Neonatal Herpes Simplex Virus Disease Research Articles

Clinical progress note: Evaluation and management of neonatal herpes simplex virus disease.

Clinical progress note: Evaluation and management of neonatal herpes simplex virus disease.

Real-World Data on Cutaneous Recurrences Following Neonatal Herpes Simplex Virus Disease

Though primarily used to improve neurodevelopmental outcomes, suppressive oral acyclovir therapy following neonatal herpes simplex virus disease also decreases cutaneous recurrences. Skin recurrences can still occur, however, and understanding their frequency is helpful in managing patients with this rare disease.

Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease

BackgroundNeonatal herpes simplex virus (HSV) disease has been treated with high-dose (20 mg/kg/dose) acyclovir since 1991. AimsDetermine the safety of acyclovir in infants with neonatal HSV treated with high-dose acyclovir; examine the association between acyclovir dose and exposure with adverse events (AEs). Study designWe obtained demographic information and acyclovir dosing via medical records. Acyclovir exposure was calculated using an established pharmacokinetic model. SubjectsInfants <120 days of age with neonatal HSV discharged from four academic children's hospitals. Outcome measuresWe identified clinical and laboratory adverse events (AEs). Results and conclusionsWe identified 49 infants with neonatal HSV treated with acyclovir; 42 infants had complete 21-day dosing information. Median mean daily dose was 59 mg/kg/day. Clinical AEs were common among all gestational and postnatal age groups. Rash was the most common clinical AE (37 %). Mild laboratory AEs occurred in 2–37 % of infants. The median maximum doses (mg/kg/day) were higher among infants with hypokalemia, elevated blood urea nitrogen, and thrombocytosis. For all other laboratory AEs, the median maximum doses for infants without events were higher or equal to the median maximum dose of infants with the AE. The odds of experiencing any clinical or laboratory AE did not differ by predicted acyclovir exposure for either area under the curve (AUC) or maximum concentration (Cmax) (odds ratio [OR] = 1.00 [0.98, 1.03] and OR = 1.01 [0.93, 1.12], respectively). Although AEs were common with high-dose acyclovir exposure, severe AEs were rare. Acyclovir exposure was not associated with AEs.

210 Antibody function, antigenic target and glycans determine the transfer of herpes simplex virus (HSV) antibodies (Abs) from mothers to newborns and transfer is altered by SARS-CoV-2

OBJECTIVES/GOALS: Murine and clinical data suggest that antibody-dependent cellular cytotoxicity (ADCC) is associated with greater protection against disseminated neonatal HSV disease. To quantify the relative transfer of Abs with different functions and targets, we conducted a prospective study of mother-infant term and preterm dyads pre and during COVID-19 METHODS/STUDY POPULATION: Total and HSV lysate, glycoprotein D (gD) and glycoprotein B (gB)-specific IgG, IgG1 and IgG3 as well as HSV neutralizing Abs (nAbs) and ADCC were quantified in paired 3rd-trimester pregnant women and their newborns (cord) blood. Transfer ratios (TR) were defined as cord:maternal Ab levels. IgG1 and IgG3 subclass and gD or gB-specific Abs were isolated by column purification and glycan profiles were assessed by mass spectrometry. The study population included 21 term and 15 preterm dyads who were HSV-1 (+/- HSV-2) seropositive enrolled between 2018-2019 (pre-COVID) and 25 additional HSV-1 (+/- HSV-2) seropositive term dyads whose mothers were SARS-CoV-2 PCR and COVID Ab+ at delivery; 14 were asymptomatic and 11 had mild-moderate COVID disease. None of the mothers had active genital HSV lesions during delivery RESULTS/ANTICIPATED RESULTS: Anti-HSV IgG, IgG1 and IgG3 TR were higher in term vs. preterm dyads (p&lt;0.05). The nAb TR was 2.4 in term vs. 0.8 in preterm (p&lt;0.001) but the ADCC TR was &lt; 1.0 for both. To determine if the latter reflected antigenic target, subclass or glycans, we enriched for gD and gB specific and IgG1 and IgG3 Abs. The gD Abs were IgG1 and had only neutralizing activity. In contrast, gB Abs were polyfunctional and included IgG1 and IgG3 but only the IgG1 Abs had ADCC activity. The gD Abs were enriched for glycans associated with an affinity for the neonatal Fc receptor (FcRn); gB Abs expressed glycans associated with both FcRn and FcγRIIIa binding. There was no significant difference in total HSV-specific IgG TR in pre-COVID vs post-COVID dyads but the nAb TR was lower (p=0.018) and ADCC TR higher (p&lt;0.001) in the COVID compared to pre-COVID cohort DISCUSSION/SIGNIFICANCE: HSV ADCC Abs, which may provide greater protection than nAbs against neonatal disease, transfer poorly particularly to preterm newborns. However, in the setting of SARS-CoV-2, the TR of HSV ADCC is significantly higher. This may reflect alterations in the placental architecture and/or glycan composition which is currently being investigated.

