ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Neonatal herpes simplex virus infection: Management and prevention

Neonatal herpes simplex virus infection: Management and prevention
Literature review current through: Jan 2024.
This topic last updated: Jan 10, 2023.

INTRODUCTION — Herpes simplex virus (HSV) infection during pregnancy poses a significant risk to the developing fetus and newborn. Neonates can acquire HSV infection by intrauterine, perinatal, or postnatal transmission of the virus; most cases are acquired perinatally. Neonatal HSV infection causes serious morbidity and mortality and leaves many survivors with permanent sequelae. Strong clinical suspicion, timely diagnosis, and early antiviral treatment are critical to improving outcome.

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 — Supportive measures for the critically ill neonate with disseminated or central nervous system (CNS) disease include:

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")

Management of shock, if present (see "Neonatal shock: Management")

Respiratory support (see "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Overview of mechanical ventilation in neonates")

Nutritional support (see "Overview of enteral nutrition in infants and children" and "Parenteral nutrition in infants and children")

Control of seizures (see "Treatment of neonatal seizures")

Management of disseminated intravascular coagulation (see "Disseminated intravascular coagulation in infants and children", section on 'Management')

Antimicrobial treatment for secondary bacterial infections (eg, gram-negative enteric bacteria and gram-positive bacteremia such as Staphylococcus aureus) [1] (see "Management and outcome of sepsis in term and late preterm neonates", section on 'Antibiotic therapy')

INITIAL ANTIVIRAL THERAPY

Indications — Indications for acyclovir therapy include [2-5]:

Virologically proven HSV disease (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV')

Clinically suspected HSV disease (figure 1), pending viral studies (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations')

Asymptomatic infants with significant perinatal or postnatal exposure (eg, maternal active genital lesions) (algorithm 1) (see 'Management of asymptomatic exposed infants' below)

The indications for initiation of empiric acyclovir are not standardized. There is universal agreement that empiric acyclovir is indicated for neonates with clinical features suggestive of HSV infection, which include mucocutaneous vesicles (picture 1A-C), seizures, lethargy, respiratory distress, thrombocytopenia, coagulopathy, blood oozing from intravascular catheter sites, hypothermia, sepsis-like illness, hepatomegaly, ascites, or markedly elevated transaminases (figure 1) [2-5]. Many experts recommend empiric treatment for ill-appearing neonates with fever or cerebrospinal fluid (CSF) pleocytosis until results of HSV workup are known. However, expert opinions differ regarding the relative benefits, risks, and cost-effectiveness of empiric acyclovir before virologic confirmation in other clinical situations (eg, fever without localizing signs in an infant ≤21 days of age, CSF pleocytosis in an otherwise well-appearing neonate, persistent or recurrent erythema or purulence/crusting at the site of a scalp electrode, etc) [2-4,6]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'.)

Management of asymptomatic newborns exposed to HSV at delivery or postnatally is discussed below. (See 'Management of asymptomatic exposed infants' below.)

The full course of acyclovir therapy should be administered for infants with positive HSV cultures or polymerase chain reaction (PCR), and infants with negative virologic studies in whom neonatal HSV is strongly suspected. (See 'Duration of therapy' below.)

Timing — Intravenous (IV) acyclovir should be administered at the time the diagnosis of neonatal HSV is suspected. Prompt administration improves outcome [7-11]. Acyclovir therapy should be continued while clinical observation and results of laboratory and imaging evaluations are completed.

Pretreatment evaluation — A comprehensive laboratory evaluation for HSV should be performed before initiation of acyclovir therapy. The evaluation should include (if the infant is clinically stable enough to undergo it) [5,12]:

Testing to detect HSV, including all of the following, which are discussed in greater detail separately (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV'):

Surface HSV cultures or HSV PCR from the conjunctivae, mouth, nasopharynx, and rectum

HSV culture or HSV PCR of swabs/scrapings of skin and mucous membrane lesions, if present; direct immunofluorescence assay may be used in addition to culture to permit rapid detection

CSF HSV PCR

Whole blood or plasma HSV PCR

Viral culture or HSV PCR of other specimens that are readily available (eg, tracheal aspirates in intubated patients)

Testing to determine the degree of organ involvement and studies to exclude other diseases that may cause similar symptoms (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Additional studies'):

Complete blood count, including differential and platelet count.

Liver function tests, including transaminases and total and direct bilirubin; if these are abnormal, additional testing should include coagulation studies (prothrombin time, activated partial thromboplastin time) to evaluate hepatic synthetic function and ammonia to exclude fulminant liver failure and/or metabolic disease.

Blood urea nitrogen (BUN), creatinine, and urinalysis (to assess kidney function and hydration status).

CSF cell count and differential, glucose, protein.

Ophthalmologic examination.

Neuroimaging. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Brain imaging'.)

Electroencephalogram (EEG) in neonates suspected to have CNS disease. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Electroencephalogram'.)

Chest radiograph, for neonates with respiratory distress.

Blood and CSF cultures to evaluate for bacterial sepsis.

Acyclovir therapy — We recommend acyclovir as the antiviral agent of choice for the treatment of all categories of neonatal HSV disease, including skin, eye, and mouth (SEM); central nervous system (CNS); and disseminated disease (table 1) [5,8,9,13].

The following sections review the dosing, efficacy, adverse effects, and monitoring for neonatal acyclovir therapy. Additional details, including the mechanism of action, pharmacokinetics, and toxicity of acyclovir, are discussed separately. (See "Acyclovir: An overview".)

Dose — The dose of acyclovir for all forms of neonatal HSV is 60 mg/kg per day IV divided every eight hours [8]. The dose of acyclovir must be adjusted for neonates with kidney impairment. Once the infant is ≥3 months old, a lower dose (45 mg/kg per day) is used.

The efficacy of the 60 mg/kg dosing for neonates was established in an open-label study in which 72 neonates with CNS or disseminated HSV were treated with acyclovir 60 mg/kg per day for 21 days [8]. Their outcomes were compared with those of neonates in an earlier trial who were treated with acyclovir 30 mg/kg per day for 10 days [9]. The higher dose was associated with increased survival at 24 months (odds ratio 3.3, 95% CI 1.5-7.3).

