Herpes Simplex Virus Encephalitis During Suppressive Therapy With Acyclovir in a Premature Infant
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《小儿科》
the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
ABSTRACT
Cutaneous herpes simplex virus type 2 (HSV-2) infection was recognized at 19 days of age in a 1415-g female infant born at 31 weeks of gestation. Cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) was negative, and MRI of the brain was normal. After a 14-day course of high-dose intravenous acyclovir, the infant developed a cutaneous recurrence at 38 days of age. CSF HSV PCR again was negative. She was subsequently begun on oral acyclovir to prevent cutaneous reactivation of HSV. At 3 months of age, the infant developed HSV encephalitis as manifested by fever, seizures, abnormal CSF indices, abnormal brain MRI, and positive CSF HSV PCR. No cutaneous disease was present. It is not known whether the HSV encephalitis in our patient represented reactivation of previously unrecognized central nervous system infection or new onset of central nervous system disease as a result of spread from other tissue or site to the brain. The failure of oral acyclovir to prevent such an occurrence, however, highlights gaps in our understanding of the pathogenesis of neonatal HSV disease and questions the use of acyclovir suppression to prevent neurologic sequelae.
Key Words: herpes simplex virus acyclovir encephalitis prophylaxis
Abbreviations: HSV, herpes simplex virus SEM, skin, eye, and mouth CBC, complete blood cell WBC, white blood cell CSF, cerebrospinal fluid RBC, red blood cell PCR, polymerase chain reaction CT, computed tomography CNS, central nervous system
Despite the availability of specific antiviral therapy and provision of a longer treatment course with high-dose acyclovir, significant morbidity persists after neonatal herpes simplex virus (HSV) infections.1,2 The majority of neonates who survive HSV encephalitis and disseminated disease suffer from significant neurodevelopmental problems that include spastic quadriplegia, psychomotor retardation, learning disabilities, and blindness. On the other hand, only 2% of neonates with HSV infection that is limited to the skin, eye, or mouth (SEM) and who receive intravenous acyclovir therapy have long-term neurologic sequelae.2,3 Whitley et al4 associated abnormal neurologic outcome in these infants with the occurrence of 3 skin recurrences with HSV-2 in the first 6 months of age. For these reasons, the use of oral acyclovir for suppression of skin recurrences with HSV-2 has been widely implemented despite the lack of evidence of a beneficial effect.
We report a premature infant with neonatal HSV-2 cutaneous disease who developed encephalitis due to HSV during administration of suppressive therapy with oral acyclovir. This report highlights the importance of placebo-controlled, randomized studies to determine if the practice of oral acyclovir suppression after neonatal HSV infection is beneficial.
CASE REPORT
A 1415-g female infant was delivered vaginally at 31 weeks of gestation to a 29-year-old gravida VI, para V black woman. Prenatal serologic tests revealed an absence of antibodies to the human immunodeficiency virus, a negative hepatitis B surface antigen, and immunity to rubella. The mother had received treatment for syphilis 10 years before the pregnancy, and she had no history of genital HSV infection. Five days before delivery, there was rupture of fetal membranes. The mother subsequently developed intrapartum fever, and she received ampicillin and gentamicin. No HSV lesions were noted at delivery, and a fetal scalp electrode was used during labor for monitoring of the fetal heart rate. Examination of the placenta revealed necrotizing acute chorioamnionitis and necrotizing funisitis.
The infant had Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. She experienced mild respiratory distress at birth that resolved after 2 days without need for supplemental oxygen. Chest radiograph was normal and the infant's blood culture was sterile, but she received ampicillin and gentamicin for 7 days for presumed sepsis. A serum rapid plasma reagin test was nonreactive. The infant received mostly expressed breast milk for the first 2 to 3 weeks of age. Cranial ultrasonography was normal at 4 and 14 days of age.
She remained well in the neonatal intensive care unit until she was 19 days old, when a vesicular lesion with an erythematous base was noted on her chest. She had no fever, lethargy, apnea, or feeding intolerance, and her physical examination was otherwise normal without hepatosplenomegaly. A complete blood cell (CBC) count revealed a hemoglobin level of 10.4 g/L, a hematocrit level of 31%, a white blood cell (WBC) count of 12.7 x 109/L (with 14% segmented neutrophils, 3% metamyelocytes, 73% lymphocytes, 7% monocytes, and 3% eosinophils), and a platelet count of 540 x 109/L. Liver-function tests were normal, with a total bilirubin of 0.4 mg/dL and a direct component of 0.1 mg/dL, alanine aminotransferase of 9 IU/L, aspartate aminotransferase of 30 IU/L, and alkaline phosphatase of 155 IU/L. The lumbar puncture yielded bloody cerebrospinal fluid (CSF); microscopic examination showed 17950 red blood cells (RBCs) per mm3, 31 WBCs per mm3 (54% segmented neutrophils, 33% lymphocytes, 10% monocytes, and 3% eosinophils), and glucose and protein concentrations of 45 and 360 mg/dL, respectively. A polymerase chain reaction (PCR) test (Mayo Medical Labs, Rochester, MN) of the CSF did not detect HSV DNA. The infant was treated with acyclovir (20 mg/kg intravenously every 8 hours). Viral cultures of the vesicular lesion, conjunctiva, throat, rectum, buffy coat, and CSF were performed, and HSV-2 was isolated only from the vesicle and a combined specimen of the conjunctiva, throat, and rectum. MRI of the brain performed on the 12th day of acyclovir therapy was normal. In addition, an ophthalmologic examination and hearing evaluation were normal. The patient's WBC count and creatinine remained normal during high-dose acyclovir therapy. At 33 days of age, a 14-day course of acyclovir was completed, and the infant was discharged from the hospital solely on ferrous sulfate for anemia.