Neonatal herpes simplex virus disease transmitted from mother to infant through breast lesions: a case report

Neonatal herpes simplex virus disease transmitted from mother to infant through breast lesions: a case report

Neonatal Herpes Simplex Virus Infection: Epidemiology and Outcomes in the Modern Era.

Over the past several decades, there have been advances in diagnosis and treatment of neonatal herpes simplex virus (HSV) disease. There has been no recent comprehensive evaluation of the impact of these advances on the management and outcomes for neonates with HSV. Clinical data for initial presentation, treatment, and outcomes were abstracted from medical records of neonates with HSV treated at Seattle Children's Hospital between 1980 and 2016. One hundred thirty infants with a diagnosis of neonatal HSV were identified. Between 1980 and 2016, high-dose acyclovir treatment for neonatal HSV infection increased from 0% to close to 95%, with subsequent decrease in overall HSV-related mortality from 20.9% to 5.6%. However, even among infants treated with high-dose acyclovir, mortality was 40.9% for infants with disseminated (DIS) disease, and only 55% of infants with central nervous system (CNS) disease were without obvious neurologic abnormalities at 24 months. Over the study period, the time between initial symptoms and diagnosis decreased. Skin recurrences were more common with HSV-2 than HSV-1 (80% vs 55%; P = .02) and in infants with lesions at initial diagnosis (76% vs 47%; P = .02). Changes in the standard of care for management of neonatal HSV disease have led to improvements in timeliness of diagnosis and outcome but mortality in infants with DIS disease and neurologic morbidity in infants with CNS disease remain high. Future research should focus on prevention of perinatal infection and subsequent recurrences.

Hyperferritinemia: A Diagnostic Marker for Disseminated Neonatal Herpes Simplex Virus Infection?

Although the prognosis of neonatal herpes simplex virus (HSV) infection has improved with intravenous acyclovir, the morbidity and mortality of disseminated disease remains high. Transaminitis and thrombocytopenia have been reported to be sensitive markers of neonatal HSV disease; however, early diagnosis remains a challenge due to a lack of specific clinical and laboratory indicators for this disease process. Ferritin, an acute phase reactant known for its use in diagnosing hemophagocytic lymphohistiocytosis, has recently been reported as extremely elevated in neonates with disseminated HSV due to its high inflammatory nature. We report three cases of neonates at a single institution with hyperferritinemia in the setting of disseminated HSV. Based on this case series, we discuss whether ferritin can be used as an early diagnostic marker in the setting of suspected neonatal HSV disease. [Pediatric Annals. 2021;50(6):e264-e267.].

Postnatal Exposure to Herpes Simplex Virus: To Treat or Not to Treat?

