Predictors of Morbidity and Mortality in Neonates with Herpes Simplex Virus Infections

Whitley, Richard J.; Arvin, Ann M.; Prober, Charles G.; Corey, Lawrence; Burchett, Sandra; Plotkin, Stanley А.; Starr, Stuart E.; Jacobs, Richard L.; Powell, Dwight A.; Nahmias, André J.; Sumaya, C; Edwards, Kathryn M.; Alford, Charles A.; Caddell, Gary; Soong, Seng-Jaw

doi:10.1097/00006254-199107000-00013

Cited by 49 publications

(36 citation statements)

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“…11,12 Should all neonates for whom HSV testing is performed receive empiric acyclovir treatment, or should empiric treatment be reserved for a high-risk subset of patients, such as those with hypotension or disordered coagulation, whose illness severity at presentation has been associated with worse outcomes? 4,13 The relationship between delayed initiation of acyclovir therapy and outcomes is not known. Previous studies on this topic used historical comparison groups, were conducted before the advent of HSV polymerase chain reaction testing, and were not designed specifically to study the association of early versus late initiation of acyclovir treatment for infants with diagnosed HSV.…”

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confidence: 99%

Delayed Acyclovir Therapy and Death Among Neonates With Herpes Simplex Virus Infection

Shah

Aronson²,

Mohamad³

et al. 2011

Pediatrics

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WHAT'S KNOWN ON THIS SUBJECT:Neonatal herpes simplex virus (HSV) infection, although uncommon, is associated with significant mortality and neurologic morbidity. Acyclovir therapy reduces mortality rates. The association between the timing of acyclovir treatment initiation and mortality is not known. WHAT THIS STUDY ADDS:In this multicenter observational study of neonates with HSV infection, delayed initiation of acyclovir therapy was associated with in-hospital death. Our data support the use of empiric acyclovir therapy for neonates undergoing testing for HSV infection. abstract OBJECTIVE: To determine the association of delayed acyclovir therapy with death among neonates with herpes simplex virus (HSV) infection. METHODS:A multicenter, retrospective, cohort study was conducted between January 1, 2003, and December 31, 2009, with 1086 neonates (age: Յ28 days) with HSV infection from 41 tertiary care children's hospitals. Early acyclovir therapy was defined as initiation of intravenous acyclovir treatment within 1 day after hospital admission, and delayed acyclovir therapy was defined as initiation of treatment Ͼ1 and Յ7 days after hospital admission. Multivariate logistic regression models determined the association between delayed acyclovir therapy and death, with the use of propensity scores for each neonate's likelihood of receiving delayed acyclovir treatment to control for differences in illness severity between groups. RESULTS:The median age was 10 days. Delayed acyclovir therapy was administered to 262 neonates (24.1%). In most cases (86.2%) of delayed receipt, acyclovir administration occurred on the second or third day of hospitalization. The overall mortality rate was 7.3% (95% confidence interval: 5.8%-9.0%); 9.5% of those who received delayed acyclovir treatment and 6.6% of those who received early acyclovir treatment died. In a multivariate analysis, delayed acyclovir therapy was associated with significantly greater odds of death (adjusted odds ratio: 2.63 [95% confidence interval: 1.36 -5.08]) compared with early acyclovir therapy. CONCLUSIONS:In this multicenter observational study of neonates with HSV infection, delayed initiation of acyclovir therapy was associated with in-hospital death. Our data support the use of empiric acyclovir therapy for neonates undergoing testing for HSV infection.

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Delayed Acyclovir Therapy and Death Among Neonates With Herpes Simplex Virus Infection

Shah

Aronson²,

Mohamad³

et al. 2011

Pediatrics

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“…Apoptosis was induced not only in HSV-1 antigenexpressing cells but also in cells not expressing detectable viral proteins. Addition of anti-Fas antibody, anti-Fas-ligand antibody or a mixture of both had no effect on HSV-1-induced apoptosis, indicating that the Fas-Fas-ligand pathway did not contribute to HSV-1-induced apoptosis.Herpes simplex virus (HSV) causes severe infection with high mortality in human neonates (Whitley et al, 1991). The low frequency of specific T lymphocytes responding to HSV at birth is thought to be responsible for the severity of primary HSV infection in neonates (Hayward et al, 1984).…”

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confidence: 99%

“…Herpes simplex virus (HSV) causes severe infection with high mortality in human neonates (Whitley et al, 1991). The low frequency of specific T lymphocytes responding to HSV at birth is thought to be responsible for the severity of primary HSV infection in neonates (Hayward et al, 1984).…”

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Apoptosis of cord blood T lymphocytes by herpes simplex virus type 1.

