INTRODUCTION — Neonatal infection with herpes simplex virus (HSV) occurs in 1 out of every 3200 to 10,000 live births, causes serious morbidity and mortality, and leaves many survivors with permanent sequelae [1-4]. Despite this seemingly low prevalence, neonatal HSV accounts for 0.2 percent of neonatal hospitalizations and 0.6 percent of in-hospital neonatal deaths in the United States, and is associated with substantial health care resource utilization [5-8].

Since the discovery of neonatal HSV disease in the 1930s, important breakthroughs in understanding how HSV is transmitted to the fetus and neonate, molecular methods to diagnose HSV, and antiviral treatment strategies have improved diagnosis and treatment [5]. However, despite these advances, neonatal HSV remains a clinical challenge.

The clinical features and diagnosis of neonatal HSV infection will be reviewed below. The management, outcome, and prevention of neonatal HSV infection and non-neonatal HSV infections are discussed separately. (See "Neonatal herpes simplex virus infection: Management and prevention" and "Genital herpes simplex virus infection and pregnancy" and "Herpetic gingivostomatitis in young children" and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)

VIROLOGY — HSV is a member of the Herpesviridae family of viruses. It contains a double-stranded linear DNA genome that consists of 150,000 base pairs that encode for more than 80 polypeptides, a capsid consisting of 162 capsomeres arranged in icosahedral symmetry that is covered by a tightly adherent membranous tegument, and an envelope consisting of 11 glycoproteins (gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, and gM), lipids, and polyamines that surrounds the viral nucleocapsid (picture 1) [5]. Like all Herpesviridae viruses, HSV shares the biologic properties of latency and reactivation, which causes recurrent infections in the host.

HSV enters the human host through inoculation of oral, genital, or conjunctival mucosa or breaks in skin, infects the sensory nerve endings, and then transports via retrograde axonal flow to the dorsal root ganglia, where it remains for the life of the host. The fetus may be infected transplacentally or through retrograde spread through ruptured or seemingly intact membranes [5]. Latent virus is not susceptible to antiviral drugs, and infection (even after antiviral therapy) is lifelong. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Outcome'.)

HSV replicates efficiently in cell cultures, quickly producing lytic cytopathic effect in one to three days in most cell lines used in clinical virology laboratories (picture 2). The virus can be typed into HSV type 1 and HSV type 2 using serologic and molecular techniques. The DNA of HSV-1 and HSV-2 contain many homologous sequences distributed over the entire genome of both types, which produce both unique (gG) and antigenically similar polypeptides [5]. This cross-reactivity between HSV-1 and HSV-2 glycoproteins is the reason most commercially available serologic assays cannot distinguish between HSV-1 and HSV-2 antibodies.

EPIDEMIOLOGY AND TRANSMISSION

Incidence and prevalence — The estimated incidence of neonatal HSV infection ranges from 3 to 30 per 100,000 live births [1-4,9,10]. The wide variation is likely due to differences in the prevalence of genital herpes in different areas around the world and differences in reporting practices. There are an estimated 1500 cases of neonatal HSV infection annually in the United States [11]. As the baseline prevalence of HSV-2 genital infection increases in the general population, the incidence of neonatal HSV disease is also likely to increase. Some data suggest that the incidence of severe neonatal HSV disease, including disseminated and central nervous system (CNS) disease, has increased since 2000 [5,12,13]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Epidemiology'.)

The prevalence of HSV among young infants presenting to an emergency department setting with signs of CNS infection was investigated in a multicenter retrospective study of >25,000 infants <60 days old (median age 28 days) who underwent lumbar puncture for evaluation of fever or other clinical concern [14]. Testing for HSV was performed in 35 percent of patients. HSV infection was identified in 1.2 percent of infants tested (0.4 percent of the entire cohort), 39 percent of whom had skin, eye, and mouth (SEM) disease, 32 percent of whom had CNS disease, and 29 percent of whom had disseminated disease. HSV prevalence peaked in the second week of life and declined substantially in the second month of life. Despite the low prevalence of HSV in this setting, testing and empiric treatment for HSV are often warranted in ill-appearing febrile neonates because early treatment has been shown to improve survival and reduce long-term sequelae. This issue is discussed briefly below and is reviewed in greater detail separately. (See 'Clinical suspicion' below and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Acyclovir therapy' and "The febrile infant (29 to 90 days of age): Management", section on 'Herpes simplex virus'.)

Transmission — Neonatal HSV has three distinct periods of acquisition: intrauterine, perinatal, and postnatal.

●Intrauterine – Intrauterine HSV occurs rarely (estimated incidence of 1 in 250,000 deliveries).

