Original Article
Predictors of Morbidity and Mortality in Neonates with Herpes Simplex Virus Infections
N Engl J Med 1991; 324:450-454February 14, 1991
- Abstract
- Abstract
Background.
In a controlled trial comparing acyclovir with vidarabine in the treatment of neonatal herpes simplex virus (HSV) infection, we found no significant difference between the treatments in adjusted mortality and morbidity. Hence, we sought to define for the entire cohort (n = 202) the clinical characteristics that best predicted the eventual outcome in these neonates.
Methods.
Data were gathered prospectively at 27 centers between 1981 and 1988 in infants less than one month of age who had virologically confirmed HSV infection. We examined the outcomes by multivariate analyses of 24 variables. Disease was classified in one of three categories based on the extent of the involvement at entry into the trial: infection confined to skin, eyes, or mouth; encephalitis; or disseminated infection.
Results and Conclusions. There were no deaths among the 85 infants with localized HSV infection. The mortality rate was significantly higher in the 46 neonates with disseminated infection (57 percent) than in the 71 with encephalitis (15 percent). In addition, the risk of death was increased in neonates who were in or near coma at entry (relative risk, 5.2), had disseminated intravascular coagulopathy (relative risk, 3.8), or were premature (relative risk, 3.7). In babies with disseminated disease, HSV pneumonitis was also associated with greater mortality (relative risk, 3.6). In the survivors, morbidity was most frequent in infants with encephalitis (relative risk, 4.4), disseminated infection (relative risk, 2.1), seizures (relative risk, 3.0), or infection with HSV type 2 (relative risk, 4.9). With HSV infection limited to the skin, eyes, or mouth, the presence of three or more recurrences of vesicles was associated with an increased risk of neurologic impairment as compared with two or fewer recurrences. (N Engl J Med 1991;324:450–4.)
Media in This Article
Figure 1
Survival of Babies with Neonatal HSV Infection, According to the Extent of Disease. P<0.001 for all comparisons.Figure 2
Survival of Babies with Neonatal HSV Infection, According to Level of Consciousness at the Initiation of Therapy and Extent of Disease.Article Activity
- Article
NEONATAL herpes simplex virus (HSV) infection is one of the most life-threatening of all infections in newborns, affecting approximately 1500 to 2200 babies per year in the United States.1 2 3 4 Although several clinical trials have documented the severity of the disease,3 , 5 6 7 8 9 10 11 they have evaluated insufficient numbers of babies and lacked a standardized data base, limiting the evaluation of prognostic factors.
The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group reported that there were no detectable differences in mortality and morbidity for vidarabine therapy as compared with acyclovir therapy of neonatal HSV infection.8 These data also provided an opportunity to ascertain clinical, laboratory, and outcome factors that influenced prognosis. The analysis of these variables will assist clinicians in predicting outcomes as well as permitting stratification according to risk in future efforts to evaluate interventions.
Methods
Study Population and Clinical Observations
The data for these analyses were obtained from the study of newborns (less than one month of age) with virologically confirmed HSV infection who were entered in a therapeutic trial.8 Classification according to the extent of disease and the methods of the trial were as reported by Whitley et al.8 in this issue of the Journal.
Data Assessment
Data were obtained from standardized case-record forms and analyzed at the University of Alabama at Birmingham. The clinical and laboratory data for the infected newborns and their mothers were analyzed simultaneously for their effect on outcome with use of a multivariate regression method based on a rank regression procedure.12 A stepwise method was used to identify a set of dominant prognostic factors. Twenty-three variables were weighed in these analyses: treatment, type of virus, seizures, fever, disseminated intravascular coagulopathy, apnea, HSV pneumonia, hypothermia, presence or absence of skin vesicles, sex, race, prematurity, age, duration of disease, hepatitis, level of consciousness, microcephaly, disease classification, chorioretinitis, concomitant diseases, pleocytosis and cerebrospinal fluid proteinosis, history of HSV infections in the mother and her sexual partners, and route of delivery. Relative risk, as adjusted for other factors, was calculated when relevant.12 Survival curves were calculated according to the method of Kaplan and Meier, and the log-rank test was used to compare differences. Multivariate prognostic-factor analysis was performed within each disease classification. It should be noted that the number of babies in each subgroup was relatively small as compared with the whole group; thus, there was less power to identify key variables associated with the disease outcome. The 95 percent confidence intervals for the relative risks estimated in each subgroup were accordingly wider. All P values were calculated by a two-tailed test.
