Neonatal Herpes Simplex Virus Infection: a Challenging, Life-threatening Diagnosis
Jeremy Alan Franklin, MD, Texas Tech University Health Sciences Center?Lubbock
Published Online: May 17, 2007 - 11:48:21 PM (CDT)
Jeremy Alan Franklin, MD, FAAP Assistant Professor, Department of Pediatrics Chief, Division of Pediatric Infectious Disease Texas Tech University Health Sciences Center?Lubbock
Neonatal herpes simplex virus infection is a devastating disease associated with high morbidity and mortality. Infection may be limited to the skin, eyes, and mouth; however, many infants will have encephalitis or disseminated disease at the time of presentation. Diagnosis may be difficult in infants presenting without the characteristic vesicular rash. Infants may present with nonspecific symptoms, such as fever, lethargy, and poor feeding. Physicians must suspect this condition in any infant younger than 1 month who presents with clinical sepsis and negative bacteriologic cultures. Early diagnosis and initiation of high-dose intravenous acyclovir are essential for the proper care of infants with this type of infection. This article discusses the epidemiology, diagnosis, therapy, and prevention of neonatal infection with the herpes simplex virus.
Neonatal herpes simplex virus (HSV) infection can be difficult to recognize and is associated with significant morbidity and a high risk of mortality. Infants may present with disease limited to the skin, eyes, and mouth; isolated herpes simplex encephalitis; or disseminated disease.
HSV Virology The HSV type 1 and 2 (HSV-1 or HSV-2) is a large, double-stranded DNA virus with an icosahedral nucleocapsid. The herpes virus belongs to the Herpesviridae family, the Alphaherpesvirinae subfamily, and the Simplexvirus genera. The genomes of HSV-1 and HSV-2 exhibit great homology, but the HSV-2 genome has an inherently higher mutation rate than HSV-1. Important viral glycoproteins include1: (1) gD, which is a potent inducer of neutralizing antibody and is important in viral attachment and entry into cells; (2) gB, which is required for infectivity; (3) gH through gL, which are important in viral attachment and entry into cells; and (4) gG, which provides antigenic specificity, allowing serologic differentiation of HSV-1 from HSV-2 (gG-1 and gG-2, respectively).
After initial infection, HSV virions spread by retrograde axonal flow to sensory ganglia, where the virions establish latency.1 The neurovirulence of HSV is attributable to the thymidine kinase gene.1 Reactivation of the virus occurs periodically in response to stressors (eg, illness, fatigue, ultraviolet light, tissue damage1) despite host humoral and cellular immunity.
Clinical Manifestations Neonatal HSV infection was initially described independently by Hass and by Batignani in the 1930s.1 This infection may present as localized disease in the skin, eyes, and mouth, isolated herpes encephalitis, or as disseminated disease.2 Infection limited to the skin, eyes, and mouth occurs in 42% of cases, isolated herpes encephalitis occurs in 35% of cases, and disseminated infection in 23% of cases.3
Common clinical manifestations include fever, temperature instability, lethargy, irritability, vesicular rash, and seizures.2 Approximately 17% to 39% of all neonates with HSV infection lack cutaneous lesions.4 Between 39% and 70% of neonates with disseminated HSV infection lack cutaneous lesions.2,4 Limited skin (Figure), eye, and mouth infection has a very low mortality rate; however, 70% of those infected will progress to isolated herpes encephalitis or to disseminated infection if not treated appropriately.1
Disseminated infection generally presents on the fifth to seventh day of life and most frequently involves the liver, central nervous system (CNS), and lungs.2,5 Affected infants may present with elevated liver function tests, thrombocytopenia, disseminated intravascular coagulation, and viral pneumonia. Infants with congenital HSV infection may present with microcephaly, intracranial calcifications, hydrocephalus, chorioretinitis, microphthalmia, and cutaneous lesions.1
Illustrative Case A 5-day-old male infant was brought to the emergency department after 2 episodes of apnea associated with perioral cyanosis, lethargy, and poor breastfeeding. He had no fever, vomiting, diarrhea, cough, rhinorrhea, or rash, and no significant ill contacts. He had been born at term by vaginal delivery to a 17-year-old primiparous mother with no prenatal complications. Neither parent had a history of HSV infection and no genital HSV lesions had been noted at the time of delivery. Mother and infant had been discharged 48 hours after delivery.
In the emergency department, physical examination was remarkable only for extreme lethargy. Laboratory and radiographic findings were normal, except for elevated liver function tests, with total bilirubin, 3.1 mg/dL; aspartate aminotransferase, 527 IU/L; and alanine aminotransferase, 126 IU/L. Cultures of blood, urine, and cerebrospinal fluid (CSF) were obtained. Also, viral culture and HSV polymerase chain reaction (PCR) testing were ordered on the CSF. The infant was prescribed ampicillin, cefotaxime, and acyclovir (Zovirax) empirically.
