Herpes Simplex Virus DNAemia Preceding Neonatal Disease Joseph B. Cantey, MD1, Alan M. Klein, MD2, and Pablo J. Sanchez, MD3 Polymerase chain reaction testing of blood for herpes simplex virus (HSV) is recommended for newborns delivered to mothers with active genital HSV lesions at delivery. We report an infant who had a positive blood HSV polymerase chain reaction test before the onset of clinical signs of HSV disease. (J Pediatr 2015;166:1308-9).

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erpes simplex virus (HSV) infection remains a major cause of neonatal morbidity and mortality.1 Most neonates acquire the infection during delivery and are born without any clinical signs of disease. Recent guidance from the American Academy of Pediatrics suggests that in addition to mucosal (“surface”) HSV cultures, polymerase chain reaction (PCR) testing of blood for HSV be performed at 24-36 hours of age on all infants born to mothers with active genital HSV lesions.2 Blood HSV PCR testing has been shown to aid in diagnosis of neonatal HSV infection,3 but it is not known whether, by following this guidance, HSV DNAemia can be detected before the onset of clinical manifestations. We report an infant whose HSV infection was detected by a positive blood HSV PCR test that was performed before the onset of clinical disease. This finding may provide insight into the pathogenesis of neonatal HSV infection.

Case Report A 3070 g female infant was born by cesarean delivery after 39 weeks and 3 days of gestation to a 15-year-old gravida 1, para 1 mother who lacked antibodies to HIV, had a nonreactive rapid plasma reagin test, and had antibodies to rubella virus. The mother had three prenatal care visits, and the pregnancy was complicated by trichomoniasis that was treated in the third trimester. Serum was screened for past genital HSV infection and was positive for type-specific HSV IgG antibodies to both HSV-1 and HSV-2. The mother was prescribed valacyclovir for HSV suppression but did not obtain it from the pharmacy. Two days before delivery, she had the onset of a painful ulcerative genital lesion. She was afebrile and had never experienced a similar lesion. On the day of delivery, she had uterine contractions and was admitted to the labor and delivery suite where culture of the genital lesion was performed, from which HSV-2 was identified two days after delivery. Because of suspected genital HSV infection and nonreassuring fetal heart rate pattern, a cesarean delivery was performed with rupture of fetal membranes occurring at delivery. A fetal scalp electrode was not used. The infant girl was vigorous at birth; Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. She was admitted to

HSV PCR

Herpes simplex virus Polymerase chain reaction

the newborn nursery; physical examination was normal and weight (2680 g, 20%), length (19.5 cm, 50%), and head circumference (33.5 cm, 50%) were appropriate for gestational age. At 24 hours of age, mucosal swab specimens were taken from the conjunctiva, nasopharynx, and rectum for HSV culture, as well as blood specimen for HSV PCR.4 The mucosal cultures were negative for HSV, but the blood PCR test detected HSV-2 DNA at approximately 48 hours of age. Acyclovir was administered at 20 mg/kg/dose intravenously every 8 hours. Approximately 24 hours later, at 3 days of age and after 1 day of acyclovir therapy, the infant developed vesicular lesions on the scalp and cheek. The scalp lesion was positive for HSV-2 DNA by PCR testing. At that time, complete blood count showed normal hematocrit and platelet count. Cerebrospinal fluid obtained on the third day of acyclovir therapy had 5 white blood cells/mm3 and normal glucose and protein concentrations; cerebrospinal fluid HSV PCR was negative. The alanine aminotransferase concentration was normal (29 units/L). Brain magnetic resonance imaging and ophthalmologic examination at 13 and 21 days of age, respectively, were normal. The infant received 21 days of acyclovir therapy for presumed subclinical disseminated infection and was discharged to home at 25 days of age on suppressive oral acyclovir therapy (300 mg/m2/dose orally every 8 hours). The infant was seen in the infectious diseases clinic at 2 and 4 months of age. The physical examination and development were normal. She remained on suppressive acyclovir therapy and had not had any cutaneous recurrences.

Discussion Testing of blood in neonates by HSV PCR reduces the time to diagnosis of HSV infection3 and is now recommended as part of the evaluation of infants suspected of having HSV infection.5 Its inclusion in the management of healthy newborns delivered to mothers with active genital HSV infection at delivery is based on expert opinion2 as prospective analysis of

From the 1Department of Pediatrics, University of Texas Southwestern Medical Center; 2Department of Pediatrics, Methodist Dallas Medical Center, Dallas, TX; and 3 Department of Pediatrics, Center for Perinatal Research, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.01.042

