Neonatal Herpes Simplex Virus Infection Research Articles

Seroprevalence of Neonatal Herpes Simplex Virus Infection at A Tertiary Teaching Hospital in Malaysia

INTRODUCTION: Neonatal herpes simplex virus (HSV) infection is generally infrequent, despite being a life-threatening illness. Knowledge of its prevalence is limited in Malaysia since most cases are asymptomatic infections and only limited routine neonatal HSV screening is conducted. This study therefore provides a comprehensive investigation of the seroprevalence of HSV-1 and HSV-2 in neonates. MATERIALS AND METHODS: Serological screening for HSV-1 IgG and HSV-2 IgG antibody tests using the Electrochemiluminescence assay was performed on serum samples of 215 neonates delivered from January until December 2022 at Hospital Universiti Sains Malaysia. RESULTS: Of the neonates, 54.4% were found to be HSV-1 positive, while 4.2% were HSV-2 positive. All the HSV-2 neonates were co-infected with HSV-1. Newborns aged 0–10 days were the most infected group by HSV-1 (92.3%) and HSV-2 (55.6%). The most reported clinical presentation was small gestational age (SGA) (60%). Microcephaly and macrocephaly were observed in one neonate each. The clinical presentations of reactive HSV-1 and HSV-2 cases revealed the presence of fever with rash in both cases. CONCLUSION: The high seroprevalence of HSV-1 is alarming. It is hoped that these data will support the advocacy of screening women for HSV before or during pregnancy as a precautionary approach to reducing the risk of vertical transmission.

PA08 Extensive congenital epidermal skin loss with sparing of the palms, soles and head: strikingly similar appearances in four patients with neonatal herpes simplex infection

PA08 Extensive congenital epidermal skin loss with sparing of the palms, soles and head: strikingly similar appearances in four patients with neonatal herpes simplex infection

Acyclovir Dosing Practices Across a Multicenter Cohort of Neonatal Intensive Care Units.

Acyclovir is the first-line therapy for neonatal herpes simplex virus infections. Therapy can mitigate morbidity and mortality but carries a risk for toxicity. We aimed to compare acyclovir dosing in neonatal intensive care units to published recommendations based on population pharmacokinetic (PopPK) analysis. We performed a multicenter cohort study of infants in neonatal intensive care units managed by the Pediatrix Medical Group from 1997 to 2020. We included all infants who received acyclovir with complete dosing information. Our primary outcome was the proportion of courses with dosing within 80%-120% of the PopPK recommended daily dose and at the recommended dosing frequency. We compared dosing before and after the publication of the 2014 PopPK recommendations using linear probability modeling. We identified 6862 infants with complete dosing information across 308 centers. Dosing met PopPK recommendations for 41% of treatment courses for infants <30 weeks postmenstrual age (PMA), 71% for infants 30 to <36 weeks PMA and <1% for infants ≥ 36 weeks PMA. Comparison of dosing from 1997 to 2013 with that from 2015 to 2020 showed a significant increase in dosing meeting PopPK recommendations for infants <30 weeks PMA (P = 0.008) and infants 30 to <36 weeks PMA (P = 0.02) but not infants ≥ 36 weeks PMA (P = 0.29). No significant increase in dosing meeting PopPK recommendations was seen for any PMA group when comparison was limited to more recent years (2008-2013 vs. 2015-2020). Dosing meeting PopPK recommendations increased over time for some PMA groups, but dosing different than PopPK recommendations remains common. More research is needed to clarify optimal dosing strategies in these infants.

Estimated Incidence, Mortality, and Costs of Neonatal Herpes Simplex Virus Infections in the United States, 2019 [ID 2683519

INTRODUCTION: Neonatal herpes simplex virus (nHSV) infection is rare but can cause serious morbidity and mortality. This study assessed the incidence, mortality, and costs of nHSV infections in the United States in 2019. METHODS: Inpatient records of neonates aged 28 days or less at admission were examined using the 2019 Healthcare Cost and Utilization Project Kids' Inpatient Database, a nationally representative sample of U.S. pediatric discharges. Neonatal herpes simplex virus cases were defined as those with ICD-10-CM codes for herpes simplex virus (B00.xx, A60.xx, or P35.2), and hospital stays greater than 5 days or resulting in death. Cases involving readmission or transfer from another hospital were excluded. Incidence, mortality, and costs were estimated by sociodemographic factors including race, U.S. region, primary payer, and median household income. RESULTS: In 2019, there were an estimated 561 nHSV cases in the United States (15.7 per 100,000 births), with a 4.6% mortality rate. Incidence rates were highest in neonates of Black race (27.3), in the South (21.3), with public insurance coverage (25.2), and born into a household with a median income less than $48,000 (24.5). The incidence rate of nHSV in preterm (41.8) was three times that of term neonates (13.0). The median hospital stay was 15 days with a median cost of $109,562. CONCLUSION: We found disparities in nHSV incidence, with infants in the South and born to Black birthing parents disproportionately affected. Higher incidence rates were also found in infants with public insurance coverage and lower household income. Prevention efforts and early detection are crucial to mitigate these disparities.

