Vertical mother-to-infant transmission of herpes simplex virus 2 is correlated with tropism due to mutations in viral UL13.

Although neonates are commonly exposed to vaginal herpes simplex virus (HSV)-2, neonatal herpes is rare. Therefore, we analyzed paired infant and maternal HSV-2 isolates from two cases of mother-to-infant transmission to identify viral factors contributing to vertical transmission. Sixteen infant isolates with neonatal herpes and 27 genital isolates in their third trimester were included. The infant isolates were significantly more temperature-independent than the maternal isolates. Sequence comparison revealed viral UL13 protein kinase (UL13-PK) mutation in the infant isolates in both cases. In the expanded cohort, infant isolates (5/18) had significantly more UL13-PK mutations than genital isolates (1/29). Isolates within 8 days post-birth (3/4) had a significantly higher frequency of UL13-PK mutation than those after 9 days (2/14), suggesting a close association between UL13-PK mutations and vertical transmission. Elongation factor 1-delta was identified as a target of UL13-PK by proteomic analysis of UL13-PK-positive and -negative HepG2 cells. The mixed infant isolates with the intact and mutated UL13-PK conferred altered cell tropism, temperature independence adapting to fetal temperature, and better growth properties in Vero and hepatoblastoma HepG2 cells than in HSV-2 with intact and mutated UL13-PK alone, indicating that viral UL13-PK mutation is essential for vertical HSV-2 transmission.

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 6 weeks 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 42 days 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.

Postpartum Disseminated Herpes Simplex Virus Type 1 Infection With Hemophagocytic Lymphohistiocytosis and Fulminant Neonatal Herpes Infection.

The present study describes a 19-year-old woman with systemic herpes simplex virus (HSV)-1 infection and hemophagocytic lymphohistiocytosis (HLH) postpartum, and a fatal course of neonatal herpesvirus infection. Functional investigation of cells from the mother demonstrated significantly impaired induction of antiviral interferons and cytokines in the context of normal activation of the transcription factors NF-κB and IRF3. Whole-exome sequencing did not reveal any functionally validated genetic variants. We suggest that the functionally impaired antiviral responses, potentially caused by a variant in CASP8 or other variants in noncoding regions of the genome, contributed to the unusually severe disease course observed in two generations.

Estimating Neonatal Herpes Simplex Virus Incidence and Mortality Using Capture-recapture, Florida.

BACKGROUND: Neonatal herpes simplex virus infection (nHSV) leads to severe morbidity and mortality, but national incidence is uncertain. Florida regulations require that healthcare providers report cases, and clinical laboratories report test results when herpes simplex virus (HSV) is detected. We estimated nHSV incidence using laboratory-confirmed provider-reported cases and electronic laboratory reports (ELR) stored separately from provider-reported cases. Mortality was estimated using provider-reported cases, ELR, and vital statistics death records. METHODS: For 2011-2017, we reviewed: provider-reported cases (infants ≤ 60 days of age with HSV infection confirmed by culture or polymerase chain reaction [PCR]), ELR of HSV-positive culture or PCR results in the same age group, and death certificates containing International Classification of Disease, Tenth Revision, codes for herpes infection: P35.2, B00.0-B00.9, and A60.0-A60.9. Provider-reported cases were matched against ELR reports. Death certificates were matched with provider and ELR reports. Chapman's capture-recapture method was used to estimate nHSV incidence and mortality. Mortality from all 3 sources was estimated using log-linear modeling. RESULTS: Providers reported 114 nHSV cases, and ELR identified 197 nHSV cases. Forty-six cases were common to both datasets, leaving 265 unique nHSV reports. Chapman's estimate suggests 483 (95% confidence interval [CI], 383-634) nHSV cases occurred (31.5 infections per 100 000 live births). The nHSV deaths were reported by providers (n = 9), ELR (n = 18), and vital statistics (n = 31), totaling 34 unique reports. Log-linear modeling estimates 35.8 fatal cases occurred (95% CI, 34-40). CONCLUSIONS: Chapman's estimates using data collected over 7 years in Florida conclude nHSV infections occurred at a rate of 1 per 3000 live births.

Murine Model of Maternal Immunization Demonstrates Protective Role for Antibodies That Mediate Antibody-Dependent Cellular Cytotoxicity in Protecting Neonates From Herpes Simplex Virus Type 1 and Type 2.