Shortly after admission, the infant had an episode of apnea, bradycardia, and rightward deviation of the eyes. Magnetic resonance imaging of the brain and ophthalmologic evaluation were normal. Electroencephalogram (EEG) was markedly abnormal, with persistent discharges of sharp wave activity over both hemispheres, especially the left parietal and temporal areas.
Empiric antibiotics were discontinued after bacteriologic cultures were negative for 48 hours. The CSF HSV PCR test and viral culture were positive for HSV-1 infection. The patient was treated for 21 days with IV acyclovir, without complications. Repeat CSF HSV PCR testing and viral culture on day 16 of treatment were negative. While taking acyclovir, the patient improved clinically, his liver function tests returned to normal, and the EEG improved. Since discharge, he had 1 HSV cutaneous relapse at age older than 1 month, which was treated with oral acyclovir.
Epidemiology Neonatal HSV infection occurs in 11.4/100,000 to 1.6/1000 live births in the United States.6,7 Peripartum transmission of HSV infection is most common (85%-90%), but the infection can also be transmitted in utero (4%-5%) or postnatally (5%-10%).1,8 HSV-2 is responsible for up to 73% of cases of neonatal HSV infection in the United States.4
Factors associated with an increased risk of vertical transmission are listed in Table 1. Factors associated with an increased risk of morbidity and mortality are listed in Table 2. Of all infants with proven HSV infection, 74% to 88% lack a history of maternal genital herpes.9,10 Explanations for this discrepancy include parents? misreporting because of the social stigma associated with sexually transmitted diseases, as well as HSV infection that can occur with atypical or subclinical manifestations.2 For instance, up to 68% of pregnant women who are infected with HSV have subclinical infections.11
Diagnosis The diagnosis of neonatal HSV infections is often difficult and should be considered in any infant younger than 1 month who presents with sepsis and negative bacteriologic cultures.
Viral culture remains the definitive diagnostic test. In cases of suspected neonatal HSV infection, viral culture samples should be taken from the eyes, mouth, umbilicus, rectum, blood, urine, and any vesicular lesion.2 The herpes virus grows rapidly in cell culture, and more than 90% of cultures that become positive demonstrate the cytopathic effect typical of HSV infection within 4 days.2 HSV is rarely isolated from CSF.2 In cases of isolated herpes encephalitis, CSF viral cultures will be positive only in about 4% of adult patients and in 20% to 40% of neonatal patients.12,13
CSF findings in isolated herpes encephalitis include a mild mononuclear pleocytosis with elevated protein, usually without hypoglycorrachia. The presence of red blood cells in the CSF is neither pathognomonic nor required for the diagnosis of this infection.13 Infants may have normal CSF findings early in the course of isolated herpes encephalitis.2 PCR of the CSF has become the preferred diagnostic test for isolated herpes encephalitis.12 The sensitivity and specificity of HSV PCR tests on CSF for isolated or disseminated disease range from 70% to 100% and 71% to 100%, respectively.1,12 False-positive PCR results are usually due to contamination of the PCR equipment. False-negative PCR results may be due to obtaining the sample too early in the disease process, obtaining the specimen after the patient has been taking acyclovir for more than 7 days, poor laboratory technique in the amplification process, or the presence of PCR inhibitors, such as heme.12,14 HSV infection may be detected by PCR in the CSF up to 1 week after initiating antiviral therapy.14 HSV PCR testing should be repeated at the end of the treatment course.1
Persistence of HSV PCR positivity after 21 days of IV acyclovir therapy is associated with increased morbidity and mortality,1,12,14 and patients should therefore continue to receive IV acyclovir until the HSV PCR results are negative.1 When the diagnosis of isolated herpes encephalitis is strongly suspected, but the PCR results and viral cultures are negative, a brain biopsy should be considered. Brain tissue can be sent for viral culture, PCR testing, and histopathologic examination.2,12
Neuroradiographic imaging may show temporal lobe abnormalities or may be normal in early herpes encephalitis infection. EEG may demonstrate paroxysmal lateralizing epileptiform discharges, but this is not pathognomonic for isolated herpes encephalitis. Serology is not helpful in the diagnosis of neonatal HSV infection.1
Acyclovir Therapy Vidarabine was the first systemic antiviral treatment available in the United States for HSV infections with definite benefit and tolerable toxicity.1 Low-dose IV acyclovir, first used for the treatment of neonatal HSV infections in the early 1980s, demonstrated equivalent efficacy to vidarabine but with reduced toxicity and greater ease of administration.1 High-dose IV acyclovir retained the characteristics of decreased toxicity and increased ease of administration with the added benefit of improved efficacy in the treatment of neonatal HSV infection.1
The use of high-dose IV acyclovir is associated with a decrease in the overall neonatal HSV fatality rate from more than 70% to 20%,13 as well as a nearly 7-fold decrease in neurologic sequelae in survivors.15 The 2-year mortality rate for disseminated infection, however, remains 31%, even with high-dose IV acyclovir treatment.15
IV acyclovir should be administered at a dose of 60 mg/kg daily in 3 divided doses for 14 days in disease limited to the skin, eyes, or mouth and for a minimum of 21 days in HSV encephalitis and in disseminated disease.1,15 Oral acyclovir should never be used to treat neonatal HSV infection (ie, during the first month), because it has only a 10% to 20% bioavailability, and CNS concentrations of acyclovir are only about 50% of the serum concentrations.16 For recurrences that are limited to skin and mucous membranes, oral acyclovir may be considered.