Results
Study Population
Since among the 202 babies with neonatal HSV infection there were no differences in mortality or morbidity, either overall or within specific disease classifications, between those receiving vidarabine and those receiving acyclovir, the clinical, laboratory, and outcome data for both treatments were combined within each disease classification.8 Thus, 85 infants had infections of the skin, eyes, or mouth, 71 had encephalitis, and 46 had disseminated disease.
Factors Influencing Mortality
As summarized in Table 1Table 1
Prognostic Factors Identified by Multivariate Analyses for Neonates with HSV Infection.*, on the basis of relative risk the clinical characteristics that influenced mortality after multivariate adjustments were the disease classification (P<0.0001), the level of consciousness at the start of therapy (P<0.0001), and prematurity (P = 0.0015). In addition, pneumonitis (P<0.0001) and the development of disseminated intravascular coagulopathy (P<0.0007) were associated with an increased risk of death in babies with disseminated infection.As shown in Figure 1Figure 1
Survival of Babies with Neonatal HSV Infection, According to the Extent of Disease. P<0.001 for all comparisons., classification according to the extent of disease significantly predicted mortality (P<0.0001). Mortality was greatest with disseminated disease, 26 of 46 babies (57 percent) having died in spite of antiviral therapy (relative risk, 33). Fewer babies with central nervous system infection died —11 of 71 infants (15 percent; relative risk, 5.8). None of the 85 babies with disease limited to the skin, eyes, or mouth died. The duration of disease before the start of therapy was similar in the three groups (mean ±SE, 4.4±0.4, 4.8±0.4, and 4.8±0.5 days for infants with disseminated disease, central nervous system involvement, and infections of the skin, mouth, or eyes, respectively). Since only babies with encephalitis or disseminated disease died, subsequent survival analyses were confined to these groups.The level of consciousness at the initiation of therapy correlated with outcome (Fig. 2Figure 2
Survival of Babies with Neonatal HSV Infection, According to Level of Consciousness at the Initiation of Therapy and Extent of Disease.). Five of the 58 alert or lethargic newborns with central nervous system infection (9 percent) were dead one year after therapy, as compared with 6 of 13 (46 percent) of those who were semicomatose or comatose (P = 0.0003; relative risk, 6.1). When the infection was disseminated, 13 of 30 alert or lethargic babies (43 percent) died, as compared with 13 of 16 (81 percent) who were semicomatose or comatose (P = 0.005; relative risk, 3.9). The mean (±SE) duration of disease before treatment in babies with central nervous system infection who were alert or lethargic was 4.8±0.5 days, as compared with 5.1±1.1 days in those who were semicomatose or comatose. The corresponding values among infants with disseminated infection were 4.4±0.6 days in those who were alert or lethargic and 4.4±0.6 days in those who were semicomatose or comatose. These differences were not significant.Additional factors that influenced survival included HSV pneumonitis, disseminated intravascular coagulopathy, prematurity, and virus type. Fifteen of 19 babies with HSV pneumonitis (79 percent) died (relative risk, 3.6). None of the seven babies with both pneumonitis and disseminated intravascular coagulopathy survived. The mortality rate among babies with pneumonitis in the absence of disseminated intravascular coagulopathy was 67 percent (8 of 12 babies). The median survival for these 26 babies was five days.
Prematurity influenced outcome in babies with encephalitis. Six of 15 premature babies (mean gestational age, 31.3 weeks) with encephalitis died (40 percent; relative risk, 5.2) after a median survival of 19.5 days. Among term infants with encephalitis, 5 of 56 (9 percent) died after a median of 162 days. Overall, the babies with disseminated disease who died had a shorter median survival than those with central nervous system infection (5 vs. 25 days, P = 0.0006).
As shown in Figure 3Figure 3
Survival of Babies with Neonatal HSV Infection, According to Type of Virus and Extent of Disease., babies with HSV type 1 disseminated infection had poorer outcomes than those with HSV type 2 infection (P = 0.01). This difference can be accounted for by the distribution of infants with pneumonitis and disseminated intravascular coagulopathy in these subgroups — five and two infants, respectively. There was no significant difference in survival between babies with type 1 infection and those with type 2 infection of the central nervous system.In the univariate analysis, the duration of disease before the start of therapy correlated with mortality (P = 0.048). Babies who had had the disease either less than two days or more than eight days had lower mortality rates than those infected for two to eight days (Fig. 4Figure 4
One-Year Mortality in Infants, According to the Duration of HSV Infection before the Initiation of Therapy.).Factors Influencing Morbidity
If the child survived the acute illness, the factors predicting morbidity at one year of life included classification of disease (P<0.0001), seizures (P<0.0001), and infection with HSV type 2 (P = 0.0154). For these analyses, we compared children with any neurologic impairment (microcephaly, spastic quadriplegia, a persistent seizure disorder, blindness, or a developmental delay of more than six months) with those judged to be totally normal.