●Perinatal – The majority (85 percent) of neonatal HSV infections are acquired perinatally [11]. HSV is acquired perinatally when HSV infection, either symptomatic or asymptomatic, is present in the genital tract of the pregnant woman at the time of delivery. Factors that may influence perinatal transmission include the type of maternal HSV infection (primary versus recurrent), maternal HSV antibody status, duration of ruptured membranes, use of fetal scalp monitors, and mode of delivery (cesarean versus vaginal) [13]. However, most neonates with HSV disease are born to mothers without a history of HSV infection or other identifiable risk factors [15]. Maternal fever is a risk factor [15-20]. (See "Genital herpes simplex virus infection and pregnancy".)

●Postnatal – Approximately 10 percent of neonatal HSV infections are acquired postnatally [11]. Postnatal acquisition of neonatal HSV occurs when a caretaker with active HSV infection, such as herpes labialis, has close contact with the newborn infant.

CLINICAL MANIFESTATIONS

Intrauterine HSV — Intrauterine or congenital HSV infection is rare and results from either maternal viremia associated with primary HSV infection during pregnancy or ascending infection:

●Intrauterine infection due to maternal primary infection - Intrauterine infection that results from maternal primary HSV infection and viremia during pregnancy is associated with placental infarcts; necrotizing, calcifying funisitis (inflammation of the umbilical cord); plasma cell deciduitis; lymphoplasmacytic villitis (picture 3); hydrops fetalis; and fetal in utero demise. Demonstration of the virus in placenta tissue by immunohistochemistry or by molecular techniques is necessary for diagnosis of HSV involvement of the placenta because other placental findings are nonspecific. (See "Nonimmune hydrops fetalis" and "Stillbirth: Incidence, risk factors, etiology, and prevention".)

Survivors of in utero HSV infection may exhibit a characteristic triad of skin vesicles, ulcerations, or scarring (picture 4); eye damage; and severe central nervous system (CNS) manifestations, including microcephaly or hydranencephaly [21-24]. However, the characteristic triad occurs in less than one-third of cases and a high index of suspicion is necessary to make the diagnosis [24].

●Intrauterine infection due to ascending infection - In utero congenital HSV infection from ascending infection usually occurs after prolonged rupture of membranes in mothers with active HSV infection near the time of delivery. Ascending transplacental infection of the fetus through intact amniotic membranes may also occur, and neonatal HSV infection has been documented after cesarean section in mothers with intact amniotic membranes [25,26]. The clinical presentation of newborns with intrauterine HSV acquired by ascending infection may be mild, with only cutaneous skin lesions or cutaneous scarring present, to severe, with signs and symptoms of disseminated HSV disease and fatal neonatal pneumonitis [27,28].

Neonatal HSV — Neonatal HSV may be classified into three main categories for therapeutic and prognostic considerations: localized skin, eye, and mouth (SEM); CNS with or without SEM; and disseminated disease (table 1). There is some overlap in these categories (figure 1). For example, disseminated HSV disease may have SEM and/or CNS involvement in addition to other organs, and SEM disease may progress to CNS or disseminated disease if not treated early. Both HSV-1 and HSV-2 may cause SEM, CNS, or disseminated disease; however, HSV-2 has been associated with a poorer outcome [5,13,16,29]. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Outcome'.)

Skin, eye, and mouth disease — SEM disease accounts for approximately 45 percent of neonatal HSV [10,11]. Neonatal HSV SEM disease may appear benign at onset of illness but is associated with a high risk of progression to CNS or disseminated disease if not treated. SEM disease usually presents in the first two weeks of life but may occur at any time during the first six weeks of life [30].

Localized skin disease is associated with coalescing or clustering vesicular lesions with an erythematous base (picture 5C) [5]. Vesicles may begin or cluster at the presenting part of the body, or at sites of localized trauma, such as scalp monitor sites (picture 5B). Skin vesicles also may appear late in the course of disseminated disease.

HSV infection of the eye may initially appear asymptomatic. In the neonate, early signs include excessive watering of the eye, crying from apparent eye pain, and conjunctival erythema (picture 5A). Periorbital skin vesicles may or may not be present at the time of presentation. HSV keratoconjunctivitis may progress to cataracts and chorioretinitis and result in permanent vision impairment [5,21].

HSV infection of the oropharynx may initially be asymptomatic, but also may be characterized by localized ulcerative lesions of the mouth, palate, and tongue. It should be differentiated from other causes of oral lesions in the newborn such as local trauma or other viral infections (eg, enterovirus). (See "Soft tissue lesions of the oral cavity in children", section on 'Infections' and "Soft tissue lesions of the oral cavity in children".)

Neonates with evidence of SEM disease should undergo a thorough evaluation for CNS and disseminated disease. Infants with SEM disease may have associated HSV viremia. However, if there is no evidence systemic disease (eg, no liver, lung, kidney, cardiovascular, or CNS involvement), most experts would not consider such infants as having disseminated HSV disease. If SEM disease is treated early, before CNS or disseminated disease occurs, the outcome is favorable. (See 'Detection of HSV' below and 'Laboratory evaluation' below and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Outcome'.)

