Herpes simplex virus (HSV) infection in newborn infants can present with the following manifestations:
More than 80% of neonates with SEM disease have skin vesicles. Those patients without skin vesicles have infection limited to the eyes and/or oral mucosa. Approximately two-thirds of neonates with disseminated or CNS disease have skin lesions, but other symptoms may be present before these lesions can be seen. When skin lesions are not present, it can be challenging to diagnose neonatal HSV infection. Disseminated infection is a consideration when neonates present with sepsis syndrome, negative bacteriologic culture results, severe liver dysfunction, or consumptive coagulopathy in the first 30 days. HSV may be the causative agent in neonates who present with a fever, a vesicular rash, or abnormal cerebrospinal fluid (CSF) findings. This probability increases when the infant also has a history of seizures or presents at times when enteroviruses are not reported in the community. Asymptomatic HSV infection is common in older children but rare in neonates.
Initial signs of HSV infection can occur anytime between birth and approximately 6 weeks of age, although almost all infected infants develop clinical disease within the first month of life. Infants with disseminated disease and SEM disease have an earlier age of onset, typically presenting between the first and second weeks of life. Infants with CNS disease usually present with illness between the second and third weeks of life.
HSVs are enveloped, double-stranded, DNA viruses. Two distinct HSV types exist: HSV-1 and HSV-2.
However, either type of virus can be found in either area, and both HSV-1 and HSV-2 cause herpes disease in neonates. As with all human herpesviruses, HSV-1 and HSV-2 establish latency following primary infection, with periodic reactivation to cause recurrent symptomatic disease or asymptomatic viral shedding.
The incidence of neonatal HSV infection is estimated to range between 1 in 3000 to 1 in 20,000 live births. HSV is transmitted to a neonate most commonly during birth through an infected maternal genital tract but can be caused by an ascending infection through ruptured or intact amniotic membranes. Other less common sources of neonatal infection include postnatal transmission from a parent or other caregiver, most often from a non-genital lesion, for example on the mouth or hands.
The risk of HSV transmission to a neonate born to a mother who acquires primary genital infection near the time of delivery is estimated to be 25% to 60%. In contrast, the risk to a neonate born to a mother shedding HSV as a result of reactivation of infection acquired during the first half of pregnancy or earlier is less than 2%. Distinguishing between primary and recurrent HSV infections in women by history or physical examination alone may be impossible because primary and recurrent genital infections may be asymptomatic or associated with nonspecific findings (e.g., vaginal discharge, genital pain, or shallow ulcers). History of maternal genital HSV infection is not helpful in diagnosing neonatal HSV disease, because more than three-quarters of infants who contract HSV infection are born to women with no history or clinical findings suggestive of genital HSV infection during or preceding pregnancy and who, therefore, are unaware of their infection.
Histologic examination of lesions with a Tzanck smear has low sensitivity but may positive for the presence of multinucleated giant cells and eosinophilic intranuclear inclusions typical of HSV.
Neonatal HSV infection is clinically challenging. Early manifestations may be subtle and nonspecific. Neonatal HSV can mimic other diseases, including bacterial illnesses (sepsis or meningitis) and other viral illnesses, particularly enterovirus. Prompt treatment requires early consideration of neonatal HSV as a possibility in neonates with mucocutaneous lesions, CNS abnormalities, or a sepsis-like picture. Early in the clinical course, some neonates with HSV infection may present with persistent fever and negative bacterial cultures.
Neonatal HSV infection should be suspected in neonates and infants up to 6 weeks of age with the following:
HSV grows readily in cell culture. Special transport media are available that allow transport to local or regional laboratories for culture. Cytopathogenic effects typical of HSV infection usually are observed 1 to 3 days after inoculation. Methods of culture confirmation include fluorescent antibody staining, enzyme immunoassays (EIAs), and monolayer culture with typing. Cultures that remain negative by day five likely will continue to remain negative.
Polymerase chain reaction (PCR) assay often can detect HSV DNA in CSF from neonates with CNS infection (neonatal HSV CNS disease) and from older children and adults with HSE and is the diagnostic method of choice for CNS HSV involvement. PCR may also be used to try to diagnose HSV from skin lesions. PCR assay of CSF can yield negative results in cases of HSE, however, especially early in the disease course. In difficult cases in which repeated, CSF PCR assay results are negative, histologic examination and viral culture of a brain tissue biopsy specimen is the most definitive method of confirming the diagnosis of HSE. Detection of intrathecal antibody against HSV also can assist in the diagnosis. Viral cultures of CSF from a patient with HSE usually are negative.
To diagnose neonatal HSV infection, the following specimens should be obtained:
Positive cultures obtained from any of the surface sites more than 12 to 24 hours after birth indicate viral replication and are, therefore, suggestive of infant infection rather than merely contamination after intrapartum exposure.
Parenteral acyclovir is the treatment for neonatal HSV infections. Parenteral acyclovir should be administered to all neonates with HSV disease, regardless of manifestations and clinical findings.
The dosage of acyclovir is 60 mg/kg per day in 3 divided doses (20 mg/kg per dose)
The best outcomes in terms of morbidity and mortality are observed among infants with SEM disease. Approximately 50% of infants surviving neonatal HSV experience cutaneous recurrences, with the first skin recurrence often occurring within 1 to 2 weeks of stopping parenteral acyclovir treatment.
All infants with neonatal HSV disease regardless of disease classification should have an ophthalmologic examination and neuroimaging to establish baseline brain anatomy. Magnetic resonance imaging (MRI) is the most sensitive neuroradiologic imaging modality but also may require sedation, so computed tomography (CT) or ultrasonography of the head are acceptable alternatives.