For children with disease localized to the skin, eyes, or mouth, 67 of 71 (94 percent) developed normally and without any neurologic impairment. Four children had neurologic impairment. Among the infants with central nervous system infection or disseminated disease, the number of surviving babies developing normally at one year decreased to 21 of 58 (36 percent) and 10 of 17 (59 percent), respectively. The rates in these two groups differed significantly from those among babies with disease of the skin, eyes, or mouth (central nervous system infection: relative risk, 4.4; P<0.001; disseminated disease: relative risk, 2.1; P<0.001). There was no significant difference in morbidity between babies with central nervous system infection and those with disseminated disease (P = 0.10).
In the group of infants with central nervous system disease, 27 of the 29 babies with seizures (93 percent) had neurologic impairment, as compared with 10 of the 29 without seizures (34 percent) (P<0.001; relative risk, 3.4). Similarly, 5 of the 6 babies who had seizures (83 percent) were developing abnormally as compared with 2 of the 11 without seizures (18 percent) (P = 0.03).
Overall, the duration of disease before the start of therapy correlated significantly with morbidity, but only before multivariate analysis. Among those in whom the duration of disease was either less than two days or more than eight days, 4 of 52 babies (8 percent) were severely impaired at one year. In contrast, 22 of 94 babies (23 percent) infected for two to eight days were severely impaired (P = 0.017).
Among the infants with disease limited to the skin, eyes, or mouth, all 30 with HSV type 1 infection had normal development. In contrast, 4 of the 29 babies (14 percent) with type 2 infection were impaired (P = 0.05; relative risk, 14). Similarly, in the group with central nervous system disease, morbidity was higher in children with type 2 infection: 30 of 40 newborns (75 percent) were impaired as compared with 3 of 11 (27 percent) with type 1 infection (P = 0.01). This was not statistically significant; however, none of the 4 babies who survived a type 1 infection were impaired, whereas 7 of the 13 (54 percent) surviving a type 2 infection had neurologic deficits.
When skin vesicles recurred fewer than three times during the first six months of life, all babies with disease localized to the skin, eyes, or mouth developed normally. However, only 79 percent of those with three or more recurrences of skin vesicles developed normally. Of the babies with HSV type 2 infection, 4 of the 14 (29 percent) with three or more recurrences were impaired, as compared with none of the 15 babies with fewer than three recurrences (P = 0.04; relative risk, 21). Neurologic outcome could not be correlated with the frequency of skin recurrences in babies with central nervous system infection or disseminated disease, since many babies had neurologic impairment at the end of treatment.
Discussion
These studies have provided knowledge about the natural history and outcome of neonatal HSV infection. The reported findings emphasize the broad spectrum of neonatal HSV infection, as reflected by the three classifications based on extent of disease. Mortality and morbidity, although influenced by several factors, were related most closely to the extent of disease. Furthermore, although the findings in this study were largely anticipated on the basis of clinical experience, these data document the prognostic factors for neonatal HSV infection: level of consciousness, development of disseminated intravascular coagulopathy or pneumonitis, gestational age, and under certain circumstances, type of virus.
We were surprised to find that morbidity from HSV type 1 infection of the central nervous system is associated with a better prognosis than type 2 infection, as has been suggested.13 It is known from in vitro studies that HSV type 2 is less susceptible to acyclovir than HSV type 1. The observation of differences between HSV type 1 and type 2 disease in infants along with lower in vitro efficacy for HSV type 2 provides a rationale for higher dosing regimens. The development of drugs that penetrate the central nervous system to a greater extent than acyclovir would be advantageous, since brain tissue can retain viable virus even after many days of acyclovir therapy.
Three or more skin recurrences in six months correlated with long-term neurologic sequelae; the babies all had HSV type 2 infection. Severe neurologic impairment has been noted previously in babies with apparently limited disease.6 , 7 These findings suggest the possibility that with cutaneous lesions, subtle viremia and seeding of the central nervous system may occur. Insidious reactivation of latent central nervous system virus might lead to impairment. Because of this observation, we will evaluate oral acyclovir therapy to determine whether the suppression of recurrent cutaneous lesions improves the neurologic outcome.