Duration of therapy — The duration of acyclovir therapy for neonatal HSV infection depends upon the pattern of illness and response to therapy [5,7,8,13]:

SEM disease – Localized SEM disease should be treated for a minimum of 14 days if disseminated and CNS disease have been excluded (table 1).

Disseminated and CNS disease – Disseminated and CNS disease should be treated for a minimum of 21 days. Because the persistence of HSV DNA in the CSF is associated with poor outcome, lumbar puncture should be repeated near the end of therapy to ensure that CSF HSV PCR is negative [5,7,12,14-17]. (See 'Monitoring during treatment' below and 'Persistent disease' below.)

Efficacy — The efficacy of acyclovir for neonatal HSV is supported by observational studies demonstrating that early treatment is associated with improved survival [8-10]. In addition, two open-label trials demonstrated superior two-year survival in neonates treated with high-dose acyclovir (60 mg/kg per day for 21 days) compared with low-dose (30 mg/kg per day for 10 days) [8,9].

Before antiviral therapy was available, the one-year mortality rates for neonates with disseminated and CNS HSV disease were 85 and 50 percent, respectively [18]. With the advent of antiviral therapy, mortality rates declined to 29 and 4 percent, respectively [8,9,12]. Antiviral therapy also has increased the proportion of survivors of disseminated disease who have normal neurologic development (from 50 to approximately 80 percent), though mortality associated with disseminated disease remains high [8,12,18,19]. (See 'Disseminated disease' below.)

Antiviral therapy does not appear to have affected the proportion of survivors of CNS disease with normal neurologic development (approximately 30 percent both before and after antiviral therapy became available) [8,12,18,19]. (See 'Outcome' below.)

Early antiviral treatment of infants with SEM disease prevents progression to CNS or disseminated disease [20]. Between 50 and 60 percent of infants with SEM who do not receive antiviral therapy progress to CNS or disseminated disease, whereas those with isolated SEM disease rarely, if ever, will die of the infection [19].

Limited data are available comparing the efficacy of acyclovir relative to other antiviral agents. In a randomized controlled trial, the morbidity and mortality were similar among infants treated with acyclovir and vidarabine [9]. However, vidarabine has systemic toxicity and a dosing schedule that requires 12-hour infusions and is no longer routinely used.

Adverse effects — Systemic acyclovir therapy is well tolerated by most neonates and side effects are unusual. Potential adverse effects include:

Kidney injury caused by crystallization in the renal tubules, which is more likely to occur if the neonate is dehydrated

Dose-dependent reversible neutropenia [7,8,12]

Ulceration at the site of peripheral extravasation

Seizures, especially if the dose is not adjusted in patients with kidney impairment

Monitoring during treatment — Routine monitoring for neonates receiving IV acyclovir includes the following:

Kidney function – BUN and creatinine are monitored once or twice weekly, depending on the clinical status of the patient. For patients with acute kidney injury and/or severe disseminated HSV disease, BUN and creatinine should be monitored daily. In addition, the infant's hydration status should be monitored by assessing intake and output and measuring urine specific gravity. In our practice, we aim to keep urine specific gravity <1.010 during acyclovir therapy to reduce nephrotoxicity. The acyclovir dose should be adjusted if creatinine clearance is lower than expected for age of patient.

Absolute neutrophil count (ANC) – ANC should be followed approximately twice per week during the course of therapy [8,12]. The acyclovir dose should be reduced or granulocyte colony-stimulating factor should be administered if the ANC remains <500/microL for an extended period of time without an alternative explanation for the neutropenia.

Infusion site – Monitoring of the local infusion site is important because local infiltration can cause superficial or deep ulcerative lesions. If possible, administration through central access or a peripherally-inserted central catheter is preferred.

Repeat lumbar puncture – For neonates with CNS disease or disseminated HSV, CSF PCR should be repeated near the end of planned the 21-day treatment course. Persistently positive CSF PCR may correlate with a poorer neurologic outcome and requires additional treatment [21]. (See 'Persistent disease' below.)

Quantitative plasma or whole blood PCR levels – If available at the center, monitoring quantitative plasma or whole blood PCR levels may be helpful since high levels of HSV viremia are associated with severe disease and may help guide management [22,23]. However, these tests may not be available in all settings.

The author of this topic's practice for neonates with documented viremia is to repeat the blood HSV PCR at the end of the 21-day treatment course to assess for viremia clearance. Data from a small cohort of infants (n = 6) with disseminated HSV disease who were monitored with serial plasma HSV PCR levels during treatment suggest that acyclovir therapy has a predictable effect on plasma HSV levels regardless of the baseline viral level, and that this monitoring can be used to help guide duration of therapy [22]. If the blood HSV PCR is persistently positive, additional IV acyclovir therapy is provided and evaluation for primary immune is undertaken. (See 'Persistent disease' below.)

Persistent disease

Continued antiviral therapy – Infants with persistently positive CSF, blood, or plasma HSV PCR despite 21 days of acyclovir therapy should be continued on antiviral treatment. Blood and/or CSF HSV PCR testing should be repeated weekly until negative [5,12]. Consultation with a pediatric infectious disease specialist is warranted to guide management decisions in these cases.

Evaluation for primary immune disorder – In our practice, we perform an evaluation for primary immune disorders in any neonate who has persistent or progressive symptoms or persistently positive CSF, blood, or plasma HSV PCR despite 21 days of acyclovir therapy. Disorders of T cell or natural killer (NK) cell function are the most likely disorders in this setting. In particular, toll-like receptor 3 (TLR3) deficiency is associated with high risk of developing severe HSV encephalitis. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

Evaluation of persistent neurologic symptoms – Persistence of neurological symptoms such as irritability, movement disorders, or seizures after completing antiviral therapy should raise concern for postinfectious complications of HSV, particularly autoimmune encephalitis (eg, anti-N-methyl-D-aspartate [NMDA] receptor encephalitis) [24]. The diagnosis is confirmed by detecting NMDA receptor antibodies in the serum or CSF. At our institution, we routinely evaluate for anti-NMDA receptor autoimmune encephalitis in any neonate with confirmed HSV CNS disease who has persistence of neurological symptoms despite appropriate treatment. It is important to be aware of autoimmune encephalitis since the treatment includes immunosuppressive therapy in addition to prolonged antiviral treatment. Consultation with a pediatric neurologist and/or neuroimmunologist is warranted. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-NMDA receptor encephalitis'.)