Acyclovir side effects Neutropenia is a well-known consequence of prolonged high-dose acyclovir use.1,15 Approximately 20% of patients will develop neutropenia with an absolute neutrophil count (ANC) of <1000/μL.1,15 The neutropenia may resolve during acyclovir therapy, or it may persist until acyclovir has been discontinued.1 Patients with moderate acyclovir-induced neutropenia (ANC 500-1000/μL) generally do not manifest adverse sequelae related to the neutropenia.15 In patients with persistent, severe acyclovir-induced neutropenia (ANC <500/μL), the dose should be reduced or the patient should be given granulocyte colony-stimulating factor.1
Nephrotoxicity is another concern with prolonged acyclovir use. In one study, grade III to IV nephrotoxicity was found in 6% of the neonates treated with this medication.15 All these neonates had disseminated HSV infection, which could contribute to or completely explain the nephrotoxicity.15
Passive immunotherapy with monoclonal antibodies directed at glycoproteins gB and gD has shown promise as an adjuvant treatment for neonatal HSV infection in animal models. Clinical data support the role of antibodies in mitigating neonatal HSV infection, showing that infants with higher neutralizing antibody titers have lower HSV infection rates and are less likely to present with disseminated disease.1
Oral acyclovir Oral acyclovir is frequently used near the end of pregnancy in women with a history of recurrent genital herpes. Between 1984 and 1998, the Acyclovir in Pregnancy Registry demonstrated no differences in fetal outcomes and no increase in the incidence of birth defects in women receiving oral acyclovir during pregnancy.17 A decrease in cesarean section rates was also demonstrated.17
Prevention Cesarean sections performed within 4 to 6 hours after rupture of membranes in women with active genital HSV lesions can reduce the risk of neonatal HSV infection.8 In 1999, the American College of Obstetricians and Gynecologists (ACOG) issued updated guidelines recommending that women with active genital HSV lesions or prodromal symptoms consistent with HSV infection present at the time of delivery should undergo cesarean section.18 Based on implementation of ACOG recommendations, it is estimated that 1580 excess cesarean sections are performed to prevent 1 case of adverse neonatal outcome, 0.57 maternal deaths resulting from cesarean section occur to prevent 1 case of neonatal death, and $2.5 million are spent to prevent 1 case of neonatal infection.19
One study evaluating targeted screening for HSV infection in pregnant women demonstrated identifiable risk factors, such as mother younger than 25 years, father younger than 20 years or age unknown, inadequate prenatal care, prolonged rupture of membranes, and intrapartum fever; however, such a targeted screening approach would be cost-prohibitive and still fail to prevent 40% of neonatal HSV infection cases.10
Recurrence Approximately 50% of infants with a history of HSV infection limited to the skin, eyes, and mouth will develop between 1 and 12 recurrences of cutaneous lesions within the first year of life.20 In these patients, neurologic outcome is correlated with the number of cutaneous recurrences in the first 6 months. No neurologic sequelae are seen in children with fewer than 3 recurrences, whereas 21% of children with 3 or more recurrences have some neurologic sequelae.3 Daily suppressive acyclovir significantly decreases the number of recurrences; however, approximately 50% of infants receiving daily suppressive therapy develop neutropenia, and breakthrough infections can occur.20
Vaccine on the horizons Currently, no vaccine is available to prevent HSV infection. Several HSV vaccines using varied methodologies are being studied and have demonstrated variable efficacy. Two separate phase 3 trials with an HSV-2gD vaccine demonstrated nearly 75% efficacy in preventing genital HSV disease and 38% efficacy in preventing HSV-2 infections in seronegative women.21 No efficacy was demonstrated in men or in women who were HSV-1 positive before vaccination.21
Conclusion The case described here demonstrates a characteristic clinical presentation of disseminated neonatal HSV infection. Such infection is life-threatening, with frequent neurologic sequelae in survivors. Recognizing this illness can be difficult in patients without a vesicular rash. Timely diagnosis and initiation of high-dose IV acyclovir are essential to optimize the clinical outcome and reduce the risk of death.