All infants with CNS involvement should have a repeat lumbar puncture performed near the end of therapy to document that the CSF is negative for HSV DNA on PCR assay. In the unlikely event that the PCR result remains positive near the end of a 21-day treatment course, intravenous acyclovir should be administered for another week, with repeat CSF PCR assay performed near the end of the extended treatment period and another week of parenteral therapy if it remains positive. Consultation with an infectious diseases specialist is warranted in these cases.
Oral acyclovir suppressive therapy for the 6 months following treatment of acute neonatal HSV disease improves neurodevelopmental outcomes in infants with HSV CNS disease and prevents skin recurrences in infants with any disease classification of neonatal HSV.
Infants surviving neonatal HSV infections of any classification of infection (disseminated, CNS, or SEM) should receive oral acyclovir suppression at 300 mg/m2 per dose, administered three times daily for six months; the dose should be adjusted each month to account for growth.
Absolute neutrophil counts should be assessed at 2 and 4 weeks after initiating suppressive therapy and then monthly during the treatment period. Longer durations or higher doses of antiviral suppression do not further improve neurodevelopmental outcomes. Valacyclovir has not been studied for longer than 5 days in young infants, so it should not be used routinely for antiviral suppression in this age group.
Infants with ocular involvement attributable to HSV infection should receive a topical ophthalmic drug (1% trifluridine, 0.1% iododeoxyuridine, or 0.15% ganciclovir) as well as parenteral antiviral therapy. An ophthalmologist should be involved in the management and treatment of acute neonatal ocular HSV disease.
Differential diagnosis can be broad.
Mothers with a history of HSV should consider prophylactic acyclovir at the time of delivery. They should report any symptoms that could be consistent with active HSV disease at the time of delivery.
The management of congenital HSV is by an interprofessional team because of multi-system involvement. The best outcomes in terms of morbidity and mortality are observed among infants with SEM disease. Approximately 50% of infants surviving neonatal HSV experience cutaneous recurrences, with the first skin recurrence often occurring within 1 to 2 weeks of stopping parenteral acyclovir treatment.
All infants with neonatal HSV disease regardless of disease classification should have an ophthalmologic examination and neuroimaging to establish baseline brain anatomy. Magnetic resonance imaging (MRI) is the most sensitive neuroradiologic imaging modality but also may require sedation, so computed tomography (CT) or ultrasonography of the head are acceptable alternatives. Presentation with seizures should be evalauted with an electroencephalogram (EEG) which may show periodic epileptiform discahrges (PEDs).
Routine audiology screening should occur for all infants infected with HSV.
In addition, infants with CNS involvement should have a repeat lumbar puncture performed near the end of therapy to document that the CSF is negative for HSV DNA on PCR assay. Consultation with an infectious diseases specialist is warranted in these cases.
|||Brenner N,Mentzer AJ,Butt J,Michel A,Prager K,Brozy J,Weißbrich B,Aiello AE,Meier HCS,Breuer J,Almond R,Allen N,Pawlita M,Waterboer T, Validation of Multiplex Serology detecting human herpesviruses 1-5. PloS one. 2018; [PubMed PMID: 30589867]|
|||Deverell M,Phu A,Zurynski Y,Elliott E, Australian Paediatric Surveillance Unit Annual Report, 2016. Communicable diseases intelligence quarterly report. 2017 Sep 1; [PubMed PMID: 29720077]|
|||Francis SS,Wiemels JL,Yang W,Shaw GM, Herpesvirus Infection in Infants with Gastroschisis. Epidemiology (Cambridge, Mass.). 2018 Jul; [PubMed PMID: 29634591]|
|||Neuberger I,Garcia J,Meyers ML,Feygin T,Bulas DI,Mirsky DM, Imaging of congenital central nervous system infections. Pediatric radiology. 2018 Apr; [PubMed PMID: 29550865]|
|||Antiviral Drugs in Newborn and Children., Poole CL,Kimberlin DW,, Pediatric clinics of North America, 2017 Dec [PubMed PMID: 29173793]|
|||Drumm CM,Caufield MC,DeKlotz CM,Pasieka HB,Abubakar KM, Intrauterine Herpes Simplex Virus Infection Presenting as a Zosteriform Eruption in a Newborn. AJP reports. 2018 Jan; [PubMed PMID: 29492329]|
|||Voekt CA,Rinderknecht T,Hirsch HH,Blaich A,Hösli IM, Ultrasound indications for maternal STORCH testing in pregnancy. Swiss medical weekly. 2017; [PubMed PMID: 29185251]|
|||Poole CL,Kimberlin DW, Antiviral Approaches for the Treatment of Herpes Simplex Virus Infections in Newborn Infants. Annual review of virology. 2018 Sep 29 [PubMed PMID: 30265626]|
|||Otto WR,Myers AL,LaRussa B,Kimberlin DW,Jackson MA, Clinical Markers and Outcomes of Neonates With Herpes Simplex Virus Deoxyribonucleic Acid Persistence in Cerebrospinal Fluid in Disseminated and Central Nervous System Infection. Journal of the Pediatric Infectious Diseases Society. 2018 May 15 [PubMed PMID: 28510722]|
|||Henderson B,Kimberlin DW,Forgie SE, Delayed Recurrence of Herpes Simplex Virus Infection in the Central Nervous System After Neonatal Infection and Completion of Six Months of Suppressive Therapy. Journal of the Pediatric Infectious Diseases Society. 2017 Nov 24 [PubMed PMID: 28379476]|