Five days after completion of acyclovir therapy, the infant had recurrence of a skin vesicle at the same site of the initial lesion. Therapy with intravenous acyclovir (20 mg/kg per dose) was reinstituted. Culture of the vesicle grew HSV-2 that was susceptible to acyclovir (median effective dose: 0.25 μg/mL; Viromed Laboratories, Minnetonka, MN). CBC count and liver transaminase concentrations were normal, and CSF analysis showed 15 WBCs per mm3 (3% neutrophils, 71% lymphocytes, and 26% monocytes), 2 RBCs per mm3, a glucose level of 40 mg/dL, and protein concentration of 97 mg/dL. CSF HSV PCR was negative, and after 4 days of intravenous acyclovir, the infant was discharged from the hospital. Acyclovir (20 mg/kg per dose every 6 hours) was provided orally for 5 days until the skin lesion healed; the infant then received acyclovir (300 mg/m2 per dose orally 3 times a day) to suppress additional skin recurrences. Tolerance and adherence to the acyclovir therapy was excellent, and WBC counts remained normal without neutropenia.
The infant remained well until 3 months of age, when she presented to the emergency department with fever of up to 104°F for 4 days and focal seizures for 1 day. No skin lesions suggestive of HSV were present. A CBC count showed a hemoglobin concentration of 10 g/dL and hematocrit level of 30%, a WBC count of 7.7 x 109/L (18% neutrophils, 2% band forms, 5% monocytes, and 76% lymphocytes), and a platelet count of 267 x 109/L. Electrolytes, glucose, calcium, phosphorus, and magnesium were normal. Liver-function tests showed alanine aminotransferase of 17 IU/L, aspartate aminotransferase of 49 IU/L, alkaline phosphatase of 124 IU/L, and total bilirubin of <0.1 mg/dL. Examination of CSF revealed 1415 RBCs per mm3, 97 WBCs per mm3 (46% segmented neutrophils, 27% lymphocytes, and 27% monocytes), a glucose level of 47 mg/dL, and a protein concentration of 131 mg/dL. Intravenous therapy with acyclovir (20 mg/kg per dose every 8 hours), ceftriaxone, and fosphenytoin was initiated. Viral cultures of CSF, mouth, rectum, and buffy coat were negative. CSF enteroviral PCR was negative, but CSF HSV PCR (ARUP Laboratories, Salt Lake City, UT) was positive. Electroencephalography was consistent with left-sided focal seizures. A cranial computed tomography (CT) scan without contrast showed a subtle region of increased density in the left parietal lobe with surrounding edema, and subsequent MRI of the brain revealed multifocal cortical and subcortical edema throughout the cerebral hemispheres and nodular peripheral enhancement involving the cerebellar hemispheres consistent with encephalitis (Fig 1). Ophthalmologic evaluation was normal. The infant gradually improved over the following 5 days, and ceftriaxone was discontinued after bacterial cultures were sterile. Phenobarbital was started and continued at discharge. A repeat evaluation of the CSF after 9 days of acyclovir therapy revealed 3 RBCs per mm3; 88 WBCs per mm3 (68% lymphocytes and 32% monocytes), a glucose level of 44 mg/dL, and a protein concentration of 246 mg/dL. CSF HSV PCR and viral culture at this time were negative. The infant received intravenous acyclovir for 21 days followed by reinitiation of oral acyclovir suppression.
Acyclovir was discontinued at 6 months of age. MRI of the brain at 12 months of age revealed generalized cortical volume loss and macrocystic encephalomalacia involving the majority of the left temporal and parietal lobes (Fig 2). At 13 months of age, her physical examination was normal. Developmental assessment using Bayley Scales of Infant Development II for an adjusted age of 12 months showed mild developmental delay in cognitive abilities, primarily in the areas of language and problem solving. Her fine and gross motor development was within normal limits. Her Mental Developmental Index was 74 (confidence interval: 68-86) and her Psychomotor Developmental Index was 101 (confidence interval: 91-111), corresponding to developmental ages of 9 and 12 months, respectively.
DISCUSSION
HSV infection occurs in 1 in 2000 to 5000 neonates per year.1 Approximately 45% of these infections are confined to the skin, eye, or mouth, whereas 30% manifest as encephalitis and 25% as disseminated disease.2 The use of intravenous acyclovir has reduced the mortality in infants with central nervous system (CNS) disease from 40% to 15%, and in disseminated disease, from 70% to 50%. In contrast, all infants with SEM disease survive their infection if it does not disseminate or result in encephalitis. Acyclovir also is responsible for the significant improvement in morbidity seen among survivors of neonatal HSV infection. Recently, Kimberlin et al5 demonstrated that higher doses of acyclovir provided for 21 days further improved the outcome of these infants. For disseminated disease, such therapy was associated with improved survival at 24 months. In addition, recipients of high-dose acyclovir were 7 times more likely to have normal development at 12 months of age than historical control infants who had received standard-dose therapy for 10 days.
