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In 2001, Kimberlin and colleagues1 compared the diagnosis and management of neonates with HSV infections during 2 time periods in the “acyclovir era.” These researchers from the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG) concluded that no progress had been made (from 1981 to 1988 and from 1989 to 1997) in reducing the interval between onset of HSV symptoms and administration of antiviral therapy.1 They further maintained that appreciation by pediatricians of the significance of neonatal HSV infections and application of available diagnostic and therapeutic modalities, such as polymerase chain reaction (PCR) and use of high-dose acyclovir (60 mg/kg/day), represented the only available means of reducing infection-associated morbidity and mortality. Although the techniques for viral detection and strategies for management of primary and recurrent HSV infection continue to evolve, clinicians still fail to include HSV in the differential diagnosis of the ill neonate, as demonstrated in a small survey of British pediatricians in 2004.2 Thus, HSV infections still remain an underappreciated cause of neonatal disease.
The characteristics of neonatal HSV infections have been further
delineated since their initial descriptions by Batignani3
and Hass4 in the mid-1930s. The classifications of infection
(based on the CASG-derived system) are disseminated disease
(25% of all cases6) involving the liver, respiratory tract,
adrenal glands, and CNS, isolated HSV CNS disease (nearly
30% of all cases6), and infection localized to the skin,
eye, and/or mucous membranes (SEM disease, approximately 45%
of all cases).6 Morbidity and mortality from neonatal HSV infections
can be predicted based on this classification scheme.7 Most
infections present between 1 and 3 weeks of age, with HSV
encephalitis presenting later (average, 16 to 19 days of age)
than SEM or disseminated disease (10 to 12 days of age).1,8 Infants
with disseminated disease have higher rates of mortality1 but
have demonstrated the most dramatic improvement in survival
with the evolution of antiviral therapy, with a reduction
in mortality from 85% (no acyclovir therapy) to 29%
(high-dose acyclovir).6,9 Furthermore, some infants with SEM
disease manifest evidence of CNS infection (as detected by
retrospective PCR analysis10), suggesting a continuum of the
3 disease types mediated by maternal and neonatal factors.
Despite the definition of the clinical entity, incidence data
on neonatal HSV infections in the United States are not uniform,
making it difficult for clinicians to recognize the frequency
of the disease. The best data evolved from a large prospective
analysis of nearly 60,000 live births at 7 hospitals in the
Seattle area, revealing an estimated incidence of neonatal
HSV of 1 in 3200 live births11.
With approximately 4 million live births annually in the United
States, this estimate translates into 1500 HSV cases per year.
However, this number may be misleading. As noted in their
retrospective analysis summarized in this newsletter, Xu and
associates maintain that the higher incidence of neonatal
HSV disease in their Northwest cohort (the states of Washington
and Oregon) relative to their California cohort may be due
to a greater number of non-Hispanic white residents, who are
more likely to be seronegative for HSV.12,13
Primary maternal HSV infection in pregnancy is a known risk
factor for vertical transmission and neonatal infection.6,14
Thus, data from the prospective trial may reflect numbers
of neonatal HSV cases in an at-risk population, resulting
in an overestimation of the national incidence. Further attempts
at prospective incidence determination are currently limited,
since as of January 2008, only 8 US states and New York City
have mandated the reporting of neonatal herpes infections
to public health authorities (as noted in the Whitley et al.
article reviewed herein and by others).15
Retrospective determination of neonatal HSV incidence has
remained equally difficult. Three articles discussed in this
review analyzed archived clinical and laboratory databases
to identify the incidence/prevalence of neonatal HSV infections.
In addition to known problems with disease documentation using
retrospective analysis (ie, incorrect coding, missing laboratory
or clinical data), several other problems with documentation
of neonatal HSV infections were highlighted. Most importantly,
as noted by Whitley and coworkers in this issue, no specific
ICD-9 code exists for neonatal HSV infections. The studies
by Xu et al. and Whitley et al. (discussed herein) relied on a
combination of billing codes for all HSV infections (0.54.xx
series) and nonspecific HSV-associated diagnoses (encephalitis,
viremia) to screen for and identify cases, although as noted
by Xu and coworkers, the positive predictive value of the
2 most commonly used codes was low. These studies calculated
a higher (Whitley et al.) or lower (Xu et al.) incidence compared
with the aforementioned prospective analysis.11
Xu and collaborators attributed these discrepancies to differences
in study methodology (prospective vs retrospective), the previously
mentioned population differences in HSV seroprevalence,12,13 and other maternal and neonatal factors. Finally,
prevalence data from the single-center study by Caviness and
associates were complicated by limited viral analysis performed
in the infants evaluated.
An equally prominent barrier to the diagnosis of neonatal
HSV infections is the paucity of disease-specific symptoms
in the newborn in the absence of dermatologic findings. Of
neonates with HSV infections, approximately 70% of mothers16
have no history of genital HSV disease. In the NIAID natural
history study,1
no single set of signs and symptoms identified all newborns
with HSV infections, and only 61% of all neonates with
disseminated disease (who often present with nonspecific signs/symptoms
of illness) developed skin lesions before, during, or after
study enrollment. In an older study, fever was reported at
equal rates in neonatal HSV and bacterial infections.17
However, in the aforementioned article by Caviness and colleagues
reviewed herein, neonates with HSV infections were less likely
than those with bacterial infections to be febrile at presentation.
