Outline. The Scarlet H : Neonatal herpes simplex virus infection in the 21 st century. Ancient History. Ancient History. History.

Transcription

1 The Scarlet H : Neonatal herpes simplex virus infection in the 21 st century J.B. Cantey, MD Pediatric Grand Rounds University of Texas Health San Antonio September 15, 2017 Outline Historical perspectives Updates in management of: Pregnant women Asymptomatic, exposed infants Infants with suspected infection Ancient Descriptions of vesicular skin lesions have been found on Sumerian clay tablets, the earliest known form of writing (~3000 BC) Ebers Papyrus (~1600 BC) also contains notations of similar vesiculo-ulcerative lesions Ancient The term herpes was used in Hippocratic writings (~400 BC) to refer to a variety of cutaneous lesions Celsus (30 BC) is credited as being the first physician to use the term herpes specifically for lesions that we would call herpes Ancient In 170 AD, Galen described cutaneous recurrences of herpes in the same anatomic location, specifically the lips O er ladies lips, who straight on kisses dream / Which oft the angry Mab with blisters plagues / Because their breaths with sweetmeats tainted are Romeo and Juliet, Act 1, Scene 4 1

2 More than 1500 years passed before the association between herpes and genital infection was recognized by Jean Astruc, Professor of Dermatology at University of Paris (and one of King Louis XIV s personal physicians) Astruc studied Parisian commercial sex workers ( puellae publicae ) and documented their illnesses His A Treatise on the Diseases of Women, published in 1736, contains the first modern description of herpes genitalis Astruc s work ushered in several decades of heightened interest in venereal diseases, including herpes In 1896, Fournier another French dermatologist recommended treating herpes genitalis by avoiding alcohol, tobacco, wine, and sexual excesses. The association between affected women and infected infants apparently was not recognized during this period The risk of horizontal transmission between adults was viewed as minimal Paul Unna, a German dermatologist, called genital herpes one of the most benign of affections, both to the patient and her public. In 1919, Lowenstein, a German pathologist who also identified cytomegalovirus, demonstrated that vesicle scrapings collected from patients with herpes genitalis caused keratitis in rabbits In the same year, Lowenstein published the first description of the microscopic findings of herpes, including the characteristic inclusion bodies in infected cells Neonatal herpes In 1934, Batignani, an Italian ophthalmologist, reported the case of an infant with acute keratoconjunctivitis In 1935, Hass, an American pathologist, published the autopsy findings of an infant who died from culture-negative sepsis; HSV inclusion bodies were found in the liver and adrenals In 1941, Smith reported HSV inclusions in neuronal tissue from an infant who presented with fever and seizures 2

3 Neonatal herpes The clinical presentation of these 3 cases Skin, eye, mouth [SEM]; Central nervous system [CNS]; and Disseminated; are the disease categories we still use more than 75 years later Diss. Mortality Morbidity Disseminated (+/- CNS) 50% 10% of survivors CNS (+/- SEM) 10% >50% SEM alone 0% 5%* SEM CNS *Thought to be due to CNS recurrences Neonatal herpes In ,000 years after the first written description of herpes Andy Nahmias documented vertical transmission of HSV from a mother with cervical (primary) genital herpes to her infant What s New? 1. Update on epidemiology 2. Management of pregnant women 3. New concepts in pathophysiology and diagnosis guidance on asymptomatic, exposed newborns 5. Targeted versus empiric acyclovir for symptomatic infants Epidemiology Not clear exactly how many infants are affected by neonatal HSV infection annually Classic estimate is 1:3000 to 1:10,000, but: Not reportable Not always diagnosed Changing seroprevalence in women of childbearing age has likely increased incidence Not reportable Handsfield HH, et al. Sex Trans Dis

4 Not always diagnosed Lopez E, et al. J Pediatr infants who died with HSV infection at 2 centers (Parkland, Dallas Children s) 3 infants diagnosed only at autopsy (23% of cohort) Epidemiology is changing Bradley H, et al. J Inf Dis 2013 Compared National Health and Nutrition Examination Survey (NHANES) serologic testing between and Seroprevalence of HSV-1 from 61% to 54% Seroprevalence of HSV-2 unchanged (16%) >80% of seropositive adults have never experienced an outbreak Brown ZA, et al. JAMA 2003 Yikes. So how do we prevent vertical transmission? 4

