History of Medicine

Neonatal Herpes Simplex Virus Infections Past Progress and Future Challenges Joseph B. Cantey, MD, and Pablo J. Sánchez, MD Key Words: herpes simplex, neonate, history (Pediatr Infect Dis J 2013;32:1205–1207)


eonatal herpes simplex virus (HSV) infection is a potentially devastating sequela of maternal genital tract infection.1 Without treatment, the mortality from neonatal HSV infection exceeds 50%, and even in the acyclovir era morbidity and mortality remain high.2,3 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.4,5 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.6 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.7 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.8 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 1736.9,10 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. Accepted for publication June 20, 2013. From the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Joseph B. Cantey, MD, University of Texas Southwestern Medical Center, Department of Pediatrics, 5323 Harry Hines Blvd., Dallas, TX 75390–9063. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/13/3211-1205 DOI: 10.1097/INF.0b013e3182a1915e

In 1896, Fournier,11 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,12 a German dermatologist, called herpes infections “…one of the most benign of affections, both to the patient and her public.” In 1919, Lowenstein,13 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.14 These advances allowed the recognition of HSV infection in other clinical settings, including neonatal disease. In 1934, Batignani,15 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,16 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 al17 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.2 In 1967, Schneweis and Nahmias18 demonstrated the antigenic and clinical differences between herpes simplex virus type 1 and 2. In the same year, Nahmias et al19 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,20 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 al2 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.21 Recently, PCR testing has been applied to blood22 and cerebrospinal fluid,23 and viral culture of the brain was supplanted in the 1990s by more sensitive PCR testing for identification of CNS infection.24 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

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Cantey and Sánchez

infection.25 Vidarabine significantly reduced infant mortality compared with no treatment. In 1974, acyclovir was synthesized by Howard Schaeffer at Wellcome Research Laboratories (now GlaxoSmithKline). In 1977, acyclovir was developed further by Gertrude Elion and George Hitchings. The 3 investigators were awarded the Nobel Prize in Physiology or Medicine in 1988 for their joint efforts. Acyclovir was approved by the Food and Drug Administration in 1982. In 1991, acyclovir in a dosage of 30 mg/kg/day was shown to be equivalent to vidarabine for treatment of neonatal HSV disease.26 However, in 2001, another CASG trial of a larger dose of acyclovir (60 mg/kg/day) resulted in improved outcomes when compared with a historical cohort of infants who had received the smaller dose of acyclovir.27 High dosage acyclovir remains the standard of care today. In 2011, the CASG demonstrated that oral acyclovir suppression provided to infants for 6 months after treatment of CNS infection decreased skin recurrences and improved mental developmental scores by Bayley Scales of Infant Development testing at 12 months of age.28 At present, we have an understanding of the risks associated with vertical transmission of the virus, increased awareness of the disease, a variety of diagnostic tests that are specific and sensitive, a treatment option that is effective, safe and well tolerated and a prophylaxis option that may improve long-term neurodevelopmental outcomes in one of the most severe manifestations of neonatal HSV infection. Other questions remain unanswered. What should be done during pregnancy for women with a history of genital herpes? Prophylactic antiviral therapy in the third trimester decreases HSV recurrences at the time of delivery—and therefore the need for Caesarian section—but there is no evidence that this strategy protects infants from HSV infection.29 A recent case series of neonatal HSV infections in infants born to mothers who received antiviral prophylaxis suggests that this strategy is not completely protective, probably because it does not completely suppress asymptomatic genital shedding.30 What should be done for wellappearing infants born to mothers with active genital lesions at delivery? An algorithm has been published by the American Academy of Pediatrics31 that takes into account risk factors for infant infection, including maternal HSV serology, but this algorithm has not been prospectively evaluated and does not apply to infants born to mothers without lesions at delivery, the most common situation seen among HSV-infected neonates. What is the best approach to identifying these women in order to evaluate their infants and possibly provide preemptive therapy? Should neonates suspected of having an infection be empirically treated with acyclovir, and if so, what is the optimal cutoff age?4,5 Would making neonatal HSV a reportable disease, as has been recommended by some experts, improve our understanding of its epidemiology or would it inform prevention strategies such as an HSV vaccine?32,33 What is the role for HSV PCR testing of blood?34 Finally, would novel antiviral or immunomodulatory therapy such as steroids improve outcomes?35 In conclusion, HSV disease has been present since antiquity. Herpes genitalis was described in the 1730s, but neonatal HSV infection was not recognized until 200 years later. The past 75 years have been marked by significant advances in knowledge about the natural history, diagnosis and treatment of neonatal HSV infections that have led to improved outcomes in affected infants. We cannot rest or be satisfied while questions remain unanswered. “Restlessness is discontent and discontent is the first necessity of progress. Show me [satisfaction]… and I will show you failure.”36 REFERENCES 1. Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med. 2009;361:1376–1385.