Anti-NMDA receptor encephalitis following neonatal HSV CNS disease also may be associated with an underlying primary disorder of cellular immune function. Thus, an immune evaluation is also warranted in these cases.

If acyclovir is not available — If IV acyclovir is not available, we suggest IV ganciclovir as the preferred alternative agent. This is consistent with guidance from the American Academy of Pediatrics Committee on Infectious Diseases [25-27]. The dose is 6 mg/kg IV every 12 hours for infants ≤90 days of age and 5 mg/kg IV every 12 hours for infants >90 days. A second-line alternative is foscarnet 60 mg/kg IV every 12 hours.

ADJUNCTIVE THERAPIES USED IN SEVERE CASES

Intravenous immune globulin (IVIG) – The role of IVIG in the management of severe neonatal HSV infection is uncertain, and practice varies. The author's practice is to administer IVIG in critically ill neonates with severe disseminated HSV who were born to mothers with primary HSV infection (ie, neonates who likely did not receive transplacental transfer of HSV-specific antibodies). However, there are very few data to support this practice [28] and other experts may omit IVIG therapy in this setting. The practice is largely based on the rationale that maternal HSV serostatus plays an important role in neonatal disease severity [29,30]. IVIG is unlikely to directly neutralize the virus, but it may enhance antibody-dependent cellular cytotoxicity.

Glucocorticoids – Glucocorticoids generally do not play a role in the management of neonatal HSV. Their use is limited to the most severe cases when HSV infection triggers cytokine release syndrome or neonatal hemophagocytic lymphohistiocytosis (HLH) [31]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

ORAL SUPPRESSIVE THERAPY — Following parenteral treatment for all forms of neonatal HSV disease (skin, eye, and mouth [SEM], central nervous system [CNS], and disseminated disease) (table 1), we suggest suppressive therapy with oral acyclovir 300 mg/m2 per dose three times per day for six months; the dose should be adjusted each month to account for growth [5,17,32]. This recommendation is based on a randomized clinical trial in which suppressive therapy reduced cutaneous recurrences and was associated with improved neurologic outcomes in infants with CNS disease [32]. If HSV keratitis is present, many experts suggest oral suppression for up to one year with careful follow-up for recurrences [23]. (See 'Treatment of eye disease' below.)

Acyclovir is preferred to valacyclovir because the safety and efficacy of valacyclovir have not been established in infants younger than two years of age. Furthermore, since only tablet form is available, an extemporaneously compounded valacyclovir oral suspension (25 to 50 mg/mL) must be specially prepared for infants [33]. Based on limited data on the pharmacokinetics and safety of valacyclovir in pediatric patients, doses of 10 to 20 mg/kg of extemporaneously compounded valacyclovir oral suspension, administered twice daily, produce favorable acyclovir blood concentrations and appear well tolerated in most children [34,35].

The effectiveness of long-term suppression with oral acyclovir in reducing the risk of CNS recurrence after neonatal HSV disease is unknown. CNS recurrence in neonates receiving long-term oral suppression has been documented [36]. Nonetheless, oral acyclovir suppression appears to be associated with improved neurodevelopmental outcome. In a multicenter trial, 74 infants (45 with CNS HSV disease, 29 with SEM HSV disease) were randomly assigned to oral acyclovir 300 mg/m2 per dose three times per day or placebo immediately following parenteral acyclovir treatment [32]. In children with CNS involvement, acyclovir suppression was associated with higher mean infant development scores at 12 months of age (88 versus 68 on the Bayley Scales of Infant Development, second edition, in which scores range from 50 to 150). The incidence and degree of neutropenia were similar in the treatment and placebo groups.

Adverse effects of oral acyclovir suppression may include dose-dependent reversible neutropenia (in one-half to two-thirds of infants in previous studies) and emergence of HSV mutants that are acyclovir resistant [7,12,36,37]. We monitor the ANC monthly in neonates receiving oral suppressive therapy. (See 'Monitoring during treatment' above.)

TREATMENT OF RECURRENCES

Cutaneous recurrences – Cutaneous recurrences are common [38]. The optimal management of cutaneous recurrence is not established. Our approach is as follows:

Early treatment at the time of each cutaneous recurrence – Treatment consists of oral acyclovir (10 to 20 mg/kg per dose three times per day for young infants or 10 to 15 mg/kg per dose four to five times per day for older infants and children) for 7 to 14 days. This may be administered to reduce the discomfort and shedding associated with the lesions.

Preemptive treatment – The same regimen can be used preemptively when a cutaneous recurrence is anticipated, such as times of high stress or exposure to sunlight.

Long-term oral suppression for patients with frequent recurrences – In patients with frequent cutaneous recurrences that are painful or disruptive to daily life, long-term oral suppression may be of benefit. There is a broad range of acceptable doses. The author of this topic generally prefers acyclovir 20 mg/kg per dose twice per day. In some patients, 10 mg/kg per dose twice per day is sufficient. If no cutaneous recurrences are documented after a 12-month period, suppression may be discontinued. (See 'Oral suppressive therapy' above.)

Breakthrough recurrence while on oral suppressive therapy – For patients with breakthrough recurrences while receiving twice-daily oral suppressive therapy, we increase the dosing frequency to three or four times daily for 7 to 14 days. Recurrences that occur while the patient is receiving suppressive acyclovir therapy three to four times per day should be cultured and the HSV isolate tested for acyclovir resistance.

