hsv presentation in neonates

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INTRODUCTION

The management and prevention of neonatal HSV infection will be reviewed here. The clinical features and diagnosis of neonatal HSV infection and genital HSV infection during pregnancy are discussed separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis" and "Genital herpes simplex virus infection and pregnancy" .)

SUPPORTIVE MEASURES

● Fluid and electrolyte maintenance and avoidance of hypoglycemia (see "Fluid and electrolyte therapy in newborns" and "Management and outcome of neonatal hypoglycemia" )

● Management of hepatic and kidney failure, if present (see "Neonatal acute kidney injury: Evaluation, management, and prognosis" )

Herpes Simplex Virus (HSV) Infection in Newborns

(neonatal herpes simplex virus infection).

• Diagnosis |
• Prognosis |
• Prevention |
• Treatment |

Herpes simplex virus infection usually causes only annoying, recurring blisters in healthy adults but can cause severe infection in newborns.

Newborns may become infected at birth or after birth.

The main symptom is a rash of blisters.

The diagnosis is typically based on tests of samples taken from the blisters.

Many untreated children die.

To prevent spreading the infection, infected women may have a cesarean delivery.

(See also Overview of Infections in Newborns and Herpes Simplex Virus Infections in adults.)

Infection with herpes simplex virus is very common in adults. The virus can be transmitted sexually and cause infection of the genital tract. The virus never goes completely away and remains dormant (inactive) in various tissues for life. Sometimes the virus reactivates.

Usually, herpes simplex virus (HSV) is transmitted during delivery through the mother’s infected genital tract. Even infected mothers who do not have any symptoms of herpes can still transmit the infection. Sometimes newborns become infected after birth when the infection is spread by someone with an active infection. In newborns, HSV infection can lead to death or chronic problems.

Symptoms of HSV Infection in Newborns

Symptoms of herpes simplex virus infection usually start between the first and third weeks of life but rarely may not appear until the fourth week. The first symptom is usually a rash of small, fluid-filled blisters. The blisters can also appear inside the mouth and around the eyes.

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

DR M.A. ANSARY/SCIENCE PHOTO LIBRARY

By permission of the publisher. From Demmler G: Congenital and perinatal infections. In Atlas of Infectious Diseases: Pediatric Infectious Diseases. Edited by CM Wilfert. Philadelphia, Current Medicine , 1998.

In some newborns, the infection affects only certain areas (localized). For example, the infection may involve only the eyes, skin, or mouth. Sometimes, only the brain and nervous system are affected. If localized infection is not treated, some newborns develop widespread disease.

In other newborns, the infection is widespread and affects many areas. In these infants, organs such as the eyes, lungs, liver, brain, and skin are all affected. Symptoms include sluggishness, diminished muscle tone, breathing problems, pauses in breathing (apnea), and seizures.

Diagnosis of HSV Infection in Newborns

Testing of a sample taken from blisters and other body fluids

To diagnose herpes simplex virus infection, doctors take samples of material from the blisters and other body fluids and send the samples to a laboratory to grow (culture) the virus and identify the herpes simplex virus. Doctors may also do the polymerase chain reaction (PCR) test on the samples. This test looks for the genetic material of the virus and enables doctors to rapidly identify the virus.

If doctors suspect the newborn has a brain infection, a spinal tap (lumbar puncture—see figure How a Spinal Tap Is Done ) to obtain a sample of spinal fluid may be done.

Prognosis for HSV Infection in Newborns

If herpes infection of the newborn is not treated, it usually progresses to severe problems. About 85% of babies with untreated widespread herpes infection die. About 50% of newborns with untreated brain infection die. Death is not common among newborns whose infection is limited to the skin, eyes, or mouth. Without treatment, at least 65% of survivors of widespread disease or brain infection have severe neurologic problems.

Appropriate treatment with antiviral medications decreases the death rate and significantly increases the likelihood of normal development.

Prevention of HSV Infection in Newborns

Efforts to prevent transmission from the mother to the newborn have not been very effective. However, women who have blisters on their genitals near the time of delivery should be tested for herpes simplex infection.

If women have an active herpes infection at the time of delivery, cesarean delivery (C-section) may be done to decrease the risk of transmitting the infection to the newborn. Also, fetal scalp monitors would not be used during labor on a newborn whose mother may have active genital herpes because the monitors stick into the scalp and create a break in the skin that could spread the infection. Newborns who are born to women who have an active herpes infection should be tested for herpes simplex virus infection.

Treatment of HSV Infection in Newborns

Newborns who have a widespread infection are given the antiviral medication acyclovir by vein (intravenously) for 3 weeks and then by mouth for 6 months. Newborns who have a localized infection are given acyclovir intravenously for 2 weeks. This medication does not cure the infection but helps keep it from spreading and limits the symptoms.

Additional care, such as fluids and breathing support, is provided as needed.

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CAROLINE M. RUDNICK, M.D., PH.D., AND GRANT S. HOEKZEMA, M.D.

Am Fam Physician. 2002;65(6):1138-1142

A patient information handout on herpes in pregnancy, written by the authors of this article, is provided on page 1143 .

Neonatal herpes simplex virus infections can result in serious morbidity and mortality. Many of the infections result from asymptomatic cervical shedding of virus after a primary episode of genital HSV in the third trimester. Antibodies to HSV-2 have been detected in approximately 20 percent of pregnant women, but only 5 percent report a history of symptomatic infection. All primary episodes of HSV and secondary episodes near term or at the time of delivery should be treated with antiviral therapy. If active HSV infection is present at the time of delivery, cesarean section should be performed. Symptomatic and asymptomatic primary genital HSV infections are associated with preterm labor and low-birth-weight infants. The diagnosis of neonatal HSV can be difficult, but it should be suspected in any newborn with irritability, lethargy, fever or poor feeding at one week of age. Diagnosis is made by culturing the blood, cerebrospinal fluid, urine and fluid from eyes, nose and mucous membranes. All newborns suspected to have or who are diagnosed with HSV infection should be treated with parenteral acyclovir.

Neonatal herpes simplex virus (HSV) infections are transmitted from an infected mother, usually vertically, during delivery. The incidence of infection is approximately one per 3,000 to 20,000 live births. 1 A woman who experiences a primary episode of genital HSV during the third trimester and who has not completed seroconversion by the onset of labor has a 33 percent chance of transmitting the virus to her infant. 2 In contrast, a woman experiencing a secondary reactivation of HSV during the intrapartum period has approximately a 3 percent chance of transmitting the virus to her infant. 2 Of known infected infants, only 30 percent have mothers who had symptomatic HSV or a sexual partner with clinical infection. 3 Many neonatal infections occur because of asymptomatic cervical shedding of virus, usually after a primary episode of HSV infection. 3

The prevalence worldwide of herpes simplex virus type 2 (HSV-2) seropositivity is alarmingly high (25 percent seropositivity in the United States). 3 Antibodies to HSV-2 have been detected in approximately 20 percent of pregnant women; however, only 5 percent report a history of symptomatic infection. 4 Primary genital HSV infections during pregnancy occur at rates similar to those in nonpregnant women, and often these infections are asymptomatic. There is a 2 to 3 percent seroconversion rate in pregnant women. 5 Transmission occurs from an HSV-2-positive partner and is often traced to asymptomatic shedding of virus. Symptomatic and asymptomatic primary genital HSV infections are associated with preterm labor and low-birth-weight infants. 6 , 7 Because of the high prevalence of HSV among adults, physicians should be aware of the risk of a primary HSV infection in a pregnant woman and its potential consequences to the fetus.

Clinical Presentation

A neonatal HSV infection can be devastating to an infant. 8 Most of these infections are caused by HSV-2, but 15 to 30 percent are found to be caused by herpes simplex virus type 1 (HSV-1). Most cases occur in the intrapartum period, but they may occur in utero and postnatally through contact with oral or skin lesions. Many infants infected with HSV are born prematurely and subsequently have a low birth weight. Congenital HSV infection (approximately 4 percent of all neonatal HSV infections) can result in an infant born with microcephaly, hydrocephalus, chorioretinitis and vesicular skin lesions. 9 Three subtypes of natally acquired or postnatally acquired infection have been identified: (1) disease localized to the skin, eye or mouth; (2) encephalitis, with or without skin, eye or mouth involvement; (3) disseminated infection that involves multiple sites, including the central nervous system, lung, liver, adrenals, skin, eye or mouth.

The diagnosis of neonatal HSV can be difficult initially. The presentation is nonspecific, with signs and symptoms such as irritability, lethargy, fever or failure to feed at about one week of age ( Table 1 ) . Infants often do not have skin lesions (less than 50 percent of infants with encephalitis or disseminated disease). By the time diagnosis is made, many infants have severe disease and have developed complications. When diagnosis is delayed, mortality is high despite antiviral therapy. There is virtually no mortality among infants with disease limited to the skin, eyes and mouth, but mortality increases to 15 percent among infants with encephalitis and 57 percent among infants with disseminated disease, even with antiviral therapy. Long-term morbidity is common in infants who survive with encephalitis or disseminated disease, and may include seizures, psychomotor retardation, spasticity, blindness or learning disabilities ( Table 2 ) . 8

Illustrative Case

A male infant was born vaginally at 39 weeks of gestation with a birth weight of 7 lb, 3 oz to a 35-year-old gravida 1 para 1 woman. The mother had an uncomplicated pregnancy and no known history of HSV infection. Rupture of membranes was spontaneous and labor was augmented. Delivery occurred approximately 20 hours after rupture of membranes. There was no intrapartum fever. The infant developed mild respiratory distress at delivery that resolved with bulb and orogastric suction and administration of free-flow oxygen. Apgar scores were 8 at one minute and 9 at five minutes. The newborn had a normal physical examination and an uncomplicated stay in the newborn nursery and was discharged home on the second day of life.

