Neonatal Herpes Infection: Case Report and Discussion

Discussion

Fever (defined as temperature higher than 100.4°F) with an unidentifiable source is a common problem encountered in pediatric primary care. Myriad algorithms exist to aid the clinician in diagnostic and treatment options when a child presents with fever. The primary aim of these algorithms is to determine which children are at risk for serious bacterial infection. Most algorithms suggest that a newborn younger than 29 days of age should be admitted to the hospital for workup and observation. Suggested workup includes a complete blood count with differential, a urinalysis with culture, blood cultures, CSF analysis and cultures, intravenous antibiotics (usually ampicillin and gentamicin), and observation for 48 hours or until a source of fever is found.¹

The prevalence of HSV infection in hospitalized 0- to 28-day-old infants is thought to be about 0.2%, not statistically different from that of bacterial meningitis at 0.4%. HSV infection is thought to account for illness in 0.3% to 0.9% of febrile neonates.^2,3 An estimated 25% of US women are seropositive for HSV2 (positive immunoglobulin G), and though the number is similar for pregnant women, only 5% of pregnant women report a history of symptomatic infection.⁴ Two percent to 3% of women seroconvert during pregnancy. During a primary HSV outbreak, there is a 33% risk of vertical transmission from mother to newborn; this number drops to 3% during a secondary reactivation. Perinatal transmission of HSV occurs in three ways: antenatal (5%), intrapartum (85%), and postnatal (10%, primarily HSV1). HSV2 accounts for 50% to 70% of neonatal HSV infection, mainly antenatal and intrapartum infections, although 75% of neonatal HSV1 infections are transmitted not postnatally but from recently acquired maternal genital infections.^4–6

Given that the majority of women with HSV seropositivity do not report a history of symptoms consistent with HSV, that antenatally acquired infections are likely to result in a spectrum of findings such as microcephaly and hydrocephalus, and that postnatal infections are most likely to be HSV1, our patient was probably infected with HSV2 during the intrapartum period.

Neonatal HSV infection manifests in three forms, which are not always discrete. Approximately 45% of cases have mucocutaneous infection, which presents with only skin, eye, or mucosal findings—lesions begin as erythematous macules, which develop into vesiculopustules, crusts, or erosions. There is no evidence of systemic or central nervous system involvement: CSF, chest radiograph, and LFTs are normal, and mortality is highly unlikely. There is minimal morbidity, as well (only 5% may develop neurologic abnormalities).⁶

Central nervous system HSV, which accounts for approximately 30% of cases, may present with lethargy, poor feeding, irritability, or seizures, though neonates may appear to have completely normal behavior. Diagnosis is made by abnormal brain magnetic resonance imaging or abnormal CSF findings such as pleocytosis (defined as CSF WBC count >25 cells/μL in infants younger than 28 days old and >10 cells/μL in patients aged 29–90 days; the CSF WBC count should be corrected for the number of red blood cells using a ratio of 500:1)⁷ in conjunction with positive surface cultures and/or a finding of HSV DNA in the CSF. Sixty-eight percent of these patients also have skin involvement. Even with treatment, there is a 4% to 14% mortality rate and the majority of survivors will have long-term neurologic sequelae.^6,8

Disseminated HSV is responsible for 25% of cases. Disseminated disease often starts with systemic symptoms that may progress rapidly to jaundice, hypotension, disseminated intravascular coagulation (DIC), and shock. The lung, liver, and adrenal glands are the most commonly affected sites outside of the CNS. Disseminated HSV carries a 20% to 60% mortality rate, usually related to coagulopathy (secondary to hepatic failure) or pulmonary involvement. Fifteen percent to 25% of survivors will have neurologic sequelae.^8,9 Fortunately for our patient, despite his disseminated disease, his clinical course remained relatively benign; at one point, the team questioned whether the initial PCR result could have been a false positive. As noted above, he has not developed known neurologic problems.

Despite these numbers and potentially poor outcomes, it is not routinely recommended to treat neonates with fever empirically for HSV; it is instead recommended that evaluation for HSV is considered when risk factors for or symptoms of HSV are present.¹ The most important risk factor is maternal infection at time of delivery, though this is often unknown. Other risk factors that increase the risk of intrapartum transmission if the mother is infected include the use of fetal scalp electrodes; vaginal delivery; prolonged rupture of membranes; CSF pleocytosis; and skin, eye, or mouth lesions.¹ HSV infection should also be considered in any infant who presents during the first month of life with lethargy, poor feeding, irritability, or seizures.^2,4 Some sources recommend that if a neonate is not improving while taking antibiotics, treatment for HSV should be considered (Table 1).¹ In our case, the patient was treated empirically with acyclovir because of his elevated LFTs, CSF pleocytosis, and age.