Disseminated or central nervous system (CNS) disease – Recurrence of disseminated or CNS disease are treated with intravenous (IV) acyclovir treatment, as described above (see 'Acyclovir therapy' above). In addition, these patients should undergo evaluation for a primary immune disorder of cellular function, including toll-like receptor 3 (TLR3) protein disorders [39,40]. (See "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

TREATMENT OF EYE DISEASE

Initial therapy – Neonates with ocular HSV involvement (eg, keratitis) should be referred to an ophthalmologist for consultation. Treatment consists of topical ophthalmic therapy in addition to systemic acyclovir therapy [5,23]. (See 'Acyclovir therapy' above.)

Acceptable topical agents include 1% trifluridine, 0.15% ganciclovir, or 0.1% idoxuridine (iododeoxyuridine; not available in the United States).

Long-term suppressive therapy – We suggest long-term suppressive therapy (up to one year) with oral acyclovir (300 mg/m2 per dose three times per day or 10 to 20 mg/kg per dose three times per day) for patients with HSV involvement of the eye, particularly keratitis, because of the risk of impaired vision with reactivation [7,12,17,23]. (See 'Oral suppressive therapy' above.)

Treatment of recurrences – For patients who develop recurrences of eye disease after receiving antiviral suppression for one year, suppressive therapy should be continued indefinitely. In addition, an evaluation should be performed to assess for primary immune disorders that may be contributing to the ophthalmic persistence.

MANAGEMENT OF ASYMPTOMATIC EXPOSED INFANTS

Perinatal exposure — The optimal management of asymptomatic infants who are exposed to maternal HSV at delivery (as documented by maternal virologic testing or active genital lesions) is uncertain as data to inform these decisions are limited [13,17,41]. However, experts and professional societies provide some guidelines regarding the need for testing and prophylactic or anticipatory antiviral therapy based upon the risk of transmission under various circumstances (algorithm 1) [5,13,42-46]. (See 'Society guideline links' below.)

The following sections review the approach to managing asymptomatic neonates with potential perinatal exposure to HSV. All neonates who are born to individuals with current or prior genital HSV (with or without active lesions at the time of delivery) should be monitored during the first six weeks after birth for development of concerning findings (eg, skin or scalp rashes, conjunctival lesions, irritability, sepsis, etc) (figure 1) [5]. Infants who develop clinical evidence of HSV infection should undergo full clinical and laboratory evaluation and should receive treatment with acyclovir pending results of virologic evaluation. (See 'Pretreatment evaluation' above and 'Initial antiviral therapy' above.)

Our suggested approach is generally consistent with guidelines from the American Academy of Pediatrics, which provide guidance on the evaluation and management of asymptomatic neonates in settings where type-specific HSV polymerase chain reaction (PCR) testing with rapid turnaround time is available [5]. In addition, we provide guidance for settings where type-specific HSV serologic testing with rapid turnaround time is not available.

Consultation with a pediatric infectious disease specialist is suggested for guidance in challenging clinical situations.

Risk of transmission — The risk of transmission to the infant depends upon a number of factors, including [5,17,46,47]:

Whether the maternal infection is primary or recurrent (the risk is highest with primary infection because the neonate may not have received transplacental transfer of HSV-specific antibody in utero)

Delivery method (vaginal versus cesarean; the risk is higher with vaginal delivery)

Duration of rupture of membranes (the risk is higher if ≥4 hours)

Maternal HSV antibody status

Integrity of the infant's mucocutaneous barriers (eg, use of fetal scalp electrodes)

Availability of type-specific PCR or culture testing of maternal genital lesions and type-specific maternal HSV serology permits more accurate characterization of the type of maternal infection (table 2) and, therefore, estimation of the risk of transmission [46,47].

A more detailed discussion of the risk of transmission is provided separately. (See "Genital herpes simplex virus infection and pregnancy", section on 'Vertical transmission'.)

Maternal history of HSV, no active lesions — The risk of transmission of HSV to infants born to individuals with a history of genital HSV but no active genital lesions at the time of delivery is very low. Such infants who are asymptomatic do not routinely require any additional evaluation of treatment [5]. However, they should be monitored for clinical evidence of HSV infection during the first six weeks of life [5]. The infant's parents and caregivers should be educated about the signs of neonatal HSV infection.

Maternal history of HSV, active lesions — The risk of transmission of HSV to infants born to individuals with a prior history of genital HSV and active genital lesions at the time of delivery is relatively low (<2 percent) [5,17,46,47].

For asymptomatic newborns in this category, we suggest performing the following evaluation at approximately 24 hours of age (regardless of whether the neonate was born via vaginal or cesarean delivery) (algorithm 1) [5,17,46]:

Surface HSV cultures or HSV PCR from the conjunctivae, mouth, nasopharynx, and rectum

Urine viral culture (optional)

Whole blood or plasma HSV PCR

Testing should not be performed immediately after birth since positive cultures or PCR on surface swabs obtained before 12 to 24 hours may reflect contamination during delivery, rather than infection. The sensitivity of viral cultures for detecting neonatal HSV infection in infants whose mothers were treated with antiviral medication during pregnancy is not known [5].

If HSV is detected in any of the specimens listed above, the neonate should undergo a complete clinical and laboratory evaluation and should receive treatment with acyclovir. (See 'Pretreatment evaluation' above and 'Initial antiviral therapy' above.)

We do not suggest routine prophylactic acyclovir for all asymptomatic neonates who are born to mothers with a prior history of genital HSV and active genital lesions at the time of delivery since the risk of HSV transmission is low in this setting [5,46]. However, prophylactic treatment may be warranted if there are additional risk factors for transmission (eg, rupture of membranes >4 to 6 hours, gestation <37 weeks, scalp electrode, skin lacerations) [46,47]. If acyclovir is initiated for such patients, a full clinical and laboratory evaluation should be performed before initiating therapy. Acyclovir should be discontinued after three to five days if the infant remains asymptomatic and HSV PCR and viral cultures are negative.