The infant was brought to the emergency department the following day with a one-day history of poor breast-feeding, lethargy and an axillary temperature of 38.7°C (101.6°F). The examination was significant for mild lethargy, mild jaundice and a few scattered petechiae on the chest. Sepsis work-up was done and the cerebrospinal fluid (CSF) showed a white blood cell count of 2 per mm 3 (2 × 10 6 per L) and a red blood cell count of 17 per mm 3 (17 × 10 6 per L). The white blood count differential was 1 percent lymphocytes, 3 percent segmented neutrophils and 96 percent mononuclear cells. The cerebrospinal fluid glucose level was normal at 62 mg per dL (3.4 mmol per L) and the protein level was elevated at 62 mg per dL (0.62 g per L). After two days of negative bacterial cultures, intravenous antibiotics (ampicillin and cefotaxime [Claforan]), and clinical improvement, he was discharged home. On the seventh day of life, the infant experienced a seizure. He was admitted to the hospital with rapid decline and multiorgan failure. He died the following day. He was found to have positive cultures for HSV-1 from multiple sites (nasopharyngeal swab, liver biopsy). His mother also had a positive culture for HSV-1 from a breast lesion. This case illustrates the nonspecificity of the signs and symptoms of an HSV infection in a neonate, the lack of a history of HSV in the mother and the often tragic outcome of this disease.

Diagnosis of HSV Infections

The hallmark of primary episode genital HSV infections in adults is multiple painful vesicles in clusters on an inflamed surface. Associated symptoms may include pruritus, dysuria, vaginal discharge and tender regional lymphadenopathy. There is often a systemic prodrome of fever, malaise and myalgias one to two days before the appearance of lesions.

Secondary episodes of genital herpes are similar, but they often are associated with fewer lesions and are unilateral on the genitals. The symptoms of secondary episodes are usually less severe with few systemic symptoms. A suspected genital HSV infection should be confirmed with a diagnostic test. Traditionally, this has been viral culture of vesicular fluid. Typically, it may take two to three days to receive a report. More rapid diagnosis may be obtained by direct immunofluorescent staining using fluorescein-conjugated monoclonal antibodies to HSV. 10 The sensitivity of this test is 80 to 90 percent compared with viral culture. The polymerase chain reaction (PCR) is a more sensitive assay. An additional 9 percent of culture-negative women were PCR positive for HSV-2. 11

Diagnosis of an HSV infection in an infant requires a high index of suspicion because the history of an active infection, primary or secondary, in a mother is often not given. HSV infections should be considered in all neonates who present in the first month of life with nonspecific symptoms such as fever, poor feeding, lethargy or seizure. Any vesicular rash in an infant up to eight weeks of age should be cultured and the infant immediately started on antiviral therapy with acyclovir (Zovirax) pending culture results. Cultures of blood, CSF, urine and fluid obtained from the eyes, nose and mucous membranes should also be obtained. CSF should be tested for HSV by PCR assay.

Antiviral Therapy for HSV Infections

All primary episodes of genital HSV infections should be treated with antiviral medications, including primary episodes occurring in pregnant women. This recommendation is supported by a recent statement of the American College of Obstetricians and Gynecologists (ACOG). 12 Currently available antiviral medications are acyclovir, famciclovir (Famvir) and valacyclovir (Valtrex). They are nucleoside analogs that selectively inhibit viral replication. They reduce the duration of active painful vesicular lesions and the duration of symptomatic and asymptomatic shedding of virus. 13 , 14 Acyclovir was the first drug developed in this class and has a high safety profile. It is selective against HSV-infected cells. The two newer medications, famciclovir and valacyclovir, have a higher bioavailability with greater absorption resulting in higher plasma levels. They require less frequent daily dosing. Acyclovir is not teratogenic when given to women during the first trimester of pregnancy. 15

Studies are underway to determine the efficacy of using antiviral therapy in pregnant women who develop HSV infections or as a prophylactic measure in high-risk pregnant women during the third trimester to prevent symptomatic infections or asymptomatic viral shedding. 16 – 18 Currently, the data suggest prophylactic acyclovir will lower the recurrence rate of HSV infection in women who experience their first episode of HSV during pregnancy. In one study 16 of 46 women who experienced their first episode of genital herpes during pregnancy, the cesarean section rate was significantly decreased in the women prophylactically treated with acyclovir from 36 weeks of gestation up to delivery to prevent a secondary recurrence of infection.

All infants suspected to have or who are diagnosed with an HSV infection should be treated with parenteral antiviral therapy. The duration of disease before antiviral therapy is initiated is significantly correlated with morbidity and mortality. Currently, suggested therapy is acyclovir 60 mg per kg per day in three divided doses intravenously for 14 days for disease limited to skin, eyes and mucous membranes, and 21 days for central nervous system or disseminated disease. 1 , 19

Reduction of Risk for Neonatal HSV Infections

A history of HSV in a pregnant woman and her partner should be obtained at the first prenatal visit ( Table 3 ) . 1 , 12 , 17 , 20 Women with a negative personal history of HSV (especially those with a positive history in the male partner) should be counseled on ways to avoid infection, especially during the third trimester. Use of condoms or abstinence must be emphasized in this high-risk set of patients, even if the male partner has no active lesions. Women who have multiple sexual partners should be counseled on reducing the risk of sexually transmitted diseases. Weekly cervical cultures in late pregnancy for women with a history of genital HSV infection are no longer recommended. Type-specific serologic testing of pregnant women at high risk of primary HSV infection has been suggested. 4 At the present time, type-specific serologic tests are not widely available and their reliability is questionable.

Prophylactic acyclovir should be considered in the third trimester for women at especially high risk of having an active HSV infection at the time of labor. This would include women who have frequent outbreaks of genital herpes. 17 , 20

Antiviral therapy with acyclovir should be given to pregnant women who have a primary episode of genital HSV. It should also be given to women with an active genital herpes infection, primary or secondary, near term or at the time of delivery. A recent statement by ACOG supports the use of antiviral therapy in pregnant women with outbreaks of genital herpes. 12 Acyclovir has proved safety and efficacy and may prevent neonatal HSV infection. All use of acyclovir during pregnancy should be reported to the Acyclovir in Pregnancy Registry. 21

Women should be asked carefully about symptoms of herpes infections at the onset of labor. To look for any further signs of infection, a vaginal speculum examination should be performed on any woman who has any signs or symptoms suggesting HSV infection at the onset of labor. Any patient who has a suspected active genital HSV infection or prodromal symptoms of HSV infection should undergo cesarean section, regardless of whether the membranes have ruptured. There is no difference in the management of a primary or secondary episode of HSV at the time of delivery. The current standard of care is that any woman with an active HSV lesion is delivered by cesarean section. Although the risk of vertical transmission from a secondary reactivation is low (approximately 3 percent), it is still present and most importantly, it is often difficult to differentiate between primary and secondary herpes infections.

Cesarean section alone does not completely remove the risk of transmission of HSV to the infant, and such potentially exposed infants should be handled with caution. Rupture of membranes for more than four to six hours before delivery increases the risk of transmission of HSV to the infant. 22 The use of fetal scalp electrode monitoring during labor also provides a potential port of entry for the virus into the infant. 12 Nongenital herpes lesions do not necessitate a cesarean delivery, but the lesions should be covered with an occlusive dressing before vaginal delivery. 12

The HSV-exposed neonate should be monitored closely for any signs of infection. Initial cultures should be performed at 24 to 48 hours, then weekly cultures of conjunctiva, nose, mouth, urine and rectum for HSV-1 or HSV-2 have been suggested. 1 Empiric acyclovir may be instituted in infants born to mothers with suspected primary HSV infection because the risk of infection in the infant is 33 to 50 percent. 1 Any exposed infant with clinical signs of HSV should be cultured (conjunctiva, nose, mouth, urine, rectum, CSF, blood buffy coat), CSF should be sent for PCR analysis, and the infant should be immediately started on intravenous acyclovir therapy. There have been no studies to date assessing benefits of prophylactic antiviral medications given to a clinically well exposed neonate, because the duration of effective prophylaxis is not known. The use of acyclovir may suppress the virus but may not eradicate it in an exposed infant. Infants born to women with active genital HSV lesions should be managed with contact precautions and be kept in a private room. 1

Postpartum women, family members and nursery personnel with active herpetic lesions of the mouth or skin should be instructed to use contact precautions with the infant. Nursery personnel with an active herpetic whitlow should not have direct care of neonates. 1

American Academy of Pediatrics. Committee on Infectious Diseases. In: Pickering LK, ed. 2000 Red book: report of the committee on infectious diseases. 25th ed. Elk Grove Village, Ill.: American Academy of Pediatrics, 2000:309–18.

Brown ZA, Benedetti J, Ashley R, Burchett S, Selke S, Berry S, et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med. 1991;324:1247-52.

Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 1997;337:1105-11.

Brown ZA. Genital herpes complicating pregnancy. Dermatol Clin. 1998;16:805-10.

Brown ZA, Selke S, Zeh J, Kopelman J, Maslow A, Ashley RL, et al. The acquisition of herpes simplex virus during pregnancy. N Engl J Med. 1997;337:509-15.

Brown ZA, Vontver LA, Benedetti J, Critchlow CW, Sells CJ, Berry S, et al. Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med. 1987;317:1246-51.

Brown ZA, Benedetti J, Selke S, Ashley R, Watts DH, Corey L. Asymptomatic maternal shedding of herpes simplex virus at the onset of labor: relationship to preterm labor. Obstet Gynecol. 1996;87:483-8.

Jacobs RF. Neonatal herpes simplex virus infections. Semin Perinatol. 1998;22:64-71.

Jones CL. Herpes simplex virus infection in the neonate: clinical presentation and management. Neonatal Netw. 1996;15:11-5.

Pouletty P, Chomel JJ, Thouvenot D, Catalan F, Rabillon V, Kadouche J. Detection of herpes simplex virus in direct specimens by immunofluorescence assay using a monoclonal antibody. J Clin Microbiol. 1987;25:958-9.

Cone RW, Hobson AC, Brown Z, Ashley R, Berry S, Winter C, et al. Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women. JAMA. 1994;272:792-6.

ACOG practice bulletin.. Management of herpes in pregnancy. No. 8. October 1999. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet. 2000;68:165-73.

Baker DA. Antiviral therapy for genital herpes in nonpregnant and pregnant women. Int J Fertil Womens Med. 1998;43:243-8.