Central nervous system disease — Approximately one-third of neonatal HSV disease involves the CNS [11,30]. It may occur as a result of localized retrograde spread from the nasopharynx and olfactory nerves to the brain or through hematogenous spread in neonates with disseminated disease. Neonatal HSV CNS disease (also called neonatal HSV meningoencephalitis) usually presents in the second or third week of life, but may occur at any time during the first six weeks of life [30]. CNS disease may occur with or without SEM involvement and with or without disseminated disease. Between 60 and 70 percent of neonates with HSV CNS disease have skin vesicles at some point during the disease course [11].

Clinical manifestations of neonatal HSV CNS disease include seizures (focal or generalized), lethargy, irritability, tremors, poor feeding, temperature instability, and full anterior fontanel [29,31,32]. Early in the course of HSV CNS disease, none of these signs or symptoms may be apparent.

Cerebrospinal fluid (CSF) analysis in neonates with HSV CNS disease classically shows a mononuclear cell pleocytosis, normal or moderately low glucose concentration, and mildly elevated protein; however, CSF studies may be normal early in the course of the illness. Abnormalities of the CSF may be more pronounced as CNS disease progresses. Red blood cells are not significantly associated with neonatal HSV CNS disease and are more likely to be caused by an apparent "bloody tap" [15].

The electroencephalogram (EEG) often is abnormal very early in the course of CNS disease and may show focal or multifocal periodic epileptiform discharges [5,33]. (See 'Electroencephalogram' below.)

Computed tomography (CT) and magnetic resonance (MR) imaging of the brain may be normal early in the course of CNS disease. Several days to a week into illness, neuroimaging studies may show parenchymal brain edema or attenuation, hemorrhage, or destructive lesions involving the temporal, frontal, parietal, or brainstem regions of the brain (image 1 and image 2) [5,31]. (See 'Diagnostic imaging' below.)

In the absence of vesicles, the initial presentation of HSV CNS disease may be indistinguishable from other causes of neonatal sepsis or meningitis [11,12]. Many experts recommend evaluation for HSV CNS disease with HSV DNA polymerase chain reaction (PCR) and other CSF studies (ie, cell counts, protein, and glucose), and empiric treatment with acyclovir in all neonates with aseptic meningitis or other signs and symptoms of meningoencephalitis without an obvious bacterial cause [34,35]. (See 'Laboratory evaluation' below and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Acyclovir therapy' and "Viral meningitis in children: Management, prognosis, and prevention".)

Disseminated disease — Approximately one-fourth of neonatal HSV disease is the disseminated form, which is sepsis-like presentation, involving multiple organs [5,11,20,30,36]:

●Liver (picture 6 and picture 7), including hepatitis with elevated liver transaminases, ascites, and direct hyperbilirubinemia that can progress to liver failure requiring liver transplantation [37] (see "Acute liver failure in children: Etiology and evaluation" and "Acute liver failure in children: Management, complications, and outcomes")

●Lungs (picture 8), including pneumonia and hemorrhagic pneumonitis, with or without effusion, that can progress to respiratory failure, requiring mechanical ventilation or extracorporeal life support [38]

●CNS, which is involved in 60 to 75 percent of cases, usually through a hematogenously acquired meningoencephalitis [30] (see 'Central nervous system disease' above)

●Heart, including myocarditis and myocardial dysfunction in severe disseminated neonatal HSV.

●Adrenal glands (picture 9 and picture 7)

●Bone marrow and coagulation system, including disseminated intravascular coagulation (DIC), thrombocytopenia, and neutropenia (see "Disseminated intravascular coagulation in infants and children")

●Kidneys. (see "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis")

●Gastrointestinal tract, including necrotizing enterocolitis. (see "Neonatal necrotizing enterocolitis: Clinical features and diagnosis")

●Skin and mucous membranes lesions, which may appear late in the course of disseminated HSV disease; however, 20 to 40 percent of neonates with disseminated HSV disease do not have vesicles [11] (see 'Skin, eye, and mouth disease' above)

Neonates with disseminated HSV often present in the first week of life with nonspecific signs and symptoms of neonatal sepsis, including temperature dysregulation (fever or hypothermia), apnea, irritability, lethargy, respiratory distress, abdominal distension, hepatomegaly, and ascites [5,20]. Rarely, neonates with HSV infection may present with fever alone [39]. In advanced disseminated neonatal HSV disease, fever is often absent, and hypothermia is more prominent [5,20].

The diagnosis of disseminated neonatal HSV disease often is delayed until the second week of life, awaiting the results of evaluation for bacterial sepsis. Mortality exceeds 80 percent in untreated disseminated neonatal HSV. Unfortunately, the diagnosis is often made or confirmed at autopsy, after extensive organ damage has occurred (picture 7 and picture 6 and picture 8 and picture 9). Efforts are focused on identifying high-risk neonates with a sepsis-like picture, meningoencephalitis, progressive pneumonitis, or hepatitis, who should undergo testing for HSV and empiric antiviral therapy [7,15,19,40]. (See 'Evaluation and diagnosis' below and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Acyclovir therapy'.)