Neonatal herpes: case series in two obstetric centres over a 10-year period (2013-2023), France.

Neonatal herpes simplex virus (HSV) infection (HSV infection in infants less than 6weeks of age) is rare but mortality and morbidity rates are high after disseminated disease and encephalitis.In France, the epidemiology is poorly described, and two decades ago, incidence was estimated to be 3 per 100,000 live births a year. We describe determinants, epidemiologic and clinical characteristics of neonatal HSV infection in a managed-care population attending in two major obstetric and paediatric centres, Paris, France, over a 10-year period. This retrospective case series study was conducted from 2013 to 2023, in infants less than 42days of age who had virologically confirmed HSV infection. We report an overall rate of neonatal herpes of 5.5 per 100,000 live births a year and an incidence of symptomatic cases of 1.2 per 100,000 live births a year. HSV-1 was the major serotype involved (84.2%) and post-natal acquisition through the orolabial route reached 63.2%. All neonates who had neonatal HSV PCR screening (owing to clinical signs in parents) and who received prompt acyclovir treatment remained asymptomatic. Symptomatic forms accounted for 21.1% cases of the total and mortality was high (62.5% of symptomatic forms). Conclusion: This case series confirms that neonates at risk for HSV disease and poor outcome are those born to HSV-seronegative mothers, preterm infants, and those who received acyclovir after onset of symptoms (mainly because mothers did not present evidence of acute HSV infection). Our study confirms the major role of HSV-1 and the frequency of its early post-natal acquisition. What is known: •Neonatal herpes simplex virus infection is rare but motality and morbidity rates are high after disseminted disease and encephalitis. National recommendations exist worldwide but mangement of this disease is not always easy. What is new: •As in France epidemiology of neonatal herpes is poorly described, our report is potentially an important addition to the existing literature. Moreover, we describe local practice that may be useful to physicians.

Clinical utility of maternal TORCH screening in fetal growth restriction: A retrospective two-centre study.

The aim of this study was to evaluate the indications for maternal TORCH (Toxoplasma gondii, rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV)) serology, with a focus on the yield in isolated fetal growth restriction (FGR). A retrospective review of antenatal TORCH testing between January 2014 and December 2018 was carried out at two hospitals in Melbourne, Australia. TORCH testing ordered for pregnancy losses and stillbirth was excluded. Medical records of 718 pregnancies were reviewed, representing 760 fetuses. Isolated FGR was the indication for TORCH screening in 71.2% of pregnancies. Screens ordered for isolated FGR were positive in 7.4% (95% CI 5.5-10.0%). There were 49 positive maternal immunoglobulin M (CMV = 34, Toxoplasma = 15). Two acute maternal infections during pregnancy were diagnosed (CMV = 1, Toxoplasma = 1), with both screens ordered to assess symptomatic maternal illness. There was one neonatal CMV infection, born to a woman with symptomatic primary CMV. No maternal or neonatal rubella or HSV infections were identified. We found a diagnostic yield of TORCH screening for isolated FGR of 0.0% (95% CI 0.00-0.8%). An estimated AUD$64 269.75 was expended on maternal TORCH screens in this study. Maternal TORCH testing for isolated FGR is of no diagnostic yield and should be abandoned.

Challenges for early diagnosis of neonatal herpes infection in Japan.

This study aimed to analyze the recent prevalence of neonatal herpes simplex virus infection, maternal symptoms in the presence of neonate who has herpes simplex virus infection, and mode of delivery in Japan. We requested 2.078 obstetrical facilities that are members of the Japan Association of Obstetricians and Gynecologists (JAOG) to provide information on neonatal herpes simplex virus infection involving deliveries at or after 22 weeks of gestation between 2020 and 2022. Of these, 1.371 (66.0%) facilities responded with information that could undergo statistical analysis. There were 10 cases of neonatal herpes simplex virus infection, and the incidence of neonatal herpes simplex virus infection in Japan was about 1 in 1.4 × 105 live births. There were no characteristic maternal findings common to cases of neonatal herpes simplex virus infection. The incidence of neonatal herpes simplex virus infection in Japan was low. We could not identify any characteristic maternal findings common to cases of neonatal herpes simplex virus infection.

Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2022.

For 30 years the Australian Paediatric Surveillance Unit (APSU) has conducted national surveillance of rare communicable diseases and rare complications of communicable diseases. In this report, we describe the results of thirteen such studies surveyed by the APSU in 2022, including reported case numbers and incidence estimates, demographics, clinical features, management and short-term outcomes. Conditions described are: acute flaccid paralysis (AFP); congenital cytomegalovirus (cCMV); neonatal and infant herpes simplex virus (HSV) infection; perinatal exposure to human immunodeficiency virus (HIV) and paediatric HIV infection; severe complications of influenza; juvenile-onset recurrent respiratory papillomatosis (JoRRP); congenital rubella infection/syndrome; congenital varicella syndrome (CVS) and neonatal varicella infection (NVI); and the new conditions dengue; Q fever; and severe acute hepatitis. In 2022, cases of severe complications of influenza were reported to the APSU for the first time since 2019. This likely reflects the easing of government-mandated restrictions imposed in 2020-2021 to curb the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the re-emergence of a range of infectious diseases. As previously, AFP surveillance by the APSU contributed to Australia achieving a minimum target incidence of one AFP case per 105 children aged less than 15 years. Cases of JoRRP and NVI were reported in 2022. This indicates potential gaps in human papillomavirus (HPV) and varicella vaccination coverage respectively, especially in high-risk groups such as young migrant and refugee women of childbearing age from countries without universal vaccination programs. Paediatric HIV case numbers resulting from mother-to-child-transmission (MTCT) of HIV remain low in Australia due to use of effective intervention strategies. However, there has been an increase in the number of imported cases of HIV in children (mainly perinatally-acquired) from countries with a high HIV prevalence. Without effective vaccines, there has been no decline in the incidence of congenital CMV and neonatal HSV, indicating the importance of early identification and management to reduce morbidity and mortality. The first cases of dengue, Q fever and severe acute hepatitis were received by APSU in 2022, including two cases of acute hepatitis in which aetiology has not been confirmed to date. The APSU has an important ongoing role in monitoring rare childhood infections.

Neonatal herpes simplex virus infection: From the maternal infection to the child outcome.

This review examines the recent literature on the management of herpes simplex virus (HSV) infections in neonates. We summarized the three clinical categories of maternal HSV infection during pregnancy (primary first episode, nonprimary first episode, or recurrent episode) and the mechanisms of fetal damage. Considering when the transmission of the infection from the mother to the fetus/newborn occurs, three types of neonatal infection can be distinguished: intrauterine infection (5% of cases), postnatal infection (10% of cases), and perinatal infections (85% of cases). Neonatal presentation could range from a limited disease with skin, eye, and mouth disease to central nervous system disease or disseminated disease: the treatment with acyclovir should be tailored according to symptoms and signs of infection, and virological tests. These children need a multidisciplinary follow-up, to timely intercept any deviation from normal neurodevelopmental milestones. Prevention strategies remain a challenge, in the absence of an available vaccine against HSV.

Herpes simplex virus infection among neonates suspected of invasive bacterial infection: a population-based cohort study

ObjectiveTo estimate the incidence of neonatal herpes simplex virus (HSV) infection and the number of neonates with suspected invasive bacterial infection (IBI) needed to treat (NNT) with acyclovir to ensure...

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

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

The management of neonatal herpes simplex virus infection in a small for gestational age neonate - Case report

Neonatal herpes simplex virus infections are rare, normally acquired through vertical transmission in the peripartum period, usually manifesting before 14 days of life and being identified on the basis of history, clinical and laboratory evaluation. We present the case of a small for gestational age male infant born at 38 weeks gestational age with neonatal herpes simplex virus infection. The diagnosis was delayed because the attention was focused on an unidentified bacterial infection. In cases where a clinical picture suggestive of infection is described, with laboratory tests that support the diagnosis of infection, but with cultures that do not highlight bacterial or mycological agents, we must not forget about viral agents, specifically among those newborns from intrauterine growth restricted pregnancies. Neonatal HSV infections can be present even in the absence of herpetic vesicles in the newborn and even if the mother is asymptomatic.

Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2021.