Neonatal herpes simplex virus (HSV) infection carries significant morbidity and mortality. In contrast to perinatal exposure, there are no clear guidelines for the management of postnatal HSV exposure. This review focuses on the risk of HSV infection following postnatal exposure and suggests an approach to management. While many infants are protected by transplacentally transferred maternal anti-HSV antibodies, infants of seronegative mothers with significant postnatal HSV exposure may be at risk of severe disease. Individual risk assessment, appropriate investigations, and empiric acyclovir treatment should be considered in postnatally exposed newborns, even if asymptomatic. In all cases, close clinical follow-up is indicated, as well as education of families on the symptoms of neonatal HSV disease. Finally, measures to reduce the risk of postnatal HSV infection should be considered, such as discouraging individuals, particularly those with a history of recurrent cold sores, from kissing newborns.

Herpes Simplex Virus Infection in Infants: 13 Year Evaluation (2005-2017) of Laboratory Confirmed Cases in Queensland, Australia.

National neonatal surveillance for herpes simplex virus (HSV) disease suggests that the incidence of HSV disease may be higher in Queensland (QLD) than in other Australian States. We sought to investigate the incidence via a retrospective 13-year evaluation of statewide laboratory data, autopsy data and linked clinical records of infants with laboratory confirmed infection. All positive polymerase chain reaction HSV 1 and 2 results were obtained for infants 0-3 months of age from January 1, 2005 to December 31, 2017. Clinical data were obtained from patient records and parent questionnaires were used to evaluate long-term sequelae. One hundred seventy-two infants with HSV positive polymerase chain reaction results: 121 (70.3%) with HSV 1. Of 104 (60.5%) infants with signs of HSV disease, 76 (73.1%) were neonates (≤28 days of age) [incidence 9.6 (95% confidence interval, 7.0-11.5) per 100,000 live births] and 28 (26.9%) were young infants (29-90 days of age) [3.6 (95% confidence interval, 2.4-5.4) per 100,000 live births]. The annual incidence of neonatal HSV disease increased significantly in Queensland over the study period (P < 0.01). Of the 76 neonates with HSV disease, 58 (76.3%) presented with the skin, eye, mouth (SEM) disease, 17 (22.4%) with HSV encephalitis and 11 (14.5%) had disseminated disease. Young infants presented with HSV skin, eye, mouth disease (21, 75.0%) or HSV encephalitis (6, 21.4%). Death occurred in 12/104 (11.5%) infants (all neonates) with 10 attributable to HSV disease. The incidence of neonatal HSV disease in QLD is almost 3 times the national reported incidence. Further research is being undertaken to explore reasons for this change and implications for practice.

Evaluation of suspected neonatal herpes simplex virus infection in preterm versus term newborns in the neonatal intensive care unit.

While national guidelines are available for the evaluation and management of term infants at risk for herpes simplex virus (HSV) infection, such guidelines are lacking for preterm infants. We sought to determine the risk factors and clinical characteristics of preterm vs. term infants who were evaluated and treated empirically for HSV infection in the neonatal intensive care unit (NICU). In a retrospective cohort study, medical records of all infants who were admitted to our NICU (2009-2016) and who were evaluated and empirically treated for HSV were reviewed for mothers' and infants' demographics, clinical characteristics, and laboratory findings. During the study period 4.2% (103/2,471) of all preterm infants, and 6.0% (112/1,865) of all term infants were evaluated and treated empirically for neonatal HSV. Among all infants who were evaluated and treated for HSV, 5.5% (12/215) had neonatal HSV disease, of whom 83.3% (10/12) were preterm infants. In comparison to term, preterm infants were more likely to be evaluated and treated, if they had a maternal history of HSV [OR 2.51 (95% CI: 1.41-4.48)], prolonged rupture of membranes [2.64 (1.221-5.73)], leukopenia [3.65 (1.94-6.87)] and thrombocytopenia [2.25 (0.85-5.89)]. HSV disease was associated with a higher mortality compared to those without disease [25% (3/12) vs. 4.4% (9/203) respectively; p = <0.05]. Preterm infants evaluated and empirically treated for HSV have a higher burden of HSV infection than term infants. HSV should be considered in the management of preterm infant with a maternal history of HSV, prolonged rupture of membranes, and thrombocytopenia.