Wald A, Zeh J, Barnum G, Davis LG, Corey L. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996;124(1 pt 1):8-15.

Centers for Disease Control and Prevention.. Pregnancy outcomes following systemic acyclovir exposure—June 1, 1984-June 30, 1993. MMWR Morb Mortal Wkly Rep. 1993;42:806-9.

Scott LL, Sanchez PJ, Jackson GL, Zeray F, Wendel GD. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. 1996;87:69-73.

Stray-Pedersen B. Acyclovir in late pregnancy to prevent neonatal herpes simplex [Letter]. Lancet. 1990;336:756.

Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson GL, Wendel GD. Acyclovir suppression to prevent clinical recurrences at delivery after first episode genital herpes in pregnancy: an open-label trial. Infect Dis Obstet Gynecol. 2001;9:75-80.

Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, et al. Safety and efficacy of high-dose intravenous acyclovir in the mangement of neonatal herpes simplex virus infections. Pediatrics. 2001;108:230-8.

Prober CG, Corey L, Brown ZA, Hensleigh PA, Frenkel LM, Bryson YJ, et al. The management of pregnancies complicated by genital infections with herpes simplex virus. Clin Infect Dis. 1992;15:1031-8.

Andrews EB, Yankaskas BC, Cordero JF, Schoeffler K, Hampp S. Acyclovir in pregnancy registry: six years' experience. The Acyclovir in Pregnancy Registry Advisory Committee. Obstet Gynecol. 1992;79:7-13.

Nahmias AJ, Josey WE, Naib ZN, Freeman MG, Fernandez RJ, Wheeler JH. Perinatal risk associated with maternal genital herpes simplex infection. Am J Obstet Gynecol. 1971;110:825-37.

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Neonatal Herpes Simplex Virus (HSV) Infection

• Symptoms and Signs |
• Diagnosis |
• Prognosis |
• Treatment |
• Prevention |
• Key Points |

( See also Herpes Simplex Virus (HSV) Infections in adults and Overview of Neonatal Infections .)

Neonatal herpes simplex virus (HSV) infection has high mortality and significant morbidity. Incidence estimates range from 1/3,000 to 1/20,000 births. HSV type 2 causes more cases than HSV type 1.

HSV is usually transmitted during delivery through an infected maternal genital tract. Transplacental transmission of virus and hospital-acquired spread from one neonate to another by hospital personnel or family may account for some cases. Mothers of neonates with HSV infection tend to have newly acquired genital infection, but many have not had symptoms at the time of delivery.

Symptoms and Signs of Neonatal HSV Infection

Manifestations generally occur between the 1st and 3rd weeks of life but rarely may not appear until as late as the 4th week. Neonates may present with local or disseminated disease. Skin vesicles are common with either type, occurring in about 70% overall. Neonates with no skin vesicles usually present with localized central nervous system (CNS) disease. In neonates with isolated skin or mucosal disease, progressive or more serious forms of disease frequently follow within 7 to 10 days if left untreated.

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

DR M.A. ANSARY/SCIENCE PHOTO LIBRARY

By permission of the publisher. From Demmler G: Congenital and perinatal infections. In Atlas of Infectious Diseases: Pediatric Infectious Diseases . Edited by CM Wilfert. Philadelphia, Current Medicine, 1998.

Localized disease

Neonates with localized disease can be divided into 2 groups. One group has encephalitis manifested by neurologic findings, cerebrospinal fluid pleocytosis, and elevated protein concentration, with or without concomitant involvement of the skin, eyes, and mouth. The other group has only skin, eye, and mouth involvement and no evidence of CNS or organ disease.

Disseminated disease

Neonates with disseminated disease and visceral organ involvement have hepatitis, pneumonitis, disseminated intravascular coagulation, or a combination, with or without encephalitis or skin disease.

Other signs, which can occur singly or in combination, include temperature instability, lethargy, hypotonia, respiratory distress, apnea, and seizures.

Diagnosis of Neonatal HSV Infection

HSV culture or polymerase chain reaction (PCR) testing

Sometimes immunofluorescent testing of lesions or electron microscopy

Rapid diagnosis by viral culture or HSV PCR is essential. The most common site of retrieval is skin vesicles. The nasopharynx, eyes, rectum, blood, and cerebrospinal fluid should also be tested. In some neonates with encephalitis, virus is present only in the CNS. Diagnosis of neonatal HSV also can be made by immunofluorescence of lesion scrapings, particularly with use of monoclonal antibodies, and electron microscopy.

If no diagnostic virology facilities are available, a Tzanck test of the lesion base may show characteristic multinucleated giant cells and intranuclear inclusions, but this test is less sensitive than culture, and false-positives can occur.

Prognosis for Neonatal HSV Infection

Death is uncommon in neonates with local disease limited to the skin, eyes, or mouth. However, without treatment, many of these neonates will progress to disseminated disease or CNS disease that may be unrecognized.

Treatment of Neonatal HSV Infection

Supportive therapy

acyclovir 300 mg/m 2 3 times a day for 6 months; this long-term regimen improves neurodevelopmental outcomes at 1 year of age but may cause neutropenia.

Vigorous supportive therapy is required, including appropriate IV fluids, alimentation, respiratory support, correction of clotting abnormalities, and control of seizures.

For localized disease (skin, mouth, or conjunctivae), treatment is acyclovir treatment of herpetic keratoconjunctivitis ).

Prevention of Neonatal HSV Infection

Efforts to prevent neonatal transmission have not been very effective. Universal screening has not been recommended or shown to be effective, and most maternal infections with risk of transmission are asymptomatic. However, women with genital lesions at term should have testing and serology to diagnose HSV and determine the risk of transmission as well as to direct the care of the exposed but asymptomatic neonate. Cesarean delivery for women known to have a high risk of transmission (eg, active genital lesions present at term) has been shown to decrease transmission and is recommended even if the membranes have ruptured. Also, fetal scalp monitors should not be used during labor on infants whose mothers have suspected active genital herpes. Asymptomatic neonates born to women with active genital lesions at the time of delivery should be evaluated and tested for HSV infection. Additional information is available from the American Academy of Pediatrics ( 1 ).

Prevention reference

1. Kimberlin DW, Baley J, Committee on infectious diseases, Committee on fetus and newborn : Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics 131(2):e635-646, 2013. doi: 10.1542/peds.2012-3216

Neonatal herpes may be localized to the skin, eyes, or mouth, the central nervous system, or may be disseminated.

Encephalitis and disseminated disease have a high mortality rate, and neurologic sequelae are common among survivors.

In suspected cases, presumptive therapy and rapid diagnosis by HSV PCR of cerebrospinal fluid, blood, or lesions are essential to optimize outcomes.

Do cesarean delivery if the mother has active genital herpes lesions present at term.

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Herpes simplex virus (HSV) in neonates

Key messages.

• Herpes simplex virus (HSV) is a congenital infection that can occur during pregnancy or the peripartum period.
• Neonatal infection is usually the result of HSV 2, as this is the main virus associated with genital infection.
• 85% of Neonatal HSV infections are acquired perinatally, intrauterine infection accounts for <5% of cases. 
• Avoid using scalp electrodes where there is a suspicion of active maternal HSV.
• Nosocomial infection can occur and vigorous infection control measures should be instituted.

In June 2023, we commenced a project to review and update the Maternity and Neonatal eHandbook guidelines with a view to completion in 2024. Please be aware that pending this review, some of the current guidelines may be out of date. In the meantime, we recommend that you also refer to more contemporaneous evidence.

There are a number of organisms that can cause congenital neonatal illness many with devastating long-term consequences.

The timing of infection is important in regards to the severity of neonatal illness and in relation to the organism involved. Primary infection in the mother generally results in greater risk of consequences to the developing fetus compared with ‘reactivation’ of the infection.

Incidence and risk of infection

Issues to note about the incidence of herpes simplex virus (HSV) include:

• HSV 1 and HSV 2 are uncommon, but important, causes of neonatal illness.
• Neonatal infection is usually the result of HSV 2 as this is the main virus associated with genital infection (HSV 1 is usually spread via the respiratory route).
• The overall rate of genital HSV infection varies from country to country and many women (and men) remain asymptomatic, with no history of infection despite shedding virus.
• HSV can remain latent for long periods, with shedding or re-activation occurring at any time.
• There is a 1 per cent chance of women with a history of genital HSV infection shedding virus at the time of delivery.
• In cases of neonatal infection, only 30 per cent of mothers have a history of active genital herpes at the time of delivery.
• Babies born to mothers with a primary genital infection at the time of birth have a 25-50 per cent risk of developing infection, compared with less than <1 per cent in cases of recurrent infection present at the time of delivery.

Clinical presentation

Clinical presentations of HSV include:

• Neonatal HSV usually presents within two weeks of birth.
• Infection occurs in less than five per 100,000 births (up to 10 times more in the USA).
• 90 per cent are acquired during passage through the birth canal or through ascending infection.
• 5 per cent have 'congenital' HSV infection.
• 5 per cent have postnatal-acquired infection.

Usual clinical presentations

Skin/eye/mouth (SEM) localised disease Clinical features of skin, eye or mouth disease include:

• isolated vesicles or 'crops’
• occasionally other skin reactions can be present, including zoster-like eruptions
• keratoconjunctivitis with dendritic ulcers
• chorio-retinitis
• single or multiple oral vesicular lesions can be present.

If untreated, more than 70 per cent will progress to disseminated disease; 25 per cent will have virus in CSF at initial presentation.

Disseminated disease Features of disseminated disease include:

• poor prognosis, with over 70 per cent mortality if untreated
• poor feeding
• respiratory distress
• hepatomegaly

Pneumonitis Features of pneumonitis include:

• tends to occur day 4 to 7
• respiratory distress and can develop into haemorrhagic pneumonitis
• chest x-ray shows diffuse pneumonic change
• rare but dissemination is common if untreated.

Meningo-encephalitis Features of meningo-encephalitis include:

• isolated or part of disseminated disease
• encephalopathy (mean 11 days of age)
• seizures are common and often intractable
• absent gag-reflex is a particular feature.