The Australian Paediatric Surveillance Unit (APSU) has been conducting surveillance of rare communicable and non-communicable conditions in children since its inception in 1993. In this report, the results are described of surveillance of ten communicable diseases (and complications) for 2021, including the numbers of cases and incidence estimates; demographics; clinical features; and management and short-term outcomes. The included diseases are: acute flaccid paralysis (AFP); congenital cytomegalovirus (CMV); neonatal herpes simplex virus (HSV) infection; paediatric human immunodeficiency virus (HIV) infection; perinatal exposure to HIV; severe complications from influenza; juvenile-onset respiratory papillomatosis (JoRRP); congenital rubella syndrome; congenital varicella syndrome; and neonatal varicella infection. In 2021, cases of JoRRP were reported to the APSU for the first time since 2017, indicating potential gaps in HPV vaccination. AFP surveillance by APSU again contributed to Australia achieving a minimum target incidence of one AFP case per 100,000 children aged < 15 years. There were no cases of children with severe complications of influenza. No cases of varicella or congenital rubella were reported; however, at-risk populations, especially young migrant and refugee women from countries without universal vaccination programs, need to be screened and prioritised for vaccination prior to pregnancy. Cases of perinatal exposure to HIV continue to increase; however, the rate of mother-to-child-transmission remains at low levels due to the use of effective intervention strategies. Case numbers of congenital CMV and neonatal HSV remain steady in the absence of vaccines, prompting the need for greater awareness and education, with recent calls for target screening of at-risk infants for congenital CMV.

Maternally transferred mAbs protect neonatal mice from HSV-induced mortality and morbidity.

Neonatal herpes simplex virus (nHSV) infections often result in significant mortality and neurological morbidity despite antiviral drug therapy. Maternally transferred herpes simplex virus (HSV)-specific antibodies reduce the risk of clinically overt nHSV, but this observation has not been translationally applied. Using a neonatal mouse model, we tested the hypothesis that passive transfer of HSV-specific human mAbs can prevent mortality and morbidity associated with nHSV. The mAbs were expressed in vivo via vectored immunoprophylaxis or recombinantly. Through these maternally derived routes or through direct administration to pups, diverse mAbs to HSV glycoprotein D protected against neonatal HSV-1 and HSV-2 infection. Using in vivo bioluminescent imaging, both pre- and post-exposure mAb treatment significantly reduced viral load in mouse pups. Together these studies support the notion that HSV-specific mAb-based therapies could prevent or improve HSV infection outcomes in neonates.

Congenital Infections: Priorities and Possibilities for Resource-limited Settings.

Congenital Infections: Priorities and Possibilities for Resource-limited Settings.

Monoclonal antibody therapy of herpes simplex virus: An opportunity to decrease congenital and perinatal infections.

The fetal/neonatal period represents both a unique window of opportunity for interventions as well as vulnerability to a number of viral infections. While Herpesviruses such as herpes simplex virus (HSV) are highly prevalent and typically of little consequence among healthy adults, they are among the most consequential infections of early life. Despite treatment with antiviral drugs, neonatal HSV (nHSV) infections can still result in significant mortality and lifelong neurological morbidity. Fortunately, newborns in our pathogen-rich world inherit some of the protection provided by the maternal immune system in the form of transferred antibodies. Maternal seropositivity, resulting in placental transfer of antibodies capable of neutralizing virus and eliciting the diverse effector functions of the innate immune system are associated with dramatically decreased risk of nHSV. Given this clear epidemiological evidence of reduced risk of infection and its sequelae, we present what is known about the ability of monoclonal antibody therapies to treat or prevent HSV infection and explore how effective antibody-based interventions in conjunction with antiviral therapy might reduce early life mortality and long-term morbidity.

A Rare Cause of Fever in a Term Neonate.

A Rare Cause of Fever in a Term Neonate.

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.