Acute Kidney Injury During Treatment with Intravenous Acyclovir for Suspected or Confirmed Neonatal Herpes Simplex Virus Infection

To describe the epidemiology of and risk factors associated with acute kidney injury (AKI) during acyclovir treatment in neonates and infants. We conducted a multicenter (n=4), retrospective cohort study of all hospitalized infants age <60days treated with intravenous acyclovir (≥1 dose) for suspected or confirmed neonatal herpes simplex virus disease from January 2011 to December 2015. Infants with serum creatinine measured both before acyclovir (baseline) and during treatment were included. We classified AKI based on changes in creatinine according to published neonatal AKI criteria and performed Cox regression analysis to evaluate risk factors for AKI during acyclovir treatment. We included 1017 infants. The majority received short courses of acyclovir (median, 5 doses). Fifty-seven infants (5.6%) developed AKI during acyclovir treatment, with an incidence rate of AKI at 11.6 per 1000 acyclovir days. Cox regression analysis identified having confirmed herpes simplex virus disease (OR, 4.35; P=.002), receipt of ≥2 concomitant nephrotoxic medications (OR, 3.07; P=.004), receipt of mechanical ventilation (OR, 5.97; P=.001), and admission to an intensive care unit (OR, 6.02; P=.006) as risk factors for AKI during acyclovir treatment. Among our cohort of infants exposed to acyclovir, the rate of AKI was low. Sicker infants and those exposed to additional nephrotoxic medications seem to be at greater risk for acyclovir-induced toxicity and warrant closer monitoring.

2078. Adherence to Laboratory Screening Recommendations for Neonatal Herpes Simplex Virus Infection at a Tertiary Children’s Hospital

BackgroundThough American Academy of Pediatrics (AAP) publications detail the precise laboratory evaluation to perform for suspected neonatal herpes simplex virus (HSV) infection, significant practice variability persists. The primary aim of this study was to assess adherence to AAP laboratory testing guidance for neonatal HSV at our hospital. Other aims included: (1) comparing adherence rates for infants tested due to concern for symptomatic infection with those screened due to maternal genital lesion presence at birth and (2) determining the rate of infected infants among those tested.MethodsChart review was performed for infants ≤42 days old hospitalized from February 1, 2013–June 30, 2016 and tested for HSV. Subjects were categorized as asymptomatic neonates born to mothers with active genital HSV lesions at delivery or as symptomatic with concern for neonatal HSV disease. Those tested as outpatients and asymptomatic newborns of mothers with a history of genital HSV but no active lesions at delivery were excluded. Demographics and maternal HSV status were collected. Evaluations were classified as complete or incomplete based on AAP recommendations.ResultsOf 245 subjects, 24 (10%) were asymptomatic newborns of mothers with lesions at delivery, while 221 (90%) were tested due to possible symptomatic disease. Only 4/245 (1.6%) had HSV infection. Complete evaluations were more likely for asymptomatic infants (P < 0.01), but only 27 total subjects (11%) had a complete evaluation. Blood PCR and surface cultures were omitted most frequently—missing from 196 (80%) and 150 (61%) evaluations, respectively. Of those lacking surface cultures, 58 (39%) had surface PCRs. CSF PCRs were not obtained for 118/221 (53%) symptomatic evaluations. No association was found between known maternal history of genital HSV prior to delivery and evaluation completeness (P = 0.19).ConclusionAdherence to AAP testing recommendations for neonatal HSV was poor, though evaluation completeness was more likely for asymptomatic infants of mothers with lesions at delivery than for symptomatic infants. Despite a low incidence of neonatal HSV, education regarding appropriate laboratory testing is needed. Bundling computerized electronic orders for testing may improve adherence.Disclosures All authors: No reported disclosures.