EEG EEG shows characteristic temporal/parieto-temporal focus with periodic slow and fast waves.

Brain imaging (CT/MRI) Brain imaging (CT/MRI) shows disease particularly affecting the temporal areas.

Later calcification and cerebral atrophy can develop.

Investigations

Neonatal HSV infection is uncommon and a high level of vigilance is needed, since most affected newborns are born to mothers with no history of current genital HSV lesions. Issues to note about investigative procedures:

• The unwell baby should be examined for vesicles including oral.
• Skin vesicles swab for viral culture and HSV PCR.
• Throat and eye swabs should be performed. The use of immunoflourescence can provide rapid evidence of infection. Viral culture can take five days to demonstrate typical cytopathic changes.
• Lumbar puncture  is mandatory, with CSF sent for PCR and viral culture. However, negative PCR testing on CSF does not completely rule out HSV infection and the clinical picture of herpes encephalopathy is important in determining treatment.
• EEG and brain imaging are useful adjuncts in cases where diagnosis of CNS infection is in doubt.
• Serological studies are of little value early on as IgM may take two weeks to appear and IgG titres may not rise in babies and may reflect maternal antibody status.

Supportive care as always is vitally important, with attention to general care.

Specific early treatment is with:

• Acyclovir  20 mg/kg/dose IV as 1-2 hour infusion
• If <30 weeks - 24 hourly, if 30-32 weeks - 18 hourly, if >32 weeks - 12 hourly
• Pre-emptive therapy (high risk asymptomatic infant) - 10 days
• Laboratory confirmed or clinical disease confined to skin, eye, mouth 10-14 days
• Encephalitis or disseminated disease 21 days
• Vidarabine  10-15 mg/kg/day 12-hourly, IV for 10 days is also effective but acyclovir has a higher selectivity, lower inhibitory concentration and higher potency
• eye lesions require topical treatment (such as idoxuridine) and ophthalmological referral is essential.

Mortality and morbidity rates for disseminated and CNS disease are very high, even with early and aggressive treatment. Other points to note:

• Even in the setting of localised SEM disease, 10 per cent of infants have long-term neurological sequelae.
• Recurrent skin and eye eruptions can occur.
• Oral acyclovir has a role in this setting.

Survivors of laboratory confirmed infection should be closely monitored for recurrence, eye disease, hearing impairment & neurological sequelae.

Babies born to mothers with primary active genital herpes infection at the time of birth are at highest risk.

Preventative issues include:

• The choices are to proceed with vaginal birth (avoiding routine use of instruments) or to have LUSCS. There is currently insufficient information to clearly support one option over the other; however, risk of transmission with vaginal birth is low and must be weighed up against risk of LUSCS to mother.
• Some research also suggests mother’s be treated with Acyclovir from 36 weeks gestation.
• Babies born vaginally in the face of active genital lesions require careful observation.
• Swabs from the baby's eyes, mouth, nasopharyx and skin should be sent at 24-48 hours.
• If swabs are positive, treat the baby with acyclovir systematically. However, consideration to treatment even in the setting of LUSCS should be given, especially if delay in getting results occurs.
• Nosocomial infection can occur and vigorous infection control measures should be used.
• Relatives or staff with 'cold-sores' should be discouraged from handling newborn infants as there is a risk of infection.
• Mothers with cold-sores present a low-risk to the infant as passive antibody protection of the baby should be present.

More information

Further reading.

• Palasanthiran, P. (et al). ' Management of Perinatal Infections '. Australian Society for Infectious Diseases. 2014
• Isaacs D, Moxon ER. ‘Handbook of Neonatal Infections - a practical guide’. WB Saunders, London. 1999.
• Remington JS, Klein JO. ‘Infectious Diseases of the Fetus and Newborn Infant" 5Th Ed. WB Saunders, Philadelphia. 2000.
• Davies EG, Elliman DAC, et al. ‘Manual of Childhood Infections’. WB Saunders, London, 1996.
• Jeffries DG, Hudson CN. ‘Viral infections in Obstetrics and Gynaecology’. Arnold, London, 1999.
• Jacobs RF. ‘Neonatal herpes simplex virus infections’. Seminars in Perinatology. 22(1):64-71, 1998 Feb.
• Riley LE. ‘Herpes simplex virus’, Seminars in Perinatology. 22(4):284-92, 1998 Aug.
• Neonatal Pharmacopoeia RWH
• Shann, F. ' Drug Doses '. Royal Children's Hospital Parkville, 2014.

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Sample description and data collection, variables and statistical analysis, conclusions, acknowledgement, evaluation for neonatal hsv in infants undergoing workup for serious bacterial infection: a 5-year retrospective review.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Schondelmeyer is supported by the Agency for Healthcare Research and Quality (award K08HS026763). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Agency for Healthcare Research and Quality. Her contribution to this article was in part funded by this grant. Funders had no role in the study design; in the collection, analysis, or interpretation of data; in the decision to submit for publication; or in the writing of the manuscript; the other authors have indicated they have no financial relationships relevant to this article to disclose.

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Laura H. Brower , Paria M. Wilson , Eileen Murtagh-Kurowski , Joshua D. Courter , Samir S. Shah , Amanda C. Schondelmeyer; Evaluation for Neonatal HSV in Infants Undergoing Workup for Serious Bacterial Infection: A 5-Year Retrospective Review. Hosp Pediatr June 2020; 10 (6): 463–470. https://doi.org/10.1542/hpeds.2020-0033

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To describe the characteristics of infants evaluated for serious bacterial infection, focusing on empirical testing and treatment of herpes simplex virus (HSV) and describe the characteristics of HSV-positive patients.

We included infants aged 0 to 60 days undergoing evaluation for serious bacterial infection in the emergency department. This descriptive study was conducted between July 2010 and June 2014 at a tertiary-care children’s hospital. Eligible patients were identified on the basis of age at presentation to the hospital and laboratory specimens. Infant characteristics, symptoms on presentation, and laboratory workup were compared between HSV-positive and HSV-negative patients by using the 2-sample t test or the Wilcoxon rank test.

A total of 1633 infants were eligible for inclusion, and 934 (57.2%) were 0 to 28 days of age. HSV was diagnosed in 19 infants, 11 of whom had disseminated disease. Compared with those without HSV, HSV-positive infants were younger, less likely to be febrile and to present with nonspecific symptoms, and more likely to have a mother with HSV symptoms ( P < .05). Testing from all recommended locations was only performed in 22% of infants. Infants tested or empirically treated with acyclovir had a longer median length of stay compared with children who were not tested or treated ( P < .01).

The absence of fever should not preclude a workup for HSV in neonates, and when a workup is initiated, emphasis should be placed on obtaining samples from serum, cerebrospinal fluid, and surface specimens. Physicians may benefit from a guideline for evaluation of HSV with specific guidance on high-risk features of presentation and recommended testing.

Neonatal herpes simplex virus (HSV) infection carries a high risk of mortality and, among survivors, morbidity, including developmental delay and seizures. 1   Accurate and timely diagnosis, which is necessary to reduce mortality, 2   is complicated by the range of clinical presentations, which can include few or no signs, symptoms, or characteristic laboratory findings. 3 – 8   Although diagnosis in infants with skin-eye-mucosal (SEM) disease may be immediately apparent on the basis of the presence of vesicles, 9   other manifestations of HSV may be more difficult to identify. 10 , 11   Infants with disseminated disease, for example, can present with fulminant sepsis and disseminated intravascular coagulation or simply with hypothermia and lethargy. 3 , 12 , 13   Similarly, infants with isolated central nervous system (CNS) HSV can present with few nonspecific clinical and laboratory findings, especially early in the disease. 5 , 14  

Guidelines for the evaluation of serious bacterial infections (SBIs) in infants aged 0 to 60 days presenting with fever and signs of illness are well established, 15   but a workup for HSV is at the discretion of the treating physician. The American Academy of Pediatrics provides recommendations for the diagnosis of HSV, 16   but there is controversy concerning which infants merit evaluation, which leads to variation in testing and empirical treatment. 17 – 21   The epidemiology of neonatal HSV may be changing because of increased risk of first-time genital HSV infections in younger women of childbearing age, 22 – 26   which poses the highest risk of vertical transmission. 27 , 28   The most recent estimates indicate that the incidence of disease is on the rise and currently thought to occur in 4.5 patients in 10 000 births. 20 , 29   Thus, it is important to establish an understanding of how clinicians approach identifying infants at a high risk of infection while balancing the potential harms of overtreatment with the risk of delayed diagnosis. In view of the potential changing epidemiology of neonatal HSV infection, 29   it is important to better understand the characteristics of infants being evaluated for HSV.

Our goals in this study were to (1) describe the characteristics of infants evaluated for SBI at our hospital over a 5 year period, focusing on empirical testing and treatment of HSV; (2) describe the characteristics of HSV-positive patients at our hospital over the same time period; and (3) compare HSV-negative infants who were empirically tested and treated for HSV with those who were not.

We conducted a descriptive study of young infants undergoing evaluation for SBI, with a focus on HSV evaluation, between July 2010 and June 2014 at a Midwest tertiary-care children’s hospital. This time period was chosen because it preceded implementation of a clinical pathway that standardized diagnostic evaluation of infants receiving lumbar puncture. 30   The hospital has ∼120 000 emergency department (ED) visits and 35 000 admissions annually. This study was approved by the institutional review board.

We included infants aged 0 to 60 days undergoing evaluation for SBI in the ED. The evaluation for SBI was defined on the basis of the local febrile neonate guideline 31   and the intent of the medical team as the presence of blood, urine, and cerebrospinal fluid (CSF) cultures for infants 0 to 28 days of age and the presence of blood and urine cultures for infants 29 to 60 days of age.

We identified eligible patients on the basis of age at presentation to the hospital and at collection of laboratory specimens. We performed an initial electronic medical record (EMR) review to determine if the infant had undergone evaluation for SBI. For infants with multiple visits during the study period, each visit was included independently for data extraction. Additionally, we reviewed all positive HSV polymerase chain reaction (PCR) test results during the study period to ensure that no patients with HSV were missed because of an incomplete initial diagnostic evaluation in the ED or because the initial workup was performed at an outside facility but HSV testing was performed after transfer.