Variability in HSV Testing and Empiric Treatment in Febrile Infants

Source: Treasure JD, Shah SS, Hall M, et al for the Pediatric Research in Inpatient Settings Network and the Collaborative Antiviral Study Group. Variation in diagnostic testing and empiric acyclovir use for HSV infection in febrile infants. Hospital Pediatrics. 2021;11(9):922–930; doi.10.1542/hpeds.2020-003129Investigators from multiple institutions conducted a retrospective study to describe testing for herpes simplex virus (HSV) in febrile infants <60 days old, assess variation in testing and treatment across hospitals, and evaluate the effect of HSV testing on length of hospital stay (LOS) in these patients. For the study, data in the Pediatric Health Information System (PHIS) database were reviewed. PHIS includes administrative data such as demographics, diagnostic and procedure codes, and laboratory and pharmacy orders from encounters at pediatric hospitals. For the current study, data from 44 hospitals in 26 states and the District of Columbia were reviewed. Study participants were children ≤60 days old evaluated in the ED with an ICD-9 or ICD-10 code indicative of fever. Data abstracted on these children included use of HSV testing (culture or PCR), imaging and other diagnostic evaluations, hospital, demographics, orders for acyclovir, LOS, ICD-9 or ICD-10 codes for HSV infection, and severity of illness, as estimated in All Patient Refined-Diagnosis Related Groups (APR-DRG). The primary study outcome was rate of HSV testing, measured at the patient and hospital level. The hospital-level rates of acyclovir orders were also assessed. Secondary outcomes included rate of HSV infection in study patients. LOS was compared in study patients tested for HSV and those not tested using regression analyses and accounting for confounding variables such as age, hospital and APR-DRG estimated illness severity. Analyses were stratified by age (<22 days and 22–60 days).Data were analyzed on 24,534 ED encounters, including 6,027 (24.6%) patients <22 days old and 18,508 (75.4%) 22 to 60 days old. There were 108 children (0.44%) with a diagnostic code indicative of HSV infection, yielding rates of HSV disease of 1.08% for those <22 days old, and 0.23% for those 22 to 60 days of age. Rates of HSV testing were 39.4% and 12.0%, respectively, for children <22 and 22 to 60 days old. At the hospital level, the rate of HSV testing was 35.6% (interquartile range [IQR], 28% to 53%) for the younger age cohort, and 12% (IQR, 9% to 16%) for those 22 to 60 days old. There also was substantial variation in hospital-level rates of empiric acyclovir use (IQR, 68% to 90% for children <22 days old and 44% to 73% for those 22 to 60 days of age). The prevalence of additional testing also varied by age group and hospital. After adjusting for age, severity of illness and hospital, LOS was significantly longer in patients with HSV testing than in those not tested (mean LOS, 2.6 and 1.9 days, respectively; P <0.001).The authors conclude that substantial variation in diagnostic use of HSV testing in febrile infants ≤60 days old.Dr Winer has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The diagnosis and care of potential meningitis/encephalitis in young infants with fever has continually evolved over time (See AAP Grand Rounds. 2010;24[2]:17). As hospitals have moved away from HSV culture and toward HSV PCR testing and the delay in obtaining results has shortened, the safety and cost-effectiveness calculations leading to optimal strategy continue to change.1Although the current investigators were limited in their ability to evaluate duration of empiric acyclovir in children for whom HSV testing is negative, this likely has shortened over time. The LOS was longer for patients who had HSV testing performed, likely related to clinical concern by the physicians that led to the decision to test in the first place.HSV testing continues to evolve, with many hospitals starting to use multiplex PCR array panels which test for multiple viral (including HSV), bacterial, and even fungal pathogens.2 Some evidence exists that initial CSF results are not sensitive enough to preclude a meningitis/encephalitis panel,3 but concerns also exist about overdiagnosis and overtreatment with universal use of these panels.Significant variability exists in the testing and empiric acyclovir usage in febrile infants. Patients tested for HSV have longer LOS than those for whom no test is performed.Fever in young infants is relatively common; neonatal HSV infection, relatively rare. Unfortunately, the results of the current study underscore the need for guidance to allow informed HSV diagnostic and therapeutic decisions. (See AAP Grand Rounds. 2018;39(5):56.)4

A Preterm With Disseminated Neonatal Herpes Simplex Virus (HSV) After Kangaroo Mother Care: Role of Prevention and Early Treatment

Disseminated neonatal herpes simplex virus (HSV) infection represents the most severe form of neonatal herpes, which is associated with high morbidity and mortality. It can be completely prevented and early antiviral treatment can significantly reduce its adverse outcomes. Its early recognition in the neonate can be difficult, since the clinical presentation often mimics bacterial sepsis especially in absence of cutaneous vesicles. We report a case of preterm (twin 1) baby who during the hospital stay developed disseminated neonatal HSV type 1 infection, possibly acquired during kangaroo mother care, as on examination mother was noticed to have herpes labialis. The other twin 2 baby also developed few macular papular rash and was immediately started on antiviral treatment. The purpose of this report is to alert healthcare providers to this potential route of transmission. Furthermore, it is essential to consider neonatal HSV infection in any sick infant who is not responding to standard empirical antibiotic management, even in the absence of herpetic lesions.