609. Acute Kidney Injury During Treatment with Intravenous Acyclovir (AKITA) for Suspected Neonatal Herpes Simplex Virus Infection

BackgroundIntravenous (IV) acyclovir is often administered empirically in neonates with suspected herpes simplex virus (HSV) disease. Acute kidney injury (AKI) can occur within 1–2 days after starting acyclovir due to crystal nephropathy, but the epidemiology of acyclovir-associated AKI in infants is not well-described. Our objective was to detail the incidence and timing of AKI among acyclovir-exposed infants.MethodsWe identified all hospitalized infants age <60 days treated with ≥1 dose of IV acyclovir for suspected or confirmed neonatal HSV disease from January 2011 to December 2015 at four US hospitals. Subjects were included if they had both a baseline (lowest value obtained before initiation of acyclovir) and follow-up serum creatinine (SCr; obtained after at least one dose of acyclovir [Day 0] through 48 hours after completion) recorded. Infants with congenital kidney disease were excluded. We defined AKI using Kidney Disease: Improving Global Outcomes SCr criteria: ≥50% increase from baseline, or ≥0.3 mg/dL change within any 48-hour period.ResultsWe identified 3,374 infants who received IV acyclovir, 1,535 of whom (45.5%) had SCr as defined for inclusion in our analyses (range 52–898 infants per hospital); 50% were white, 44% were female, and the median gestational age was 37 weeks (IQR 35 – 39). On acyclovir Day 0, the median age was 6 days (IQR 2–18), and 50.0% (n = 768) were admitted to the NICU. The median acyclovir dose was 59.5 mg/kg/day (IQR: 55.8–61.2) and the median duration of treatment was 3 days (IQR: 3–6). Thirty-two infants had confirmed HSV disease (10 CNS, 14 disseminated, and eight skin, eye, and mucous membrane disease). In all, 96 infants (6.3%) had AKI detected after acyclovir initiation including 62 (64.5%) on Day 0, 20 (20.8%) on Day 1 or 2, and 14 (14.6%) on/after Day 3. Of those with AKI on Day 1 or later, 41% (n = 14) had Stage 2 AKI (doubling of SCr or more from baseline). Seven of 32 (21.8%) infants with confirmed HSV had AKI including 4 on Day 0, 2 on Days 1–2, and 1 on Day 12.ConclusionThe incidence of AKI among infants treated with IV acyclovir in our study was low. Most AKI was detected soon after acyclovir initiation, potentially owing to more severe illness at the start of treatment and/or drug toxicity, but AKI also developed later. SCr monitoring should be considered throughout acyclovir treatment in infants.Disclosures B. L. Haltzman, Pfizer, Inc.: Study Coordinator, Salary. K. J. Downes, Pfizer, Inc.: Investigator, Research support. Merck, Inc.: Investigator, Research support. S. E. Coffin, Merck, Inc.: Investigator, Research support.

Antiviral Approaches for the Treatment of Herpes Simplex Virus Infections in Newborn Infants.

Herpes simplex virus (HSV) infections in newborns are associated with severe disease and death. Trials conducted by the Collaborative Antiviral Study Group have established the standard of care for the treatment of neonatal HSV disease with marked improvements in morbidity and mortality. We review the studies that have contributed to our understanding of the epidemiology and clinical course of neonatal HSV disease and discuss the landmark trials that have resulted in safe and effective treatment together with improved diagnostics. Although significant advances have been made, neonatal HSV disease continues to have an unacceptably high mortality rate with significant sequelae in survivors. Further research is urgently needed for prevention.

Neonatal HSV Disease: Balancing the Low Incidence With the Need to Treat Promptly.