We created a standardized data collection tool using a secure data entry platform. 32   For infants meeting inclusion criteria, we completed detailed EMR data extraction to obtain data on HSV status, age and symptoms at presentation, sex, gestational age at delivery, HSV exposure history, presence of complex chronic conditions (CCCs), 33   laboratory testing, acyclovir use, length of stay (LOS), and record of extravasation. For this study, we used a previously developed definition for CCCs that includes congenital anomalies in the following categories: neurologic, cardiac, pulmonary, gastrointestinal, gastrourinary, endocrine or metabolic, and genetic. 33   For the EMR abstraction, we classified symptoms at presentation as follows: respiratory symptoms included cough, congestion, cyanosis, difficulty breathing, and apnea; neurologic symptoms included seizure, altered mental status, an abnormal neurologic examination, excessive sleepiness or fussiness, and irritability; skin and soft tissue symptoms included vesicular or petechial rash, blanching rash, abscess, mastitis, cellulitis, and bruising; and head, neck, eyes, ears, nose, and throat symptoms included otitis and conjunctivitis. The symptoms on presentation were not mutually exclusive, and neonates could have presented with multiple symptoms in a single category or different categories. For patients with HSV, we collected additional data on age at symptom onset, hours to acyclovir initiation, ICU admission, need for intubation or inotropic support, and death.

For our first objective, we grouped infants by HSV status and, for those without HSV, by age (0–28 days and 29–60 days). We defined SEM disease as a PCR test from only the skin, eyes, or mouth positive for HSV. CNS disease was defined as a CSF PCR test (with or without skin findings) positive for HSV. Disseminated HSV was defined as the presence of a positive serum PCR test result in addition to hepatitis, pneumonitis, disseminated intravascular coagulation, or other end-organ damage other than isolated CNS manifestations (with or without skin findings). 12 , 16   We classified infants as HSV-positive if they had any positive HSV PCR testing results or if they received a 21-day treatment course of acyclovir for presumed HSV. The remainder of the infants were classified as HSV-negative. Because HSV is a progressive illness if left untreated, we classified infants with no testing for HSV as HSV-negative at time of visit. HSV-positive and HSV-negative infants were compared on the basis of age at presentation, sex, gestational age at delivery, HSV exposure (maternal HSV symptoms or household contact with HSV), and symptoms or physical examination findings at presentation. Descriptive statistics were used to summarize types of testing performed and acyclovir use. We defined complete testing evaluation on the basis of published recommendations 16   as HSV PCR testing from the CSF, serum, surface (conjunctiva, nasopharynx, or rectum), and vesicle or lesion (if present on examination) as well as hepatic transaminase testing.

For our second objective, we used descriptive statistics to summarize characteristics of infants diagnosed with HSV, including testing results and outcomes. For our third objective, we grouped HSV-negative infants on the basis of whether they underwent empirical testing or treatment of HSV, defined as undergoing any HSV PCR test or receiving ≥1 dose of acyclovir. We compared the following dependent variables between these 2 groups: (1) median LOS, (2) presence of intravenous extravasation, (3) development of acute kidney injury (AKI). AKI was defined as an absolute serum creatinine level ≥1.5 mg/dL or a rise in serum creatinine levels of 1.5 times the initial value. 34  

Data were analyzed by using Stata 14.0 (Stata Corp, College Station, TX). Categorical variables were described by using percentages and compared by using Fisher’s exact test. Continuous variables were described by using means and SDs for normally distributed data and medians and interquartile ranges (IQRs) for skewed data. Analyses were completed by using the 2-sample t test or the Wilcoxon rank test.

A total of 1633 infants were eligible for inclusion, and 934 (57.2%) were 0 to 28 days of age. Twenty-nine patients had multiple evaluations for SBI over the study period; 1 infant had 3 visits, and the remainder had 2 visits. Four of the 29 revisits were for infants with HSV who presented after completion of hospitalization and treatment of their initial HSV disease for a second evaluation of fever. Eleven of the 29 infants with revisits underwent evaluation for SBI because of a history of a previous positive blood culture result. Table 1 reveals the demographic variables and characteristics of infants evaluated for SBI. No infants with HSV had a previously diagnosed CCC. Of the HSV-negative infants, 16 had gastrourinary conditions, 14 had cardiac conditions, 11 had genetic conditions, 10 had neurologic conditions, 6 had gastrointestinal conditions, and single infants had pulmonary, endocrine, or metabolic conditions.

Characteristics of Infants Evaluated for SBI

GI, gastrointestinal; HEENT, head, neck, eyes, ears, nose, and throat; PE, physical examination; —, not applicable.

In infants >34 wk gestation.

P < .05. Two-sample t test was used for age at presentation. Fisher’s exact test was used for all other variables.

HSV was diagnosed in 19 infants. Compared with those without HSV, HSV-positive infants were younger (mean: 11.3 vs 26.4 days; P < .05) and more likely to have a mother with HSV symptoms (32% vs 0.8%; P < .05). On presentation to the ED, HSV-positive neonates were less likely to be febrile but more likely to present with nonspecific findings, including ill appearance, hypothermia, difficulty breathing, and poor feeding.

Characteristics of the specific HSV cases are presented in Table 2 . All but one patient with SEM disease presented at <21 days of age. Although the overall numbers are small, patients with disseminated disease presented at a younger age than those with SEM or CNS disease. The average patient age in days for each disease type at presentation was 9.7 days for disseminated disease, 14.5 days for CNS disease, and 18 days for SEM disease. Of the 19 cases of neonatal HSV, all but 2 cases had positive PCR testing results. One of the infants with negative PCR testing results had a complete negative PCR evaluation but a rash that was concerning for cutaneous HSV, a mother with active oral HSV, and no CSF cell counts because of inadequate CSF volume. The second infant with negative PCR testing results had fever and poor feeding, with mononuclear CSF pleocytosis, but an inadequate CSF volume to obtain CSF PCR testing. Both infants were presumed positive for HSV and treated with 21 days of intravenous acyclovir. More than half of the HSV-positive infants had disseminated disease ( n = 11); 5 were CNS-positive, and 3 had an unknown CNS status because of the lack of an adequate CSF volume (secondary to severe illness).

HSV Case Review by Type of HSV Disease

ALT, alanine aminotransferase; AMS, altered mental status; AST, aspartate aminotransferase; BAL, bronchoalveolar lavage; NR, not reported; PE, physical examination; RBC, red blood cell; seg, segmented neutrophil; WBC, white blood cell; —, not applicable.

Potential patients with HSV are those without positive HSV testing results but who received a full 21-d course of acyclovir for possible HSV.

All of the patients with disseminated HSV and CNS unknown status were too ill at presentation for lumbar punctures.

CSF PCR results were negative but were treated as CNS-positive on the basis of abnormal CSF cell counts.

No CSF cell counts were available because of low CSF volume and traumatic lumbar puncture.

HSV high-risk symptoms and PE findings are based on common HSV symptoms in published case series of HSV-positive infants.

Probable maternal HSV based on signs and symptoms, but no access to maternal medical record to verify.

For each patient who died, the LOS is days in the hospital before death.

Neonatal AKI definitions were adapted from Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics . 2015;136(2). Available at: www.pediatrics.org/cgi/content/full/136/2/e463 .

For infants without HSV, PCR testing was more prevalent in younger infants (0–28 days) compared with older infants (29–60 days) ( Table 3 ). The CSF HSV PCR was the most common test obtained in all groups (31.7% of entire cohort). No HSV-negative older infants underwent complete testing for HSV per American Academy of Pediatrics recommendations. All infants with HSV received acyclovir; 39% of HSV-negative young infants and 11% of HSV-negative older infants were empirically started on acyclovir. The median number of acyclovir doses received was 44 (IQR: 11–64) for the HSV-positive infants. The young HSV-negative infants received a median of 2 doses (IQR: 2–3), whereas the older HSV-negative infants received a median of 3 doses (IQR: 2–4).

Laboratory Testing and Empirical Acyclovir for All Infants Evaluated for Serious Infection by Age at Presentation and HSV Status

ALT, alanine aminotransferase; AST, aspartate aminotransferase; —, not indicated.

A lesion or vesicle PCR was only obtained when the patient had a suspicious skin finding.

Complete evaluation was defined as HSV PCR testing from the CSF, serum, surface, and lesion (if present) as well as ALT or AST testing.

Acyclovir was initiated within 24 hours of presentation in 84% of infants with HSV. All 5 (26%) deaths occurred in infants with disseminated disease. Acyclovir was initiated >24 hours after presentation for 3 infants with nonspecific symptoms at presentation, including altered mental status and ill appearance. Four infants developed AKI, all with disseminated disease. Eight infants (42%) required endotracheal intubation, and 5 required inotropic support (26%) ( Table 2 ). For HSV-negative infants, 33% were tested for HSV or empirically treated with at least 1 dose of intravenous acyclovir. When compared with infants not evaluated for HSV, infants who were tested or empirically treated had a longer median LOS (48 [IQR: 41.2–71.3] vs 42.6 [IQR: 39.3–50.3] hours; P < .01). There were no significant differences between the groups in terms of cases of extravasation or AKI.

In this 5-year retrospective chart review, we described the characteristics of infants evaluated for SBI and highlighted presenting historical and physical examination findings that should raise suspicion for HSV infection. We found that HSV-positive infants commonly presented without fever and with nonspecific symptoms, such as poor feeding and difficulty breathing, that might not necessarily prompt specific concern for HSV infection. For the 19 infants diagnosed with HSV at our institution over the study period, we found that a complete evaluation was not consistently performed, suggesting that physicians may benefit from a guideline for evaluation of HSV with specific guidance on high-risk features of presentation and recommended testing. Finally, we showed that HSV-negative infants who received empirical testing and treatment of HSV have a longer LOS than those not tested or treated. These findings contribute to a growing understanding of the epidemiology and management of this rare entity.