Self-assessment test 1. All the following statements are true, except: A. HSV-1 and HSV-2 are DNA viruses B. Infants with HSV limited to the skin, eyes, and mouth are not at risk for neurologic sequelae C. HSV-2 is responsible for most cases of neonatal HSV infection in the United States D. Most infants with proven HSV infection do not have a mother with a history of genital herpes
2. All the following situations are associated with an increased risk of vertical transmission of HSV infection, except: A. Prematurity B. Invasive fetal monitoring C. Cesarean delivery D. First episode of primary genital maternal HSV infection
3. Which of the following regimens is the treatment for disseminated neonatal HSV infection? A. Acyclovir, 60 mg/kg daily in 3 divided doses for 21 days B. Acyclovir, 30 mg/kg daily in 3 divided doses for 21 days C. Acyclovir, 30 mg/kg daily in 3 divided doses for 14 days D. Acyclovir, 60 mg/kg daily in 3 divided doses for 14 days
4. What is the preferred diagnostic modality for HSV encephalitis? A. CSF viral culture B. Electroencephalogram C. Viral culture D. HSV DNA PCR testing performed on CSF
5. Prolonged high-dose acyclovir use may be associated with which of the following adverse events? A. Neutropenia B. Thrombocytopenia C. Nephrotoxicity D. A and C
2. American Academy of Pediatrics. Herpes simplex. In: Pickering LK, Baker CJ, Long SS, et al, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2006: 361-371.
3. 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.
4. Kimberlin DW, Lin CY, Jacobs RF, et al, for 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: 223-229.
5. Verma A, Dhawan A, Zuckerman M, et al. Neonatal herpes simplex virus infection presenting as acute liver failure: prevalent role of herpes simplex virus type I. J Pediatr Gastroenterol Nutr. 2006; 42:282-286.
6. Kohelet D, Katz N, Sadan O, et al. Herpes simplex virus infection after vacuum-assisted vaginally delivered infants of asymptomatic mothers. J Perinatol. 2004; 24: 147-149.
7. Gutierrez KM, Falkovitz Halpern MS, Maldonado Y, et al. The epidemiology of neonatal herpes simplex virus infections in California from 1985 to 1995. J Infect Dis. 1999; 180:199-202.
8. Henrot A. Mother-infant and indirect transmission of HSV infection: treatment and prevention [in French]. Ann Dermatol Venereol. 2002; 129:533-549.
9. Brown ZA, Benedetti JK, Watts DH, et al. A comparison between simple and detailed histories in the diagnosis of genital herpes complicating pregnancy. Am J Obstet Gynecol. 1995; 172:1299-1303.
10. Mark KE, Kim HN, Wald A, et al. Targeted prenatal herpes simplex virus testing: can we identify women at risk of transmission to the neonate? Am J Obstet Gynecol. 2006;194: 408-414.
11. Gardella C, Brown Z, Wald A, et al. Risk factors for herpes simplex virus transmission to pregnant women: a couples study. Am J Obstet Gynecol. 2005; 193:1891-1899.
12. Boivin G. Diagnosis of herpesvirus infections of the central nervous system. Herpes. 2004; 11(suppl 2):48A-56A.
13. Simko JP, Caliendo AM, Hogle K, et al. Differences in laboratory findings for cerebrospinal fluid specimens obtained from patients with meningitis or encephalitis due to herpes simplex virus (HSV) documented by detection of HSV DNA. Clin Infect Dis. 2002; 35:414-419.
14. Atkins JT. HSV PCR for CNS infections: pearls and pitfalls. Pediatr Infect Dis J. 1999; 18: 823-824.
15. Kimberlin DW, Lin CY, Jacobs RF, et al, for 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: 230-238.
16. Frenkel LM. Challenges in the diagnosis and management of neonatal herpes simplex virus encephalitis [published correction appears in Pediatrics. 2005;115:1454]. Pediatrics. 2005; 115:795-797.
17. Reiff-Eldridge R, Heffner CR, Ephross SA, et al. Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment. Am J Obstet Gynecol. 2000; 182:159-163.
18. American College of Obstetricians and Gynecologists (ACOG). ACOG practice bulletin no 8. Management of herpes in pregnancy. Obstet Gynecol. 1999; 94:1-10.
19. Randolph AG, Washington AE, Prober CG. Cesarean delivery for women presenting with genital herpes lesions. Efficacy, risks, and costs. JAMA. 1993; 270:77-82.
20. Fonseca-Aten M, Messina AF, Jafri HS, et al. Herpes simplex virus encephalitis during suppressive therapy with acyclovir in a premature infant. Pediatrics. 2005; 115:804-809.
21. Stanberry LR, Spruance SL, Cunningham AL, et al, for the Glaxo- SmithKline Herpes Vaccine Efficacy Study Group. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med. 2002; 347:1652-1661.
