Continuing Education Activity

Herpes simplex virus (HSV) infection in newborn infants can show up as the following: Disseminated disease involving multiple organs, most prominently liver and lungs (25%) ; Localized central nervous system (CNS) disease, with or without skin involvement (30%); and Disease limited to the skin, eyes, and/or mouth (SEM disease) (45%). 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. Disseminated infection is a consideration when neonates present with sepsis syndrome, negative bacteriologic culture results, severe liver dysfunction, or consumptive coagulopathy. This activity reviews the etiology, presentation, evaluation, and management of congenital herpes simplex and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Review the types of herpes infections.
• Describe the presentation of neonatal herpes infections.
• Summarize the treatment and management options available for neonatal herpes infections.
• Outline the clinical evaluation of congenital herpes simplex and explain the role of the health professional team in coordinating the care of patients with this condition.

Introduction

Herpes simplex virus (HSV) infection in newborn infants can present with the following manifestations: 

1. Disseminated disease involving multiple organs, most prominently liver and lungs (25%) 
2. Localized central nervous system (CNS) disease, with or without skin involvement (30%)
3. Disease limited to the skin, eyes, and/or mouth (SEM disease) (45%)

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.[1][2][3]

Etiology

HSVs are enveloped, double-stranded, DNA viruses. Two distinct HSV types exist: HSV-1 and HSV-2. 

• Infections with HSV-1 usually involve the face and skin above the waist; however, an increasing number of genital herpes cases are attributable to HSV-1. 
• Infections with HSV-2 usually involve the genitalia and skin below the waist in sexually active adolescents and adults.

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.

Epidemiology

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.

Histopathology

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. 

History and Physical

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.[4][5][6][7]

Neonatal HSV infection should be suspected in neonates and infants up to 6 weeks of age with the following:

• Mucocutaneous vesicles 
• Sepsis-like illness (fever or hypothermia, irritability, lethargy, respiratory distress, apnea, abdominal distension, hepatomegaly, ascites)
• CSF pleocytosis
• Seizures
• Focal neurologic signs
• Abnormal neuroimaging
• Respiratory distress, apnea, or progressive pneumonitis
• Thrombocytopenia
• Elevated liver transaminases, viral hepatitis, or acute liver failure
• Conjunctivitis, excessive tearing, or painful eye symptoms

Evaluation

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: 

1. Swab specimens from the mouth, nasopharynx, conjunctivae, and anus (“surface cultures”) for HSV culture and, if desired, for HSV PCR assay; 
2. Specimens of skin vesicles for HSV culture and, if desired, for PCR assay; 
3. CSF sample for HSV PCR assay;
4. Whole blood sample for HSV PCR assay; and 
5. Whole blood sample for measuring alanine aminotransferase (ALT). 

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. 

Treatment / Management

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)

• Given intravenously for 14 days in SEM disease 
• Given intravenously for a minimum of 21 days in CNS disease or disseminated disease.[8]

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.[9]

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.[10]

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

Differential diagnosis can be broad.

Skin Lesions

• Erythema toxicum neonatorum (ETN): ETN presents with multiple erythematous macules and papules (1 to 3 mm in diameter) that rapidly progress to pustules on an erythematous base. The lesions are distributed over the trunk and proximal extremities, sparing the palms and soles. They may be present at birth but typically appear within 24 to 48 hours. The rash usually resolves in 5 to 7 days, although it may wax and wane before complete resolution. The diagnosis of ETN is usually made based on the clinical appearance. It can be confirmed by microscopic examination of a Wright-stained smear of the contents of a pustule that demonstrates numerous eosinophils and occasional neutrophils. However, this usually is not necessary. ETN resolves spontaneously. No treatment is necessary.
• Transient neonatal pustular melanosis: Transient neonatal pustular melanosis (TNPM) is less common than ETN. It mostly affects full-term black infants, although it is described in all ethnic groups. The diagnosis of TNPM is usually based on the clinical appearance. Microscopic examination of a Wright-stained smear of the contents of a pustule demonstrates numerous neutrophils and, in contrast with ETN, rare eosinophils. However, this is usually not necessary. Culture, if performed, yields no organism.
• Infantile acne: Infantile acne is an uncommon and distinct entity from neonatal cephalic pustulosis. It typically presents at 3 to 4 months of age but may rarely occur in the first few weeks of life
• Miliaria: Miliaria is a common finding in newborns, especially in warm climates. It is caused by an accumulation of sweat beneath eccrine sweat ducts that are obstructed by keratin at the level of the stratum corneum.
• Infantile acropustulosis: Infantile acropustulosis (IA) is a benign vesiculopustular condition with an often more chronic course than other benign neonatal lesions. The etiology is unknown. A nonspecific hypersensitivity reaction to scabies has been postulated because many patients have been treated for scabies before being diagnosed with IA.
• Sucking blisters: Congenital sucking blisters, a diagnosis of exclusion, are noninflammatory, oval, thick-walled vesicles or bullae that contain sterile fluid. The lesions may be unilateral or bilateral and typically are located on the dorsal or radial aspect of the wrists, hands, or fingers of neonates who are noted to suck excessively at the involved regions.

Eye Disease

• Viral conjunctivitis due to adenovirus or enterovirus
• Bacterial conjunctivitis (Chlamydia trachomatis, Neisseria gonorrhoeae) 

CNS Disease

• Bacterial meningitis
• Viral meningoencephalitis (other than HSV), particularly Enterovirus and Parechovirus 
• Inborn errors of metabolism

Disseminated Disease

• Sepsis due to bacterial etiology
• Adenovirus or Enterovirus and Parechovirus 
• Viral hepatitis (other than HSV), drug-induced hepatitis, or causes of neonatal liver disease 
• Other neonatal infections, such as Cytomegalovirus, Toxoplasmosis, Syphilis, and Rubella 

Deterrence and Patient Education

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.  

Enhancing Healthcare Team Outcomes

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.