Neonatal herpes simplex

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: SEM, Neonatal herpes

Overview

Neonatal herpes simplex infection is caused by HSV-1 and HSV-2. The transmission of infection is by vertical transmission in utero or by direct contact from the genital tract. The disease presentation varies with majority of the cases limiting to only skin, eye and mouth (SEM), but it can also involve the CNS and other organ systems. Documentation of maternal history of genital herpes and classification of maternal infection type based on serology has a significant role in the management of neonatal herpes. The risk of transmission is high in patients with primary disease and low in patients with recurrent disease. A high suspicion of neonatal herpes infection should be present in all infants born to mothers with genital lesions in the third trimester. Surface cultures and CSF analysis should be done to establish the infection and empiric IV acyclovir must be initiated for better outcomes. The duration of the treatment is based on the extent of involvement of the disease, it should be followed by a 6 month duration of suppressive acyclovir therapy.

Historical Perspective

• In 1935, the first case resembling neonatal HSV, was described with the presence of intranuclear inclusion bodies in a premature infant in the liver and the adrenals.

Classification

Neonatal Herpes Simplex Classification

Neonatal herpes simplex is classified based on the organ system involvement in the neonate into the following:

• Disseminated herpes simplex: Involving visceral organs such as lung, liver, adrenal glands, skin, eye, and/or brain.
• Central nervous system disease: Involvement of the CNS with or without skin lesions.
• SEM Disease: Disease limited to the involvement of skin, eye and mouth.

Maternal Genital Herpes Classification

Maternal genital herpes is classified based on HSV type and maternal serology. It is essential to distinguish the type of maternal infection, as the type of infection influences the management approach.

• Primary Infection: It when a women has exposure to either HSV-1 or HSV-2 for the first time. The serology will be negative for antibodies against both the types.
• Recurrent Infection: It is when a women has clinical lesions demonstrating the same type of HSV to which the serology is positive.
• Non-primary first episode: It is the first clinically recognized episode and serology demonstrates either HSV-1 or HSV-2 antibodies indicating a prior exposure.

Classification of maternal infection	PCR / Culture from the genital lesion	Maternal HSV-1/ HSV-2 Antibody status
First episode primary infection	Positive for either virus	Negative for both
Recurrent infection	Positive for HSV-1	Positive for HSV-1
	Positive for HSV-2	Positive for HSV-2
First episode Non-primary infection (Patient is immune to one type of HSV)	Positive for HSV-1	Positive for HSV-2
	Positive for HSV-2	Positive for HSV-1

Pathophysiology

Pathogenesis

• Majority of infants with diagnosed neonatal herpes do not have maternal history of genital lesions because of asymptomatic shedding of the virus.
• Transmission of virus takes place when the pregnant women is shedding the virus in the genital tract either symptomatically or asymptomatically.
• The risk of transmission of infection to the neonate from an infected mother is high (30-50%) who have first episode of genital herpes at term and low (<1%) in mothers with prenatal history of recurrent herpes or who have genital HSV during the first and second trimester.

Timing of infection

• Exposure to the fetus from active genital herpes lesions during delivery, accounts for majority of neonatal herpes simplex cases.
• Intrauterine infection accounts for 5% of cases with neonatal herpes simplex and the infant presents with clinical features at birth which include hydraencephaly and microcephaly.
• Postnatal transmission by contact with HSV shed from infected patients. It accounts for 10% of the cases.

Factors that influence transmission of HSV from the mother to the neonate

The factors that influence the transmission of infection include:

• Women with primary infection have higher rate of infection transmission when compared to women with recurrent infection.
• Maternal HSV antibody status, women with recurrent infection have IgG antibodies aganist HSV which can protect the fetus from infection.
• Prolonged duration of rupture of membranes increases the risk of infection transmission.
• Use of scalp electrodes disrupts the integrity of mucocutaneous barrier increasing the risk of transmission.
• Vaginal delivery has a higher risk of transmission of infection compared to cesarean section.

Microscopic Pathology

• Tzank test: Microscopic examination of the skin lesions demonstrate multinucleated gaint cells and eosinophilic intranuclear inclusions.

Epidemiology and Demographics

• The annual incidence of neonatal herpes is estimated to be 10 cases per 100,000 livebirths.

Risk Factors

The cause for neonatal herpes simplex is the presence of active lesions at the time of delivery, therefore all the risk factors which predispose patients to aquire genital herpes are risk factors for developing neonatal disease also. The risk factors include:

• Low family income
• Minority ethnic group
• Longer duration of sexual activity
• History of other sexually transmitted infections
• Multiple sexual partners

Screening

• Routine screening for HSV in pregnancy is not recommended.