EVALUATION AND DIAGNOSIS

Overview — Neonatal HSV infection is clinically challenging. Early manifestations may be subtle and nonspecific. Neonatal HSV can mimic other diseases, including bacterial illnesses (sepsis or meningitis) and other viral illnesses (particularly enterovirus). Prompt treatment requires early consideration of neonatal HSV as a possibility in neonates with mucocutaneous lesions, central nervous system (CNS) abnormalities, or a sepsis-like picture. (See 'Differential diagnosis' below and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Acyclovir therapy'.)

Clinical suspicion — Neonatal HSV infection should be suspected in neonates and infants up to six weeks of age with [6,30]:

●Mucocutaneous vesicles (picture 5A-C)

●Sepsis-like illness (fever or hypothermia, irritability, lethargy, respiratory distress, apnea, abdominal distension, hepatomegaly, ascites)

●Cerebrospinal fluid (CSF) pleocytosis

●Seizures

●Focal neurologic signs

●Abnormal neuroimaging

●Respiratory distress, apnea, or progressive pneumonitis

●Thrombocytopenia

●Elevated liver transaminases, viral hepatitis, or acute liver failure

●Conjunctivitis, excessive tearing, or painful eye symptoms

Early in the clinical course, some neonates with HSV infection may present with persistent fever and negative bacterial cultures.

Neonatal HSV infection remains a possibility in infants born to women who received suppressive therapy during pregnancy. Although suppressive therapy markedly reduces the risk of asymptomatic shedding, it does not completely eliminate it. Neonates with perinatal exposure to HSV (particularly maternal active genital lesions) should be monitored for evidence of HSV infection (algorithm 1). (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Management of the asymptomatic exposed infant'.)

Detection of HSV — The laboratory diagnosis of neonatal HSV infection may be established through isolation of HSV in traditional or enhanced viral culture, detection of viral DNA using polymerase chain reaction (PCR) assays, and detection of viral antigens using rapid direct immunofluorescence assays (DFA). Serology is generally not helpful in the diagnosis of neonatal HSV at the time of presentation.

Specimens to collect — Neonates with suspected HSV disease should have all of the following specimens obtained to evaluate for HSV infection [30]:

●Surface swabs – Swab specimens should be collected from the conjunctivae, mouth, nasopharynx, and rectum. Some experts suggest these be obtained with a single swab, starting with eyes and ending with the rectum, and placed in one viral transport media tube. Alternatively, they may be collected with multiple swabs, which are then placed in a single viral transport media tube. Viral culture is the test of choice for detection of HSV in surface specimens. However, HSV PCR assays are also acceptable. Surface cultures are positive in ≥90 percent of cases and provide the greatest diagnostic yield of all methods to detect HSV, regardless of disease classification [29]. Positive cultures from these sites that are obtained >12 to 24 hours after birth indicate viral replication and are suggestive of infection, rather than contamination from intrapartum exposure. The performance of PCR assay on skin and mucosal specimens has not been studied in neonates, and therefore HSV viral culture is generally the preferred test, if available [30]. (See 'Viral culture' below and 'Other sites' below.)

●Swabs/scrapings of skin lesions – If skin or mucous membrane lesions are present, swabs/scrapings should be obtained and viral culture performed. DFA of skin lesion scrapings may permit rapid detection of HSV; however, DFA is not as sensitive as culture and therefore viral culture should also be performed. As stated above, the performance of PCR on skin and mucosal specimens has not been studied in neonates, and is generally not recommended. (See 'Viral culture' below and 'DFA and EIA' below and 'Other sites' below.)

●CSF – All neonates with suspected HSV, even infants who appear to have isolated skin, eye, and mouth (SEM) disease, should undergo lumbar puncture because clinical findings may be absent early in the course of CNS disease. PCR is the test of choice for detection of CNS involvement and has a sensitivity of 75 to 100 percent and specificity 71 to 100 percent [36]. Viral culture of CSF samples is less sensitive (approximately 25 to 40 percent) [36]. (See 'CSF' below.)

●Blood or plasma – Neonates with suspected HSV disease, of any classification, should have a whole blood or plasma sample tested for HSV using PCR. Detection of HSV DNA in the blood or plasma confirms the diagnosis and provides the opportunity for early initiation of antiviral therapy. (See 'Blood' below.)

●Other specimens – Viral culture or HSV PCR should be performed on other specimens that are readily available (eg, tracheal aspirates in intubated infants, peritoneal fluid in neonates undergoing peritoneal drainage or laparotomy for other reasons). (See 'Viral culture' below.)

●Additional studies – Additional testing should be performed to assess the degree of organ involvement. (See 'Additional studies' below.)

