A 10-day-old infant has a 12-hour history of fever, irritability, and decreased oral intake. She was delivered vaginally at 39-week gestation to a gravida 2, para 1 woman after an uncomplicated pregnancy with routine prenatal care. The infant went home on day 2 of life. She has surpassed her birth weight of 3.7 kg and had been well until today. On examination, she has a temperature of 101.5°F (38.6°C), and she is fussy. Her only finding on physical examination is a small cluster of 2-mm, fluid-filled lesions surrounded by an erythematous base on her parietal scalp. The infant has an episode in the emergency department of right-sided body shaking that then generalizes. The episode lasts approximately 2 minutes, and subsequently she is somnolent. Initial lumbar puncture results show 850 white blood cells with 90% lymphocytes, 200 red cells, and a protein of 200 mg/dL; a blood count reveals a platelet count of 57,000/mm3.
What is the most likely diagnosis?
What are the potential complications of this condition?
ANSWERS TO CASE 43: Neonatal Herpes
Summary: A 10-day-old previously healthy infant with fever, irritability, decreased oral intake, and vesicles on her scalp has an episode of seizure-like activity. Laboratory studies reveal lymphocytic meningitis and thrombocytopenia.
• Most likely diagnosis: Neonatal herpes.
• Potential complications of this condition:Left untreated, the majority of infants with disseminated or central nervous system (CNS) infection die. The use of high-dose intravenous and long-duration antiviral therapy has reduced mortality and improved long-term outcomes among survivors.
1. Recognize the importance of early recognition of neonatal herpes infection.
2. Know how to diagnose neonatal herpes infection.
3. Know the appropriate management of neonatal herpes infection.
A young infant with fever and irritability is presumed to have a serious bacterial or viral infection. Bacterial causes in this age include group B Streptococcus,Listeria, and gram-negative pathogens. The history in this case of a focal seizure, the finding of vesicles on the infant’s scalp, and the laboratory findings make herpes simplex virus (HSV) the most likely pathogen. The absence of a maternal history of herpes is not unusual; only 15% to 20% of mothers of HSV-infected infants have a history of herpes and only approximately 25% have relevant symptoms at delivery. The risk of maternal passage of HSV to the neonate is higher in cases of primary herpes outbreaks because the viral inoculum in the genital tract is high and protective antibody is not present. Most cases of transmission occur during delivery. Postpartum infection is infrequent but presents similarly. Intrauterine infection typically will cause chorioretinitis and microcephaly prior to birth.
Blood, urine, and cerebrospinal fluid (CSF) specimens are obtained for routine bacterial cultures. HSV cultures are obtained from the blood, nasopharynx, eyes, urine, stool or rectum, CSF, and from any vesicular lesion. Cerebrospinal fluid is tested by polymerase chain reaction (PCR) for HSV. A complete blood count and liver function and coagulation studies may reveal abnormalities. Pending test results, this infant is placed on intravenous antibiotics and antiviral therapy.
Suspected Neonatal Herpes Infection
NEONATE: Infant who is 60 days old or less.
GENITAL HERPES: Infection of the genital tract with HSV type 1 or 2, the majority caused by HSV-2.
PRIMARY HERPES INFECTION: HSV infection in a previously seronegative host. Most primary infections are subclinical, but they can cause localized lesions or severe systemic symptoms.
RECURRENT INFECTION: Reactivation of a latent infection in an immune host. Lesions tend to be localized and are not associated with systemic symptoms.
Approximately 20% to 30% of American women of childbearing age have antibodies to HSV-2, with a higher rate in women of lower socioeconomic groups and those in crowded living conditions. Approximately 75% of congenital herpes cases are caused by HSV-2. Usually HSV-2 is transmitted through sexual contact, and most genital diseases are the result of type 2 infection; HSV-1 can be transmitted sexually and occasionally is found in the genital tract. HSV-2 is associated with greater morbidity among congenital infection survivors than HSV-1.
Cesarean delivery is generally indicated in delivering women with an outbreak of genital herpes or symptoms of HSV infection. The infant’s risk of HSV infection is increased significantly if the maternal outbreak represents primary infection. As many as 50% of such infants will become infected if delivered vaginally, whereas fewer than 5% will acquire the disease if the outbreak is recurrent disease. HSV surveillance cultures are not recommended in pregnant women; women at greatest risk for infecting their infants are those without prior infection history.
Neonatal HSV disease will present with one of the following: localized skin, eye, and mouth involvement (SEM), or CNS disease/encephalitis, or disseminated disease with multiorgan involvement. SEM usually presents at 1 to 2 weeks of life; it requires intravenous treatment to prevent progression to one of the other presentations. CNS disease typically occurs at 2 to 3 weeks of life. Fever is uncommon and only 60% of cases will have vesicles. The infant will be lethargic, irritable, or have seizures. Recognition of the symptoms and lab findings is important as 50% of neonates without treatment will die. Disseminateddisease has multiple signs and symptoms in the 1- to 2-week-old neonate: fever, lethargy, irritability, anorexia, vomiting, respiratory distress, apnea, jaundice, a bulging fontanelle, seizures (focal or generalized), decerebrate posturing, or coma. Skin vesicles will be present in approximately two-thirds of cases. Hepatitis, pneumonitis, shock, and disseminated intravascular coagulation (DIC) can occur in severe cases; 30% of these neonates will not survive.
