April 2015 38. Schulman KA, Berlin JA, Harless W, Kerner JF, Sistrunk S, Gersh BJ, et al. The effect of race and sex on physicians’ recommendations for cardiac catheterization. N Engl J Med 1999;340:618-26. 39. Patzer RE, Sayed BA, Kutner N, McClellan WM, Amaral S. Racial and ethnic differences in pediatric access to preemptive kidney transplantation in the United States. Am J Transplant 2013;13: 1769-81. 40. Institute of Medicine (IOM). Race, Ethnicity, and Language Data: Standardization for Health Care Quality Improvement. Washington, DC: The National Academies Press; 2009.

41. Institute of Medicine (IOM). Child and Adolescent Health and Health Care Quality: Measuring What Matters. Washington, DC: The National Academies Press; 2011. 42. Flores G, Abreu M, Chaisson CE, Meyers A, Sachdeva RC, Fernandez H, et al. A randomized trial of the effectiveness of community-based case management in insuring uninsured Latino children. Pediatrics 2005; 116:1433-41. 43. Flores G, Snowden-Bridon C, Torres S, Perez R, Walter T, Brotanek J, et al. Improving asthma outcomes in minority children: a randomized, controlled trial of parent mentors. Pediatrics 2009;124:1522-32.

Quantitative Herpes Simplex Virus Concentrations in Neonatal Infection


eonatal herpes simplex virus (HSV) infection fortumerase chain reaction (PCR) in infants with neonatal HSV nately is uncommon, occurring in an estimated 1 in infection.8 Unlike many of the earlier reports in the litera3200 deliveries in the US. Perinatal HSV infection ture, nearly all of the subjects in the present study received clinically is categorized as skin, eye, and/or mouth (SEM) disthe currently recommended parenteral acyclovir dose of ease, central nervous system (CNS) disease, or disseminated 60 mg/kg/d, making these results contemporary. The trial disease.1 Clinical trials conducted by the represents the most robust attempt to See related article, p 827 date to define the expected viral dynamics National Institute of Allergy and Infectious of HSV DNA concentrations and their clinical correlation Diseases Collaborative Antiviral Study Group over the course in the setting of neonatal HSV infection. The authors’ objecof 40 years have demonstrated these clinical classifications to tive was to assess the utility of quantitative HSV PCR in the be predictive of both morbidity and mortality.2-5 SEM disclinical management and outcome of infants receiving ease accounts for approximately 45% of neonatal HSV infectreatment with acyclovir. In order to do this, they reviewed tions, and by definition does not involve the CNS or other the medical records of 63 infants treated for neonatal HSV organ systems. Infants with CNS disease make up about infection at Seattle Children’s Hospital over the span of 30% of neonatal HSV infections and also may have mucocualmost 20 years. This group has performed seminal work taneous lesions, but by definition lack involvement of visceral in HSV molecular diagnostics over many years, and since organ systems. Infants with disseminated disease make up the 1993 their standard diagnostic evaluation for neonatal remaining 25% of neonatal HSV infections and also may HSV has included HSV PCR from plasma and CSF. Thus, have infection of the CNS.6 the current paper reports PCR data obtained at the time The advent of antiviral therapy significantly improved the of clinical presentation, rather than by retrospectively asclinical outcomes of neonatal HSV disease, although sessing archived specimens for HSV DNA by PCR. By pairmorbidity and mortality remain unacceptably high. It ing these prospectively gathered virologic data with currently is recommended that neonates with HSV disease retrospectively reviewed clinical data as documented in be treated with intravenous acyclovir given at a dose of the medical record, the researchers were able to investigate 60 mg/kg/d divided every 8 hours.5 Disseminated and CNS the clinical significance of DNAemia in the setting of diseases should be treated for at least 21 days, and neonates neonatal HSV infection. with only SEM disease should receive 14 days of therapy. AfA completely novel aspect of the current report is the dyter completion of the appropriate course of parenteral thernamics of viral clearance reported in a subset of patients apy, transition to a suppressive course of oral acyclovir at a with disseminated disease. Clearance of HSV DNA from dose of 300 mg/m2/dose by mouth 3 times a day (usually unplasma was remarkably predictable, displaying a viral decay til the age of 6 months) improves neurodevelopmental outrate indicative of single-phase exponential clearance. The pricomes in CNS disease and reduces the frequency of skin mary clearance phase had a median viral half-life of 1.26 days. recurrences in all perinatal disease classifications.7 One subject demonstrated low-level DNAemia that perIn this issue of The Journal, Melvin et al report the findsisted for over 2 months after the primary clearance phase, ings of a large cohort study of HSV DNA concentrations in despite the fact that acyclovir was restarted. This novel inforplasma and cerebrospinal fluid (CSF) via quantitative polymation may have significant applicability in the evaluation of combination antiviral therapy, such as the Collaborative CNS CSF HSV PCR SEM

Central nervous system Cerebrospinal fluid Herpes simplex virus Polymerase chain reaction Skin, eye, and/or mouth