Viral culture — Isolation of HSV by viral cell culture is the definitive laboratory method of establishing the presence of an active HSV infection in the neonate. Isolation of HSV from surface sites of the neonate (ie, skin lesions, conjunctivae, mouth, nasopharynx, and rectum) obtained >12 to 24 hours after birth is always a significant finding and is the most common and noninvasive method to obtain evidence of active infection with HSV [5,30].

Isolation of HSV by viral culture of other specimens (eg, CSF, blood, tracheal aspirates, duodenal aspirates, peritoneal fluid in neonates with ascites) can also establish the diagnosis, but these are less commonly performed. For CSF and blood samples, PCR is preferred over viral culture because it has greater sensitivity. (See 'CSF' below and 'Blood' below.)

HSV grows readily on most cell lines used in clinical diagnostic virology laboratories. Evidence of viral cytopathic effect (picture 1) is usually evident under light microscopy in one to three days. Fresh vesicular lesions of the skin often are positive within 24 hours of incubation, whereas isolation from CSF or other sites may require several days. Viral cultures that remain negative at 10 days usually remain negative. HSV isolated in cell culture can be quickly and reliably typed as HSV-1 or HSV-2 using commercially available type-specific immunofluorescence assay reagents.

Twenty-four-hour cell culture enhancement systems, such as shell vial centrifugation fluorescent foci cultures (SVC) and enzyme-linked virus inducible systems (ELVIS), are used in many clinical laboratories and provide rapid detection of HSV in clinical systems within 24 to 48 hours [41,42]. The performance of these systems is generally comparable to cell culture in detecting HSV in skin and mucous membrane lesions, but not all these assays are able to distinguish and type HSV-1 or HSV-2.

PCR testing

CSF — The detection of HSV DNA in the CSF of a neonate confirms the diagnosis of CNS involvement. CSF HSV PCR is more sensitive than viral culture; however, blood or high protein in the CSF may interfere with some PCR assays and produce false negative results [43-48]. False negative results have also been reported with CSF specimens obtained early in the course of illness and samples obtained several days into antiviral therapy [5,43,45,48]. If the initial CSF HSV PCR is negative, yet neonatal HSV CNS disease is strongly suspected, the CSF PCR should be repeated during the first week of illness [49]. In neonates with evidence of CNS involvement, such as seizures, focal neurologic signs, abnormal CSF, or abnormal brain imaging, the detection of HSV DNA confirms the diagnosis of HSV meningoencephalitis. However, neonates may have CNS HSV infection without overt clinical, laboratory, or imaging signs of meningoencephalitis. Approximately 25 percent of neonates with HSV apparently localized to the SEM, and more than 90 percent of neonates with disseminated HSV disease, have HSV DNA detected in their CSF by PCR [5]. Thus, it is imperative to include a CSF examination and CSF HSV PCR in all neonates with suspected or proven neonatal HSV infection.

Blood — In neonates with signs and symptoms of disseminated HSV disease, detection of HSV DNA in the blood or plasma confirms the diagnosis and provides the opportunity for early initiation of antiviral therapy [5,15,40,47,50,51]. Results may differ somewhat depending on the sample type (whole blood versus plasma) and type of assay (qualitative versus quantitative). In a study of 63 infants treated for neonatal HSV at a single institution (1993 to 2012), plasma HSV PCR was positive in 78 percent of neonates with SEM, 64 percent with CNS disease, and 100 percent with disseminated disease [51]. Quantitative plasma HSV PCR levels were highest in infants with disseminated disease and levels >7 log₁₀ copies/mL were associated with an increased risk of death.

Other sites — PCR testing of other samples may be helpful in certain circumstances:

●In intubated patients, detection of HSV DNA in tracheal aspirates can help support a diagnosis of HSV pneumonitis.

●Detection of HSV DNA in amniotic fluid is diagnostic of in utero or congenital HSV.

●In neonates with necrotizing enterocolitis managed with peritoneal drainage or laparotomy, detection of HSV DNA in peritoneal fluid provides evidence of HSV disease.

●Detection of HSV DNA in the eye or conjunctivae may help establish the diagnosis of neonatal blepharoconjunctivitis or keratitis due to HSV, particularly in neonates in whom pretreatment with antiviral ophthalmic drops or systemic therapy may influence the viral culture results.

Many hospital-based and reference laboratories offer validated HSV PCR assays for skin and mucous membrane surface samples, and this is an acceptable method for detecting HSV in these samples. However, if available, viral culture is our preferred method for testing surface samples. (See 'Viral culture' above.)

DFA and EIA — DFA and enzyme immunoassays (EIA) methods permit rapid detection of HSV antigens in skin and mucous membrane lesions [42,52]. DFA has high specificity for HSV infection, and typing of the HSV antigens may be done directly on material on the slide. However, DFA is not as sensitive as culture and accuracy depends on obtaining an adequate specimen containing cells from scrapings of the base of mucocutaneous lesions [52].

