High-dose acyclovir reduces mortality associated with neonatal HSV

January 2003

NEW YORK CITY — Strides have been made in managing herpes simplex virus (HSV) infections in the neonate, but more needs to be done to close the gap between the onset of symptoms and initiation of antiviral therapy.

David W. Kimberlin, MD, discussed the issue of neonatal HSV at the 15th Annual Infectious Diseases in Children Symposium, held here.

	Studies have shown that babies on higher doses of acyclovir, as in 21 days of 60 mg/kg/day, have demonstrated reduced mortality and morbidity rates, particularly in disseminated HSV disease.
Source: Philip A. Brunell, MD

Kimberlin said that it is a disease that varies greatly in different parts of the world. Data from the United States indicate that one baby is born with neonatal herpes in every 2,500 live births.

He said generally, there are three different types of neonatal HSV, disseminated, encephalitis (central nervous system, CNS) and skin eye and mouth disease (SEM). He said most cases, about 95%, are acquired intrapartum or postpartum.

Kimberlin said about 25% of cases will be disseminated, and these are the sickest HSV patients. About 30% of cases will be CNS, and the remainder will be SEM disease. Many of these cases might not have any skin involvement initially, making an accurate diagnosis difficult.

“Anywhere between 17% and 42% of babies coming in with neonatal herpes won’t have an outwardly visible manifestation upon which to base a diagnosis and early intervention of antiviral therapy,” Kimberlin said. “That’s why this is so difficult to diagnose and intervene at an earlier time point.”

Generally, he said, seizures are present in about 57% of cases with CNS disease and about 22% of those cases with disseminated disease. The time of presentation differs somewhat between those babies with SEM and disseminated disease, which present at 11 or 12 days postpartum, and those with CNS disease, which present about day 18.

Risk factors for HSV

So, if diagnosis is difficult, pinning down the things that can predispose a baby to acquiring neonatal HSV is important, Kimberlin said.

The type of maternal infection, transplacental passage of antibody and the duration of the rupture of membranes all play a role in whether or not a baby will present with neonatal HSV.

Antibodies come into play particularly in women with recurrent infection. In studies, less than 2% of women with recurrent disease pass HSV to their babies, in contrast to 30 to 60% of women who have their first episode of disease and transmit infection to their babies. He said this has much to do with the passage of antibody and the amount of virus shed in the genital tract.

Kimberlin also cautioned physicians to “treat the patient, not the labs,” because he said, polymerase chain reaction tests are not infallible and false negatives have occurred.

On medication for HSV, Kimberlin said that studies have shown that babies on higher doses of acyclovir, as in 21 days of 60 mg/kg/day, have demonstrated reduced mortality and morbidity rates, particularly in disseminated HSV disease.

A study conducted in late 2001 by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group supported the use of the high dose. The study evaluated doses higher than the FDA recommended standard dose of 30 mg/kg/day and also examined the mortality and morbidity of treated neonates with HSV.

The first 16 patients enrolled received intermediate-dose acyclovir and the next 72 patients received high-dose acyclovir. Study researchers found the survival rate for the infants with disseminated HSV disease when treated with a high dose was significantly higher than those in a previous study that were treated with standard-dose acyclovir. However, approximately 20% of those patients in the high-dose group experienced neutropenia.

As such, Kimberlin said, physicians prescribing the higher dosage should observe patients twice weekly for neutropenia by monitoring absolute neutrophil count levels.

Kimberlin said that prognostic factors that can predict mortality for disseminated infection include severe hepatitis, depressed level of consciousness, and seizures. For CNS disease, seizures and premature birth could predict mortality.

He said it is also important for physicians to try to obtain a mother’s disease history if possible, to determine the risk for infection. Sometimes though, even a history can be misleading, since in 60 to 80% of cases there is no maternal history of genital herpes, “[so] history alone may or may not help you.” A history of genital HSV in the mother not generally available, given that 60%-80% of infected infants are born to mothers with no maternal history of genital HSV. Furthermore, history may not be particularly helpful, since it is women with known history of genital HSV who actually are at lesser risk of transmission to their babies compared with women acquiring HSV during pregnancy.

For more information:

• Kimberlin D. Neonatal herpes simplex virus disease. Presented at the 15th Annual Infectious Diseases in Children Symposium. Nov. 16-17, 2002. New York City.
• Kimberlin DW, Lin C-Y, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108:230-8.
• Kimberlin DW, Lin C-Y, Jacobs RF, et al. The natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108:223-9.

• Dr. Kimberlin has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.