Despite intravenous acyclovir therapy, as many as 40% to 60% of infants with disseminated and CNS disease, respectively, experience abnormal neurologic outcomes. In an effort to reduce such sequelae, acyclovir provided orally has been used to suppress reactivation of latent virus that might lead to additional CNS injury. In a retrospective descriptive study of 6 patients, 5 infants 13 to 42 days old and one 4-year-old child, with HSV encephalitis, Gutman et al6 found that HSV encephalitis in infants may result in late persistent or recurrent disease of the CNS and suggested that suppressive acyclovir therapy may improve outcome. In this study, 2 infants had recurrence or worsening of HSV encephalitis within several days of completing an initial course of intravenous vidarabine or acyclovir therapy for 10 days. They had not received suppressive oral therapy with acyclovir before their deterioration, and both were treated with a second course of antiviral therapy. Two infants who did not receive acyclovir suppression had late developmental deterioration that was associated with elevation of CSF protein or pleocytosis in the first year after their acute HSV encephalitis. One of these infants had worsening of seizures and irritability with progressive cerebral atrophy and hydrocephalus and died at 18 months of age, whereas the other had recurrent episodes of irritability, fever, and loss of developmental milestones and developed severe and progressive neurologic impairment at 16 months. An additional infant had elevated CSF protein concentration and severe impairment at 4 months of age. In contrast, 2 infants who received oral acyclovir at a dose of 1800 mg/m2 per day after completion of parenteral acyclovir therapy had mild neurologic impairment at 1 year of age and no CNS recurrence.
Among neonates with SEM disease treated with intravenous acyclovir, 2% to 6% experience adverse neurologic sequelae including spastic quadriplegia, microcephaly, blindness, persistent seizure disorder, and developmental delay.3–5 A direct correlation exists between the frequency of cutaneous recurrences after SEM disease and abnormal sequelae. Whitley et al4 found that among 85 infants with SEM disease, the likelihood of normal development was 100% if the infants had <3 cutaneous recurrences within the first 6 months of age, as compared with 79% of infants who had 3 recurrences. All the infants with neurologic impairment had cutaneous infection with HSV-2. It is known that after the initial episode of SEM disease, 50% of infants will develop from 1 to 12 cutaneous recurrences in the first year of age. It has been proposed that viremia with HSV during a cutaneous recurrence could result in invasion of the CNS.4 Alternatively, these infants may have had unrecognized CNS infection at the time of their initial infection, with subclinical reactivation of latent CNS virus subsequently resulting in neurologic impairment.7 In the latter situation, a cutaneous recurrence may be only a marker for CNS reactivation. In either case, suppression of these cutaneous recurrences could provide protection for the CNS.4
In a phase I/II trial performed by the Collaborative Antiviral Study Group and sponsored by the National Institutes of Allergy and Infectious Diseases, 13 (81%) of 16 infants with neonatal HSV SEM disease had no cutaneous recurrence after the administration of acyclovir at a dose of 300 mg/m2 orally 3 times a day for 6 months.8 However, almost half of the infants who received acyclovir developed neutropenia while on therapy. In addition, after completion of 6 months of suppressive therapy, 1 infant had HSV that was resistant to acyclovir isolated from a cutaneous recurrence. Supporting the possibility of CNS invasion during cutaneous recurrence was the finding of a positive CSF HSV DNA PCR despite normal CSF indices and a negative CSF HSV culture in 1 infant with a recurrent skin vesicle after HSV-2 SEM disease. This infant was in the second month of acyclovir suppression (300 mg/m2 per dose) when the recurrence occurred, and no additional antiviral therapy was administered. At 1 year of age, the infant's neurodevelopment was normal. The Collaborative Antiviral Study Group is currently conducting a phase III trial of oral acyclovir versus placebo in infants with HSV SEM or CNS disease to evaluate whether suppressive therapy with acyclovir improves neurologic outcome. Our case highlights the need for such a randomized, placebo-controlled study. Unfortunately, our patient was not eligible for this trial because her CSF was hemorrhagic.
Mandyla et al9 reported 2 infants who had recurrence of HSV encephalitis at 8 and 11 months of age while receiving acyclovir suppression at a dose of 15 mg/kg provided orally twice a day. Both infants, however, had experienced clinically apparent HSV encephalitis in the neonatal period, and neither had cutaneous disease. At 3 months of age, our patient developed HSV encephalitis as manifested by fever, seizures, abnormal CSF indices, abnormal brain MRI, and positive CSF HSV PCR despite receiving suppressive doses of oral acyclovir. The reason for the occurrence of encephalitis in our patient is unclear. It is possible that this infant had CNS infection during her initial cutaneous disease and that the encephalitis at 3 months of age was caused by reactivation of the virus. Supporting this view is the elevated protein content of the CSF during the initial episode, although the CSF specimen was bloody with >17000 RBCs per mm3 and thus difficult (if not impossible) to interpret. The infant, however, had no systemic signs of HSV disease, the CSF HSV PCR was negative, and the brain MRI on day 12 of therapy was normal. PCR, however, may fail to detect HSV DNA in the initial CSF of infants despite having abnormal CSF indices and focal electroencephalographic abnormalities, suggesting that viral replication could be limited to only small or localized areas of the brain.10 In retrospect, repeat evaluation of CSF for routine indices and PCR may have been helpful to ascertain whether CNS disease was present. In addition, the 14-day duration of acyclovir therapy that our patient received for presumed SEM disease may not have been sufficient, although it is the currently recommended treatment for this form of neonatal herpes infection.11 It also is possible that a longer duration of acyclovir therapy during the cutaneous recurrence at 38 days of age or repeat CNS imaging may have impacted on the subsequent occurrence of CNS disease.