EIA is primarily used to screen asymptomatic or pregnant women for HSV genital infection [52]. Both false positive and false negative results may occur, and combination with cell culture is recommended to optimize accuracy. The performance of rapid EIA in the diagnosis of neonatal HSV infection is not well-established, highlighting the need for cell culture to confirm the diagnosis of HSV in neonates. (See 'Viral culture' above.)

Serology — Serologic tests generally are not helpful in the diagnosis of neonatal HSV infection but may be used to identify HSV-2 infection in pregnant women so that steps can be taken to prevent neonatal infection. (See "Genital herpes simplex virus infection and pregnancy".)

Interpretation/diagnosis — Interpretation of diagnostic testing for HSV in neonates depends upon the clinical circumstances (table 1). Most infected infants have positive viral culture and/or PCR in one or more of the specimens listed above. (See 'Specimens to collect' above.)

Similarly, infants with negative viral culture/PCR in all of the above listed specimens are unlikely to be infected with HSV. However, in the setting of highly suggestive clinical, laboratory, or radiologic findings, negative results do not exclude HSV infection.

●SEM disease – The diagnosis of SEM disease is based upon the following clinical and laboratory parameters:

•Localized skin disease with the characteristic vesicular lesions (picture 5C and picture 5B); eye involvement; and/or localized ulcerative lesions of the mouth, palate, and tongue, AND

•Absence of CNS disease (including negative CSF HSV PCR) or other organ system involvement, AND

•One or more of the following:

-Isolation of HSV in surface cultures or skin lesion swabs/scraping collected >12 to 24 hours after birth (present in >90 percent)

-Positive HSV DNA PCR in the blood or plasma (present in 75 to 80 percent and does not necessarily signify disseminated disease)

-Detection of HSV in skin lesion scraping by DFA (less sensitive than viral culture)

●CNS disease – The diagnosis of CNS disease is based upon the following clinical, laboratory, and radiographic parameters:

•Positive CSF HSV DNA PCR (present in 75 to 100 percent; if the initial CSF HSV PCR is negative, yet neonatal HSV CNS disease is strongly suspected, the CSF PCR may be repeated during the first week of illness)

OR

•Clinical evidence of CNS involvement (eg, seizures, abnormal neurologic examination, abnormal electroencephalogram [EEG], and/or abnormal neuroimaging), AND

•Either or both of the following:

-Isolation of HSV in surface cultures or skin lesion swab/scraping collected >12 to 24 hours after birth (present in >90 percent)

-Positive HSV DNA PCR in the blood or plasma (present in approximately 65 percent)

●Disseminated disease – The diagnosis of disseminated disease is based upon the following clinical, laboratory, and radiographic parameters:

•Clinical signs of systemic involvement (eg, severe sepsis syndrome, hepatitis, pneumonia, disseminated intravascular coagulation, and/or thrombocytopenia), AND

•One or more of the following:

-Isolation of HSV in surface cultures or skin lesion swabs/scraping collected >12 to 24 hours after birth (present in >90 percent of neonates with SEM disease)

-Positive HSV DNA PCR in the blood or plasma (present in 100 percent)

-Positive CSF HSV DNA PCR (present in >90 percent)

-Detection of HSV in skin lesion scraping by DFA (less sensitive than viral culture)

Additional studies — A comprehensive evaluation should be performed in all neonates with suspected or proven HSV disease. This evaluation is necessary, even in infants who appear to have isolated SEM disease because clinical findings may be absent early in the course of CNS and disseminated disease. In addition to routine laboratory tests, ophthalmologic examination and neuroimaging should be performed in all infants with virologically confirmed HSV infection, and EEG should be performed in neonates with CNS involvement [5,31]. (See 'Electroencephalogram' below and 'Diagnostic imaging' below.)

Laboratory evaluation — Laboratory evaluation in neonates with suspected or proven HSV disease includes all of the following tests which determine the degree of organ involvement and exclude other diseases that may cause similar clinical symptoms [5,15,30,40] (see 'Differential diagnosis' below)

●Complete blood count, including differential and platelet count

●Liver transaminases, total and direct bilirubin, ammonia (ammonia should be performed to exclude liver failure and metabolic disease in neonates with elevated liver enzymes and fulminant sepsis, but is not necessary for all neonates with suspected HSV)

●Blood urea nitrogen (BUN), creatinine, and urinalysis (to assess renal function and hydration status)

●CSF cell count, glucose, and protein

●Blood and CSF cultures to evaluate for possible bacterial sepsis (most neonates with neonatal HSV disease have negative blood cultures; however, bacterial coinfections can occur, especially in neonates with liver and intestinal involvement, where gram-negative bacteremia and sepsis may compound the clinical presentation of neonatal HSV) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants" and "Bacterial meningitis in the neonate: Clinical features and diagnosis")

●Evaluation for metabolic disease as indicated by the clinical scenario (see "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management")

Eye examination — All infants with neonatal HSV disease, regardless of disease classification, should have an ophthalmologic examination in addition to conjunctival HSV cultures to evaluate for eye involvement [30].