BACKGROUND: Neonatal herpes simplex virus (HSV) disease results in unacceptable morbidity and mortality. The primary humoral immune response to natural infection is neutralizing antibodies (Abs). However, Abs that activate Fc gama receptors (FcγRs) and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) may play a dominant role in protection. In adult mice, a single-cycle HSV candidate vaccine deleted in glycoprotein-D (ΔgD-2) that induces ADCC provided complete protection against HSV disease and prevented the establishment of latency. Passive transfer studies showed that Abs were sufficient for protection. The current study tested the hypothesis that maternal immunization with ΔgD-2 would protect neonates. METHODS: C57BL/6 female mice were vaccinated 3 weeks apart with ΔgD-2, and pups were challenged at different times postnatally with lethal doses of HSV-1 or HSV-2. Concentration and functionality of Abs and immune cells were assessed. RESULTS: Maternal ΔgD-2 immunization provided significant protection and reduced viral dissemination after lethal challenge with HSV-1 or HSV-2. Protection correlated with Abs acquired transplacentally or from breastmilk that mediated ADCC. Protection was reduced when pups were challenged on Day 1 of life, and this was associated with decreased ability of newborn cells to mediate Ab-dependent cell killing. CONCLUSIONS: Antibodies mediating ADCC provide significant protection against neonatal HSV.

Neonatal Herpes Simplex Virus: The Long Road to Improved Outcomes.

Herpes simplex virus (HSV) acquired during delivery places the neonate at risk for mortality or long-term neurodevelopmental disability. Exposure generally occurs from recurrent genital herpes infection, although primary infections result in the highest risk of neonatal disease. Neonates generally present in the second or third week of life with lesions. Encephalitis with seizures indicates the presence of central nervous system involvement, and other end organs may also be impacted. Clinical suspicion for neonatal HSV infection warrants immediate initiation of appropriate antiviral therapy. In the last 50 years, antiviral therapy has progressed from agents with prohibitive toxicity or cumbersome administration to herpes virus-specific agents that dramatically improve clinical outcomes with manageable toxicity. Multicenter clinical trials have demonstrated the superiority of high-dose intravenous acyclovir for acute therapy, followed by long-term oral suppressive therapy. This work has dramatically reduced morbidity and mortality from neonatal HSV, representing the benchmark for future clinical trials in neonatal pharmacotherapy.

Mortality from neonatal herpes simplex viremia causing severe hepatitis.

Neonatal herpes simplex viral infections are rare in the setting of appropriate prenatal care; however, under circumstances where prenatal care is not delivered, these infections can lead to significant disease. We report a fatal case of herpes simplex virus with severe herpes hepatitis in a 14-day old male neonate. The clinical history was limited and nonspecific, however there was no prenatal care and a known history of drug abuse in the family. Autopsy revealed extensive necrosis and hemorrhage of the liver and cerebellum. Histologically, the liver revealed viral intranuclear ground glass inclusions, characteristic of herpes virus. Immunohistochemistry for herpes simplex virus performed on the both the liver and cerebellum showed strong diffuse staining in the liver and negative staining in the cerebellum. Neonatal herpes simplex virus infection is a disease of low prevalence with significant morbidity and mortality, and an exceptionally high rate of fatality in those with disseminated disease with associated fulminant hepatic failure.

Pathogenesis of Non-Zika Congenital Viral Infections.

A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 from South and Central America and the Caribbean. Although the full spectrum of ZIKV infection of the newborn has yet to be determined, other maternal viral infections resulting in transmission to the fetus provide instructive lessons that can be applied to the prospective evaluation of individuals with ZIKV infection. This review focuses on those other congenital infections, including rubella, congenital cytomegalovirus, human immunodeficiency virus, hepatitis B virus, and neonatal herpes simplex virus, from which lessons for the evaluation of ZIKV in the newborn can be applied.

[How I treat a neonatal Herpes simplex virus infection]. / Comment je traite l'infection néonatale à Herpès simplex.

Neonatal herpes simplex virus infection is rare but important to recognize because of the major risk of sequelae or death. The diagnosis is mainly based on specific clinical and biological analyses. Aciclovir is the treatment of choice, duration of administration depending on the severity of the disease. A six-month treatment with suppressive-dose oral aciclovir is recommended to improve the child's prognosis. From a clinical case, we reviewed the literature to improve the management.

L'infection néonatale à Herpès est peu fréquente mais importante à reconnaître vu le risque important de séquelles ou de mortalité. Le diagnostic repose principalement sur des analyses cliniques et biologiques spécifiques. L'aciclovir est le traitement de choix, la durée d'administration varie en fonction de l'importance de l'atteinte. Un traitement de 6 mois par voie orale est conseillé pour améliorer le pronostic de l'enfant. A partir d'un cas clinique, nous avons revu la littérature pour connaître les dernières recommandations afin d'améliorer la prise en charge.

Recognition and nursing management of sepsis in early infancy.