Ito

Koide²,

Watanabe³

et al. 1997

Journal of General Virology

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We investigated apoptosis induced by herpes simplex virus type 1 (HSV-1) in cord blood T lymphocytes by using agarose gel electrophoresis, DNA content analysis and the terminal deoxytransferase (TdT)-mediated dUTP nick end-labelling (TUNEL) method. DNA fragmentation and the hypodiploid fraction in the cell cycle were both increased in HSV-1-infected CD4 and CD8 lymphocytes stimulated with phytohaemagglutinin (PHA) compared to mock-infected lymphocytes. The percentage of cells in the S phase was decreased in HSV-1-infected CD4 and CD8 lymphocytes. HSV-1 antigen, glycoprotein D (gD) and regulatory protein ICP27 were detected in 8-18 % of the hypodiploid fraction of PHA-stimulated, HSV-1-infected lymphocytes. Apoptosis was induced not only in HSV-1 antigenexpressing cells but also in cells not expressing detectable viral proteins. Addition of anti-Fas antibody, anti-Fas-ligand antibody or a mixture of both had no effect on HSV-1-induced apoptosis, indicating that the Fas-Fas-ligand pathway did not contribute to HSV-1-induced apoptosis.Herpes simplex virus (HSV) causes severe infection with high mortality in human neonates (Whitley et al., 1991). The low frequency of specific T lymphocytes responding to HSV at birth is thought to be responsible for the severity of primary HSV infection in neonates (Hayward et al., 1984). Human herpesviruses, such as HSV-1 (Tropea et al., 1995), varicellazoster virus (Sadzot-Delvaux et al., 1995) and Epstein-Barr virus (EBV ; Kawanishi et al., 1993), induce apoptosis. In addition virus-induced apoptosis of lymphoid cells may be a major cause of immunosuppression (Groux et al., 1992 ;Razvi et al., 1993). The effect of HSV-1 infection on lymphocytes from neonates has not been fully investigated. In this study, we have investigated the induction of apoptosis by HSV-1 in T Author for correspondence : Masahiro Ito.Fax j81 59 231 5213. e-mail virus!clin.medic.mie-u.ac.jp lymphocytes from neonates and the relationship between apoptosis and impaired immune function.HSV-1 (KOS strain) was grown at an m.o.i. of 0n1 in Vero cells that were cultured in minimum essential medium (MEM, Gibco BRL) supplemented with 10 % foetal bovine serum (FBS, Gibco BRL) at 37 mC. After 48 h, the supernatant was collected and cell debris was removed by centrifugation. The supernatant virus stock was stored at k70 mC. The titre of HSV-1 in the virus stock was 2i10' p.f.u.\ml. Supernatant medium from uninfected Vero cells was used for mock-infected controls.Cord blood was obtained from the placental end of the cord at full-term birth, and mononuclear cells (MNC) were separated by Ficoll-Hypaque (Histopaque 1077, Sigma) gradient centrifugation. MNC at the interface were collected and washed three times with RPMI-1640 (Gibco BRL) and suspended in RPMI-1640 supplemented with 10 % FBS. CD4-and CD8-rich lymphocytes were obtained by using Dynabeads M-450 CD4 and M-450 CD8 (Dynal). These procedures resulted in yields of 95 % CD4 and CD8 cells.Lymphocytes (1i10' cells) were centrifuged at 1500 r.p.m. for 5 min. The pellete...

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“…To date, neonatal HSV infection has been described as the result of contact between the newborn and HSV-1 or HSV-2 present in the birth canal of an asymptomatic mother during delivery (4,30,42). However, the possibility of vertical transmission has not been analyzed.…”

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Hematogenous Vertical Transmission of Herpes Simplex Virus Type 1 in Mice

Burgos

Ramı́rez

Guzman-Sanchez

et al. 2006

J Virol

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Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that causes severe disease and death in newborn humans but, to date, it remains unclear how neonatal infection occurs. We show here that the vertical transmission of HSV-1 in mice is mainly hematogenous and involves the colonization of the neonate central nervous system (CNS). HSV-1 DNA was mainly detected in the blood and CNS of the offspring born to latently infected mothers; no significant differences were seen between the viral DNA concentrations in the blood of these mothers and their female progeny (either neonate or adult). The administration of acyclovir during gestation reduced or eliminated both the maternal and the neonatal viral DNA in the blood. Embryo transfer was performed to ensure (as far as possible) that only vertical hematogenous infection took place. Immunohistochemical analysis detected viral proteins in the encephalon of the offspring. Immunofluorescence studies provided immunoreactive evidence of HSV-1 proteins in the neurons of the hippocampus and showed that these viruses can molecularly reactivate after hyperthermia. Neonatal HSV-1 infection therefore appears to be mainly caused by hematogenous vertical transmission, and the viruses that colonize the offspring CNS are capable of molecular reactivation after a period of latency.

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Predictors of Morbidity and Mortality in Neonates with Herpes Simplex Virus Infections

Cited by 49 publications

References 0 publications

Delayed Acyclovir Therapy and Death Among Neonates With Herpes Simplex Virus Infection

Delayed Acyclovir Therapy and Death Among Neonates With Herpes Simplex Virus Infection

Apoptosis of cord blood T lymphocytes by herpes simplex virus type 1.

Hematogenous Vertical Transmission of Herpes Simplex Virus Type 1 in Mice

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