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Vol. 166, No. 5  May 2015 blood HSV PCR testing in this setting has not been performed. Previous retrospective studies6,7 describe the detection of HSV DNA in dried blood spots of newborns, which lends plausibility to the recommendation that blood HSV PCR testing may be a useful adjunct to the early identification of infected newborns. Barbi et al6 detected HSV DNA in the dried blood spots of 4 neonates (obtained from 2-16 days of age) who later developed disseminated HSV disease within 5 days of dried blood spot collection. Similarly, Lewensohn-Fuchs et al7 detected HSV DNA in dried blood spots of seven (3 disseminated, 3 central nervous system, and 1 skin/eye/mouth disease) of 28 HSV-infected neonates at 4-14 days of age. The dried blood spots of these 7 neonates had been obtained from 5 days before to 6 days after the onset of clinical signs of HSV infection. All dried blood spots that had been obtained more than 5 days before the onset of HSV infection were negative for HSV DNA. In each of these studies, HSV DNA also was identified in the dried blood spots of 2 “control” infants without signs of HSV infection. These false-positive results raise concerns about methodology or specificity of HSV DNAemia. A major challenge to development of effective screening and prevention strategies is that the pathogenesis of neonatal HSV infection is not understood completely. The majority of neonatal HSV infection is thought to occur as a result of exposure to maternal virus in the genital tract at the time of delivery, with only a minority of infants infected in utero by either a transplacental or ascending route. Exposed infants develop infection within 3 weeks after birth that is either “localized” to the skin, eye, and/or mouth, or thought to be disseminated following mucocutaneous replication of HSV and hematogenous spread, or isolated central nervous system disease as a result of retrograde axonal transport of the virus.8 The finding of HSV DNA in blood from our patient at 24 hours of age when she had no cutaneous lesions challenges these assumptions regarding pathophysiology and suggests that the initiating event in the neonatal HSV infections may be HSV viremia.9,10 However, not all infants have DNAemia at the time of clinical illness.3 The optimal time to screen infants exposed to maternal HSV has yet to be determined and requires a more thorough understanding of the pathophysiology of neonatal HSV infection. It is not known if initiation of early empiric acyclovir therapy in our patient modified the disease course. The clinical findings were consistent with HSV skin/eye/mouth disease for which standard therapy is 14 days of acyclovir intravenously.5 Our patient was given 21 days of acyclovir because of the positive blood HSV PCR test result, even though she did not have clinical signs of disseminated or central nervous system disease. Whether infants who have blood HSV DNAemia should be regarded as having disseminated disease is not known. Current recommendations do not equate HSV DNAemia with disseminated infection and do not recom-

mend extending the duration of therapy based on a positive blood PCR test.5,11 In fact, in prospectively collected plasma HSV PCR results for 63 neonates with HSV disease, 78% of 18 infants with shin-eye-mouth disease alone had DNAemia.12 The finding of HSV DNAemia in our case before the onset of clinical disease adds support to the current guidance for diagnosis evaluation. Acyclovir therapy was initiated in our case prior to onset of clinical skin lesions, and the infant had an excellent short-term outcome. Understanding the role of HSV DNAemia in transmission, pathogenesis, and prognosis will help inform optimal screening and management approaches in neonatal HSV infection. n We thank the infant’s mother for allowing us to report her daughter’s medical history. Submitted for publication Oct 23, 2014; last revision received Dec 17, 2014; accepted Jan 22, 2015. Reprint requests: Joseph B. Cantey, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9063. E-mail: [email protected]

References 1. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr Clin North Am 2013;60:351-65. 2. 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; 131:383-6. 3. Cantey JB, Mejias A, Wallihan R, Doern C, Brock E, Salamon D, et al. Use of blood polymerase chain reaction testing for diagnosis of herpes simplex virus infection. J Pediatr 2012;161:357-61. 4. Hukkanen V, Rehn T, Kajander R, Sjoroos M, Waris M. Time-resolved fluorometry PCR assay for rapid detection of herpes simplex virus in cerebrospinal fluid. J Clin Microbiol 2000;38:3214-8. 5. Committee on Infectious Diseases. Herpes simplex. In: Pickering L, ed. Red Book, 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. 6. Barbi M, Binda S, Primache V, Tettamanti A, Negri C, Brambilla C. Use of Guthrie cards for the early diagnosis of neonatal herpes simplex virus disease. Pediatr Infect Dis J 1998;17:251-2. 7. Lewensohn-Fuchs I, Osterwall P, Forsgren M, Malm G. Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible. J Clin Virol 2003;26:39-48. 8. Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol 2007;31:19-25. 9. Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J 1999;18: 487-9. 10. Malm G, Forsgren M. Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed 1999;81:F24-9. 11. James SH, Kimberlin DW. Quantitative herpes simplex virus concentrations in neonatal infection. J Pediatr. In press. 12. Melvin AJ, Mohan KM, Schiffer JT, Drolette LM, Margaret A, Corey L, et al. Plasma and CSF herpes simplex virus levels at diagnosis and outcomes of neonatal infection. J Pediatr. In press.

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Herpes Simplex Virus DNAemia Preceding Neonatal Disease.

Polymerase chain reaction testing of blood for herpes simplex virus (HSV) is recommended for newborns delivered to mothers with active genital HSV les...
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