0.40 Severe Moderate Mild Normal
Bayley Mental Score at 12 Months CASG 103 (CNS Involvement Study) Acyclovir N=16 Placebo N=12 Acyclovir N=8 CASG 104 (SEM Study) Placebo N=7 Median 90.5 66.5 95 84 Adjusted Mean 88.24 68.12 91.82 84.92 P-value by 0.046 0.263 ANCOVA * *Adjusted for covariates at baseline which were unbalanced between treatment groups: Head circumference at birth, birth weight, enrollment weight Enrollment weight N Engl J Med 2011;365:1284-92
Redbook 2012 comment: Use of oral acyclovir suppressive therapy for the six months following treatment of acute neonatal HSV disease recently has been shown to improve neurodevelopmental outcomes in infants with HSV CNS disease, and to prevent skin recurrences in infants with any disease classification of neonatal HSV. The dose that should be used is 300 mg/m 2 /dose administered three times daily for six months; absolute neutrophil counts should be assessed at 2 and 4 weeks after initiating suppressive therapy, and then monthly during the treatment period.
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