Features of HSV-positive infants identified in our study were consistent with the existing literature. Specifically, we found a similar patient age at presentation for each subtype of HSV in our cohort 5 , 6 , 35   ; similar historical factors, such as exposure to HSV 13   or a poorly healing scalp electrode site 4 , 9 , 27 , 36   ; and similar physical characteristics 6 , 13   compared with other published reports. These findings support consideration of these characteristics as ways to risk-stratify infants for a more targeted approach to evaluation for HSV. 30   In our study, we also highlight the multitude of reasons, other than fever, that prompt physicians to evaluate for SBI in infants. 5 , 9   Of the 19 cases of neonatal HSV, only 7 infants (37%) presented to the ED with fever. Temperature instability in the form of hypothermia has been associated with disseminated disease, which was noted in 22% of the neonates with HSV in our cohort; therefore, it is important that clinicians be aware of the potential for HSV to present in an afebrile child with nonspecific symptoms. 37   Historical features, such as poor feeding 3 , 6 , 35 , 38 , 39   or respiratory distress, 6 , 13 , 39 , 40   have also been identified in other case series and should alert the physician to potential HSV disease in the appropriate context.

We found that only 22% of neonates with HSV had the appropriate complete evaluation for HSV performed, including transaminases and PCRs from all body fluids, which is similar to previous literature. 21 , 38   No single test has the perfect sensitivity to identify all the variable presentations of HSV 41 – 45   ; therefore, it is imperative to attempt to obtain mucosal, serum, and CSF PCRs and transaminases to help identify early cases of HSV before infants become critically ill. In our case series, 5 HSV-positive infants died, 3 of whom had no CSF PCR testing performed. This highlights the difficulty in identifying neonates with potential HSV infection and the need for standardized high-risk criteria to help alert clinicians sooner to this disease process.

A substantial number of infants in our cohort >28 days of age underwent testing for HSV. Perinatally acquired HSV rarely presents after 28 days of age 3 , 6 , 38   ; nurse and physician education regarding the common age ranges of neonatal HSV disease may be an important part of any improvement effort to decrease unnecessary invasive tests and their associated financial costs and physical risks. 37 , 46   We also noted that 11% of infants in this older, lower-risk age group received acyclovir, which increased their LOS and exposed those neonates to the potential harms associated with acyclovir. 2 , 47 , 48   Although early recognition and treatment of HSV infection is paramount, clinicians should also be aware of the potential negative consequences of overtesting and overtreatment.

Our study has several limitations. This was a retrospective study with data limited to those that were recorded in the EMR. We used a standardized chart abstraction tool to limit the subjectivity in data collection. Although our findings are from a single-center cohort, our hospital has a wide referral base and is the only children’s hospital within a 52-mile radius; therefore, in addition to patients from the community, we anticipate that the cohort may have included a larger proportion of patients with acute illness referred for a higher level of care. Because of the low incidence of disease, this single-center case series of neonates with HSV does not fully present the variability in presentation that has been reported in previous case series of HSV.

In this 5-year retrospective review of neonates undergoing evaluation for SBI, we identified typical and nonspecific clinical features that should alert physicians to evaluate and treat for neonatal HSV. Clinicians should remain wary of using fever as a primary criteria by which to identify infants at risk for HSV infection and should recognize the full breadth of testing required to evaluate for the 3 presentations of disease.

We acknowledge the Center for Clinical and Translational Science and Training at the University of Cincinnati for allowing us to create our data collection tool in Research Electronic Data Capture.

Dr Brower conceptualized the study, directed the literature review process, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Wilson and Schondelmeyer contributed to the study development, conducted the literature review process, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Murtagh-Kurowski and Courter provided crucial clinical expertise during study development and critically reviewed and revised the manuscript; Dr Shah conceptualized and directed the study development, provided clinical expertise in the literature review process, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by The Gerber Foundation Novice Research Grant (Dr Brower). The Center for Clinical and Translational Science and Training at the University of Cincinnati is funded by the National Institutes of Health Clinical and Translational Science Award program (grant 5UL1TR001425-04).

Competing Interests

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ORIGINAL RESEARCH article

Inadequate weight gain and factors influencing it among preterm neonates in neonatal intensive care units in amhara region, ethiopia, 2022 provisionally accepted.

• 1 College of Medicine and Health Science, Wollo University, Ethiopia
• 2 University of Gondar, Ethiopia

The final, formatted version of the article will be published soon.

Adequate weight gain is crucial for the health and development of preterm neonates admitted to neonatal intensive care units (NICUs). Understanding the factors influencing weight gain in this vulnerable population is essential for improving outcomes. This study aimed to assess the weight gain status and associated factors among preterm neonates admitted to NICUs in specialized hospitals in the Amhara region of Ethiopia.A cross-sectional study design was employed, involving 363 preterm neonates admitted to NICUs in specialized hospitals within the Amhara region. Data were collected using structured questionnaires and Kobo Tool Box. Daily weight measurements were recorded for three consecutive days. Descriptive statistics, logistic regression analysis, and graphical presentations were utilized for data analysis and presentation.The study revealed that a significant proportion (80.8%) of preterm neonates experienced poor weight gain during their NICU stay. Factors significantly associated with poor weight gain were older maternal age, delayed initiation of enteral feeding, lack of kangaroo mother care, and inadequate antenatal care visits.Addressing the identified factors, such as providing adequate support during the antenatal period, promoting timely initiation of enteral feeding, and encouraging kangaroo mother care practices, is crucial for improving weight gain outcomes in preterm neonates.These findings highlight the importance of a comprehensive approach to neonatal care, targeting both maternal and neonatal factors. Policymakers and healthcare providers should prioritize interventions aimed at optimizing weight gain in preterm neonates to improve their overall well-being and long-term outcomes.

Keywords: Preterm neonates, Weight Gain, Neonatal intensive care units, specialized hospitals, Amhara region, Ethiopia

Received: 02 Feb 2024; Accepted: 22 Apr 2024.

Copyright: © 2024 Semanew, Tesfaye and Tesgera. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. Yaregal Semanew, College of Medicine and Health Science, Wollo University, Dessie, Amhara, Ethiopia

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Prevention and management of neonatal herpes simplex virus infections

Human herpes simplex virus (HSV) infection in neonates can result in devastating outcomes, including mortality and significant morbidity. All infants are potentially at risk for neonatal HSV infection. This position statement reviews epidemiology, transmission and risk factors, with a focus on intrapartum infection. It considers diagnosis and prognosis according to infection category, along with testing modalities and limitations. Recommendations for managing newborns known to have been exposed intrapartum to HSV are based on expert opinion because a randomized trial to compare management options is not feasible. Guidance is provided for the empirical management of infants with suspected clinical sepsis, including those who do not respond to antibacterial therapy. The present statement replaces a 2006 position statement by the Canadian Paediatric Society.

Chez les nouveau-nés, l’infection par le virus de l’herpès simplex humain (VHS) peut avoir des conséquences cliniques dévastatrices, y compris la mortalité et une importante morbidité. Tous les nourrissons sont vulnérables à l’infection par le VHS néonatal. Le présent document de principes contient une analyse de l’épidémiologie, de la transmission et des facteurs de risque et s’attarde tout particulièrement sur l’infection intrapartum. Il présente une évaluation du diagnostic et du pronostic selon la catégorie d’infection, de même que les modalités et les limites des examens. Les recommandations relatives à la prise en charge des nouveau-nés dont l’exposition au VHS intrapartum est confirmée se fondent sur des avis d’experts, car il est impossible de procéder à un essai aléatoire pour comparer les possibilités thérapeutiques. Des conseils sont donnés pour la prise en charge empirique des nourrissons chez qui on craint un sepsis clinique, y compris ceux qui ne répondent pas à la thérapie antibactérienne. Le présent document de principes remplace celui que la Société canadienne de pédiatrie a publié en 2006.

Français en page 207

EPIDEMIOLOGY

Estimated rates of neonatal human herpes simplex virus (NHSV) infection vary across different regions of the world.( 1 , 2 ) In Canada, the infection occurs in approximately one per 16,500 newborns, which corresponds to approximately six per 100,000 live births. ( 1 ) Transmission to newborns can occur with either genital herpes simplex virus (HSV) type 1 (HSV-1) or HSV type 2 (HSV-2). Worldwide, an estimated 75% of NHSV cases are caused by HSV-2 and 25% by HSV-1.( 3 ) One Canadian prospective study analyzing reports in the period between 2000 and 2003 found that 63% of cases were due to HSV-1.( 1 ) Studies from Ontario (conducted in 2000 to 2001)( 4 ) and British Columbia (in 1999)( 5 ) investigating infants potentially at risk for HSV-2 detected HSV-2 antibodies in 10% and 17% of pregnant women, respectively.

Many factors influence the transmission of HSV infection to newborns, including the nature of maternal infection, the mode of delivery, the duration of rupture of membranes and the use of intrapartum instrumentation.

Maternal genital HSV cases may be classified as follows:( 6 )

• ○ First-episode primary infection (mother has no serum antibodies to HSV-1 or -2 at onset);
• ○ First-episode nonprimary infection (mother has a new infection with one HSV type in the presence of antibodies to the other type); or
• Recurrent (mother has pre-existing antibodies to the HSV type that is isolated from the genital tract).