Neonatal sepsis describes serious bacterial or viral infections that manifest in the first 28 days of life, causing significant morbidity and mortality. Although most babies with early-onset neonatal sepsis are born and managed in hospital, some are born in the community, or discharged early from postnatal wards. Consequently, emergency department (ED) nurses and other healthcare professionals need to be able to identify and treat these infants effectively to improve long-term outcomes. This article discusses neonatal sepsis, including causative organisms, types of neonatal sepsis and why neonates are vulnerable to infection. The National Institute for Health and Care Excellence 2012 and 2014 guidance is also discussed in relation to management of neonatal sepsis and a case study is included to illustrate some of the challenges that ED nurses may encounter.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Herpes simplex virus: prevalence in placental tissue and incidence in neonatal cord blood samples.

Herpes simplex virus (HSV) infection is one of the most prevalent infectious diseases worldwide, with HSV-2 being primarily associated with genital infections. HSV-2 is believed to account for the majority of cases of neonatal herpes, which may cause diverse of complications in infected newborns. The present study sought to estimate the prevalence of HSV-2 in placental tissue samples and the incidence of HSV-2 in the umbilical cord blood of newborn infants. Placental tissue samples from 201 women (maternal-side and fetal-side = 402 specimens) and 184 neonatal cord blood samples, all collected at the obstetric ward of a University hospital were studied. HSV-2 was detected by means of nested PCR. The prevalence of HSV-2 in placental samples was 9.0% (n = 18), and the incidence of neonatal HSV-2 infection was 1.1% (n = 2). All HSV-2-positive patients were asymptomatic at the time of delivery and none reported genital herpes. Women with a time between rupture of membranes and delivery of ≥360 min had an approximately fourfold risk of HSV-2 infection in the placental tissue (95% CI 0.93-5.66, P = 0.01). These results suggest that HSV-2 is present in the placenta of asymptomatic women and that a risk of transmission to the neonate exists. New strategies must be implemented for the management of asymptomatic patients who are capable of transmitting the virus to the newborn.

Neonatal Herpes Reporting in the United States: Review of Current Policies by State.

Despite its devastating impact, neonatal herpes is not a nationally notifiable condition. As of 2023 it is only reportable in 6 states. A consistently applied case definition with designation as a nationally notifiable condition would optimize surveillance and preventative efforts.

Risk factors for poor outcome in congenital cytomegalovirus infection and neonatal herpes on the basis of a nationwide survey in Japan.

BACKGROUND: Congenital cytomegalovirus (CMV) infection and neonatal herpes are major mother-to-child infections, and analyses of the important clinical issues, including risk factors for prognosis, are essential. METHODS: A secondary survey of congenital CMV infection and neonatal herpes was performed using questionnaires for cases reported in the primary survey between 2006 and 2008. RESULTS: Univariate analysis of 71 cases of congenital CMV infection showed that intrauterine growth restriction (IUGR) or other specific findings on fetal ultrasonography (US), microcephaly, intracranial calcification, disseminated intravascular coagulation, abnormal findings on computed tomography, and the use of i.v. gammaglobulin were all significantly correlated with poor outcome (death or severe sequelae). Multivariate analysis showed that only IUGR was significantly associated with poor outcome. Hearing impairment is one of the major abnormalities associated with congenital CMV infection. Automatic auditory brainstem response (automatic ABR) appeared to be useful for detection of hearing impairment in comparison with conventional ABR. Moreover, univariate analysis showed that specific fetal US or abnormal magnetic resonance imaging findings were correlated with sensorineural hearing loss. In 24 cases of neonatal herpes, fever and seizure were correlated with poor outcome on univariate analysis. All patients received acyclovir treatment, although substantial numbers of patients in severe clinical categories (disseminated or central nervous system diseases) received a low dose of acyclovir (<60 mg/kg per day). CONCLUSIONS: This secondary survey has identified the risk factors associated with outcome and important issues in diagnosis and treatment of two mother-to-child infections: congenital CMV and neonatal herpes, in Japan.

Evaluation of Midwives' Practises on Herpetic Infections during Pregnancy: A French Vignette-Based Study.