Alternatively, our patient may have had new onset of clinically apparent HSV encephalitis as a result of spread from other tissues or sites to the brain at 3 months of age. Because there was no cutaneous recurrence, the source of the virus is unclear. In addition to the vesicular lesion, a combined culture of the infant's throat, conjunctiva, and rectum yielded HSV-2 at initial presentation at 19 days of age. It is conceivable that reactivation of the virus in the throat could have led to CNS disease. It has been hypothesized that encephalitis results from retrograde axonal transmission of HSV to the CNS, during which an initial focal pattern of CNS involvement subsequently becomes generalized.1 The head CT scan obtained on admission at 3 months of age in our patient revealed focal abnormalities, whereas MRI of the brain performed 2 days later showed multifocal involvement. These findings, however, may reflect the superiority of MRI over CT scan to detect changes consistent with encephalitis.12 In contrast, there was no clinical or laboratory evidence for disseminated disease at either the initial presentation or the time of CNS disease. Disseminated disease usually involves the liver and adrenal glands; our patient's hepatic enzymes were normal, and there was no bleeding diathesis. HSV PCR of blood ultimately may be more useful in diagnosing bloodstream dissemination13; however, this test was not done in our case. An HSV culture of buffy coat, however, was negative for HSV.
The bioavailability of oral acyclovir is suboptimal,8,14 which may have contributed to the occurrence of encephalitis in our patient. Acyclovir provided orally may prevent cutaneous recurrences, but the CSF levels may not be sufficiently high to prevent CNS reactivation. In our patient, acyclovir serum concentrations were not measured, but adherence was excellent by maternal report. The infant's prematurity also may have contributed to lower intestinal absorption. Valacyclovir may be a better bioavailable agent in these infants when a liquid formulation becomes available.
An additional concern was the possibility of acyclovir resistance leading to viral reactivation and CNS disease. Although an uncommon event,15 resistance to acyclovir has been reported in HSV isolates from a 10-day-old neonate with laryngeal HSV infection,16 an infant after completion of 6 months of suppressive therapy with oral acyclovir,8 a preterm infant who had recurrence of disseminated disease 8 days after completion of antiviral therapy,17 and, more recently, a fatal case of neonatal HSV disease.18 The possibility that the encephalitis in our patient could have been due to an acyclovir-resistant isolate was considered in our case. However, our patient improved clinically after institution of intravenous acyclovir therapy, and a repeat CSF HSV PCR was negative. Unfortunately, because HSV was not isolated from any site when our patient developed encephalitis, susceptibility testing was not possible.
CONCLUSIONS
We report a preterm infant who had cutaneous disease with HSV-2 and subsequently experienced HSV encephalitis despite receiving daily suppressive therapy with oral acyclovir. Although it is not known whether the HSV encephalitis in our patient represented reactivation of previously unrecognized CNS infection or new onset of clinically apparent CNS disease as a result of spread from other tissue or site to the brain, the failure of oral acyclovir to prevent such an occurrence is concerning. The practice of instituting suppressive therapy with oral acyclovir after neonatal HSV infection is becoming more prevalent without evidence to support it. It remains imperative for clinicians to know that such therapy may not prevent systemic disease. Moreover, its routine use cannot be recommended until results of an ongoing efficacy trial are known.19
ACKNOWLEDGMENTS
We acknowledge the assistance of Dr Timothy Booth and Dr Wendy Chung in the selection and review of the neuroimaging studies. We thank Cathy Boatman, MS, for performing the developmental assessment.
FOOTNOTES
Accepted Jul 27, 2004.
No conflict of interest declared.