Approaches to the control of neonatal HSV infection will be discussed briefly. The use of cultures to screen women immediately before delivery is of no value in predicting the risk of infection for the fetus.14 Alternatively, in women with a history of genital herpes, acyclovir treatment during the last four weeks of gestation would be futile, since over 70 percent of the mothers of babies with neonatal HSV infection have no evidence of genital HSV infection.10 On the other hand, if screening for previous HSV type 2 infection were the basis for prophylaxis, 20 to 40 percent of pregnant women15 , 16 would require suppressive acyclovir therapy during the last four weeks of gestation. Even if an appropriate target population were defined, patients can excrete HSV while receiving acyclovir.17 Further research is essential to identify the babies at risk for infection who can benefit from prophylactic antiviral therapy.
As with herpes encephalitis in older children and adults, the initiation of treatment before the development of central nervous system disease, disseminated disease, or a depressed consciousness significantly improves the outcome.18 19 20 The recognition of poor prognostic factors allows informed counseling of families and more accurate prediction of the eventual outcome.
Supported by a contract (NO1-AI-62554) with the Development and Applications Branch of the National Institute of Allergy and Infectious Diseases and by grants from the General Clinical Research Center Program (RR-032) and the state of Alabama.
*Members of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group include C. Laughlin, National Institutes of Health, Bethesda, Md.; R. Whitley, C. Alford, J. Benton, S.-J. Soong, A. Lakeman, S. Stagno, G. Caddell, and N. Watson, University of Alabama at Birmingham; L. Corey and S. Burchett, University of Washington, Seattle; A. Arvin, C. Prober, and A. Yeager (deceased), Stanford University, Stanford, Calif.; A. Nahmias and H. Keyserling, Emory University, Atlanta; D. Powell, M. Hilty, and M. Brady, Ohio State University, Columbus; J. Connor, S. Spector, and R. Straube, University of California, San Diego; S. Starr, R. Fleisher, S. Plotkin, and J. Puck, University of Pennsylvania, Philadelphia; P. Wright, K. Edwards, W. Gruber, C. Porch, and R. Bradley, Vanderbilt University, Nashville; C. Sumaya, S. Lipton, and V. Novelli, University of Texas, San Antonio; P. Shackelford, Washington University, St. Louis; V. San Joaquin and M. Marks, University of Oklahoma, Norman; R. Steele and R. Jacobs, University of Arkansas, Little Rock; M. Levin, University of Colorado, Denver; R. Anderson and J. Bale, University of Iowa, Iowa City; F. Hayden and J. Kattwinkel, University of Virginia, Charlottesville; F.Y. Aoki and G.W. Hammond, University of Manitoba, Winnipeg, Canada; L. Dunkle, S. Toce, W. Keenan, S. Nagvi, R. Lusk, G. Gale, and D. O'Connor, St. Louis University, St. Louis; M. Kleiman, K. Fife, and J. Gaebler, University of Indiana, Bloomington; R. Pollard, University of Texas, Galveston; R. Alexander, Centers for Disease Control, Atlanta; G. Ray, V. Fulginiti, and Z. Shehab, University of Arizona, Tucson; M. Myers, C. Harrison, L. Stanberry, and D. Bernstein, University of Cincinnati, Cincinnati; J. Modlin, Johns Hopkins University, Baltimore; M. Hirsch and R. Schooley, Massachusetts General Hospital, Boston; A. Chow and D. Scheifele, University of British Columbia, Vancouver, Canada; R. Clemons, Burroughs Wellcome Company, Research Triangle Park, N.C.; and R. Buchanan and S. Thornton, Warner-Lambert, Morris Plains, N.J.
Source Information
From the Departments of Pediatrics, Microbiology, Medicine, and Biostatistics, University of Alabama at Birmingham, Birmingham (R.W., C.A., G.C., S.-J.S.); the Department of Pediatrics, Stanford University, Stanford, Calif. (A.A., C.P.); the Department of Medicine, University of Washington, Seattle (L.C., S.B.); the Department of Pediatrics, Joseph Stokes Jr. Research Institute, Philadelphia (S.P., S.S.); the Department of Pediatrics, University of Arkansas, Little Rock (R.J.); the Department of Pediatrics, Ohio State University, Columbus (D.P.); the Department of Pediatrics, Emory University, Atlanta (A.N.); the Department of Pediatrics, University of Texas, San Antonio (C.S.); and the Department of Pediatrics, Vanderbilt University, Nashville (K.E.).
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