(1) Background: One out of two pregnant women has a history of herpes infection. Initial infections have a high risk of neonatal transmission. Our objective was to analyse the professional practises of midwives regarding the management of herpes infections during pregnancy in France; (2) Methods: A national survey conducted via an online self-questionnaire, including clinical vignettes for which the midwives proposed a diagnosis, a drug treatment, a mode of birth, and a prognosis. These responses were used to evaluate the conformity of the responses to the guidelines, as well as the influence of certain criteria, such as mode of practise and experience; (3) Results: Of 728 responses, only 26.1% of the midwives reported being aware of the 2017 clinical practise guidelines. The midwives proposed taking the appropriate actions in 56.1% of the responses in the case of a recurrence, and in 95.1% of the responses in the case of a primary infection. For the specific, high-risk case of a nonprimary initial infection at 38 weeks of gestation, reporting knowledge of the recommendations improved the compliance of the proposed care by 40% (p = 0.02). However, 33.8% of the midwives underestimated the neonatal risk at term after a primary initial infection, and 43% underestimated the risk after a primary initial infection at term; (4) Conclusions: The majority of reported practises were compliant despite a low level of knowledge of the guidelines. The dissemination of guidelines may be important to improve information and adherence to appropriate therapeutic practise.

Lifetime quality-adjusted life years lost due to genital herpes acquired in the United States in 2018: a mathematical modeling study.

Background: Genital herpes (GH), caused by herpes simplex virus type 1 and type 2 (HSV-1, HSV-2), is a common sexually transmitted disease associated with adverse health outcomes. Symptoms associated with GH outbreaks can be reduced by antiviral medications, but the infection is incurable and lifelong. In this study, we estimate the long-term health impacts of GH in the United States using quality-adjusted life years (QALYs) lost. Methods: We used probability trees to model the natural history of GH secondary to infection with HSV-1 and HSV-2 among people aged 18-49 years. We modelled the following outcomes to quantify the major causes of health losses following infection: symptomatic herpes outbreaks, psychosocial impacts associated with diagnosis and recurrences, urinary retention caused by sacral radiculitis, aseptic meningitis, Mollaret's meningitis, and neonatal herpes. The model was parameterized based on published literature on the natural history of GH. We summarized losses of health by computing the lifetime number of QALYs lost per genital HSV-1 and HSV-2 infection, and we combined this information with incidence estimates to compute the total lifetime number of QALYs lost due to infections acquired in 2018 in the United States. Findings: We estimated 0.05 (95% uncertainty interval (UI) 0.02-0.08) lifetime QALYs lost per incident GH infection acquired in 2018, equivalent to losing 0.05 years or about 18 days of life for one person with perfect health. The average number of QALYs lost per GH infection due to genital HSV-1 and HSV-2 was 0.01 (95% UI 0.01-0.02) and 0.05 (95% UI 0.02-0.09), respectively. The burden of genital HSV-1 is higher among women, while the burden of HSV-2 is higher among men. QALYs lost per neonatal herpes infection was estimated to be 7.93 (95% UI 6.63-9.19). At the population level, the total estimated lifetime QALYs lost as a result of GH infections acquired in 2018 was 33,100 (95% UI 12,600-67,900) due to GH in adults and 3,140 (95% UI 2,260-4,140) due to neonatal herpes. Results were most sensitive to assumptions on the magnitude of the disutility associated with post-diagnosis psychosocial distress and symptomatic recurrences. Interpretation: GH is associated with substantial health losses in the United States. Results from this study can be used to compare the burden of GH to other diseases, and it provides inputs that may be used in studies on the health impact and cost-effectiveness of interventions that aim to reduce the burden of GH. Funding: The Center for Disease Control and Prevention.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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.

The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids.

Intrauterine infections during pregnancy by herpes simplex virus (HSV) can cause significant neurodevelopmental deficits in the unborn/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.

Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.

Herpes simplex virus type 2 (HSV-2) infection affects 24 million births annually and is associated with adverse pregnancy outcomes, including neonatal herpes; however, the mechanisms underlying in utero transmission of HSV-2 are largely unknown. We examined the effects of primary HSV-2 infection during early pregnancy on gestational outcomes in a novel, clinically relevant mouse model. Pregnant C57BL/6 mice were infected intravaginally with 102-105 pfu/mL HSV-2 on gestation day (gd) 4.5. Controls were infected, nonpregnant, diestrus-staged mice and pregnant, uninfected mice. Compared to nonpregnant mice, pregnant mice were 100-fold more susceptible to HSV-2 infection. Three days post-inoculation (gd7.5), viral DNA was present in implantation sites, but pregnancy outcomes were largely unaffected by infection. Eight days post-inoculation (gd12.5), HSV-2 DNA persisted in placental tissues, resulting in inflammation and hemorrhage. Fetal and placental weights were reduced and fetal loss was observed with high viral doses. HSV-2 DNA and increased expression of pro-inflammatory mediators were detected in fetal tissues at gd12.5, signifying viral transmission and fetal infection, even with low viral doses. This mouse model shows a dose-dependent effect of primary HSV-2 infection on pregnancy outcomes and suggests that fetal loss may occur due to placental inflammation, thus providing valuable insight into in utero transmission of HSV-2.