NEONATAL HERPES SIMPLEX VIRUS INFECTIONS PCNA,APRIL 2013 ISSUE

BY

MAHISHMA.K

• “Herpes” – from the Greek “to creep, crawl”

• “Herpetic eruptions” were described as early as 100 AD

• 1960’s – HSV1 and HSV2 differentiated

• VIRUS :-

• Herpes Simplex Viruses(HSV-1 &HSV-2) belong to alphaherpesviridae family

• They are large and encapsulated with a icosahedral necleocapsid arranged around a linear double stranded DNA core.

VIRAL STRUCTURE

Core: Consists of a single linear molecule

of dsDNa in the form of a torus

Capsid: Surrounding the core w/ a 100 nm diameter and 162 capsomeres

Tegument: Consists of viral enzymes

Envelope: Outer layer composed ofaltered host membrane and a dozen

of viral glycoproteins

VIRAL STRUCTURE

• There is considerable cross-reactivity between HSV-1 and HSV-2 glycoproteins

• Unique antigenic determinants exist for each virus

• Eleven glycoproteins have been identified which mediate attachment, penetration and provoke immune responses

• TERMINOLOGY

• Primary infection:- acquisition of HSV-1 or 2 without prior exposure to either virus.Nopreformed antibodies.

• Nonprimary infection:- acquisition of HSV 2 infection in an individual with prior HSV-1 antibodies or vice-versa.

• Reactivation:-it is the isolation of same type of virus from genital lesions as that of pre-existing antibodies.

• Symptomatic shedding:- presence of genital lesions charecteristic of HSV and isolation of HSV 1 or 2 from the lesions.

• Subclinical shedding:-isolation of HSV-1 or 2 from the genital mucosa in the absence of lesions.

• Genital infections during pregnancy:-

• Genital herpes infections are caused by HSV1 & 2 and are mostly asymptomatic both in pregnant(two-third) &non pregnant women.

• Study states that,

HSV 2 seroprevalance among pregnant women is estimated to be between 20 to 30% and around 10% of seronegative women are living with a seropositivepartner, thus increasing the risk of transmission.

Women with history of genital herpes prior to herpes have higher risk of recurrence during pregnancy(75%) or prodromal symptoms or active lesions(14%).

• For neonatal transmission, women must be shedding virus symptomatically or asymptomatically around the time of delivery.

• The risk of transmission of HSV to neonate is higher with primary infection acquired closer to the time of delivery and less risk with recurrant infections.

• This is explained possibly by:-

(1).decreased transplacentally acquired antibody levels in the neonate

(2)exposure to increased quantities of virus.

• However the risk of neonatal transmission through a recurrence of infection during pregnancy is low.

NEONATAL HERPES

• HSV infection in a newnate is uncommon with an incidence of 1 in 3200 deliveries.

• However,when compared with other infections like syphilis,rubella,toxoplasmosis and rubella its incidence is higher.

• Factors influencing transmission of HSV to neonate:-

• (1)type of maternal infection(primary/secondary)

• (2)maternal antibody status

• (3)mode of delivery(vaginal/caesarean section)

• (4)duration of rupture of membranes

• (5)type of HSV(1 or 2)

• Type of infection:-

neonatal transmission is higher with primary or nonprimary infections of the mother and less with recurrent infections.

• Maternal antibody status:-

risk of transmission is higher with primary infection and less with reactivation.

• Type of HSV:-

studies have shown an higher incidence of transmission of HSV 1 to neonate irrespective of primary or recurrent infection.

• Caesarian delivery has been proved to be effective in preventing the transmission.

• Longer duration of rupture of membranes increases the risk of transmission

• Study also points that instrumentation during delivery and use of fetal scalp electrodes(FSE) leading to disruption of the barrier also increases the risk significantly.

• PREMATURITY:-

prematurity as a risk factor for acquisition of HSV is not well established.

However, the incidence of HSV is more in preterms than that of term babies and is associated with significant mortality & morbidity.