5 Sheffield JS, et al. OBGYN Randomized trial of 350 women with history of genital herpes outbreaks At 36 0/7 weeks, randomized to valacyclovir prophylaxis or placebo Valacyclovir group were less likely to have lesions at time of delivery (4% vs 13%, P=0.009) and therefore less likely to undergo cesarean delivery NNT to prevent 1 cesarean = 11 Pinninti SG, et al. J Pediatr infants with neonatal HSV infection despite maternal valacyclovir prophylaxis No mother had lesions at delivery 2 infants born via cesarean delivery with rupture of membranes at delivery There is no such thing as a completely protective history Highest risk: primary maternal infection with lesions at delivery High risk: first non-primary lesion (antibody to the other type of HSV) Normal risk: no lesions at delivery and no history of genital herpes Lowest risk: no lesions at delivery and history of genital herpes (protective antibody) Zero risk: no such thing Classic Pathophysiology HSVCON Pathophysiology - Disseminated Pathophysiology - SEM HSV reaches bloodstream and promptly disseminates. Infant presents with diffuse organ dysfunction (hepatitis, acute renal failure, disseminated intravascular coagulopathy, pneumonitis, etc). Median age: 7 days HSV remains on skin and replicates locally without invading. Infant presents with vesiculo-ulcerative disease on the skin or mucous membranes. Median age: 14 days 5

6 Pathophysiology - CNS Ok, but With increased use of polymerase-chain reaction (PCR) testing, the traditional pathophysiology is now coming into question HSV reaches sensory nerves and, by slow retro-axonal transmission, reaches the brain. Infant presents with encephalopathy and/or seizures. Median age: 21 days Pathophysiology Cantey JB, et al. J Pediatr 2011 Reported 21 neonates with positive blood HSV PCR tests 10 had disseminated disease 7 had SEM disease only 4 had CNS disease only HSV PCR was the first (n=5) or only (n=6) positive test in >50% of neonates Viremia identified in many infants who did not have signs of disseminated disease Diagnostic workup Blood HSV PCR added to 2015 Red Book as part of diagnostic evaluation for infants with suspected neonatal HSV infection Now includes: Mucocutaneous swab(s) at least 3 of eye, nasopharynx, throat, umbilicus, rectum Swab of vesicles (if present) Cerebrospinal fluid HSV PCR Blood HSV PCR Serum ALT Asymptomatic, exposed infants 6

7 Published by CoID and CoF&N in 2013 More aggressive than traditional Red Book recommendations, incorporated into 2015 Red Book Predicated on sending type-specific HSV-1 and HSV-2 antibodies in mother (unless there is a history of previous genital herpes) and performing full workup on infant If HSV not identified, but maternal infection is primary or firstepisode nonprimary: 10 days of pre-emptive acyclovir 2013 Guidance - reaction Many centers do not have type-specific HSV antibodies or HSV PCR in-house Many providers are uncomfortable with aspects of the algorithm: Lumbar puncture on wellappearing infant PICC line, prolonged nursery stay for 10 days of empiric therapy Cost-effectiveness not yet studied Cantey et al, J Pediatr 2015 Term infant born to 15-year-old mother with known genital HSV, recurrent lesions at delivery (did not take her valacyclovir prophylaxis) Cesarean delivery with no rupture of membranes 24 hours - Blood and surface PCRs obtained 48 hours Blood PCR positive for HSV-2, infant underwent LP and started on acyclovir ~72 hours Infant developed vesicles on scalp/cheek 21 days of treatment for SEM disease with positive blood PCR, infant did well; brain MRI and eye exam both normal Did this infant have a better outcome because of early detection / acyclovir? Asymptomatic infants I personally agree with aggressive evaluation and management of HSV-exposed infants, and it is now included in the Red Book BUT Not yet widely accepted Not clear if cost-effective Not yet subject to legal challenge as standard of care Enough nursery stuff. I am a emergency medicine doc / hospitalist / intensivist what am I supposed to do with kids who aren t asymptomatic? 7