No maternal history of HSV, active lesions — The risk of transmission of HSV to infants born to individuals with no prior history of genital HSV and active genital lesions at the time of delivery is between 25 and 60 percent [5,7,17]. These individuals likely have a primary HSV infection at delivery and may not have transmitted maternal antibody to the newborn.

For asymptomatic newborns in this category, we suggest performing the following evaluation at approximately 24 hours of age (regardless of whether the neonate was born via vaginal or cesarean delivery) (algorithm 1) [5,46]:

Surface HSV cultures or HSV PCR from the conjunctivae, mouth, nasopharynx, and rectum

Urine viral culture (optional)

Whole blood or plasma HSV PCR

Cerebrospinal fluid (CSF) HSV PCR, cell count, chemistries

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Complete blood count with differential and platelet count

In addition, we suggest sending maternal blood for type-specific HSV serology as soon as possible after delivery (if available) to more accurately characterize maternal infection (table 2) [5,46].

Newborn testing should not be performed immediately after birth since positive cultures or PCR on surface swabs obtained before 12 to 24 hours may reflect contamination during delivery, rather than infection. The sensitivity of viral cultures for detecting neonatal HSV infection in infants whose mothers were treated with antiviral medication during pregnancy is not known [5].

We suggest empiric treatment with acyclovir (60 mg/kg per day intravenously [IV] divided every eight hours) for these neonates while awaiting results of virologic testing [5,46].

The duration of acyclovir is determined by the neonate's clinical status, results of the neonate's evaluation for HSV disease, and maternal HSV infection classification (algorithm 1) [5,46]:

For neonates in whom type-specific HSV serologic testing is not available who remain asymptomatic and whose HSV evaluation is negative, we suggest continuing acyclovir for 10 days.

For neonates for whom maternal serologic testing indicates recurrent HSV infection (table 2), we suggest discontinuing acyclovir at 48 to 72 hours if the newborn remains asymptomatic and HSV PCR and viral studies are negative.

For neonates born to individuals with primary genital HSV infection or nonprimary first-episode genital HSV infection (based on serologic testing (table 2)) or assumed primary or nonprimary first-episode infection (based on strong clinical suspicion and discordant or unavailable genital and serologic test results) who remain asymptomatic and whose HSV evaluation is negative, we suggest continuing acyclovir for 10 days.

In all cases, if the infant becomes symptomatic or the HSV evaluation is abnormal (including positive PCR, culture, abnormal CSF, or serum ALT >2 times the upper limit of normal), we recommend continuing acyclovir for at least 14 days (for skin, eye, and mouth [SEM] infection) or at least 21 days (for central nervous system [CNS] or disseminated disease). In addition, the infant should undergo additional evaluation (including eye examination and neuroimaging). (See 'Pretreatment evaluation' above and 'Initial antiviral therapy' above.)

Postnatal exposure — Asymptomatic infants exposed postnatally to active HSV lesions (cold sores, herpetic whitlow, herpetic gingivostomatitis) of household or caretaker contacts should be closely monitored and the affected family member or caregiver should be counseled to avoid close contact with and avoid kissing the newborn infant. (See 'General measures' below.)

If the infant becomes symptomatic, HSV evaluation should be performed and empiric acyclovir therapy should be started while awaiting results. (See 'Acyclovir therapy' above.)

Some experts recommend performing a complete HSV evaluation and starting empiric acyclovir therapy if there is significant close and repeated contact between the infant and an affected caretaker, even if the neonate is asymptomatic [41]. However, if the exposure is from a mother with recurrent oral lesions, the newborn likely received transferred maternal antibody in utero and the risk of transmission is relatively low.

OUTCOME — The outcome of neonatal HSV disease depends upon the clinical pattern. HSV infection is lifelong, even with appropriate therapy. Recurrence of mucocutaneous lesions, eye disease, and/or central nervous system (CNS) disease may occur, even after adequate intravenous (IV) treatment and oral suppression [19].

Disseminated disease — The one-year mortality rate for disseminated disease is approximately 25 to 30 percent [8]. Factors that are associated with increased risk of mortality include [12,22,48,49]:

Severe hepatitis or acute liver failure

Severe lethargy or coma at the time of presentation

Disseminated intravascular coagulopathy

Prematurity

Pneumonitis

High levels of viremia at time of diagnosis (eg, quantitative polymerase chain reaction [PCR] >7 log10 copies/mL)

Approximately 80 percent of survivors of disseminated neonatal HSV disease may have normal neurologic development [8,12,18]. The risk of neurodevelopmental abnormalities (eg, developmental delay, hemiparesis, persistent seizures, microcephaly, blindness) is increased among infants with seizures at or before the initiation of antiviral therapy [12].

Severe hepatitis, caused by either HSV-1 or -2, may cause potentially fatal acute liver failure in neonates with disseminated disease. Liver transplantation has been carried out successfully in a few reported neonates with fulminant hepatic failure associated with disseminated neonatal HSV disease [50-52].

Central nervous system disease — The one-year mortality rate for CNS disease is 4 percent [8]. Prematurity, seizures, and coma or near-coma at the time of presentation are associated with increased risk of mortality in CNS disease [12,48,49].

Approximately 30 percent of survivors of neonatal CNS HSV have normal neurologic development [8,12,18]. The risk of neurodevelopmental abnormalities is increased among infants with seizures at or before the initiation of antiviral therapy [12].

Skin, eye, and mouth disease — Mortality is rare in neonatal HSV disease that is localized to the skin, eye, and mouth (SEM; in whom disseminated and CNS disease have been appropriately excluded). Less than 2 percent of acyclovir recipients have developmental delay after recovery from neonatal SEM HSV disease [8,9,12]. The risk of neurodevelopmental abnormalities is increased in infants with ≥3 recurrences of skin lesions before six months of age [49]. Patients with ocular involvement are at risk for long-term complications, including vision loss, and require close follow-up. If HSV eye disease is present, many experts suggest oral suppression for up to one year. (See 'Long-term follow-up' below and 'Treatment of eye disease' above.)

