Pediatrics

Neonatal Herpes Simplex Infections

Overview: What every practitioner needs to know

Are you sure your patient has neonatal herpes infection? What are the typical findings for this disease?

Neonatal herpes infection is caused by a member of the herpesvirus family called Herpes Simplex Virus (HSV), a large double stranded DNA virus. There are two types of HSV, called HSV type 1 and HSV type 2. Both types can cause neonatal disease; in the United States, HSV-2 is the more common cause while in some European countries HSV-1 is more common.

Infections in newborns can manifest in three distinct syndromes: 1) HSV encephalitis, 2) Disseminated disease and 3) Skin, eye and mouth disease (SEM). These syndromes may overlap but have different features and outcomes that will be discussed here. A fourth category is congenital HSV infection (intrauterine infection), which will be discussed separately at the end.

Clinicians should always be prepared to diagnose and promptly treat neonatal HSV infection, given the high morbidity and mortality of this illness despite newer diagnostic modalities and the availability of effective antiviral therapy.

The estimated incidence of neonatal HSV infection in the United States is 1 in every 3200 live births. Neonatal HSV is acquired before delivery (5%), at the time of delivery (85%), or shortly thereafter (10%). The lack of a maternal history of genital HSV infection generally is not helpful and should not dissuade the clinician from considering this diagnosis.

The clinical presentation depends on the site of infection and, with few exceptions reported in the literature, neonatal HSV infection is invariably symptomatic.

Depending on the initial site of infection, a constellation of features should guide the clinician to make this diagnosis. Some of the features include:

1) History of vaginal delivery

2) Sepsis-like syndrome

3) Vesicular skin rash

4) CSF pleocytosis (with monocyte predominance)

5) Absent or low grade fever

6) Irritability and/or lethargy

7) Respiratory distress and/or pneumonitis

8) Seizures

9) Coagulopathy, hepatitis and jaundice

Key Symptoms:

Seizures

Skin Rash - typically vesicular

Jaundice

What other disease/condition shares some of these symptoms?

The differential diagnoses include enteroviral neonatal disease, bacterial sepsis (i.e. Listeria monocytogenes, Gram-negative infections and group-B streptococcal infections) and skin conditions of the newborn infant, such as incontinentia pigmenti, Staphylococcus aureus newborn pustulosis, bullous or crusted impetigo and linear nevus of the newborn.

What caused this disease to develop at this time?

HSV infection can be acquired intrapartum, perinatally, or postnatally. Mothers are the source of infections acquired at the time of delivery and account for approximately 85% of the cases. Close contacts of the newborn infants, including mother, father or any other family members with oral herpes, can be the source of infection acquired postnatally.

HSV disseminated disease as well as SEM disease typically present during the first or second week of life, whereas CNS disease often occurs between the second and third weeks of life.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Any newborn baby with suspected HSV infection should have a lumbar puncture performed for CSF studies, including routine cell count, protein, glucose, as well as HSV PCR testing. In addition, cultures from skin lesions (if present), conjunctiva, oropharynx and rectum (surface cultures) should be obtained. Blood samples for HSV PCR tests, liver function tests and coagulation studies are also recommended.

Herpes virus grows readily in cell culture, typically in less than 3 days. However, some hospitals have already substituted PCR testing for cell culture isolation. Under those conditions, PCR testing should be ordered for HSV DNA. A high index of suspicion for neonatal HSV infection should lead to treatment, regardless of laboratory results.

Would imaging studies be helpful? If so, which ones?

Computed tomography (CT) or magnetic resonance imaging (MRI) can be helpful to evaluate the extent and severity of the viral infection in the central nervous system. Chest x-ray may be helpful in identifying pulmonary involvement.

If you are able to confirm that the patient has neonatal herpes infection, what treatment should be initiated?

Acyclovir at 20 mg per kg per dose should be administered intravenously every 8 hours as soon as the diagnosis of neonatal HSV infection is considered.

Supportive therapy and close monitoring in an intensive care unit is preferable for all newborns with disseminated or CNS disease. In particular, serum creatinine levels should be closely monitored because acyclovir is excreted by the kidney. Treatment of SEM disease can be carried out on a regular pediatric inpatient service. We do not recommend completing intravenous treatment at home.

The duration of therapy should be 21 days for disseminated and CNS disease and 14 days for SEM disease (disseminated and CNS disease should be carefully excluded in these cases).

Long-term suppressive therapy to prevent skin and CNS recurrences can be accomplished with oral acyclovir at 300 mg/m2/dose every 8 hours for 6 months. Suppressive therapy has also been shown to improve neurologic outcomes.

Asymptomatic neonates born vaginally or by caesarean section to women with first-episode HSV infection and active genital lesions at the time of delivery should have HSV surface cultures or, alternatively, PCR testing, depending on the tests available at each hospital laboratory. If tests results are negative, the patient should receive 10 days of pre-emptive therapy with acyclovir. If any test is positive, the newborn is considered to have proven disease and should be treated accordingly.

If the mother has active genital lesions at the time of delivery but has recurrent infection, the newborn can be discharged after virologic studies are negative and adequate education on HSV disease has been provided to the family.

What are the adverse effects associated with each treatment option?

The most common side effects of acyclovir include:

Local: inflammation at the injection site and phlebitis.