The most common and important category of NHSV acquisition is intrapartum. Even for HSV-1, >75% of cases of NHSV are acquired during delivery from genital disease that is often newly acquired and asymptomatic.( 7 ) Newborns may also acquire HSV infection through in utero or postnatal transmission. Although rare, in utero HSV infection can have teratogenic effects such as skin lesions or scars, central nervous system (CNS) disorders and chorioretinitis. ( 8 ) Postnatal infection can be acquired from the infant’s mother or from nonmaternal sources (eg, relatives or hospital personnel with orolabial herpes or asymptomatic shedding of HSV-1). ( 3 , 9 )

In most cases of NHSV infection, there is no known history of maternal genital HSV because mothers have never had or have never noticed external genital lesions. Studies show that 75% to 90% of individuals who are seropositive for HSV-2 were unaware of their infection.( 10 ) All infants, therefore, must be considered to be potentially at risk for NHSV infection. Seropositive women intermittently shed HSV in their genital tracts, with 10% to 20% of individuals with HSV-2 shedding on any given day, as detected by polymerase chain reaction (PCR) testing.( 11 )

The category of maternal infection at time of delivery influences the likelihood of NHSV acquisition, presumably because mothers who have had an HSV infection transmit HSV-neutralizing antibodies to their infant across the placenta, provided that their infant is not born before 32 weeks’ gestation. ( 7 , 12 – 14 ) Thus, infants born to mothers who have a first-episode primary infection at time of delivery are at the highest risk for acquiring HSV, with transmission rates of up to 60%, because their mother had no pre-existing neutralizing antibodies to transmit.( 3 ) For infants born to mothers who have first-episode nonprimary infections, the transmission rates are in the order of ≤30% because crossreactive antibodies are present. The lowest risk of neonatal transmission occurs with maternal recurrent infection (at <2%) because type-specific antibodies are present.( 4 )

Delivery by elective Cesarean section markedly reduces but does not eliminate the risk for newborn infection.( 15 , 16 ) Women with recurrent genital HSV are commonly prophylaxed with acyclovir (ACV) or valacyclovir from 36 weeks’ gestation until delivery. In this context, antiviral therapy near the end of pregnancy can lower recurrence of genital HSV and shedding at delivery;( 17 ) however, it is not clear whether this prophylaxis translates to a reduced risk for NHSV infection. Guidelines regarding the role of Cesarean delivery and the indications for acyclovir are published( 16 , 18 , 19 ) but are not specifically addressed in the present statement.

Obstetrical procedures that can cause scalp abrasions or a break in the infant’s skin during labour and delivery may increase risk of NHSV transmission to a newborn infant. Fetal scalp sampling and monitoring, use of forceps and vacuum-assisted deliveries( 16 , 19 – 23 ) should be avoided if possible when maternal genital lesions are present.( 16 ) Early or prolonged rupture of membranes may also increase risk.

CATEGORIES AND OUTCOMES OF NHSV INFECTION

Classifying NHSV infections can help to guide diagnosis and management, and is important for assigning prognosis.( 24 ) Intrauterine NHSV infections are rare, accounting for <5% of cases. The classification of infection acquired in the perinatal, natal and post-natal periods is as follows:

• Disseminated HSV;
• Localized CNS HSV;
• Skin, eye and mucous membrane (SEM) infection.

There may be overlap among the different syndromes. Disseminated disease involves multiple organs, notably the liver and lungs.

In most cases, the initial symptoms of NHSV infection present within the first four weeks of life. Occasionally, disease presents for the first time between four and six weeks after birth;( 4 ) therefore, infants up to 42 days of age should be fully evaluated for NHSV when clinical features are consistent with NHSV. Newborns with intrauterine infection present at birth or shortly thereafter.

The absence of skin lesions does not negate the possibility of an NHSV diagnosis. One study showed that 39% of infants with disseminated disease did not have skin lesions at any time during their illness, while 32% with CNS disease and 17% with SEM disease did not develop skin lesions.( 25 ) NHSV infection should be considered in neonates with sepsis syndrome, particularly when this condition is accompanied by liver dysfunction and even when there is no known history of maternal HSV and the infant has no skin vesicles. One study reviewed 32 infants with perinatal HSV, noting that 50% of cases came to medical attention with non-specific complaints and 75% of these had fever alone. Nonspecific presentation occurred primarily in infants whose symptoms started at <21 days of age.( 26 ) Also, HSV should be considered in neonates with fever, irritability and abnormal cerebrospinal fluid (CSF) findings, particularly when accompanied by seizures. However, a normal initial CSF examination does not necessarily exclude the diagnosis of an NHSV CNS infection.( 26 )

Infants who present with disseminated disease are less likely to survive than infants with SEM or CNS disease. Data suggest that dissemination is more common with newly acquired maternal HSV, presumably because there has not been sufficient time to transfer neutralizing antibodies in utero.( 27 , 28 ) Before antivirals, an estimated 85% of infants with disseminated HSV disease and 50% with CNS disease died.( 29 ) Treatment with ACV (60 mg/kg/day) has resulted in one-year mortality rates from disseminated and CNS disease of 29% and 14%, respectively.( 30 ) A mortality rate of 15.5% was reported in a Canadian study that documented cases occurring over a three-year period (October 2000 to September 2003).( 1 )

Among survivors enrolled in two studies of parenteral ACV for which follow-up data were available at 12 months of age, 25% of patients with disseminated disease exhibited neurological complications, compared with 70% with CNS infection alone.( 25 ) Among neonates with SEM disease (without apparent CNS disease), long-term neurological sequelae have also been documented.( 28 , 31 ) However, more recent studies demonstrate no sequelae; therefore, it appears likely that those infants with sequelae had unrecognized CNS infection.( 32 )

LABORATORY DIAGNOSIS

It is important for the clinician to speak with a laboratory specialist or infectious disease consultant when NHSV is suspected, particularly in settings where testing for NHSV is performed less frequently. Expert consultation is important because the utility of testing modalities varies according to sample type, and the laboratory must provide general as well as centre-specific advice on the types of specimens to send for testing. Each specific laboratory test for HSV has important limitations. Therefore, test results should be interpreted with careful consideration of the clinical context and results from nonspecific investigations including an electroencephalogram, computed tomography or magnetic resonance imaging, liver transaminase levels and platelet count.

HSV may be detected using the following tests:

• Viral cultures from the oropharynx, nasopharynx, skin lesions, mucous membrane (eye and mouth) swabs, rectal swabs, blood buffy coat and CSF;
• PCR testing of CSF, skin lesions, mucous membranes and blood;
• Direct immunofluorescent antibody staining of skin lesions;
• Enzyme immunoassays for HSV antigens in skin lesions.

When skin lesions are present, rapid diagnostic techniques, such as direct immunofluorescence of virus-infected cells for the presence of HSV antigens, are of value. Direct immunofluorescence staining is not reliable unless the sample was obtained from a skin lesion (as opposed to a mucous membrane or oropharyngeal swab).( 4 )

The isolation of HSV by culture is still regarded as the definitive diagnostic method for establishing HSV disease outside of the CNS.( 33 ) Some centres now only offer PCR because it is believed to be more sensitive. The detection of the virus in superficial cultures may, however, represent skin contamination by intrapartum exposure if samples are obtained within the first 24 h after birth. ( 4 ) When samples obtained >24 h after birth are positive, they are more likely to represent active viral replication than contamination. Prospective studies regarding the utility of periodic surveillance cultures in the early diagnosis of NHSV infection are lacking for infants exposed to active genital lesions.

For patients with CNS HSV, PCR is a critically important diagnostic test because it is more sensitive than culture.( 34 ) As with any PCR test, false positive and false negative test results can occur. Caution should be exercised when using a negative CSF HSV PCR to rule out CNS HSV, particularly when the sample is obtained in the early stages of illness (the first 24 h to 48 h). Because CNS disease can be very subtle, any patient with suspected NHSV infection should have a lumbar puncture performed for CSF DNA PCR testing as soon as it is clinically feasible to do so, unless there is a contraindication to performing a lumbar puncture. CNS NHSV infection may occur despite ‘normal’ CSF cell counts and biochemical features, particularly in the early stages of infection. Therefore, the CSF DNA PCR test should be performed even when these parameters are normal.

The evaluation of HSV viremia using DNA PCR is less well established than CSF DNA PCR testing. ( 35 – 37 ). One study that evaluated HSV viral load in serum and CSF using a real-time PCR assay found that patients with disseminated disease had higher viral loads in their sera, while patients with CNS infection had higher viral loads in their CSF.( 35 ) Viral loads were also higher in patients who succumbed to HSV disease, suggesting that this measure may be useful for assessing prognosis in NHSV cases. A poorer prognosis has also been associated with persistence of HSV DNA in the CSF of patients on acyclovir.( 35 )

Infant serology is not useful for diagnosing NHSV for three main reasons. First, transplacental immunoglobulin (Ig) G antibodies cannot be differentiated from IgG produced by the infant. Second, the ability of some severely affected infants to make antibodies is impaired. Third, the commercially available assays for HSV IgM antibodies have only variable and limited reliability.

MANAGING NHSV INFECTIONS

Intravenous acyclovir is the treatment of choice for treating NHSV. The dose is 60 mg/kg/day in three divided doses administered every 8 h, assuming that renal function is normal.( 30 ) The duration of therapy is dictated by the category of disease. For SEM disease, the duration of therapy is 14 days, while for disseminated or CNS disease, the minimum duration of treatment is 21 days. Oral ACV has limited bioavailability, resulting in inadequate drug levels for treatment;( 38 ) consequently, parenteral therapy is required. The use of higher doses of ACV is associated with neutropenia and adequate hydration is necessary to reduce the risk of nephrotoxicity.( 30 ) A topical agent (eg, 1% trifluridine) is recommended for use with parenteral ACV in neonates with ocular disease.( 3 )

Given the potential for significant neurological sequelae in survivors of NHSV infection, affected infants should have a structured follow-up program that allows for neurodevelopmental, ophthalmological and hearing assessments.

There has been research into the role of suppressive antiviral therapy in infants with NHSV infections. A recent randomized, double-blinded, placebo-controlled trial evaluated infants with CNS HSV or disseminated HSV with CNS involvement, while a second, parallel trial evaluated infants with SEM HSV disease. The study demonstrated improved developmental outcome in infants with CNS involvement who were randomly assigned to receive six months of treatment with oral ACV versus placebo. ( 32 ) For infants with SEM disease, the only benefit was a decreased incidence of skin recurrences.( 39 , 40 )

RECOMMENDATIONS

Laboratory diagnostics for nhsv infections.