Cutaneous recurrence — Even after successful parenteral treatment, recurrence of HSV can occur and may be a lifelong problem for the patient and family/caregivers. Fortunately, recurrence of CNS disease is rare [36,37]. However, recurrent vesicles at sites in the SEM are common and occur in 50 to 80 percent of neonates, with 1 to 12 episodes in the first year of life [5]. Infants with ≥3 cutaneous recurrences during the first six months of life are at increased risk of neurodevelopmental abnormalities at follow-up [49]. Recurrence of skin lesions may affect child care arrangements and is disruptive to the lives of patients and their families [12].

Because the risk of recurrence in survivors of neonatal HSV disease is high, long-term suppressive therapy with oral acyclovir is recommended to reduce skin or eye recurrences during infancy [7]. (See 'Oral suppressive therapy' above.)

LONG-TERM FOLLOW-UP

Neurologic and developmental follow-up – Survivors of neonatal HSV infection, especially infants with involvement of the central nervous system (CNS), should be followed closely for achievement of developmental milestones [12]. They should undergo formal neurodevelopmental assessments as indicated. Referral to early intervention programs (eg, physical therapy, occupational therapy, speech therapy) should be made at the earliest sign of potential impairment. (See "Developmental-behavioral surveillance and screening in primary care", section on 'Follow-up'.)

Audiologic assessments are usually recommended as well. However, the available evidence suggests that hearing loss is uncommon after neonatal HSV disease [53]. (See "Hearing loss in children: Screening and evaluation".)

Rarely, recurrence of HSV encephalitis may occur years later [40]. In such cases, we investigate for an underlying primary immune disorder of cellular function, especially toll-like receptor (TLR3) deficiency [39]. (See "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

Ophthalmologic follow-up – Patients with eye disease require careful follow-up with an ophthalmologist. To reduce the risk of recurrent eye disease, many experts suggest oral suppression with acyclovir for up to one year in this setting. (See 'Oral suppressive therapy' above and 'Treatment of eye disease' above.)

Late recurrences have been reported [54,55]. The family/caregivers should be counseled to seek medical care promptly if symptoms of eye disease recur.

PREVENTION

General measures — Strategies for prevention of intrauterine and perinatally acquired HSV infection, including identification of high-risk pregnant individuals, cesarean delivery, maternal antiviral therapy, and anticipatory guidance for pregnant individuals and partners, are discussed separately. (See "Genital herpes simplex virus infection and pregnancy", section on 'Screening pregnant women with no HSV history'.)

Postnatal transmission of HSV can be prevented by counseling family members with active HSV lesions (cold sores, herpetic whitlow, herpetic gingivostomatitis) or a history of cold sores or HSV lesions in the recent past to avoid close contact with and avoid kissing the newborn infant [41]. Mothers with herpetic breast lesions should not breastfeed from the affected breast until the lesions have resolved because direct contact with the lesions may transmit the HSV to the infant [56]. Mothers should use careful hand hygiene and cover any lesions with which the infant might come into contact.

The need for contact precautions during the birth hospitalization depends upon whether the mother had active lesions at the time of delivery and whether the infant has any mucocutaneous lesions (see "Infection prevention: Precautions for preventing transmission of infection", section on 'Contact precautions'):

Infants born to individuals with active HSV lesions should be managed with contact precautions during hospitalization, with a private room, or while rooming with the mother [5]. However, some experts suggest that contact precautions are not necessary for such infants who are born by cesarean delivery <4 hours after rupture of membranes.

Contact precautions also should be used for infants who are hospitalized with HSV infection if they have mucocutaneous lesions [5]. The median duration of viral shedding from skin vesicles and mucosal lesions in infants receiving acyclovir therapy is five to eight days [8]. However, contact precautions may be continued for a longer period of time if the patient is hospitalized.

Contact precautions are not necessary for infants born to individuals with a history of recurrent genital HSV who have no genital lesions at the time of delivery.

Infants and children with cutaneous recurrence of neonatal HSV should be counseled to cover the lesions to prevent potential transmission through direct contact [57].

Vaccine — There is no licensed, effective vaccine against HSV-1 or HSV-2 infection. However, both preventive and therapeutic HSV vaccines are being developed. A candidate HSV-2 vaccine containing two HSV-2 proteins, gD2 and ICP4, and Matrix-M2 adjuvant has shown promise in clinical trials [58,59].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: TORCH infections".)

SUMMARY AND RECOMMENDATIONS

Indications for antiviral therapy – We recommend antiviral therapy for neonates with virologically proven herpes simplex virus (HSV) disease (Grade 1A) and we suggest empiric therapy pending viral studies for neonates with clinically suspected HSV disease (Grade 2C). Prompt treatment is necessary to prevent serious morbidity. While the indications for initiating empiric treatment are not standardized, most experts agree that empiric therapy is indicated for neonates with mucocutaneous vesicles (picture 1A-C), seizures, lethargy, febrile illness with ill appearance, sepsis-like illness, severe liver involvement, or cerebrospinal fluid (CSF) pleocytosis with negative Gram stain. (See 'Indications' above and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'.)

In addition, we suggest empiric therapy pending viral studies in asymptomatic neonates with perinatal exposure if the mother had primary HSV infection with active genital lesions at the time of delivery (Grade 2C). The risk of transmission to the infant in this setting is estimated to be between 25 to 60 percent. (See 'No maternal history of HSV, active lesions' above.)

Pretreatment evaluation – A comprehensive laboratory evaluation for HSV should be performed before starting antiviral therapy. (See 'Pretreatment evaluation' above and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

Preferred agent – For treatment of all categories of neonatal HSV infections, including skin, eye, and mouth (SEM); central nervous system (CNS); and disseminated disease (table 1), we recommend acyclovir rather than other agents (Grade 1B). The dose is 60 mg/kg per day intravenously (IV) divided every eight hours for all forms of neonatal HSV. (See 'Initial antiviral therapy' above and 'Dose' above.)