Systemic: increased BUN and creatinine because of acyclovir nephrotoxicity. Patients on acyclovir should be well hydrated at all times to prevent acute renal failure. If the serum creatinine level reaches 1.0, the total daily dosage of intravenous acyclovir must be reduced incrementally until the serum creatinine level stabilizes.

What are the possible outcomes of neonatal herpes infection?

The outcomes of neonatal HSV depend on the site of infection:

Encephalitis: without adequate therapy, approximately 40% of patients will die, and survivors are generally neurologically impaired. Sequelae include cerebral palsy, blindness, psychomotor retardation and learning disabilities. With treatment, 85% survive.

Disseminated: mortality rates of untreated disseminated forms are 80% or more. However, with treatment, around 50% will survive.

SEM disease: survival rates were greater than 90% without treatment and approach 100% with treatment. However, recurrences are common and can progress to a more severe form of the disease.

Because CNS and eye disease are common, long term complications are common in the survivors.

What causes this disease and how frequent is it?

Neonatal HSV can be caused by HSV-1 (15%) or HSV-2 (85%). Epidemiological studies show that the incidence of this disease is approximately 1 case per 3200 live births. The rate is probably higher within the largest metropolitan areas.

Infants whose mothers acquire the infection for the first time during pregnancy are at higher risk of developing neonatal HSV infection. The risk of transmission in these infants can be as high as 50%, compared to less than 5% in infants whose mothers have a previous history of genital herpes. This difference may be explained in part by the lack of protective antibodies that can be passively transferred to the fetus in mothers with primary infection. Primary maternal infection during pregnancy is often asymptomatic, and thus, maternal history of HSV is generally not helpful in the diagnosis of neonatal HSV infection.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

In addition to the above diseases, there is another entity known as intrauterine HSV infection. HSV intrauterine infection comprises only about 5% of the cases of neonatal HSV infection. Intrauterine HSV infection is defined as any HSV infection diagnosed in a newborn within 24-48 hours after delivery. The vast majority of intrauterine infections are caused by HSV-2. Although intrauterine infections appear to be more common in women with their primary HSV infection, they can occur in women with known prior HSV disease. Most intrauterine cases show signs of skin, eye, and central nervous system involvement. Generally these infants appear sickly at birth even though the precise etiology may not be clear.

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can neonatal herpes be prevented?

Preventing exposure of the newborn infant to active genital herpetic lesions in the mother during delivery is ideal. Unfortunately, HSV infection is often asymptomatic, and thus may not be detected. Cultures for HSV during pregnancy to detect asymptomatic shedding of virus are not recommended. Careful vaginal examination and elective caesarean section in women with signs and symptoms of HSV disease is the preferred delivery modality. Nevertheless, the clinician should be aware that C-section reduces but does not eliminate the risk of HSV in the newborn period. Vaginal delivery is appropriate for women with history of recurrent HSV with no active lesions at the time of labor.

The use of suppressive therapy with valacyclovir or acyclovir during the last 4 weeks of pregnancy is controversial and has not shown to decrease shedding of virus. The American College of Obstetricians and Gynecologists recommends offering suppressive therapy to women with a known history of HSV towards the end of pregnancy. Patients born to women treated with suppressive therapy may still be at risk for HSV infection and should be evaluated accordingly regardless of the use of prophylaxis by the mother.

The use of acyclovir in exposed asymptomatic infants without documented infection is not routinely recommended.

Contact with family members with suspected oro-labial HSV infection should be avoided.

What is the evidence?

Corey, L, Wald, A. "Maternal and neonatal herpes simplex virus infections". N Engl J Med. vol. 361. 2009. pp. 1376-85.

(Review article exploring the current practices in the prevention and epidemiology of perinatal HSV disease.)

Kimberlin, DW, Whitley, RJ, Wan, W. "National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Oral acyclovir suppression and neurodevelopment after neonatal herpes". N Engl J Med. vol. 365. 2011. pp. 1284-92.

(This is a study evaluating the impact of long term suppressive therapy with acyclovir in survivors of neonatal herpes in the prevention of recurrences and neurodevelopmental outcomes.)

Caviness, AC, Demmler, GJ. "Selwyn BJ Clinical and laboratory features of neonatal herpes simplex virus infection: a case control study". Pediatr Infect DisJ. vol. 27. 2008. pp. 425-30.

(Retrospective analysis of 40 infants matched with 160 controls to determine factors associated with HSV disease in newborns.)

Kimberlin, DW. "Herpes simplex virus infections of the newborn". Semin Perinatol. vol. 31. 2007. pp. 19-25.

Pickering, LK. "Herpes simplex ". Red Book: 2009 Report of the Committee on Infectious Diseases. vol. 363. American Academy of Pediatrics. 2009.

(Concise review of the current standard of care for newborns with HSV disease.)

Kimberlin, DW, Baley, J. "Committee on Infectious Diseases; Committee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions.". Pediatrics. vol. 131. 2013. pp. 383-6.

Ongoing controversies regarding etiology, diagnosis, treatment

There is a consensus about the management and treatment of perinatally acquired HSV infection. However, a very small number of cases of neonatal HSV CNS disease continued to have a positive HSV PCR test on a CSF sample collected near the end of a 3 week course of acyclovir. Therefore, some experts recommend a repeat HSV PCR test on all neonates with CNS disease. If the test remains positive, further treatment with acyclovir is suggested for another 1-2 weeks.

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