REFERENCES
Arvin AMW, Richard J. Herpes simplex virus infections. In: Remington JSK, Jerome O, eds. Infectious Diseases of the Fetus and Newborn Infant. 5th ed. Philadelphia, PA: Saunders; 2001
Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108 :223 –229
Whitley R, Arvin A, Prober C, 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 :444 –449
Whitley R, Arvin A, Prober C, 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 :450 –454
Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108 :230 –238
Gutman LT, Wilfert CM, Eppes S. Herpes simplex virus encephalitis in children: analysis of cerebrospinal fluid and progressive neurodevelopmental deterioration. J Infect Dis. 1986;154 :415 –421
Kohl S. A hypothesis on the pathophysiology of neonatal herpes simplex virus encephalitis: clinical recurrence after asymptomatic primary infection. Pediatr Infect Dis J. 1990;9 :307 –308
Kimberlin D, Powell D, Gruber W, et al. Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase I/II trial. Pediatr Infect Dis J. 1996;15 :247 –254
Mandyla H, Anagnostakis D, Koutsovitis P, Siahanidou T, Youroukos S. Late recurrence of herpes simplex virus meningoencephalitis in two infants. Eur J Pediatr. 2001;160 :732 –735
Kimberlin DW, Lakeman FD, Arvin AM, 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 :1162 –1167
American Academy of Pediatrics. Herpes simplex. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:344–353
Koelfen W, Freund M, Guckel F, Rohr H, Schultze C. MRI of encephalitis in children: comparison of CT and MRI in the acute stage with long-term follow-up. Neuroradiology. 1996;38 :73 –79
Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J. 1999;18 :487 –489
Whitley RJ, Gnann JW, Jr. Acyclovir: a decade later. N Engl J Med. 1992;327 :782 –789
Rabalais GP, Nusinoff-Lehrman S, Arvin AM, Levin MJ. Antiviral susceptibilities of herpes simplex virus isolates from infants with recurrent mucocutaneous lesions after neonatal infection. Pediatr Infect Dis J. 1989;8 :221 –223
Nyquist AC, Rotbart HA, Cotton M, et al. Acyclovir-resistant neonatal herpes simplex virus infection of the larynx. J Pediatr. 1994;124 :967 –971
Oram RJ, Marcellino D, Strauss D, et al. Characterization of an acyclovir-resistant herpes simplex virus type 2 strain isolated from a premature neonate. J Infect Dis. 2000;181 :1458 –1461
Levin MJ, Weinberg A, Leary JJ, Sarisky RT. Development of acyclovir-resistant herpes simplex virus early during the treatment of herpes neonatorum. Pediatr Infect Dis J. 2001;20 :1094 –1097
Gutierrez K, Arvin AM. Long term antiviral suppression after treatment for neonatal herpes infection. Pediatr Infect Dis J. 2003;22 :371 –372(Monica Fonseca-Aten, MD, )
ABSTRACT
Cutaneous herpes simplex virus type 2 (HSV-2) infection was recognized at 19 days of age in a 1415-g female infant born at 31 weeks of gestation. Cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) was negative, and MRI of the brain was normal. After a 14-day course of high-dose intravenous acyclovir, the infant developed a cutaneous recurrence at 38 days of age. CSF HSV PCR again was negative. She was subsequently begun on oral acyclovir to prevent cutaneous reactivation of HSV. At 3 months of age, the infant developed HSV encephalitis as manifested by fever, seizures, abnormal CSF indices, abnormal brain MRI, and positive CSF HSV PCR. No cutaneous disease was present. It is not known whether the HSV encephalitis in our patient represented reactivation of previously unrecognized central nervous system infection or new onset of central nervous system disease as a result of spread from other tissue or site to the brain. The failure of oral acyclovir to prevent such an occurrence, however, highlights gaps in our understanding of the pathogenesis of neonatal HSV disease and questions the use of acyclovir suppression to prevent neurologic sequelae.
Key Words: herpes simplex virus acyclovir encephalitis prophylaxis
Abbreviations: HSV, herpes simplex virus SEM, skin, eye, and mouth CBC, complete blood cell WBC, white blood cell CSF, cerebrospinal fluid RBC, red blood cell PCR, polymerase chain reaction CT, computed tomography CNS, central nervous system
Despite the availability of specific antiviral therapy and provision of a longer treatment course with high-dose acyclovir, significant morbidity persists after neonatal herpes simplex virus (HSV) infections.1,2 The majority of neonates who survive HSV encephalitis and disseminated disease suffer from significant neurodevelopmental problems that include spastic quadriplegia, psychomotor retardation, learning disabilities, and blindness. On the other hand, only 2% of neonates with HSV infection that is limited to the skin, eye, or mouth (SEM) and who receive intravenous acyclovir therapy have long-term neurologic sequelae.2,3 Whitley et al4 associated abnormal neurologic outcome in these infants with the occurrence of 3 skin recurrences with HSV-2 in the first 6 months of age. For these reasons, the use of oral acyclovir for suppression of skin recurrences with HSV-2 has been widely implemented despite the lack of evidence of a beneficial effect.
We report a premature infant with neonatal HSV-2 cutaneous disease who developed encephalitis due to HSV during administration of suppressive therapy with oral acyclovir. This report highlights the importance of placebo-controlled, randomized studies to determine if the practice of oral acyclovir suppression after neonatal HSV infection is beneficial.
CASE REPORT
A 1415-g female infant was delivered vaginally at 31 weeks of gestation to a 29-year-old gravida VI, para V black woman. Prenatal serologic tests revealed an absence of antibodies to the human immunodeficiency virus, a negative hepatitis B surface antigen, and immunity to rubella. The mother had received treatment for syphilis 10 years before the pregnancy, and she had no history of genital HSV infection. Five days before delivery, there was rupture of fetal membranes. The mother subsequently developed intrapartum fever, and she received ampicillin and gentamicin. No HSV lesions were noted at delivery, and a fetal scalp electrode was used during labor for monitoring of the fetal heart rate. Examination of the placenta revealed necrotizing acute chorioamnionitis and necrotizing funisitis.
The infant had Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. She experienced mild respiratory distress at birth that resolved after 2 days without need for supplemental oxygen. Chest radiograph was normal and the infant's blood culture was sterile, but she received ampicillin and gentamicin for 7 days for presumed sepsis. A serum rapid plasma reagin test was nonreactive. The infant received mostly expressed breast milk for the first 2 to 3 weeks of age. Cranial ultrasonography was normal at 4 and 14 days of age.