8 Targeted vs. empiric acyclovir Targeted acyclovir: Acyclovir is started for infants younger than age days who have signs consistent with neonatal HSV infection: Vesicular/ulcerative mucocutaneous disease (SEM) Keratoconjunctiviits (SEM) Apnea, seizures, lethargy, pleocytosis, etc (CNS) Hepatitis, coagulopathy, acute renal failure (DISS) Targeted vs. empiric acyclovir Empiric acyclovir: Acyclovir is started along with antibacterial therapy for infants younger than age 14 (or 21, or 28) days who are evaluated for serious bacterial infection Targeted vs. empiric acyclovir Targeted vs. empiric acyclovir Targeted Empiric Advantages Maximizes pre-test probability, minimizes unnecessary acyclovir exposure Maximizes sensitivity and reduces the risk of delay in effective therapy Disadvantages Some infants with neonatal HSV present with fever alone Number needed to treat is very high Testing all neonates for HSV may prolong length of stay depending on availability of testing Caviness AC, et al. J Pediatr 2008 Single-center (Texas Children s), 5-year retrospective cohort of neonates evaluated for infection in the ED 5817 neonates 3% with urinary tract infection 1.2% with bacteremia 0.4% with bacterial meningitis 0.2% with HSV (n=10) Limiting cohort to neonates with fever and CSF pleocytosis: 1.6% with HSV 0.8% with bacterial meningitis Is delayed therapy harmful? Shah SS et al, Pediatrics 2011 Is delayed therapy harmful? Sánchez PJ, et al, PIDJ (in press) and Curfman AL, et al, J Pediatr 2017 Cohort studies of infants with proven HSV Mortality not associated with delayed therapy Disease category best predictor (50% of disseminated infants die, 10% of CNS infants, 0% of SEM infants) Disseminated more likely to be treated early; CNS more likely to be treated late 8

9 Targeted vs. empiric acyclovir I personally favor targeted acyclovir with two caveats: 1. Very low bar for what counts as CNS signs (eg, low threshold for lethargy/apnea) 2. Critical to send all 4 tests before starting empiric acyclovir Surface swabs for PCR Blood PCR CSF PCR ALT I successfully diagnosed and treated neonatal HSV! Now what? Recurrences Prophylaxis Infants with neonatal HSV are at high risk of recurrences due to immature T cell function in the first year of life Infants with SEM disease may have cutaneous recurrences Infants with CNS disease may have reactivation in the central nervous system (irritability, fever, aseptic meningitis, recurrent encephalitis) 9

10 Acyclovir prophylaxis Kimberlin DW, et al. NEJM 2011 Randomized controlled trial of 74 infants with either CNS or SEM disease Acyclovir, 300 mg/m 2 /dose PO TID x6 months versus placebo Recurrences treated with open-label acyclovir; infants taken off study drug and put on open-label acyclovir after 2 nd recurrence Primary outcome: Neurodevelopmental status at age 12 months Secondary outcome: Skin/CNS recurrences Primary outcome: Neurodevelopment Acyclovir group had higher Bayley-II mental developmental scores at 1 year of age (88 vs. 68, p=0.046) Conceptually, 20 IQ points Secondary outcome: Recurrences Acyclovir prophylaxis 6 months of acyclovir prophylaxis is standard of care for infants with SEM or CNS disease Infants with disseminated disease not included in study, but most infectious disease providers (including me) provide prophylaxis to survivors In summary 1. The epidemiology of neonatal HSV is changing, and the pathophysiology may not be what we thought it was 2. Valacyclovir prophylaxis for pregnant women with genital herpes can reduce risk of lesions at delivery / need for cesarean, but prophylaxis has not been shown to be protective for infants 3. The availability of type-specific antibody testing (HSV-1, HSV-2) for mothers and PCR testing for infants has allowed for more aggressive testing and empiric treatment, but not clear how costeffective or beneficial that aggressive management is for well-appearing newborns In summary 4. Acyclovir therapy for infants with suspected infection may be targeted or universal depending on center; data does not clearly favor one approach over the other 5. Infants with suspected HSV disease should have surface, blood, and CSF PCRs in addition to ALT 6. Infants who survive neonatal HSV infection should receive 6 months of oral acyclovir prophylaxis to prevent recurrences and improve neurodevelopmental outcomes 10

11 Thank you! 11