Treatment duration – The duration of IV acyclovir therapy for neonatal HSV infection depends upon the pattern of illness and response to therapy (see 'Duration of therapy' above):

SEM disease is treated for a minimum of 14 days

CNS and disseminated disease are treated for a minimum of 21 days

Treatment of eye disease – For neonates with ocular HSV involvement (eg, keratitis), we suggest topical ophthalmic therapy (eg, 1% trifluridine, 0.15% ganciclovir, 0.1% idoxuridine [iododeoxyuridine; not available in the United States]) in addition to systemic acyclovir therapy (Grade 2C). These patients should be managed in consultation with an ophthalmologist. (See 'Treatment of eye disease' above.)

Oral suppressive therapy – For all categories of neonatal HSV disease, including SEM, CNS, and disseminated disease (table 1), we suggest oral acyclovir suppressive therapy immediately following parenteral acyclovir (Grade 2B). In most cases, suppressive therapy is discontinued after six months. However, a longer duration of oral suppressive therapy (up to one year) is needed for infants with HSV eye disease (eg, keratitis). This is because reactivated virus in this setting has potential to threaten vision. (See 'Oral suppressive therapy' above.)

Management of asymptomatic, exposed infants – Asymptomatic infants who are exposed to HSV at delivery or postnatally should be monitored for evidence of HSV infection (eg, skin or scalp rashes, conjunctival lesions, irritability, fever (figure 1)) during the first six weeks of life. For neonates exposed to HSV during delivery, the need for evaluation and treatment depends upon the mother's history of genital HSV, maternal serologies for type-specific HSV (if available) (table 2), and presence or absence of HSV genital lesions at the time of delivery (algorithm 1). (See 'Management of asymptomatic exposed infants' above.)

Neonates who develop clinical evidence of HSV infection should undergo full diagnostic evaluation and should receive empiric therapy pending results. (See 'Pretreatment evaluation' above and 'Initial antiviral therapy' above.)

Prevention – Strategies for prevention of intrauterine and perinatally acquired HSV infection are discussed separately. (See "Genital herpes simplex virus infection and pregnancy", section on 'Pregnancy management'.)

The risk of postnatal transmission of HSV can be minimized by counseling family members with active or recent history of HSV lesions (cold sores, herpetic whitlow, herpetic gingivostomatitis) to avoid close contact with and kissing the newborn infant. (See 'General measures' above.)