* Abbreviations: ED — : emergency department HSV — : herpes simplex virus LP — : lumbar puncture PCR — : polymerase chain reaction In this issue of Pediatrics , Cruz et al1 address the following clinical question: what is the probability that an infant <60 days of age presenting to the emergency department (ED) who receives a lumbar puncture (LP) for concern of meningitis has a herpes simplex virus (HSV) infection? To answer this question, Cruz et al1 conducted a retrospective observational study and report on the incidence of HSV in infants <60 days old who had cerebrospinal fluid bacterial culture testing performed at 1 of 23 North American, tertiary-care, pediatric EDs over a 9-year period. There were 112 infants who had HSV identified, which amounts to 0.42%, or 42 of 10 000 (95% confidence interval, 35–51 of 10 000) infants evaluated. This estimate serves as the pretest probability of HSV infection in infants presenting to the ED who receive an LP for meningitis. On average, EDs saw ∼1 infant with HSV infection per year. Of neonatal HSV cases, 89.3% occurred in the first 6 weeks, with a median age of presentation of 14 days. Cruz et al1 also bring attention to an important issue on the state of affairs of hospital management of HSV in young infants: there is substantial variation in HSV testing and acyclovir administration across EDs. HSV testing ranged from 14% to 72%, and empirical acyclovir administration ranged from 4% to 53% across EDs. … Address correspondence to Sanjay Mahant, MD, Department of Paediatrics, Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada M5G1X8. E-mail: sanjay.mahant{at}sickkids.ca

Neonatal Herpes Simplex Virus Infection

Herpes simplex virus (HSV) is among the most severely debilitating viruses that can infect the neonate, and is associated with significant mortality and morbidity. Neonatal HSV infection generally is acquired in the peripartum period, and can be devastating if not diagnosed appropriately. Studies conducted over several decades have advanced our knowledge of the benefit of antiviral therapy on neonatal HSV disease outcomes. As such, many neonates now are effectively treated and experience no or fewer long-term sequelae of this potentially devastating infection. Clinicians must be astute, because early diagnosis and early treatment are key to a better prognosis.

Safety of High-dose Acyclovir in Infants With Suspected and Confirmed Neonatal Herpes Simplex Virus Infections.

Acyclovir is used to treat herpes simplex virus disease in infants. Treatment with high-dose acyclovir, 60 mg/kg/d, is recommended; however, the safety of this dosage has not been assessed in the past 15 years, and this dosage is not currently approved for infants by the US Food and Drug Administration. We included infants with neonatal herpes simplex virus disease treated with ≥14 days of intravenous acyclovir starting in the first 120 days of life admitted to 1 of 42 neonatal intensive care units managed by the Pediatrix Medical Group between 2002 and 2012. We determined the frequency and proportion of infants with clinical and laboratory adverse events (AEs) as well as the number and proportion of infant days with laboratory AEs occurring during acyclovir exposure. We identified 89 infants during the study period with 1658 days of acyclovir exposure. Almost all received high-dose acyclovir therapy (79/89, 89%). The most common clinical AEs were hypotension and seizure, both occurring in 9% of infants. Thrombocytopenia was the most common laboratory AE occurring in 25% of infants and on 9% of infant-days. Elevated creatinine occurred in 2% of infants and 0.2% of infant-days and no infants developed renal failure requiring dialysis. Overall, 45% of infants had ≥1 AE. In this cohort of infants treated during the high-dose acyclovir era, AEs were common but usually not severe. Many of the AEs reported in this cohort may be related to the underlying infection rather than due to acyclovir exposure.

Treatment of perinatal viral infections to improve neurologic outcomes.