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.2014.12.077




Antiviral Study Group’s study of brincidofovir plus acyclovir in neonatal HSV disease (ClinicalTrials.gov: NCT01610765). Although additional data are needed, viral decay and clearance may one day serve as biomarkers for enhanced therapeutic efficacy—and the foundation for that understanding lies in the outstanding work presented in the article by Melvin et al. Other important information also is contained in the current report; many findings match those seen in previous publications. A majority of subjects in whom plasma HSV PCR was performed had a positive test result, regardless of the clinical classification under which they were categorized— 100% in cases with disseminated disease, 64% in cases with CNS disease, and 78% in cases with SEM disease. Similar results have been reported by several other groups.9-14 In infants with quantitative PCR data from plasma (n = 41), the mean HSV DNA concentration at diagnosis was significantly higher in infants with disseminated disease than in those with SEM or CNS diseases (7.2 log10 copies/mL vs 2.2 log10 copies/mL and 2.8 log10 copies/mL, respectively), indicating that the initial plasma HSV concentration correlated with the clinical classification of neonatal HSV disease. Likewise, a higher concentration of plasma HSV DNA at the time of presentation was predictive of increased risk of mortality, although this reflects the correlation between higher plasma viral load and disseminated disease rather than a uniquely independent correlation. Similarly, the correlation between an increasing plasma viral load and clinical worsening certainly describes virologically that has been recognized clinically for many years, but does not add substantial new data upon which clinical decision-making can be based. Interestingly, neither CSF nor plasma HSV DNA concentration correlated with neurologic status at 2 months after completion of treatment, and there was no correlation between mean HSV DNA concentration and virus type (HSV-1 vs HSV-2). The power of the diagnostic methodologies reported in the current study also highlight the need to evaluate in the same systematic fashion the performance of HSV PCR from swabs obtained from mucosal surfaces compared with surface viral cultures. The authors state that “few infants in our sample had PCR assays performed on collected surface swabs.” Until those data are similarly available, the assessment of a baby for neonatal HSV disease will continue to include: (1) swab specimens from the mouth, nasopharynx, conjunctivae, and anus (“surface cultures”) for HSV culture and, if desired, for HSV PCR; (2) specimens of skin vesicles and CSF for HSV culture and PCR, respectively; (3) whole blood sample for HSV PCR; and (4) whole blood sample for measuring serum alanine aminotransferase concentration.15 The authors’ findings confirm that HSV PCR testing of blood specimens can be a useful adjunct to the standard diagnostic evaluation of neonatal HSV infection, especially in infants who present without cutaneous lesions. Of all the diagnostic tests performed on subjects in the current cohort, plasma HSV PCR was positive most frequently, with 83% of all infants having a positive result. Interestingly, in 5 of the patients with neonatal HSV the plasma PCR was the only positive test, meaning that the diagnosis would likely have been 794

Vol. 166, No. 4 delayed or missed entirely without this assay. These findings support the 2012 Red Book recommendations from the American Academy of Pediatrics to obtain a whole blood sample for HSV PCR as a part of the multimodal diagnostic work-up of neonatal HSV infection.15 A positive whole blood PCR should not be used to determine extent/classification of disease and, thus, duration of treatment, as the current report demonstrates that the test is positive in the majority of patients regardless of their clinical classification. This is most relevant clinically in the scenario of an infant clinically determined to have SEM disease yet found to have a positive blood HSV PCR. Based on currently available data, this scenario would not warrant reclassification as disseminated HSV disease. Advances in the clinical management of disease often begin with the systematic application of diagnostic technologies to the patient population. Once again, the Seattle group has added to our understanding of the pathogenesis of neonatal HSV disease. Their careful work over many decades is lauded by the herpes virus community. The challenge now is to apply these findings in a manner that builds upon our existing knowledge to advance the field. This likely will include incorporation of viral dynamics into new therapeutic studies that seek to break the logjam in advancing the outcomes following neonatal HSV disease by adding new drugs to our therapeutic arsenal for the first time since acyclovir was studied in the 1980s. n Scott H. James, MD David W. Kimberlin, MD Division of Infectious Diseases Department of Pediatrics University of Alabama at Birmingham Birmingham, Alabama Reprint requests: David W. Kimberlin, MD, Department of Pediatrics, University of Alabama at Birmingham, Children’s Harbor Building 303, 1600 7th Ave South, Birmingham, AL 35233-1711. E-mail: [email protected]

References 1. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 2003;289:203-9. 2. Whitley R, Arvin A, Prober C, Corey L, Burchett S, Plotkin S, et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engl J Med 1991;324:450-4. 3. Whitley RJ, Nahmias AJ, Soong SJ, Galasso GG, Fleming CL, Alford CA. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 1980;66:495-501. 4. Whitley RJ, Yeager A, Kartus P, Bryson Y, Connor JD, Alford CA, et al. Neonatal herpes simplex virus infection: follow-up evaluation of vidarabine therapy. Pediatrics 1983;72:778-85. 5. Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 2001; 108:230-8. 6. Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, Gruber WC, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 2001;108:223-9. 7. Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, et al. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med 2011;365:1284-92.


April 2015 8. Melvin AJ, Mohan KM, Schiffer JT, Drolette LM, Margaret A, Corey L. Plasma and cerebrospinal fluid herpes simplex virus at diagnosis and outcome of neonatal infection. J Pediatr 2015;166:829-33. 9. Kimura H, Futamura M, Kito H, Ando T, Goto M, Kuzushima K, 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;164:289-93. 10. 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. 11. 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.

12. 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. 13. Kimura H, Ito Y, Futamura M, Ando Y, Yabuta Y, Hoshino Y, et al. Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. J Med Virol 2002;67:349-53. 14. 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. 15. American Academy of Pediatrics. Herpes simplex. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 398-408.

Preventing Postnatal Cytomegalovirus Infection in the Preterm Infant: Should It Be Done, Can It Be Done, and at What Cost?


n 2012, 56 252 very low birth weight (VLBW,

Quantitative herpes simplex virus concentrations in neonatal infection.

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