Electroencephalogram — Electroencephalography (EEG) should be performed in all neonates suspected to have CNS involvement, particularly those with seizures, abnormal movements suspicious for seizures, or abnormal CSF.

EEG is highly sensitive for neonatal HSV infection with CNS involvement and often is abnormal before computed tomography (CT) or magnetic resonance (MR) imaging. An abnormal EEG with periodic or quasiperiodic epileptiform discharges, especially if they are focal or multifocal, is characteristic of neonatal HSV meningoencephalitis [33].

Diagnostic imaging

Brain imaging — All infants with neonatal HSV disease, regardless of disease classification, should have neuroimaging with magnetic resonance imaging (MRI), CT, or ultrasonography [30]. In neonates with CNS involvement, brain imaging with enhanced CT or MRI is recommended to determine the location and extent of brain involvement [5,31]. MRI is preferred because it has been shown to be more sensitive than CT in older patients, but CT is acceptable if MRI cannot be readily performed. Prenatal ultrasound may show fetal brain damage in intrauterine HSV disease, but neonatal ultrasound often underrepresents the extent of brain involvement and should not be used as the sole imaging study in infants with clinical evidence of CNS disease.

The imaging findings of neonatal HSV CNS disease are variable. Neuroimaging may be normal early in the course of CNS disease. Several days to a week into illness, neuroimaging studies may show parenchymal brain edema or abnormal attenuation, hemorrhage, or destructive lesions (image 1 and image 2) [5,31]. In addition to the classic temporal lobe destructive lesions, imaging abnormalities may be multifocal or limited to the brainstem or cerebellum [33].

Because neuroimaging may be normal early in the course, negative imaging with CT or conventional MRI does not exclude HSV CNS involvement. Diffusion-weighed imaging, which may show evidence of restricted diffusion, is an important adjunct to MRI in neonates suspected of having CNS involvement [31].

Chest radiograph — Chest radiographs should be obtained in infants with signs of pulmonary involvement. In neonates with primary HSV pneumonia or in infants with disseminated HSV disease, chest radiographs may demonstrate bilateral, diffuse pneumonitis.

Abdominal ultrasonography — Abdominal ultrasonography is not routinely required in the diagnostic evaluation. In neonates with HSV hepatitis and acute liver failure, ultrasonography may demonstrate ascites and enlarged liver.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of neonatal HSV is broad and includes infectious and noninfectious conditions that are associated with vesicular skin lesions, eye disease, central nervous system (CNS) manifestations, and/or systemic illness in neonates:

●Vesicular skin lesions: The differential diagnosis of vesicular skin lesions in neonates is reviewed separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant" and "Skin lesions in the newborn and infant".)

●Eye disease:

•Viral conjunctivitis due to adenovirus or enterovirus (see "Conjunctivitis", section on 'Viral conjunctivitis')

•Bacterial conjunctivitis (eg, Chlamydia trachomatis, Neisseria gonorrhoeae) (see "Chlamydia trachomatis infections in the newborn", section on 'Conjunctivitis' and "Gonococcal infection in the newborn", section on 'Ophthalmia neonatorum')

•Trauma (see "Conjunctival injury")

●CNS disease:

•Bacterial meningitis (see "Bacterial meningitis in the neonate: Clinical features and diagnosis")

•Viral meningoencephalitis (other than HSV), particularly enterovirus and parechovirus (see "Viral meningitis in children: Clinical features and diagnosis" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates')

•CNS insult (eg, anoxia, trauma, or hemorrhage) [53] (see "Clinical features, diagnosis, and treatment of neonatal encephalopathy" and "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Pathogenesis, clinical presentation, and diagnosis" and "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children")

•Neonatal abstinence syndrome (see "Neonatal abstinence syndrome")

•Inborn errors of metabolism (see "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management")

•Hypoglycemia (see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia")

●Disseminated disease:

•Bacterial sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants")

•Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Clinical presentation')

•Enterovirus or parechovirus, particularly during the enteroviral season [12] (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates')

•Other neonatal infections, such as cytomegalovirus, toxoplasmosis, syphilis, and rubella (see "Overview of TORCH infections")

•Viral hepatitis (other than HSV), drug-induced hepatitis, or causes of neonatal liver disease (see "Approach to evaluation of cholestasis in neonates and young infants" and "Acute liver failure in children: Etiology and evaluation")

•Viral pneumonia, such as respiratory syncytial virus or adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Pneumonia' and "Respiratory syncytial virus infection: Clinical features and diagnosis", section on 'Clinical manifestations')

•Inborn errors of metabolism (see "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management")

Microbiologic studies (eg, cultures, polymerase-chain reaction [PCR] tests) may help to differentiate neonatal HSV from other infectious conditions. Review of the newborn screening results and/or consultation with a geneticist can be helpful to exclude inborn errors of metabolism. Noninfectious dermatologic conditions may have a characteristic clinical course (eg, transient neonatal pustular melanosis, incontinentia pigmenti). However, given increased morbidity and mortality of neonatal HSV disease, empiric therapy for HSV may be warranted (after appropriate microbiologic specimens are obtained) pending definitive diagnosis. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Acyclovir therapy'.)

