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A 34-week-old boy with skin lesions
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A boy, gestational aged 34 weeks and 4 days, was born at an outlying hospital and transferred to the neonatal intensive care unit for evaluation of extensive skin lesions noted at delivery. The lesions were described as numerous blisters, large bullae and extensive areas of scarred skin on the trunk, anterior chest, back and extremities. Several lesions were hemorrhagic and weeping in appearance.
The infant was born to a group B streptococcal status unknown, rapid plasma reagin nonreactive, rubella immune, HIV-negative, 26-year-old woman with a history of chickenpox as a child. This was the woman’s first pregnancy and the child was delivered via primary cesarean section after premature rupture of membranes.
The pregnancy was complicated by a first genital herpes simplex virus (HSV) type 2 infection at 11 weeks gestation that was treated with a five-day course of intravenous acyclovir. She had multiple recurrences requiring intermittent treatment with oral acyclovir then valacyclovir and was placed on a daily suppressive regimen of valacyclovir for the final month of pregnancy. Though she had no lesions consistent with HSV at the time of labor, the patient opted for cesarean section to reduce the risk of vertical transmission. Other medications taken during pregnancy included 25 mg promethazine for ongoing nausea, bupropion 150 mg for depression and 6 mg/day hydromorphone for chronic pain secondary to idiopathic pancreatitis and colitis of unclear etiology. She also reported moderate tobacco and alcohol use during pregnancy. The delivery itself was essentially unremarkable, Apgar scores were 8 and 9 and the infant transitioned well.
On arrival in the NICU at 9 hours of life, the infant was febrile to 100.4°F and was breathing comfortably on room air with no signs of distress. The infant appeared appropriate for gestational age with a weight 2499 g, and was appropriately alert and active. There were no dysmorphic features, and the head circumference of 31 cm was normal for the gestational age. Examination of the skin revealed bullae, grouped vesicles on erythematous bases and patches of crusted lesions on the scalp, cheeks, trunk, chest, back and extremities (figure 1). There were no lesions of the mouth, eyes, nares, ear canal or genital area. The liver and spleen were both firm and palpable 3 cm to 4 cm below the costal margin. He was irritable only when the skin was disturbed. The remainder of physical exam was unremarkable.
What is your diagnosis?
Answer
The answer is intrauterine herpes simplex virus, type 2.
Intrauterine herpes simplex virus (HSV) is a contagious infectious disease caused by transplacental transmission of either herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). These viruses are closely related, but genetically unique, species of the herpes virus family Herpesviridae. All viruses in the herpes family have the ability to establish latency, although the site of latency varies with each species. HSV-1 infection is generally associated with orolabial infections, whereas HSV-2 is the most common cause of genital infections. Both HSV-1 and HSV-2 can be transmitted from mother to infant at the time of birth, leading to perinatal HSV infections. Compared with latent infections, primary infections with HSV are typically associated with longer duration and severity of symptoms and prolonged viral shedding. They also are more likely to cause a viremia, which is necessary for transplacental infection of the fetus.
Neonatal HSV disease is diagnosed in approximately one of every 3,000 deliveries; however, true intrauterine HSV is much more rare and occurs in only one per 100,000 births, representing just 5% of neonatal HSV infections.
Intrauterine HSV is more likely to result in disseminated fetal infection than vertically transmitted disease, increasing the potential for severe systemic consequences and fetal demise. The risk of intrauterine transmission is highest during the first 20 weeks of gestation and may result in spontaneous abortion or stillbirth, various intrauterine anomalies, premature birth and intrauterine growth restriction. Intrauterine infections caused by HSV-2 are more common than those caused by HSV-1, with 90% of those acquired in utero identified as HSV-2. Additionally, HSV-2 is responsible for most primary infections occurring around the time of delivery leading to neonatal infections. Placental deciduitis and villitis have been described with HSV infections and may carry an increased risk of maternal to fetal transmission when associated with primary maternal infections.
Among the few reported cases of intrauterine HSV infections, the largest case series described the outcome of 13 infants with intrauterine HSV-2 infection. Exam findings in this series included skin lesions and scars at birth, chorioretinitis, microcephaly, hydranencephaly and microphthalmia with all infants having a combination of these defects. Two infants died during the first week of life, 10 of the surviving infants had severe neurologic sequela and one infant was blind. Other commonly described clinical manifestations in the infant include intracranial calcifications, seizures and encephalomalacia. Rare cases have been reported describing skeletal findings, including osteopenia, delayed ossification, scoliotic posture and tibial fracture.
Babies with symptomatic intrauterine HSV disease are usually identified within the first 48 hours of life. Other intrauterine infections, particularly varicella-zoster virus and syphilis, but also the other TORCH infections, should be considered. Other conditions that may mimic intrauterine HSV skin findings include staphylococcal or streptococcal infection, epidermolysis bullosa or pemphigus.
Rapid virological confirmation of HSV is paramount to confirm the diagnosis and exclude other pathologic conditions. Growth of HSV from culture is diagnostic, and therefore, viral culture swabs of skin lesions, mucous membranes, urine, blood and cerebrospinal fluid (CSF) should be obtained. HSV can generally be identified in culture within 48 hours. CSF cultures for HSV have poor sensitivity, thus polymerase chain reaction (PCR) assays are the preferred method for detection of HSV in the CSF and serum. Screening liver function tests should be performed to evaluate for potential disseminated disease and monitored during therapy if abnormal. Ultrasound, computed tomography, and magnetic resonance imaging of the brain can help assess possible central nervous system (CNS) involvement.
