Sandbox: Reddy

WikiDoc Resources for Sandbox: Reddy
Articles
Most recent articles on Sandbox: Reddy Most cited articles on Sandbox: Reddy Review articles on Sandbox: Reddy Articles on Sandbox: Reddy in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Sandbox: Reddy Images of Sandbox: Reddy Photos of Sandbox: Reddy Podcasts & MP3s on Sandbox: Reddy Videos on Sandbox: Reddy
Evidence Based Medicine
Cochrane Collaboration on Sandbox: Reddy Bandolier on Sandbox: Reddy TRIP on Sandbox: Reddy
Clinical Trials
Ongoing Trials on Sandbox: Reddy at Clinical Trials.gov Trial results on Sandbox: Reddy Clinical Trials on Sandbox: Reddy at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Sandbox: Reddy NICE Guidance on Sandbox: Reddy NHS PRODIGY Guidance FDA on Sandbox: Reddy CDC on Sandbox: Reddy
Books
Books on Sandbox: Reddy
News
Sandbox: Reddy in the news Be alerted to news on Sandbox: Reddy News trends on Sandbox: Reddy
Commentary
Blogs on Sandbox: Reddy
Definitions
Definitions of Sandbox: Reddy
Patient Resources / Community
Patient resources on Sandbox: Reddy Discussion groups on Sandbox: Reddy Patient Handouts on Sandbox: Reddy Directions to Hospitals Treating Sandbox: Reddy Risk calculators and risk factors for Sandbox: Reddy
Healthcare Provider Resources
Symptoms of Sandbox: Reddy Causes & Risk Factors for Sandbox: Reddy Diagnostic studies for Sandbox: Reddy Treatment of Sandbox: Reddy
Continuing Medical Education (CME)
CME Programs on Sandbox: Reddy
International
Sandbox: Reddy en Espanol Sandbox: Reddy en Francais
Business
Sandbox: Reddy in the Marketplace Patents on Sandbox: Reddy
Experimental / Informatics
List of terms related to Sandbox: Reddy

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:

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.

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

Pathophysiology

Pathogenesis

• 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.
• Postnatal trasmission 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. The test has low sensitivity so not used for diagnosis of HSV.

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
• Past history of other sexually transmitted infections
• Multiple sexual partners

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 type 1
• 15% of cases are caused by HSV type 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	✔

Diagnosis

Physical Examination

Clinical manifestations of neonatal herpes simplex include :

	Clinical Manifestations in congenital varicella syndrome
Skin	Vesicular lesions Scarring Aplasia Cutis
Eye	Optic Atrophy Chorioretinitis Micropthalmia
CNS	Microcephaly Hydranencephaly ( Absent cerebral hemispheres ) Intracranial calcifications

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, skin vesicles and anus.
• Other specimens to be collected include CSF for culture and PCR assay, whole blood for PCR assay and liver function tests.
• 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

It is the first episode of genital herpes

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 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 6weeks

❑ 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. The treatment duration is based on the severity of infection. The current recommendations are as follows:

• 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 only (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 delivery 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 36weeks of gestation.