She remained well in the neonatal intensive care unit until she was 19 days old, when a vesicular lesion with an erythematous base was noted on her chest. She had no fever, lethargy, apnea, or feeding intolerance, and her physical examination was otherwise normal without hepatosplenomegaly. A complete blood cell (CBC) count revealed a hemoglobin level of 10.4 g/L, a hematocrit level of 31%, a white blood cell (WBC) count of 12.7 x 109/L (with 14% segmented neutrophils, 3% metamyelocytes, 73% lymphocytes, 7% monocytes, and 3% eosinophils), and a platelet count of 540 x 109/L. Liver-function tests were normal, with a total bilirubin of 0.4 mg/dL and a direct component of 0.1 mg/dL, alanine aminotransferase of 9 IU/L, aspartate aminotransferase of 30 IU/L, and alkaline phosphatase of 155 IU/L. The lumbar puncture yielded bloody cerebrospinal fluid (CSF); microscopic examination showed 17950 red blood cells (RBCs) per mm3, 31 WBCs per mm3 (54% segmented neutrophils, 33% lymphocytes, 10% monocytes, and 3% eosinophils), and glucose and protein concentrations of 45 and 360 mg/dL, respectively. A polymerase chain reaction (PCR) test (Mayo Medical Labs, Rochester, MN) of the CSF did not detect HSV DNA. The infant was treated with acyclovir (20 mg/kg intravenously every 8 hours). Viral cultures of the vesicular lesion, conjunctiva, throat, rectum, buffy coat, and CSF were performed, and HSV-2 was isolated only from the vesicle and a combined specimen of the conjunctiva, throat, and rectum. MRI of the brain performed on the 12th day of acyclovir therapy was normal. In addition, an ophthalmologic examination and hearing evaluation were normal. The patient's WBC count and creatinine remained normal during high-dose acyclovir therapy. At 33 days of age, a 14-day course of acyclovir was completed, and the infant was discharged from the hospital solely on ferrous sulfate for anemia.
Five days after completion of acyclovir therapy, the infant had recurrence of a skin vesicle at the same site of the initial lesion. Therapy with intravenous acyclovir (20 mg/kg per dose) was reinstituted. Culture of the vesicle grew HSV-2 that was susceptible to acyclovir (median effective dose: 0.25 μg/mL; Viromed Laboratories, Minnetonka, MN). CBC count and liver transaminase concentrations were normal, and CSF analysis showed 15 WBCs per mm3 (3% neutrophils, 71% lymphocytes, and 26% monocytes), 2 RBCs per mm3, a glucose level of 40 mg/dL, and protein concentration of 97 mg/dL. CSF HSV PCR was negative, and after 4 days of intravenous acyclovir, the infant was discharged from the hospital. Acyclovir (20 mg/kg per dose every 6 hours) was provided orally for 5 days until the skin lesion healed; the infant then received acyclovir (300 mg/m2 per dose orally 3 times a day) to suppress additional skin recurrences. Tolerance and adherence to the acyclovir therapy was excellent, and WBC counts remained normal without neutropenia.
The infant remained well until 3 months of age, when she presented to the emergency department with fever of up to 104°F for 4 days and focal seizures for 1 day. No skin lesions suggestive of HSV were present. A CBC count showed a hemoglobin concentration of 10 g/dL and hematocrit level of 30%, a WBC count of 7.7 x 109/L (18% neutrophils, 2% band forms, 5% monocytes, and 76% lymphocytes), and a platelet count of 267 x 109/L. Electrolytes, glucose, calcium, phosphorus, and magnesium were normal. Liver-function tests showed alanine aminotransferase of 17 IU/L, aspartate aminotransferase of 49 IU/L, alkaline phosphatase of 124 IU/L, and total bilirubin of <0.1 mg/dL. Examination of CSF revealed 1415 RBCs per mm3, 97 WBCs per mm3 (46% segmented neutrophils, 27% lymphocytes, and 27% monocytes), a glucose level of 47 mg/dL, and a protein concentration of 131 mg/dL. Intravenous therapy with acyclovir (20 mg/kg per dose every 8 hours), ceftriaxone, and fosphenytoin was initiated. Viral cultures of CSF, mouth, rectum, and buffy coat were negative. CSF enteroviral PCR was negative, but CSF HSV PCR (ARUP Laboratories, Salt Lake City, UT) was positive. Electroencephalography was consistent with left-sided focal seizures. A cranial computed tomography (CT) scan without contrast showed a subtle region of increased density in the left parietal lobe with surrounding edema, and subsequent MRI of the brain revealed multifocal cortical and subcortical edema throughout the cerebral hemispheres and nodular peripheral enhancement involving the cerebellar hemispheres consistent with encephalitis (Fig 1). Ophthalmologic evaluation was normal. The infant gradually improved over the following 5 days, and ceftriaxone was discontinued after bacterial cultures were sterile. Phenobarbital was started and continued at discharge. A repeat evaluation of the CSF after 9 days of acyclovir therapy revealed 3 RBCs per mm3; 88 WBCs per mm3 (68% lymphocytes and 32% monocytes), a glucose level of 44 mg/dL, and a protein concentration of 246 mg/dL. CSF HSV PCR and viral culture at this time were negative. The infant received intravenous acyclovir for 21 days followed by reinitiation of oral acyclovir suppression.