Viral culture of samples taken from various body sites and PCR of CSF are the most useful diagnostic tests. Serologic tests for herpes virus are not helpful in the acute setting (titers rise late in the infection’s course). Tzanck preparationof lesions and antigen detection methods applied to the specimens can aid in rapid diagnosis, but the sensitivity is low. Infected individuals often have moderate peripheral leukocytosis, elevated serum liver transaminase levels, hyperbilirubinemia, and thrombocytopenia. When the CNS is involved, the CSF frequently contains an elevated number of red cells, lymphocytes, and protein; CSF glucose usually is normal but may be reduced. Electroencephalography (EEG) shows characteristic patterns in acutely affected infants, and brain computed tomography (CT) will become abnormal as the disease progresses. HSV encephalitis in the neonatal period tends to be global, but electroencephalography (EEG) and magnetic resonance imaging (MRI) obtained in patients beyond the neonatal period may show temporal lobe abnormalities.
Parenteral acyclovir is the preferred treatment. It can stop the viral replication at the site of inoculation (skin, mouth, nares, eyes). Otherwise, HSV can spread in the neonate to the respiratory tract, down neurons, or enter the bloodstream, allowing hematogenous infection of the liver, adrenals, and CNS. Children with isolated skin, eye, and mouth disease generally have the best outcomes. The use of long-duration, high-dose acyclovir has reduced mortality among children with localized central nervous system disease to 4%, and to about 30% in children with disseminated disease. Most survivors of CNS disease have neurologic sequelae, but as many as 80% of survivors of disseminated infection have normal development at 12 months of age.
43.1 A 10-day-old infant has a painful, red vesicular rash in the diaper area. He is mildly fussy but afebrile, and he has good oral intake. Which of the following is the most appropriate management of this infant?
A. Hospitalize the patient, obtain HSV cultures, and initiate parenteral acyclovir.
B. Order an EEG and brain MRI immediately.
C. Perform a Tzanck smear and send the patient home if it is negative.
D. Prescribe an antifungal cream and follow up by telephone in 24 hours.
E. Schedule an appointment with a pediatric dermatologist.
43.2 A woman presents for her first prenatal visit at 9-week gestation. She reports that she is generally healthy, except that she has an outbreak of genital herpes approximately once per year. To prevent transmission of the virus to her infant, her physician should do which of following?
A. Anticipate a cesarean section delivery.
B. Order titers to determine if the infection is HSV-1 or HSV-2.
C. Perform weekly genital viral cultures starting at 36-week gestation.
D. Perform a cesarean delivery if herpetic lesions or prodromal symptoms are present when labor has begun.
E. No change in management is indicated; the risk of infant transmission is low even if she has an outbreak at delivery.
43.3 A 5-year-old with dysuria is found on examination to have herpetic genital lesions. Which of the following is the best next step in management?
A. Ask the parent to leave the room and then ask the girl in an open-ended fashion whether she has ever been inappropriately touched in her private area.
B. Prescribe oral acyclovir and ask her to follow up in 2 days.
C. Admit her to the hospital for parenteral antiviral therapy.
D. Ask how often the mother has outbreaks of genital herpes.
E. Send a urine culture and have the mother apply petroleum jelly until the lesions heal.
43.4 The results of PCR of CSF from a 15-year-old adolescent male with encephalitis demonstrate an HSV infection. His parents ask about his prognosis. Which of the following is likely to be true?
A. He will most likely die.
B. He will likely survive, but will certainly have serious neurologic impairment.
C. Most children with HSV encephalitis survive; many (but not all) are left with some permanent neurologic deficits.
D. They should consider placing him in a long-term care facility upon discharge.
43.1 A. In contrast to older children and adults, neonates with suspected herpes skin lesions require parenteral antiviral therapy to prevent more serious sequelae.
43.2 D. Even though the viral transmission risk in the setting of a recurrent HSV outbreak is low, cesarean section is indicated if lesions are present at the time of delivery. Surveillance cultures are not recommended; negative results a few days prior to delivery do not preclude a later outbreak, and results of analysis of a more recently obtained specimen may not be available.
43.3 A. The possibility of sexual abuse is considered in a child who presents with genital herpes beyond the neonatal period. It is important to know who helps to bathe the child, and whether these persons have ever had herpes, as nonsexual transmission is also possible.
43.4 C. Although the majority of children with HSV encephalitis suffer permanent neurologic impairment, good outcomes are possible with appropriate medical and rehabilitative therapy.
Most infants with neonatal herpes simplex virus are born to mothers without a prior history of herpes simplex virus infection.
The presenting signs and symptoms of neonatal herpes simplex virus may be nonspecific, without any visible herpetic lesions.
Neonates with suspected herpes simplex virus infection should be hospitalized for testing and parenteral antiviral therapy pending test results.
Neonates with herpes simplex virus skin, eye, and mouth (SEM) disease generally have the best outcomes, whereas the majority of infants with central nervous system disease develop neurologic sequelae. Approximately 30% of infants with systemic infection die despite aggressive antiviral therapy.
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