• ○ The standard tests for HSV include CSF PCR and swabs of vesicular lesions and mucous membranes (tested by the method recommended by the local laboratory). Also, blood for HSV PCR may be tested, if available.
• ○ Serum hepatic transaminase levels should be measured to provide supporting evidence for disseminated HSV infection.
• When evaluating NHSV infection in exposed asymptomatic infants, mucous membrane swabs should be obtained from the mouth, nasopharynx and conjunctivae at least 24 h after delivery. Additional swabs may be obtained (eg, from sites of scalp electrodes, if present).
• PCR testing for CSF HSV DNA is the diagnostic method of choice for CNS HSV.
• For all the above tests, clinicians and laboratory staff should work together to minimize the turn-around time for test results.

Managing asymptomatic term infants whose mothers have active lesions at delivery ( Figures 1 and ​ and2 2 )

† If type-specific serology is available and shows that the mother has recurrent herpes simplex virus (HSV) and all swabs obtained from the infant are negative, acyclovir (ACV) can be stopped and the infant discharged for close observation at home; ‡ The term ‘mucous membrane swabs’ denotes swabs taken from conjunctivae, mouth and nasopharynx; additional swabs may be obtained (eg, from sites of scalp electrodes, if present). In addition to mucous membrane swabs, some experts recommend blood for polymerase chain reaction (PCR), if this test is available. Clinicians should speak with a laboratory specialist or infectious diseases consultant when neonatal HSV (NHSV) is suspected and laboratory tests are being requested. § Also note that some experts recommend obtaining cerebrospinal fluid (CSF) cell count, chemistries and PCR when mucous membrane swabs are taken (ie, a complete work-up). IV Intravenous

* Some experts consider swabs to be optional if a Cesarean section was performed with no rupture of membranes before delivery. The term ‘mucous membrane swabs’ denotes swabs taken from conjunctivae, mouth and nasopharynx; additional swabs may be obtained (eg, from sites of scalp electrodes, if present). † Assumes observation is performed at home by parents, with or without nursing visits. Clinicians should speak with a laboratory specialist or infectious diseases consultant when neonatal herpes simplex virus (NHSV) is suspected and laboratory tests are being requested. ACV Acyclovir; CSF Cerebrospinal fluid; PCR Polymerase chain reaction

Antibodies to HSV-1 or HSV-2 (type-specific HSV antibodies) take approximately three weeks to develop following infection. ( 41 ) Their identification is useful in managing NHSV and testing should be performed if available. When a mother has active lesions at time of delivery but does not have type-specific antibodies, clinicians should presume it is a newly acquired first-episode primary infection. When she only has antibodies to the HSV type other than the type she is shedding, assume it is a first-episode nonprimary disease. When she has antibodies to both HSV-1 and HSV-2, this is likely to be a case of recurrent disease.

Evaluation and treatment at birth is indicated for exposed newborns with symptoms of NHSV.

The risk for NHSV is very low. Assuming that the infant is well, mother and child can be discharged pending results of the mucous membrane and nasopharyngeal swabs taken at 24 h of life. Reliable caregivers should be made aware of the signs of NHSV infection. Some experts also recommend testing blood with PCR, if the test is available. If HSV is detected on a swab or in blood PCR, the infant should be managed as a case of NHSV.

Note: Some experts recommend performing CSF cell count, chemistries and PCR when mucous membrane swabs are taken (ie, a complete work-up).

Where available, approved type-specific HSV antibody testing can be used to confirm whether the mother has primary, nonprimary or recurrent HSV.( 42 ) Many women who are believed to be presenting with primary disease at delivery actually have recurrent disease.

An infant’s mucous membrane swabs should be obtained and ACV started. It remains controversial whether this testing should be performed at birth (with the risk being detection of surface contamination) or at 24 h of life. Some experts also recommend testing blood with PCR, if the test is available. If the infant’s swabs or blood PCR are positive, CSF PCR must be obtained to determine the duration of ACV therapy. If the infant’s swabs are negative, ACV can be stopped if type-specific serology testing shows that the mother has recurrent HSV. If type-specific serology testing is not available or shows the mother has first-episode HSV, the infant should receive ACV for 10 days despite negative swabs.

Use the same approach as for first-episode infections before membrane rupture.

Obtain mucous membrane swabs at 24 h and the infant may be discharged pending results. Some experts also recommend testing blood for PCR, if the test is available. ACV therapy would only be indicated when the swabs or blood PCR are positive or when the infant develops signs and symptoms of NHSV infection.

Managing asymptomatic term infants whose mothers have no active lesions at delivery (including women on ACV prophylaxis)

An infant whose mother has a history of HSV but no active lesions at delivery should be observed for signs of NHSV but does not require ACV therapy. Mucous membrane swabs are not routinely recommended for this infant. In scenarios in which the first clinical evidence of HSV was documented during the third trimester or near delivery, clinicians may consider mucous membrane swabs. Parents and caregivers should be educated about the signs and symptoms of NHSV.

Managing the neonate with symptoms compatible with NHSV

Disseminated HSV can mimic bacterial sepsis, and clinicians need to consider possible NHSV infection in unwell infants <6 weeks of age. Pending laboratory confirmation, consider investigations and treatment of NHSV for the following at-risk patients:

• Infants started on IV antibiotics for suspected sepsis (especially infants presenting with seizure or yielding abnormal CSF) who do not improve rapidly and have negative bacterial cultures at 24 h incubation.
• Infants admitted with pneumonia of uncertain etiology who do not improve after 24 h on antibiotics, especially if the radiographic picture is consistent with viral pneumonia.
• Infants with unexplained bleeding from venipuncture sites or an unexplained, documented coagulopathy.
• Infants started on IV antibiotics for suspected sepsis who are found to have unexplained hepatitis.

Treatment and follow-up of infants with NHSV infections

• Early therapy with intravenous (IV) ACV improves the prognosis for all three presentations of NHSV. Therefore, infants should be started on IV ACV before laboratory confirmation of NHSV, as soon as the infection is suspected clinically.
• The dose is 60 mg/kg/day in three divided doses administered every 8 h, assuming that renal function is normal. Treatment duration should be 14 days if the disease is limited to the skin, eyes or mouth, and a minimum of 21 days if the infection involves the CNS or is disseminated.
• For infants with CNS disease, CSF should be sampled near the end of a 21-day course of therapy. If the PCR remains positive, treatment should be extended with weekly CSF sampling and ACV stopped when a negative result is obtained.
• In combination with parenteral ACV, neonates with ocular involvement should receive a topical ophthalmic agent such as trifluridine. An ophthalmology consultation is essential.
• Oral ACV is contraindicated for the acute treatment of NHSV because drugs levels are too low. Levels from oral ACV are only high enough for suppressive therapy.
• Suppressive therapy with oral ACV (300 mg/m 2 per dose administered three times per day) should be given for six months to infants with CNS disease. A tool for calculating body surface area can be found at: www.csgnetwork.com/bsacalc.html . Data are less convincing for SEM or disseminated disease, but suppressive therapy may still be offered.
• Follow-up is necessary to detect and manage adverse effects related to suppressive ACV treatment as well as for the neurodevelomental sequelae of NHSV. Complete blood count, and urea and creatinine levels should be checked monthly for adverse effects, and the dose of ACV adjusted for growth. Infants should be followed in a program that enables their evaluation for the neurodevelopmental, ophthalmological and aural consequences of NHSV infection.

Preventing NHSV infections

Strategies to prevent NHSV, including the identification of high-risk pregnancies, Cesarean delivery, maternal antiviral therapy, and anticipatory guidance for prospective mothers and partners, are largely beyond the scope of this statement. However, the following recommendations are especially pertinent to special care nurseries and neonatal intensive care units.

General infection control measures

Comprehensive infection control guidelines are available,( 43 ) but three specific target groups warrant attention here:

Neonates with HSV infection and exposed neonates

• Neonates with HSV infection should be managed using contact precautions when mucocutaneous lesions are present and until lesions have crusted.
• Asymptomatic neonates whose mothers have active HSV lesions should be managed using contact precautions until the end of the incubation period (day 14) or until samples from the infant taken after the first 24 h of life are negative. Some experts do not recommend contact precautions if an infected infant is born by Cesarean section and membranes are ruptured <4 h to 6 h.

Mothers with active HSV

• Mothers who are in hospital should be on contact precautions until their lesions have crusted.
• Mothers with herpes labialis should wear a disposable mask when caring for their infant <6 weeks of age, until lesions are crusted. Advise these mothers not to kiss their infant. There is no contraindication to breastfeeding unless there are herpetic lesions on the breast.
• Mothers with skin lesions should keep them covered whenever their newborn is present.

Staff with orofacial or skin lesions

• Staff with skin lesions due to HSV must practice meticulous hand hygiene. Individuals who have contact with infants should keep their lesions covered. If this is not possible, direct care of neonates should be avoided.
• Some experts recommend wearing a surgical mask to cover orolabial lesions because these cannot be covered by dressings.
• Staff with active herpetic whitlow should avoid contact with neonates.

Acknowledgments

This position statement has been reviewed by the Fetus and Newborn and Community Paediatrics Committees of the Canadian Paediatric Society.

CPS INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE

Members: Robert Bortolussi (past Chair); Natalie A Bridger MD; Jane C Finlay MD (past member); Susanna Martin MD (Board Representative); Jane C McDonald MD; Heather Onyett MD; Joan L Robinson MD (Chair); Marina I Salvadori MD (past member); Otto G Vanderkooi MD

Consultant: Noni E MacDonald MD

Liaisons: Upton D Allen MBBS, Canadian Pediatric AIDS Research Group; Michael Brady MD, Committee on Infectious Diseases, American Academy of Pediatrics; Janet Dollin MD, College of Family Physicians of Canada; Charles PS Hui MD, Committee to Advise on Tropical Medicine and Travel (CATMAT), Public Health Agency of Canada; Nicole Le Saux MD, Immunization Monitoring Program, ACTive (IMPACT); Dorothy L Moore MD, National Advisory Committee on Immunization (NACI); John S Spika MD, Public Health Agency of Canada

Principal authors: Upton D Allen MBBS; Joan L Robinson MD

The recommendations in this statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. All Canadian Paediatric Society position statements and practice points are reviewed on a regular basis. Retired statements are removed from the website. Please consult the Position Statements section of the CPS website ( www.cps.ca ) for the full-text, current version.