  1. Sykes SR, Sharpe EL. A Rare Case of Neonatal Disseminated Herpes Simplex Virus (HSV) With Concomitant Methicillin-Sensitive Staphylococcus aureus (MSSA) Bacteremia. Adv Neonatal Care 2022; 22:400.
  2. Caviness AC, Demmler GJ, Almendarez Y, Selwyn BJ. The prevalence of neonatal herpes simplex virus infection compared with serious bacterial illness in hospitalized neonates. J Pediatr 2008; 153:164.
  3. Long SS. In defense of empiric acyclovir therapy in certain neonates. J Pediatr 2008; 153:157.
  4. Kimberlin DW. When should you initiate acyclovir therapy in a neonate? J Pediatr 2008; 153:155.
  5. American Academy of Pediatrics. Herpes simplex. In: Red Book: 2021-2024 Report of the Committee on Infectious Diseases, 32nd ed, Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH (Eds), American Academy of Pediatrics, Itasca, IL 2021. p.407.
  6. Long SS, Pool TE, Vodzak J, et al. Herpes simplex virus infection in young infants during 2 decades of empiric acyclovir therapy. Pediatr Infect Dis J 2011; 30:556.
  7. Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev 2004; 17:1.
  8. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 2001; 108:230.
  9. Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med 1991; 324:444.
  10. Jones CA, Walker KS, Badawi N. Antiviral agents for treatment of herpes simplex virus infection in neonates. Cochrane Database Syst Rev 2009; :CD004206.
  11. Shah SS, Aronson PL, Mohamad Z, Lorch SA. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics 2011; 128:1153.
  12. Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol 2007; 31:19.
  13. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep 2021; 70:1.
  14. Mejías A, Bustos R, Ardura MI, et al. Persistence of herpes simplex virus DNA in cerebrospinal fluid of neonates with herpes simplex virus encephalitis. J Perinatol 2009; 29:290.
  15. Kimura H, Futamura M, Kito H, et al. Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum and cerebrospinal fluid. J Infect Dis 1991; 164:289.
  16. Troendle-Atkins J, Demmler GJ, Buffone GJ. Rapid diagnosis of herpes simplex virus encephalitis by using the polymerase chain reaction. J Pediatr 1993; 123:376.
  17. Gutierrez K, Pinsky B, Arvin AM. Herpes simplex viruses 1 and 2. In: Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 7th, Cherry JD, Harrison GJ, Kaplan SL, et al (Eds), Elsevier Saunders, Philadelphia 2014. p.1933.
  18. Whitley RJ, Nahmias AJ, Soong SJ, et al. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 1980; 66:495.
  19. Melvin AJ, Mohan KM, Vora SB, et al. Neonatal Herpes Simplex Virus Infection: Epidemiology and Outcomes in the Modern Era. J Pediatric Infect Dis Soc 2022; 11:94.
  20. Whitley RJ, Corey L, Arvin A, et al. Changing presentation of herpes simplex virus infection in neonates. J Infect Dis 1988; 158:109.
  21. Otto WR, Myers AL, LaRussa B, et al. Clinical Markers and Outcomes of Neonates With Herpes Simplex Virus Deoxyribonucleic Acid Persistence in Cerebrospinal Fluid in Disseminated and Central Nervous System Infection. J Pediatric Infect Dis Soc 2018; 7:e30.
  22. Melvin AJ, Mohan KM, Schiffer JT, et al. Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection. J Pediatr 2015; 166:827.
  23. Vadoothker S, Andrews L, Jeng BH, Levin MR. Management of Herpes Simplex Virus Keratitis in the Pediatric Population. Pediatr Infect Dis J 2018; 37:949.
  24. Manglani M, Poley M, Kumar A, et al. Anti-NMDAR Encephalitis After Neonatal HSV-1 Infection in a Child With Low TLR-3 Function. Pediatrics 2021; 148.
  25. Current Drug Shortages. US Food and Drug Administration. www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm314739.htm (Accessed on November 28, 2012).
  26. Shortage of intravenous acyclovir. Red Book Online Special Alert - November 28, 2012.
  27. Kimberlin DW. Ganciclovir may be used during intravenous acyclovir shortage. AAP News 2009; 30:10.
  28. Nagamori T, Koyano S, Asai Y, et al. Sequential changes in pathophysiology of systemic inflammatory response in a disseminated neonatal herpes simplex virus (HSV) infection. J Clin Virol 2012; 53:265.
  29. Kohl S, West MS, Prober CG, et al. Neonatal antibody-dependent cellular cytotoxic antibody levels are associated with the clinical presentation of neonatal herpes simplex virus infection. J Infect Dis 1989; 160:770.
  30. Yeager AS, Arvin AM, Urbani LJ, Kemp JA 3rd. Relationship of antibody to outcome in neonatal herpes simplex virus infections. Infect Immun 1980; 29:532.
  31. Sonoda M, Ishimura M, Eguchi K, et al. Prognostic factors for survival of herpes simplex virus-associated hemophagocytic lymphohistiocytosis. Int J Hematol 2020; 111:131.
  32. Kimberlin DW, Whitley RJ, Wan W, et al. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med 2011; 365:1284.
  33. Fish DN, Vidaurri VA, Deeter RG. Stability of valacyclovir hydrochloride in extemporaneously prepared oral liquids. Am J Health Syst Pharm 1999; 56:1957.
  34. Bomgaars L, Thompson P, Berg S, et al. Valacyclovir and acyclovir pharmacokinetics in immunocompromised children. Pediatr Blood Cancer 2008; 51:504.
  35. Kimberlin DW, Jacobs RF, Weller S, et al. Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in pediatric patients from 1 month through 11 years of age. Clin Infect Dis 2010; 50:221.
  36. Fonseca-Aten M, Messina AF, Jafri HS, Sánchez PJ. Herpes simplex virus encephalitis during suppressive therapy with acyclovir in a premature infant. Pediatrics 2005; 115:804.
  37. Kimberlin D, Powell D, Gruber W, et al. Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase I/II trial. Pediatr Infect Dis J 1996; 15:247.
  38. Waheed S, Nuttall L, Fidler K, et al. Neonatal Herpes Simplex Virus: Cutaneous Recurrence Is Common on Stopping Prophylactic Suppression Therapy. J Pediatric Infect Dis Soc 2022; 11:518.
  39. Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology 2014; 83:1888.
  40. Henderson B, Kimberlin DW, Forgie SE. Delayed Recurrence of Herpes Simplex Virus Infection in the Central Nervous System After Neonatal Infection and Completion of Six Months of Suppressive Therapy. J Pediatric Infect Dis Soc 2017; 6:e177.
  41. Pittet LF, Curtis N. Postnatal Exposure to Herpes Simplex Virus: To Treat or Not to Treat? Pediatr Infect Dis J 2021; 40:S16.
  42. Overall JC Jr. Empiric therapy with acyclovir for suspected neonatal herpes simplex infection. Pediatr Infect Dis J 1989; 8:808.
  43. Overall JC Jr. Herpes simplex virus infection of the fetus and newborn. Pediatr Ann 1994; 23:131.
  44. Prober CG, Corey L, Brown ZA, et al. The management of pregnancies complicated by genital infections with herpes simplex virus. Clin Infect Dis 1992; 15:1031.
  45. Scott LL. Perinatal herpes: current status and obstetric management strategies. Pediatr Infect Dis J 1995; 14:827.
  46. 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 2013; 131:e635.
  47. Brown ZA, Wald A, Morrow RA, et al. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 2003; 289:203.
  48. Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 2001; 108:223.
  49. Whitley R, Arvin A, Prober C, et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med 1991; 324:450.
  50. Verma A, Dhawan A, Zuckerman M, et al. Neonatal herpes simplex virus infection presenting as acute liver failure: prevalent role of herpes simplex virus type I. J Pediatr Gastroenterol Nutr 2006; 42:282.
  51. Twagira M, Hadzic N, Smith M, et al. Disseminated neonatal herpes simplex virus (HSV) type 2 infection diagnosed by HSV DNA detection in blood and successfully managed by liver transplantation. Eur J Pediatr 2004; 163:166.
  52. Egawa H, Inomata Y, Nakayama S, et al. Fulminant hepatic failure secondary to herpes simplex virus infection in a neonate: A case report of successful treatment with liver transplantation and perioperative acyclovir. Liver Transpl Surg 1998; 4:513.
  53. Westerberg BD, Atashband S, Kozak FK. A systematic review of the incidence of sensorineural hearing loss in neonates exposed to Herpes simplex virus (HSV). Int J Pediatr Otorhinolaryngol 2008; 72:931.
  54. Grose C. Acute retinal necrosis caused by herpes simplex virus type 2 in children: reactivation of an undiagnosed latent neonatal herpes infection. Semin Pediatr Neurol 2012; 19:115.
  55. Landry ML, Mullangi P, Nee P, Klein BR. Herpes simplex virus type 2 acute retinal necrosis 9 years after neonatal herpes. J Pediatr 2005; 146:836.
  56. American Academy of Pediatrics. Transmission of infectious agents via human milk. In: Red Book: 2018-2021 Report of the Committee on Infectious Diseases, 31st ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Itasca, IL 2018. p.115.
  57. Gutierrez KM, Whitley RJ, Arvin AM. Herpes simplex virus infections. In: Infectious Diseases of the Fetus and Newborn Infant, 7th ed, Remington JS, Klein JO, Wilson CB, et al (Eds), Elsevier Saunders, Philadelphia 2011. p.813.
  58. Bernstein DI, Flechtner JB, McNeil LK, et al. Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease. Vaccine 2019; 37:3443.
  59. Johnston C, Gottlieb SL, Wald A. Status of vaccine research and development of vaccines for herpes simplex virus. Vaccine 2016; 34:2948.
Topic 6040 Version 39.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