In terms of diagnosis of HSV, the sensitivity of PCR is only 70% early in the disease process.¹⁰ Some sources recommend that serial evaluations of the CSF should be done during the first week of illness if it is thought that HSV encephalitis is likely and initial PCR was negative.¹¹ Skin lesions or conjunctival cultures consistently provide the greatest yields, with >90% of cultures positive within 4 days in an affected infant).¹¹ Once diagnosed, HSV is treated with intravenous acyclovir (60 mg/kg/d divided three times daily for 21 days in patients with CNS or disseminated disease, 14 days if only mucocutaneous infection).⁹ A repeat lumbar puncture should be completed at the end of antibiotic therapy to ensure that HSV PCR is negative. Because our patient's PCR remained positive, acyclovir was continued another week until it was negative. Some centers repeat lumbar punctures after treatment in the case of any fever, neurologic impairment, or skin lesion because recurrence of CNS disease is quite common. Studies of the effects of long-term suppressive therapy are ongoing; some centers consider oral acyclovir after intravenous treatment is completed.¹¹

Acyclovir has been shown to improve mortality; Corey and Wald⁶ report a reduction from 85% to 31% in patients with disseminated disease and from 50% to 6% in patients with CNS disease. However, acyclovir therapy has had less impact on morbidity, which includes mental retardation, blindness, seizures, spasticity, and paralysis. Of untreated patients with disseminated disease, for example, it is very rare to find normal neurologic status at 1 year of age. This number decreases to 83% in patients with disseminated disease who have been treated.⁶ Risk factors for significant morbidity include aspartate transaminase >10 times normal, disseminated disease, DIC, encephalitis, pneumonia, HSV2, lethargy, coma, persistent positive PCR after acyclovir, prematurity, and seizures.⁹ Some studies do show that early institution of acyclovir is extremely beneficial to the outcome of HSV disease and that, as the interval between the onset of symptoms and the initiation of therapy is shortened, morbidity is lessened.^8,9 This may explain the positive outcome seen in our patient despite his risk factors for significant morbidity.

The most common adverse event associated with acyclovir is transient neutropenia. The absolute neutrophil count should be monitored twice weekly while receiving therapy, and if it remains <500 for a prolonged period, the acyclovir dose can be decreased or granulocyte colony-stimulating factor can be administered.¹² Nephrotoxicity is the other concern; in one study, incidence was 6%, but all patients with nephrotoxicity had disseminated infection, which alone could explain elevated creatinine.¹²

Prenatal prevention of HSV may include screening and education (Table 2). It has been shown that routine serologic screening of asymptomatic women does not reduce transmission to newborns, mostly because women at the highest risk are serologically negative at the time of screening.¹³ There is also no evidence that treating seronegative women decreases neonatal infection.¹³ Screening by way of checking cervical viral cultures during pregnancy does not predict viral shedding during labor and delivery, nor does a negative culture preclude the possibility of subsequent neonatal disease.⁵ Therefore, the American College of Obstetricians and Gynecologists (ACOG) does not currently recommend screening— either serologically or by cervical culture—of pregnant women for HSV.⁵ Instead, the clinician must determine whether there has been any history of HSV infection in the patient and/or her sexual partner, followed by information about consistent condom use and information about symptoms of HSV.^4,14

ACOG recommends that pregnant women with known HSV be treated with suppressive therapy starting at 36 weeks.⁵ The US Preventive Services Task Force, however, states that there is limited evidence that this prevents neonatal infection.¹³ Guidelines for Cesarean delivery also differ. ACOG recommends that a Cesarean delivery be performed for women with primary and recurrent infection who have active genital lesions or a herpes prodrome, because some studies show that Cesarean delivery within 4 hours of membrane rupture in these women can reduce the risk of transmission to neonates.⁵ However, the US Preventive Services Task Force again states that there is limited evidence that this prevents neonatal infection, and the number needed to treat with such an invasive procedure is high: 1580 Cesarean deliveries must be performed before one case of neonatal herpes is prevented.¹³ One recent study found that a rapid test for HSV PCR in laboring women had high sensitivity (99.6%) and specificity (96.7%).¹⁵ If further studies in the clinical setting support these results, this test may allow us to more appropriately manage women in labor. Postnatally, newborns with known or suspected HSV should remain in isolation with contact precautions, and skin lesions should be covered. Health care providers with lesions should have no direct patient contact with newborns.⁴