Acyclovir was discontinued at 6 months of age. MRI of the brain at 12 months of age revealed generalized cortical volume loss and macrocystic encephalomalacia involving the majority of the left temporal and parietal lobes (Fig 2). At 13 months of age, her physical examination was normal. Developmental assessment using Bayley Scales of Infant Development II for an adjusted age of 12 months showed mild developmental delay in cognitive abilities, primarily in the areas of language and problem solving. Her fine and gross motor development was within normal limits. Her Mental Developmental Index was 74 (confidence interval: 68-86) and her Psychomotor Developmental Index was 101 (confidence interval: 91-111), corresponding to developmental ages of 9 and 12 months, respectively.
DISCUSSION
HSV infection occurs in 1 in 2000 to 5000 neonates per year.1 Approximately 45% of these infections are confined to the skin, eye, or mouth, whereas 30% manifest as encephalitis and 25% as disseminated disease.2 The use of intravenous acyclovir has reduced the mortality in infants with central nervous system (CNS) disease from 40% to 15%, and in disseminated disease, from 70% to 50%. In contrast, all infants with SEM disease survive their infection if it does not disseminate or result in encephalitis. Acyclovir also is responsible for the significant improvement in morbidity seen among survivors of neonatal HSV infection. Recently, Kimberlin et al5 demonstrated that higher doses of acyclovir provided for 21 days further improved the outcome of these infants. For disseminated disease, such therapy was associated with improved survival at 24 months. In addition, recipients of high-dose acyclovir were 7 times more likely to have normal development at 12 months of age than historical control infants who had received standard-dose therapy for 10 days.
Despite intravenous acyclovir therapy, as many as 40% to 60% of infants with disseminated and CNS disease, respectively, experience abnormal neurologic outcomes. In an effort to reduce such sequelae, acyclovir provided orally has been used to suppress reactivation of latent virus that might lead to additional CNS injury. In a retrospective descriptive study of 6 patients, 5 infants 13 to 42 days old and one 4-year-old child, with HSV encephalitis, Gutman et al6 found that HSV encephalitis in infants may result in late persistent or recurrent disease of the CNS and suggested that suppressive acyclovir therapy may improve outcome. In this study, 2 infants had recurrence or worsening of HSV encephalitis within several days of completing an initial course of intravenous vidarabine or acyclovir therapy for 10 days. They had not received suppressive oral therapy with acyclovir before their deterioration, and both were treated with a second course of antiviral therapy. Two infants who did not receive acyclovir suppression had late developmental deterioration that was associated with elevation of CSF protein or pleocytosis in the first year after their acute HSV encephalitis. One of these infants had worsening of seizures and irritability with progressive cerebral atrophy and hydrocephalus and died at 18 months of age, whereas the other had recurrent episodes of irritability, fever, and loss of developmental milestones and developed severe and progressive neurologic impairment at 16 months. An additional infant had elevated CSF protein concentration and severe impairment at 4 months of age. In contrast, 2 infants who received oral acyclovir at a dose of 1800 mg/m2 per day after completion of parenteral acyclovir therapy had mild neurologic impairment at 1 year of age and no CNS recurrence.
Among neonates with SEM disease treated with intravenous acyclovir, 2% to 6% experience adverse neurologic sequelae including spastic quadriplegia, microcephaly, blindness, persistent seizure disorder, and developmental delay.3–5 A direct correlation exists between the frequency of cutaneous recurrences after SEM disease and abnormal sequelae. Whitley et al4 found that among 85 infants with SEM disease, the likelihood of normal development was 100% if the infants had <3 cutaneous recurrences within the first 6 months of age, as compared with 79% of infants who had 3 recurrences. All the infants with neurologic impairment had cutaneous infection with HSV-2. It is known that after the initial episode of SEM disease, 50% of infants will develop from 1 to 12 cutaneous recurrences in the first year of age. It has been proposed that viremia with HSV during a cutaneous recurrence could result in invasion of the CNS.4 Alternatively, these infants may have had unrecognized CNS infection at the time of their initial infection, with subclinical reactivation of latent CNS virus subsequently resulting in neurologic impairment.7 In the latter situation, a cutaneous recurrence may be only a marker for CNS reactivation. In either case, suppression of these cutaneous recurrences could provide protection for the CNS.4
In a phase I/II trial performed by the Collaborative Antiviral Study Group and sponsored by the National Institutes of Allergy and Infectious Diseases, 13 (81%) of 16 infants with neonatal HSV SEM disease had no cutaneous recurrence after the administration of acyclovir at a dose of 300 mg/m2 orally 3 times a day for 6 months.8 However, almost half of the infants who received acyclovir developed neutropenia while on therapy. In addition, after completion of 6 months of suppressive therapy, 1 infant had HSV that was resistant to acyclovir isolated from a cutaneous recurrence. Supporting the possibility of CNS invasion during cutaneous recurrence was the finding of a positive CSF HSV DNA PCR despite normal CSF indices and a negative CSF HSV culture in 1 infant with a recurrent skin vesicle after HSV-2 SEM disease. This infant was in the second month of acyclovir suppression (300 mg/m2 per dose) when the recurrence occurred, and no additional antiviral therapy was administered. At 1 year of age, the infant's neurodevelopment was normal. The Collaborative Antiviral Study Group is currently conducting a phase III trial of oral acyclovir versus placebo in infants with HSV SEM or CNS disease to evaluate whether suppressive therapy with acyclovir improves neurologic outcome. Our case highlights the need for such a randomized, placebo-controlled study. Unfortunately, our patient was not eligible for this trial because her CSF was hemorrhagic.