An electroencephalogram (EEG) may be useful for supportive diagnosis, especially in neonatal cases. An EEG demonstrating periodic lateralizing epileptiform discharges in the temporal lobe region is highly suggestive of CNS herpes infection.
All neonatal HSV infections should be treated with intravenous acyclovir, although there are no controlled trials for the treatment of intrauterine HSV. Neonates in whom HSV infection is limited to the skin, eyes and mucous membranes usually have an excellent outcome when treated with intravenous acyclovir. Conversely, in 70% of untreated neonates with infection limited to the skin, eyes and mucous membranes, the disease will progress to disseminated or CNS disease, and approximately 50% of those with disseminated disease die despite therapy. Most neonates treated for HSV encephalitis survive, but some will suffer substantial neurologic sequela.
The recommended treatment for neonatal HSV is “high dose” acyclovir at 60 mg/kg per day divided in three doses given intravenously for 14 days for infection limited to the skin, eyes and mucous membranes or at least 21 days for disseminated and or CNS disease. This dosing regimen is supported by a large multicenter study showing a small decrease in morbidity among patients treated with high dose acyclovir compared with the standard 15 mg/kg dose. The drawback is the increased occurrence of neutropenia, requiring white blood cell count monitoring. If a patient has significant neutropenia, granulocyte-stimulating factor may be added or an alternative agent (such as foscarnet) could be considered. If ocular involvement is suspected, topical treatment should be undertaken in conjunction with ophthalmology consultation. Several topical drugs (trifluridine, iododeoxyuridine, vidarabine) have been shown to be efficacious for treating HSV keratitis. Although topical corticosteroids are usually contraindicated in HSV conjunctivitis, ophthalmologists may use them in conjunction with antivirals for locally invasive disease. Standard and contact precautions should be maintained for neonates with HSV infection and mucocutaneous lesions.
In our patient, urine, blood and CSF bacterial cultures were negative and viral cultures from eyes, nares, mouth, axilla and rectum were positive for HSV-2. In addition, serum and vesicle fluid was positive for HSV-2 by PCR. Fortunately, despite an elevated CSF protein at 220 mg/dL there was no pleocytosis and the CSF HSV PCR was negative. Liver function tests completed at birth showed only a mild elevation of the aspartate transaminase at 73 U/L that peaked at age 2 days at 108 U/L and normalized by age 5 days. The alanine transaminase remained normal. The infant received antibiotics for routine sepsis evaluation along with IV acyclovir until HSV infection was confirmed at age 4 days and the antibiotics were discontinued. Repeat viral cultures from the infant’s eyes, nares, mouth, axilla and rectum obtained after seven days of antiviral therapy were negative. Ophthalmology examination on age 2 days and at age 1 month revealed no evidence of keratitis or chorioretinitis. Neurologically, the infant clinically appeared and acted normal without signs of increase irritability or seizures. However, a head ultrasound performed at age 2 days was concerning for linear echogenic areas in the basal ganglia consistent with vascular striate vasculopathy. An MRI of the brain performed five days later revealed multiple foci of abnormal T2 signal in the hypothalamus and optic radiations. The patient’s skin lesions healed well without significant scarring, although significant pigmentation abnormalities at the sites of infection continued to be noticeable at age 2 months (figure 2).
The infant was discharged home at age 13 days with a peripherally inserted central catheter line to complete a total of 21 days of IV acyclovir. He was then prescribed oral acyclovir suppression for six months. Although the infant remained neurologically normal, he remains at high risk for neurodevelopmental delay and poor cognitive outcome. A follow-up MRI is scheduled for six weeks from initial scan to follow-up on the previous described abnormal findings. He will require careful monitoring of his developmental progress and early intervention if delay is suspected.
For more information:
- Michelle R. Dunlavy, DO, Lt MC USN is a Pediatric Resident and John C. Arnold, MD, LCDR MC USN is with the pediatric infectious disease department, Navy Medical Center, San Diego. Matthew D. McLean, MD, PhD, LCDR MC USN is General Pediatrician, Naval Hospital, Camp Pendleton, Calif.
- American Academy of Pediatrics. Herpes simplex. In: Pickering LK ed. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed., Elk Grove Village, Ill.: American Academy of Pediatrics; 2006;364-370.
- Annunziato PW. Herpes simplex virus infections. Pediatr Rev. 1996;17:415-423.
- Avgil M, Ornoy A. Herpes simplex virus and Epstein-Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection. Reprod Toxicol. 2006;21:436-445.
- Brown ZA. HSV-2 specific serology should be offered routinely to antenatal patients. Rev Med Virol. 2000;10:141-144.
- Hutto C, Arvin A, Jacobs R, et al. Intrauterine herpes simplex virus infection. J Pediatr. 1987;110:97-101.
- 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.
- Koi H, Zang J, Makrigiannakis A, et al. Syncytiotrophoblast is a barrier to maternal-fetal transmission of herpes simplex virus. Biol Reprod. 2002;67:1572-1579.
- Overall JC, Jr. Herpes simplex virus infection of the fetus and newborn. Pediatr Ann. 1994;23:131-136.
- Sauerbrei A, Wutzler P. Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therap. Part 1: Herpes simplex virus infections. Med Microbiol Immunol. 2007;196:89-94.
- US Preventive Services Task Force. Screening for genital herpes: recommendation statement. Rockville, Md: Agency for Healthcare Research and Quality; 2005.
- Waggoner-Fountain LA, Grossman LB. Herpes simplex virus. Pediatr Rev. 2004;25:86-93.
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