Causes

The causative pathogen for neonatal herpes simplex is herpes simplex virus. The different types involved in the disease are as follows:

• 85% of cases are caused by HSV-1
• 15% of cases are caused by HSV-2

Differentiating Neonatal Herpes Simplex From Other Diseases

The most important congenital infections, which can be transmitted vertically from mother to fetus are the TORCH infections. These infections have overlapping features and hence, must be differentiated from neonatal herpes simplex:

Congenital Infection	Cardiac Findings	Skin Findings	Ocular Findings	Hepatosplenomegaly	Hydrocephalus	Microcephaly	Intracranial Calcifications	Hearing deficits
Congenital Varicella Syndrome		- Cicatrical Skin Lesions Skin Edema	Micropthalmus Cataracts	✔		✔	✔
Toxoplasmosis		Petechiae Purpura Maculopapular rash	Chorioretinitis	✔	✔	✔	Diffuse intracranial calcifications
Congenital Syphils		Petechiae Purpura Maculopapular rash	Chorioretinitis Glaucoma	✔
Rubella	Patent ductus arteriosus (PDA) Pulmonary artery stenosis Coarctation of the aorta Myocarditis	Petechiae Purpura	Chorioretinitis Cataracts Glaucoma Microphthalmia	✔	✔	✔		✔
Cytomegalovirus (CMV)	✔	Petechiae Purpura	Chorioretinitis	✔		✔	Periventricular calcifications	✔
Herpes simplex virus (HSV)	Myocarditis	Petechiae Purpura Vesicles	Chorioretinitis	✔	✔	✔		✔
Parvovirus B19	Myocarditis	Petechiae Subcutaneous edema	Chorioretinitis Cataracts	✔

Natural History, Prognosis and Complications

Natural History

Neonatal herpes infection is a rapidly progressive disease resulting in CNS disease and disseminated disease. Clinical presentation in the initially include vesicular skin rash, watering and redness of the eyes and mouth ulcers. Early diagnosis and treatment with acyclovir prevents the progression of disease. If left untreated the infection can progress to involve the CNS and other organ systems. Affected infants present with irritability, feeding difficulties, respiratory distress and features of DIC. Disseminated disease has poor prognosis and results in early death of the infant. Infants with CNS disease can have residual neurological deficits and developmental delay.

Prognosis

• The prognosis of SEM is good and majority of the infants have good prognosis with acyclovir suppressive therapy.
• The use of acyclovir has reduced mortality in CNS and disseminated disease but the overall prognosis is poor.

Complications

The complications of neonatal herpes infection include:

• Early death
• Neurological disabilities
• Cognitive disabilities
• Recurrent herpes infections in the infant
• Developmental delay

Diagnosis

History and Symptoms

The onset of symptoms is dependent on the extent of involvement of the disease. Skin, eye, mouth disease is the most common presentation and is seen in 50% of patients. Delay in the diagnosis and initiation of treatment results in rapid progression of disease to involve the CNS and other organ systems.

Skin, Eye, Mouth Disease

• The average age of presentation is 10 to 12days of life.
• The presenting symptoms include: redness and watering of the eye, skin rash and mouth ulcers.

CNS Disease

• The average age of presentation is around 16 to 20days of life.
• The symptoms include : Irritability, feeding difficulties, weakness of the limbs, seizures and enlarging head.
• Majority of the patients with CNS disease have features of SEM.

Disseminated Disease

• The average age of presentation is 10 to 12 days of life.
• The infant presents with symptoms such as difficulty breathing, yellowish skin, distended abdomen, seizures, reduced urine output, bleeding, skin rash.

Physical Examination

Physical examination findings in neonatal herpes simplex include :

	Clinical Manifestations in neonatal herpes simplex
Skin	Vesicular lesions with an erythematous base Scarring Aplasia Cutis
Eye	Optic Atrophy Chorioretinitis Micropthalmia Conjunctival erythema
Mouth	Ulcers on the tongue, palate and mouth
CNS Disease	Microcephaly Irritability Temperature instability Hypotonia Bulging anterior fontanelle
Disseminated Disease	Jaundice is seen in liver failure Respiratory distress Bulging anterior fontanelle Features of Disseminated intravascular coagulation such as bleeding and petechiae

Laboratory Findings

Diagnosis of maternal genital herpes

• Diagnosis of maternal herpes simplex can be done by PCR assay for HSV DNA and culture for HSV.
• PCR assay is the commonly used method for diagnosis as it takes short time for obtaining results. The major limitation of using PCR assay is its availability in remote medical facilities.
• Culture for HSV takes 4 to 5 days for results and is dependent on the stage of infection, higher viral load is present in the prodromal and vesicular stage than during the crusting stage affecting the results.
• Serological tests distinguish antibodies produced against HSV-1 and HSV-2, therefore help in determining the type of HSV causing the infection.

Diagnosis in the Neonate

• Neonates with suspicion for herpes simplex infection must be evaluated for the presence of infection before initiation of empiric treatment with acyclovir. The gold standard for diagnosis is culture for HSV. PCR of CSF should be done in neonates presenting with CNS disease.
• The specimens for surface cultures should be collected from multiple areas which include mouth, nasopharynx, conjunctivae, and anus. Skin vesicles should also be sampled for culture and PCR assay.
• Sample collection is done at 24 hours of life to eliminate a possible maternal contamination which can result in false positive results. Positive surface cultures indicate viral replication.
• Other specimens to be collected include CSF for culture and PCR assay, whole blood for PCR assay and liver function tests.
• Whole blood PCR is useful in identifying viremia, but the extent of the disease and response to therapy cannot be related to the result of blood PCR as viremia is present in SEM, disseminated and CNS HSV infections.
• Based on the laboratory findings, HSV manifestation can be differentiated into two types:

Stage of Neonate infection	Specific Findings
HSV Infection	Asymptomatic infant Positive surface culture Positive HSV blood PCR Normal CSF analysis Normal alanine transaminase
HSV Disease	Symptomatic infant ( Presence of SEM, disseminated or CNS HSV features) Positive surface culture Positive HSV blood PCR Positive CSF HSV Elevated alanine transaminase

Treatment

Approach to neonate with suspected HSV infection

Suspicion of HSV infection in asymptomatic neonate

Is the present genital herpes lesion the first episode or not

YES

Positive past history for similar lesions before pregnancy

Signifies the infection can be primary infection, first episode Non-primary infection or a recurrent infection

Signifies the infection is most likely due to reactivation of the virus

• Perform maternal serology to differentiate the stages of maternal infection AND At 24hours of life perform : • HSV surface cultures • CSF analysis and CSF HSV PCR • HSV Blood PCR • Measure serum ALT • Initiate IV Acyclovir 60mg/kg/day in 3 divided doses

At 24 hours of life perform : • Surface cultures • HSV Blood PCR • Donot start Acyclovir if the baby is asymptomatic

Primary infection or First Episode Non-primary infection

Recurrent infection

Reactivation

HSV Disease

HSV Infection

HSV Infection

• Negative neonate HSV blood PCR • Negative surface culture

• Negative blood HSV PCR • Negative surface culture

• Positive HSV blood PCR • Positive surface culture

• Continue IV Acyclovir based on the extent of the disease (14 to 21 days)

Continue IV Acyclovir for 10days to prevent progression

• Stop Acyclovir • Educate about signs and symptoms of HSV • Discharge and re-evaluate at 6 weeks

• Educate about signs and symptoms of HSV • Discharge and re-evaluate at 6 weeks

Perform CSF HSV PCR and Alanine Transaminase level

• Negative CSF PCR • Start IV Acyclovir for 10days

Positive CSF PCR and Elevated ALT • Initiate IV Acyclovir for 14 to 21days

Algorithm adopted from Guidance on Management of Asymptomatic Neonates Born to Women With Active Genital Herpes Lesions

Classification of maternal infection	PCR / Culture from the genital lesion	Maternal HSV-1/ HSV-2 Antibody status
First episode primary infection	Positive for either virus	Negative for both
Recurrent infection	Positive for HSV-1	Positive for HSV-1
	Positive for HSV-2	Positive for HSV-2
First episode Non-primary infection	Positive for HSV-1	Positive for HSV-2
	Positive for HSV-2	Positive for HSV-1

Medical Therapy

Acyclovir is the only therapeutic agent for the treatment for neonatal HSV and the treatment duration is based on the severity of infection. The current recommendations are as follows:

• All infants with skin lesions should be admitted and should be kept in isolation with contact precautions.
• Breast feeding is contraindicated when herpetic lesions are present on the breast.
• Start empiric IV acyclovir therapy in all symptomatic infants and infants with suspicion of neonatal HSV or confirmed HSV infection. IV Acyclovir is the recommended regimen and is given at a dose of 20mg/kg every 8 hours.
• The duration of acyclovir therapy is dependent on the severity of the infection, it is as follows:
  • Patients with HSV infection treatment should be continued for 10 days.
  • Patients with skin, eye, mouth involvement(SEM) duration of treatment is 14 days.
  • Patients with CNS and disseminated disease duration of treatment is 21 days.
• In patients with a initial positive CSF HSV PCR, repeat lumbar puncture should be performed at the end of therapy to assess the response to therapy. If the CSF PCR is positive at the end of therapy, acyclovir treatment should be extended for a duration of 1week. The results of the repeat lumbar puncture should be negative to stop the therapy.
• All patients should receive a 6 month duration acyclovir suppressive therapy 300mg/m²/dose, 3 times a day after IV acyclovir is stopped.
• Absolute neutrophil count should be monitored at second and fourth week after initiation of suppressive therapy initially and then once monthly.

Surgical Therapy

There are no surgical measures for the management of neonatal herpes simplex.

Prevention

Primary Prevention

• Women without known genital herpes should be counseled to abstain from vaginal intercourse during the third trimester with partners known or suspected of having genital herpes.
• Pregnant women without known orolabial herpes are advised to abstain from receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes.
• All pregnant women should be asked about history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Cesarean delivery does not completely eliminate the risk for HSV transmission to the neonate, women with recurrent genital herpetic lesions at the onset of labor should deliver by cesarean section to reduce the risk for neonatal HSV infection.
• Consistent condom use and avoidance of sexual activity during recurrences.

Secondary Prevention

• Suppressive acyclovir treatment late in pregnancy reduces the frequency of cesarean delivery among women who have recurrent genital herpes by reducing the frequency of recurrences at term. However, such treatment may not protect against transmission to neonates in all cases. Recommended Regimen : Acyclovir 400 mg orally three times a day OR Valacyclovir 500 mg orally twice a day, beginning from 36 weeks of gestation.