Mandyla et al9 reported 2 infants who had recurrence of HSV encephalitis at 8 and 11 months of age while receiving acyclovir suppression at a dose of 15 mg/kg provided orally twice a day. Both infants, however, had experienced clinically apparent HSV encephalitis in the neonatal period, and neither had cutaneous disease. At 3 months of age, our patient developed HSV encephalitis as manifested by fever, seizures, abnormal CSF indices, abnormal brain MRI, and positive CSF HSV PCR despite receiving suppressive doses of oral acyclovir. The reason for the occurrence of encephalitis in our patient is unclear. It is possible that this infant had CNS infection during her initial cutaneous disease and that the encephalitis at 3 months of age was caused by reactivation of the virus. Supporting this view is the elevated protein content of the CSF during the initial episode, although the CSF specimen was bloody with >17000 RBCs per mm3 and thus difficult (if not impossible) to interpret. The infant, however, had no systemic signs of HSV disease, the CSF HSV PCR was negative, and the brain MRI on day 12 of therapy was normal. PCR, however, may fail to detect HSV DNA in the initial CSF of infants despite having abnormal CSF indices and focal electroencephalographic abnormalities, suggesting that viral replication could be limited to only small or localized areas of the brain.10 In retrospect, repeat evaluation of CSF for routine indices and PCR may have been helpful to ascertain whether CNS disease was present. In addition, the 14-day duration of acyclovir therapy that our patient received for presumed SEM disease may not have been sufficient, although it is the currently recommended treatment for this form of neonatal herpes infection.11 It also is possible that a longer duration of acyclovir therapy during the cutaneous recurrence at 38 days of age or repeat CNS imaging may have impacted on the subsequent occurrence of CNS disease.
Alternatively, our patient may have had new onset of clinically apparent HSV encephalitis as a result of spread from other tissues or sites to the brain at 3 months of age. Because there was no cutaneous recurrence, the source of the virus is unclear. In addition to the vesicular lesion, a combined culture of the infant's throat, conjunctiva, and rectum yielded HSV-2 at initial presentation at 19 days of age. It is conceivable that reactivation of the virus in the throat could have led to CNS disease. It has been hypothesized that encephalitis results from retrograde axonal transmission of HSV to the CNS, during which an initial focal pattern of CNS involvement subsequently becomes generalized.1 The head CT scan obtained on admission at 3 months of age in our patient revealed focal abnormalities, whereas MRI of the brain performed 2 days later showed multifocal involvement. These findings, however, may reflect the superiority of MRI over CT scan to detect changes consistent with encephalitis.12 In contrast, there was no clinical or laboratory evidence for disseminated disease at either the initial presentation or the time of CNS disease. Disseminated disease usually involves the liver and adrenal glands; our patient's hepatic enzymes were normal, and there was no bleeding diathesis. HSV PCR of blood ultimately may be more useful in diagnosing bloodstream dissemination13; however, this test was not done in our case. An HSV culture of buffy coat, however, was negative for HSV.
The bioavailability of oral acyclovir is suboptimal,8,14 which may have contributed to the occurrence of encephalitis in our patient. Acyclovir provided orally may prevent cutaneous recurrences, but the CSF levels may not be sufficiently high to prevent CNS reactivation. In our patient, acyclovir serum concentrations were not measured, but adherence was excellent by maternal report. The infant's prematurity also may have contributed to lower intestinal absorption. Valacyclovir may be a better bioavailable agent in these infants when a liquid formulation becomes available.
An additional concern was the possibility of acyclovir resistance leading to viral reactivation and CNS disease. Although an uncommon event,15 resistance to acyclovir has been reported in HSV isolates from a 10-day-old neonate with laryngeal HSV infection,16 an infant after completion of 6 months of suppressive therapy with oral acyclovir,8 a preterm infant who had recurrence of disseminated disease 8 days after completion of antiviral therapy,17 and, more recently, a fatal case of neonatal HSV disease.18 The possibility that the encephalitis in our patient could have been due to an acyclovir-resistant isolate was considered in our case. However, our patient improved clinically after institution of intravenous acyclovir therapy, and a repeat CSF HSV PCR was negative. Unfortunately, because HSV was not isolated from any site when our patient developed encephalitis, susceptibility testing was not possible.
CONCLUSIONS
We report a preterm infant who had cutaneous disease with HSV-2 and subsequently experienced HSV encephalitis despite receiving daily suppressive therapy with oral acyclovir. Although it is not known whether the HSV encephalitis in our patient represented reactivation of previously unrecognized CNS infection or new onset of clinically apparent CNS disease as a result of spread from other tissue or site to the brain, the failure of oral acyclovir to prevent such an occurrence is concerning. The practice of instituting suppressive therapy with oral acyclovir after neonatal HSV infection is becoming more prevalent without evidence to support it. It remains imperative for clinicians to know that such therapy may not prevent systemic disease. Moreover, its routine use cannot be recommended until results of an ongoing efficacy trial are known.19
ACKNOWLEDGMENTS
We acknowledge the assistance of Dr Timothy Booth and Dr Wendy Chung in the selection and review of the neuroimaging studies. We thank Cathy Boatman, MS, for performing the developmental assessment.
FOOTNOTES
Accepted Jul 27, 2004.
No conflict of interest declared.
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