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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) Intrapartum transmission (85%) Postnatal (horizontal) Infection (10%) Viremia = Disseminated Disease 25% Localized (Skin, Eye, and/or Mouth) 45% Hutto C, et al. J Pediatr. 1987:110:97-101. Neuronal Spread = Localized Encephalitis 30% 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 Vaginal >C-section Duration of ROM >6 hours>> <4 hours Instrumentation Scalp elelectrode/instrument delivery >> none HSV Shedding at Delivery Maternal Infection Primary Secondary Vital titer (viral particles) >106/0.2 mL 102-103/0.2 mL Duration of shedding 14-21 days 2-5 days Cervical involvement Common Rare Absent Variable HSV Antibody 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 -70o • 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 NonPrimary Infection PCR/Culture from Genital Lesion Maternal HSV-1 and HSV-2 IgG Ab Status Positive, either virus Both negative Positive for HSV-1 Positive for HSV-2 AND negative for HSV-1 Positive for HSV-2 Positive for HSV-1 AND negative for HSV-2 Positive for HSV-1 OR HSV-2 Not available Assume First Episode (Primary or NonPrimary) Infection Negative OR not available† Recurrent Infection Negative for HSV-1 and/or HSV-2, OR not available Positive for HSV-1 Positive for HSV-1 Positive for HSV-2 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 Asymptomatic neonate following vaginal or cesarean delivery to mother with visible genital lesions that are characteristic of HSV AAP COID/COFN Pediatrics 2013;131(2):e635-e646 Obstetric provider obtains swab of lesion for HSV PCR and culture Type all positives Maternal history of genital HSV preceding pregnancy? no yes 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 First Episode Primary or First Episode Non-Primary Go to Treatment Algorithm * Immediate evaluation and treatment may be considered if: • prolonged rupture of membranes (> 4-6 hours) • prematurity (≤ 37 weeks gestation) 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 Neonatal surface cultures positive, OR blood or surface PCRs positive 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 Recurrent Infection Neonatal virology studies negative (PCRs negative; viral cultures negative at 48-72 hours Neonatal PCRs or viral cultures positive Stop acyclovir. Educate family for signs and symptoms of neonatal HSV disease and follow closely Go to Treatment Algorithm 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 Treatment Algorithm AAP COID/COFN Pediatrics 2013;131(2):e635-e646 Patient remains asymptomatic, CSF indices not indicative of infection, CSF and blood PCR negative, and normal serum ALT* No 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 Negative Continue intravenous acyclovir for 7 days more 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 Severe Moderate Mild Normal 30 mg/kg/d 60 mg/kg/d SEM Disease 30 mg/kg/d 60 mg/kg/d CNS Disease Kimberlin D. Sem Pediatr Infect Dis 2005;16:271 30 mg/kg/d 60 mg/kg/d Disseminated Disease 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 Severe Moderate Mild Normal 30 mg/kg/d 60 mg/kg/d CNS Disease CASG 101 N Engl J Med 2011;365:1284-92 60 mg/kg/d + placebo 60 mg/kg/d + suppression CNS Disease CASG 103 N Engl J Med 2011;365(14):1284-92 Percentage 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 Severe Moderate Mild Normal 30 60 mg/kg/d mg/kg/d CNS Disease CASG 101 P>0.13 60 60 mg/kg/d + mg/kg/d + placebo suppression CNS Disease CASG 103 P=0.40 Bayley Mental Score at 12 Months CASG 103 (CNS Involvement Study) CASG 104 (SEM Study) Acyclovir N=16 Placebo N=12 Acyclovir N=8 Placebo N=7 Median 90.5 66.5 95 84 Adjusted Mean 88.24† 68.12† 91.82‡ 84.92‡ P-value by ANCOVA* 0.046 0.263 *Adjusted for covariates at baseline which were unbalanced between treatment groups: †Head ‡Enrollment weight circumference at birth, birth 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/m2/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.” QR Code