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2. Whitley RJ, Nahmias AJ, Visintine AM, et al. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics. 1980;66:489–494. 3. Kimberlin DW, Lin CY, Jacobs RF, et al.; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108:223–229. 4. Kimberlin DW. When should you initiate acyclovir therapy in a neonate? J Pediatr. 2008;153:155–156. 5. Long SS. In defense of empiric acyclovir therapy in certain neonates. J Pediatr. 2008;153:157–158. 6. Roizman B, Whitley RJ. The nine ages of herpes simplex virus. Herpes. 2001;8:23–27. 7. Bryan PW. The Papyrus Ebers. London: Geoffrey Bles; 1930. 8. Cumston CG. The history of herpes from the earliest times to the nineteenth century. Ann Med Hist. 1926;8:284–291. 9. Astruc J. De Morbis Venereis Libri Sex. Paris: G Cavelier; 1736. 10. Doe J. Jean Astruc (1694–1766): a biography and bibliography. J Hist Med. 1960;15:184–197. 11. Fournier JA. Diagnostic et traitment de l’herpes genital. Rev Gen Clin Therap. 1896;10:177–178. 12. Unna PG. On herpes progenitalis, especially in women. J Cutan Vener Dis. 1883;1:321–334. 13. Lowenstein C. Uber protozoenartigen Gebilden in de Organen von Dindern. Zentralbl Allg Pathol. 1907;18:513–518. 14. Calisher C, Horzinek M. 100 Years of Virology: The Birth and Growth of a Discipline. New York: Springer; 1999. 15. Batignani DA. Congiuntivite da virus erpetico in neonato. Boll Ocul. 1934;13:1217–1220. 16. Hass M. Hepataadrenal necrosis with intranuclear inclusion bodies: report of a case. Am J Pathol. 1935;11:127. 17. Smith MG, Lennette EH, Reames HR. Isolation of the virus of herpes simplex and the demonstration of intranuclear inclusions in a case of acute encephalitis. Am J Pathol. 1941;17:55–68.1. 18. Schneweis KE, Nahmias AJ. Antigens of Herpes simplex virus type 1 and 2-immunodiffusion and inhibition passive hemagglutination studies. Z Immunitatsforsch Exp Klin Immunol. 1971;141:471–487. 19. Nahmias AJ, Josey WE, Naib ZM. Neonatal herpes simplex infection. Role of genital infection in mother as the source of virus in the newborn. JAMA. 1967;199:164–168. 20. Mitchell JE, Mccall FC. Transplacental infection by herpes simplex virus. Am J Dis Child. 1963;106:207–209. 21. Committee on Infectious Diseases. Herpes simplex. In: Pickering LK, ed. 2009 Red Book: Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:363–373. 22. Kimura H, Futamura M, Kito H, et al. Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum and cerebrospinal fluid. J Infect Dis. 1991;164:289–293. 23. Kimberlin DW, Lakeman FD, Arvin AM, et al. Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1996;174:1162–1167. 24. Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis. 1995;20:414–420. 25. Whitley RJ, Nahmias AJ, Soong SJ, et al. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics. 1980;66:495–501. 26. Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med. 1991;324:444–449. 27. Kimberlin DW, Lin CY, Jacobs RF, et al.; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108:230–238. 28. Kimberlin DW, Whitley RJ, Wan W, et al.; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med. 2011;365:1284–1292. 29. Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev. 2008(1):CD004946.

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30. Pinninti SG, Angara R, Feja KN, et al. Neonatal herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter case series. J Pediatr. 2012;161:134–8.e1. 31. 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. 2013;131: 383–386. 32. Donoval BA, Passaro DJ, Klausner JD. The public health imperative for a neonatal herpes simplex virus infection surveillance system. Sex Transm Dis. 2006;33:170–174.

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History of Neonatal HSV

33. Handsfield HH, Waldo AB, Brown ZA, et al. Neonatal herpes should be a reportable disease. Sex Transm Dis. 2005;32:521–525. 34. Cantey JB, Mejías A, Wallihan R, et al. Use of blood polymerase chain reaction testing for diagnosis of herpes simplex virus infection. J Pediatr. 2012;161:357–361. 35. Beadle JR, Hartline C, Aldern KA, et al. Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob Agents Chemother. 2002;46:2381–2386. 36. Josephson M. Edison: A Biography. 1st ed. Hoboken: Wiley; 1992.

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

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