Neonatal herpes simplex virus infections: past progress and future challenges.

N herpes simplex virus (HsV) infection is a potentially devastating sequela of maternal genital tract infection. Without treatment, the mortality from neonatal HsV infection exceeds 50%, and even in the acyclovir era morbidity and mortality remain high. the early identification of infected infants so that prompt administration of antiviral therapy can be provided is a challenge. empiric acyclovir therapy for all febrile neonates is debated, but the data to support such a practice are insufficient at best. in addition, the traditional classification of infected infants into skin, eye and/ or mouth disease, disseminated or central nervous system (cns) disease is becoming blurred as molecular methodologies such as polymerase chain reaction (Pcr) identifies less severely and sometimes asymptomatically infected infants. When viewed through the long lens of history, it becomes evident that significant progress has been achieved. our objective is to document these achievements by review of the history of neonatal HsV infection and to highlight some of the unanswered questions. descriptions of vesicular skin and genital lesions are inscribed on sumerian clay tablets, the earliest form of writing, that date from the 30th century Bc. notations of such lesions also are found on the ebers Papyrus, an egyptian medical text written during the 16th century Bc but believed to be copied from much older texts. these descriptions are nonspecific and might refer to a variety of cutaneous lesions. Although the term “herpes” was used during the time of Hippocrates (4th century Bc) to refer to any “creeping” cutaneous lesion, it was celsus in 30 Bc who is credited with the first description of a vesicular lesion consistent with herpes infection. subsequently in 170 Ad, Galen described cutaneous recurrences in the same anatomic location, specifically on the lips. More than 1500 years elapsed before the association between herpes infection and genital lesions was recognized. Jean Astruc, a Professor of dermatology at the University of Paris and one of King Louis XiV’s personal physicians, studied a cohort of Parisian commercial sex workers (“puellae publicae”). He performed serial physical examinations and documented their maladies in a collection of works, including in A Treatise on All the Diseases Instrument to Women published in 1736. this treatise remains in publication today and contains the first modern description of herpes genitalis. Astruc’s work led to several decades of heightened interest in the epidemiology, natural history and treatment of herpes genitalis. in 1896, fournier, another french dermatologist, recommended treating herpes genitalis by avoiding “. alcohol, tobacco, wine, and sexual excesses. ” the association between affected women and infected infants apparently was not recognized during this period. for that matter, the writings of the era suggest that the risk of horizontal spread to other adults was viewed as minimal. in 1883, Paul Unna, a German dermatologist, called herpes infections “. one of the most benign of affections, both to the patient and her public. ” in 1919, Lowenstein, a German pathologist who also contributed to the identification of congenital cytomegalovirus infection, demonstrated that vesicular scrapings collected from patients with herpes genitalis caused keratitis in rabbits, confirming the infectious nature of the disease. He also described the characteristic microscopic inclusion bodies in infected cells. these advances allowed the recognition of HsV infection in other clinical settings, including neonatal disease. in 1934, Batignani, an italian ophthalmologist, reported the case of an infant with acute keratoconjunctivitis. conjunctival scrapings demonstrated the characteristic inclusion bodies of HsV. one year later, Hass, an American pathologist, published the autopsy findings of an infant who died from presumed bacterial sepsis. HsV inclusion bodies were found in the adrenal glands as well as the liver. in 1941, smith et al reported finding HsV inclusions in neuronal tissue from an infant who presented with fever and seizures. the clinical presentation of these 3 cases (skin, eye and/or mouth disease, disseminated and cns) reflects the disease categories still used today. in 1967, schneweis and nahmias demonstrated the antigenic and clinical differences between herpes simplex virus type 1 and 2. in the same year, nahmias et al documented the vertical transmission of HsV from a mother with cervical herpes infection to her neonate. transplacental infection already had been described in 1963 by Mitchell and Mccall, and once the link to maternal HsV infection was recognized, the natural history of neonatal HsV infection was able to be fully characterized. in 1980, Whitley et al described the clinical course of perinatal infection, including the absence of genital lesions at delivery in most mothers and the risk of disease progression in untreated infants. diagnostic tools improved along with our understanding of the disease. Viral culture of HsV, available since 1925, was the laboratory standard for detection of the virus from mucosal sites, lesions and body fluids or tissue. recently, Pcr testing has been applied to blood and cerebrospinal fluid, and viral culture of the brain was supplanted in the 1990s by more sensitive Pcr testing for identification of cns infection. the treatment options for neonatal HsV infection also have improved during the past 30 years, largely as the result of the collaborative Antiviral study Group (cAsG) of the University of Alabama, Birmingham. in 1972, the cAsG was funded by the national institute of Allergy and infectious diseases to advance the diagnosis and treatment of viral diseases through multicenter trials. Vidarabine’s efficacy against HsV encephalitis in adults made herpes the first treatable viral infection and ushered in an era of antiviral development and treatment. in 1980, the cAsG reported a placebo-controlled trial using vidarabine therapy for neonatal HsV copyright © 2013 by Lippincott Williams & Wilkins issn: 0891-3668/13/3211-1205 doi: 10.1097/inf.0b013e3182a1915e Neonatal Herpes Simplex Virus Infections