In an additional article by Caviness and coworkers, reviewed
in this issue, the authors identified 3 independent risk factors
(1 maternal, 2 neonatal) associated with HSV infection in
infants without a rash. However, the small number of cases
over the study period weakened the statistical strength of
these factors, thus limiting the applicability of these characteristics
alone or in combination in rendering a diagnosis of neonatal
HSV infection.
Despite these epidemiologic and diagnostic limitations, recent
investigations into the diagnosis and outcomes of neonates
with HSV CNS infections have provided important information
for clinicians. Morbidity in cases of neonatal HSV encephalitis
has not improved even with the introduction of high-dose acyclovir.18
The sobering reality of complications of neonatal HSV CNS
disease is well reflected in the study by Engman and coworkers,
reviewed in this newsletter, who comprehensively describe
the neuropsychologic deficits observed in their small cohort.
This study, and the work by Vossough and colleagues, also
document the limitations of routine computerized tomography
(CT) in the diagnosis and prognosis of HSV infections. The
data from the Vossough study also demonstrates that DW-MRI,
which identifies tissue abnormalities based on the diffusion
of water molecules, may identify CNS injury in the neonate
that is routinely missed by CT or conventional MRI. Thus,
routine DW-MRI imaging, coupled with accurate PCR analysis
of the cerebrospinal fluid (CSF), may identify cases of neonatal
HSV before the results of viral cultures are available, allowing
for rapid case identification and immediate, appropriate management.
In conclusion, neonatal HSV infections must be considered in any infant with signs and symptoms of systemic organ failure or encephalopathy in the presence or absence of a rash. A key point to recognize is the small total numbers of cases included in most studies of the disease. Thus, a national reporting system is urgently needed to identify all potential cases of neonatal herpes infections, facilitating better understanding of the pathogenesis and diagnostic/prognostic factors of the illness. Whitley et al. (in the article reviewed herein) and others19 have previously proposed such reporting of neonatal herpes. Until then, neonatologists and other clinicians must maintain continued vigilance for HSV disease in neonates, using physical examination findings, available laboratory and diagnostic imaging tests, and a high index of suspicion.
Commentary References
| 1. |
Kimberlin
DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, Gruber
WC et al. and the
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(2):223-229.
|
 |
| 2. |
Fidler KJ, Pierce CM, Cubitt WD, Novelli V, Peters MJ.
Could neonatal
disseminated herpes simplex virus infections be treated earlier? J Infect.
2004;49(2):141-146. |
|
| 3. |
Batignani A. Conjunctivite da virus erpetico in neonato.
Boll Ocul. 1934;13:1217-1220. No abstract available;
article pre-dates PubMed. |
|
| 4. |
Hass GM.
Hepato-adrenal necrosis with intranuclear inclusion bodies. Am J Pathol. 1935;11(1):127-142. No abstract available; article pre-dates PubMed. |
|
| 5. |
Whitley R, Arvin A, Prober C, Burchett S, Corey L, Powell D, 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(7):444-449.
|
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| 6. |
Kimberlin DW.
Neonatal herpes simplex infection. Clin Microbiol Rev.
2004;17(1):1-13. |
|
| 7. |
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. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med.
1991; 324(7):450-454. |
|
| 8. |
Kimberlin DW, Whitley RJ.
Neonatal herpes: what have we learned. Semin Pediatr Infect Dis. 2005;16(1):7-16. |
|
| 9. |
Kimberlin DW.
Advances in the treatment of neonatal herpes simplex infections. Rev Med Virol. 2001;11(3):157-163. |
|
| 10. |
Kimberlin DW, Lakeman FD, Arvin AM, Prober CG, Corey L, Powell DA, 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(6):1162-1167.
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| 11. |
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(2):203-209.
|
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| 12. |
Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al.
Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964-973.
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| 13. |
Xu F, Markowitz LE, Gottlieb SL, Berman SM.
Seroprevalence of herpes simplex virus types 1 and 2 in pregnant women in the United States. Am J Obstet Gynecol. 2007;196(1):43.e1-43.e6.
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| 14. |
Brown ZA, Vontver LA, Benedetti J, Crtichlow CW, Sells CJ, Berry S, et al.
Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med. 1987; 317(20):1246-1251.
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| 15. |
Dinh TH, Dunne EF, Markowitz LE, Weinstock H, Berman S.
Assessing neonatal herpes reporting in the United States, 2000-2005. Sex Transm Dis. 2008;35(1):19-21.
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| 16. |
Whitley RJ, Nahmias AJ, Visintine AM, Fleming CL, Alford CA.
The natural history of herpes simplex virus infection of mother and newborn. Pediatrics. 1980; 66(4):489-494.
|
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| 17. |
Filippine MM, Katz BZ.
Neonatal herpes simplex virus infection presenting with fever alone. J Hum Virol. 2001;4(4):223-225.
|
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| 18. |
Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, et al. and the
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(2):230-238.
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| 19. |
Handsfield HH, Waldo AB, Brown ZA, Corey L, Drucker JL, Ebel CW, et al.
Neonatal herpes should be a reportable disease. Sex Transm Dis. 2005;32(9):521-525.
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