Viral infections in the fetus or newborn often involve the central nervous system (CNS) and can lead to significant morbidity and mortality. Substantial progress has been made in identifying interventions decreasing adverse neurodevelopmental outcomes in this population. This review highlights progress in treatment of important viruses affecting the CNS in these susceptible hosts, focusing on herpes simplex virus (HSV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and enteroviruses. The observation that high-dose acyclovir improves mortality in neonatal HSV disease culminated decades of antiviral research for this disease. More recently, prolonged oral acyclovir was found to improve neurologic morbidity after neonatal HSV encephalitis. Ganciclovir, and more recently its oral prodrug valganciclovir, is effective in improving hearing and neurodevelopment after congenital CMV infection. Increasing evidence suggests early control of perinatal HIV infection has implications for neurocognitive functioning into school age. Lastly, the antiviral pleconaril has been studied for nearly two decades for treating severe enteroviral infections, with newer data supporting a role for this drug in neonates. Identifying common mechanisms for pathogenesis of viral CNS disease during this critical period of brain development is an important research goal, highlighted by the recent emergence of Zika virus as a potential cause of fetal neurodevelopmental abnormalities.

Plasma and Cerebrospinal Fluid Herpes Simplex Virus Levels at Diagnosis and Outcome of Neonatal Infection

To evaluate the utility of quantitative herpes simplex virus (HSV) polymerase chain reaction (PCR) levels for prognosis and management of neonatal HSV disease. Clinical and virologic data were abstracted by medical record review from neonatal HSV cases treated at Seattle Children's Hospital between 1993 and 2012. HSV PCR results from plasma (n = 47), cerebrospinal fluid (n = 56), or both (n = 40) at the time of diagnosis were available from 63 infants; 26 with skin-eye-mouth (SEM), 18 with central nervous system (CNS), and 19 with disseminated (DIS) disease. Plasma HSV PCR was positive in 78% of the infants with SEM, 64% with CNS and 100% with DIS disease. Mean plasma viral level was 2.8 log10 copies/mL in SEM, 2.2 log10 copies/mL in CNS, and 7.2 log10 copies/mL in DIS infants. The HSV levels were higher among infants who died compared with surviving infants, 8.1 log10 copies/mL (range 7.7-8.6) vs 3.8 log10 copies/mL (range 0.0-8.6), P = .001, however, level of HSV DNA in the cerebrospinal fluid or in plasma did not correlate with neurologic outcome. Dynamics of HSV clearance from plasma during high-dose acyclovir treatment showed single-phase exponential decay with a median viral half-life of 1.26 days (range: 0.8-1.51). Plasma HSV levels correlate with clinical presentation of neonatal HSV disease and mortality, but not neurologic outcome.

Population-based surveillance of neonatal herpes simplex virus infection in Australia, 1997-2011.

Neonatal herpes simplex virus (HSV) infection is uncommon, but mortality after disseminated disease and morbidity after encephalitis are high. For the last decade, increased dose and duration of acyclovir has been advised to prevent disease progression and recurrence. We sought to determine prospectively the epidemiologic, clinical, and secular trends of this condition in Australia. This was prospective national active surveillance for neonatal HSV disease through the Australian Paediatric Surveillance Unit from 1997 to 2011. Case notification triggered a questionnaire requesting de-identified data from the pediatric clinician. We identified 131 confirmed cases of neonatal HSV disease in 15 years from 261 notifications (95% response). The reported incidence (3.27 cases per 100 000 live births overall; 95% confidence interval [CI], 2.73-3.86) was stable. Overall mortality was 18.8% (95% CI, 12.1-25.5); the mortality rate was significantly lower in the latter part of the study period, 2005-2011, compared with 1997-2004 (P = .04). There were significantly more young mothers (<20 years of age) compared with Australian birth record data (18.5% vs 4.8%; P < .001). HSV-1 infection was more common than HSV-2 (62.7% vs 37.3%; P < .001), and the rate of HSV-1 infections increased significantly over the surveillance period (P < .05). From 2002, most infants received high-dose acyclovir. The time from symptom onset to initiation of therapy in survivors did not change over time. Mortality from neonatal HSV infection has fallen but remains high. HSV-1 is the major serotype causing neonatal disease in Australia. Young mothers represent an important target group for prevention.