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: Infectious encephalitis".)

SUMMARY AND RECOMMENDATIONS

●Neonatal herpes simplex virus (HSV) infection occurs in approximately 1 in 3200 to 10,000 live births. Neonatal HSV may be acquired in utero (congenital HSV), perinatally (approximately 85 percent of cases), or postnatally (approximately 10 percent of cases). (See 'Epidemiology and transmission' above.)

●Intrauterine HSV is associated with hydrops fetalis and fetal in utero demise. Survivors may exhibit a characteristic triad of skin vesicles or scarring, eye damage, and severe central nervous system (CNS) manifestations, including microcephaly or hydranencephaly. (See 'Intrauterine HSV' above.)

●Neonatal HSV may be classified into three main categories for therapeutic and prognostic considerations: localized skin, eye, and mouth (SEM); CNS with or without SEM; and disseminated disease involving multiple organs (table 1):

•Localized SEM disease is characterized by coalescing or clustering vesicular lesions of the skin (picture 5C and picture 5B); excessive tearing, eye pain, conjunctival edema; and/or localized ulcerative lesions of the mouth, palate, and tongue.

•Clinical manifestations of neonatal HSV CNS disease include seizures (focal or generalized), lethargy, irritability, tremors, poor feeding, temperature instability (fever or hypothermia), and full anterior fontanel. (See 'Central nervous system disease' above.)

•Disseminated neonatal HSV disease involves multiple organs. Neonates with disseminated HSV often present in the first week of life with nonspecific signs and symptoms of neonatal sepsis (eg, temperature dysregulation, apnea, irritability, lethargy, respiratory distress, abdominal distension, hepatomegaly, ascites). The mortality of untreated disseminated neonatal HSV exceeds 80 percent. (See 'Disseminated disease' above.)

●Neonatal HSV can mimic bacterial illnesses sepsis or meningitis and other viral illnesses (particularly enterovirus). Prompt treatment requires early consideration of neonatal HSV. Neonatal HSV infection should be suspected in neonates with mucocutaneous lesions, CNS abnormality (cerebrospinal fluid [CSF] pleocytosis, seizures, focal neurologic signs, abnormal neuroimaging (image 1 and image 2)), or sepsis-like illness (respiratory distress, apnea, abdominal distension, ascites, hepatomegaly, progressive pneumonitis, temperature dysregulation, hepatitis, thrombocytopenia). Neonates with perinatal exposure to HSV (eg, maternal active genital lesions) should be monitored for evidence of HSV infection (algorithm 1). (See 'Overview' above and 'Clinical suspicion' above.)

●The diagnosis of neonatal HSV infection may be established through isolation of HSV in culture, detection of HSV DNA using polymerase-chain reaction (PCR) assays, and detection of HSV antigens using direct immunofluorescence assays (DFA). All of the following virologic tests should be performed in neonates with suspected HSV infection (see 'Detection of HSV' above):

•Surface cultures from the conjunctivae, mouth, nasopharynx, and rectum

•Viral culture (with or without DFA) of swabs/scrapings of skin and mucous membrane lesions

•CSF HSV PCR

•Whole blood or plasma HSV PCR

•Viral culture or HSV PCR of tracheal aspirate, if intubated

●Interpretation of diagnostic testing for HSV in neonates depends upon the clinical circumstances (table 1). Most infected infants have positive viral culture and/or PCR in one or more of the specimens listed above. Similarly, infants with negative viral culture/PCR in all of the above listed specimens are unlikely to be infected with HSV. However, in the setting of highly suggestive clinical, laboratory, or radiologic findings, negative results do not exclude HSV infection. (See 'Interpretation/diagnosis' above.)

●A comprehensive evaluation should be performed in all neonates with suspected or proven HSV infection to determine the degree of organ involvement and exclude other diseases that may cause similar clinical symptoms. This evaluation is necessary, even in infants who appear to have isolated SEM disease because clinical findings may be absent early in the course of CNS and disseminated disease. In addition to routine laboratory tests, ophthalmologic examination and neuroimaging should be performed in all infants with virologically confirmed HSV infection, and electroencephalogram (EEG) should be performed in neonates with CNS involvement. (See 'Additional studies' above.)

●The differential diagnosis of neonatal HSV is broad and includes infectious and noninfectious conditions that are associated with vesicular skin lesions, eye disease, CNS manifestations, and/or systemic illness in neonates. Pending definitive diagnosis, empiric therapy for neonatal HSV may be warranted (after appropriate microbiologic specimens are obtained). (See 'Differential diagnosis' above and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Acyclovir therapy'.)