• NEONATAL HSV DISEASE CLASSIFICATION:-

• It is acquired during:

(1)in utero – 5%

(2)peripartum – 85%

(3)postnatal – 10%

It is classified as:-

(1)Disseminated disease – 25%

(2)CNS disease – 30%

(3)skin.eye & mouth disease – 45%

• In utero:-

• It is a rare entity and occurs approximately in 1 in 300,000 deliveries.

• Affected babies present with a triad :-

• (1)cutaneous- scarring,rash,pigmentation,aplasiacutis

• (2)opthalmologic-micropthalmia,chororetinitis,opticatrophy

• (3)neurologic-microcephaly,neurologic calcifications and encephalomalacia.

Archival Photo:

HSV “In Utero”

Healed by Tim e

O f B irth – W ith

M icrocephally

• Disseminated disease:-

• Prior to antiviral therapy,it accounted for ½ to 1/3 rd the neonatal HSV disease.

• Now incidence has reduced to 25% of all HSV infections.

• Usually presents around 10-12 days of life.

• It involves multiple organs including CNS,lungs,liver,adrenal along with SEM

• Vesicular rash may be present but is not seen in around 20% of cases with disseminated disease.

• They present with viral sepis including respiratory failure,hepatic failure and DIC.

• Death may occur due to severe coagulopathy.

• CNS DISEASE:-

• 1/3rd of neonatal herpes disease present as encephalitis and are categorized as CNS disease.

• Present lately at 16-19 days of life.

• Clinical features include:-

• seizures-focal/generalized

• lethargy

• irritability,poor feeding

• temperature instability and bulging anterior fontonalle

• Skin lesions are seen in 60 to 70% of the babies

• In the absence of skin lesions,presentation is very similar to other causes of encephalitis.

• Unlike herpes encephalitis in older age group which shows a higher prediliction to temporal lobe,

neonatal herpes involves multiple areas of brain.

• Skin,Eye,Mouth disease:-

• It accounts to 45%of the cases.

• Vesicular rash is seen in 80% of the cases with SEM disease.

• It is usually seen around 10 to 12 days of life.

• Disease is limited to skin,eye,mouth/mucus membranes.

• It is associated with a good outcome without any disabilities after 1 year of treatment.

CUTANEOUS LESIONS

VESICULAR LESIONS HSV

HSV 2 Arm Lesions

9 Days of L ife

Presenting L im b in a 34 W eek

Prem ature In fant

• Evaluation of a neonate with suspected HSV infection:

• Viral culture:-

• isolation of HSV by culture is a definitive diagnostic method.

• Conjunctiva,nasopharynx,mouth and anus are swabbed to get the samples.

• CSF and blood can also be used for culture.

• PCR:-

• CSF can be subjected to PCR for identification of Herpes infection.

• Study shows that overall sensitivity of the test is about 75% to 100% and specificity is 71% to 100%.

• A negative PCR doesnot rule out the disease as it may be negative in early stages of the diasease where the viral load is low.

• Serological testing:-

• It is not recommended,as there is transplacentallyacquired maternal Ig G antibodies.

• Hence,there is no role for serology in neonatal HSV diagnosis

• Specimens to be obtained before starting antiviral therapy:-

• CSF analysis(culture & DNA PCR)

• Swab for viral culture from vesicles,suspicious areas and mucus membrane lesions for viral culture or PCR.

• Swab from mouth,conjunctiva,nasopharynx and rectum(surface cultures) or PCR

• Whole blood for HSV DNA PCR

• Blood to determine alanine aminotransferase(ALT)

• TREATMENT OF NEONATAL HSV DISEASE:-

• ACYCLOVIR is the drug of choice because of its safety profile.

• Current recommendation states that:-

acyclovir 60mg/kg/day q8th hrly

14 days in SEM

21 days in CNS/disseminated

• At the end of therapy CSF PCR should be done in all the neonates.

• It should be done to document a negative result.

• If it is positive, the therapy is continued till the PCR comes negative.

• Study states that detection of HSV in CSF after completion of treatment has been associated with poorer outcomes.

• The significance of blood DNA PCR is not studied well,hence serial measurements of BLOOD DNA PCR is not recommended.

• SUPPRESSIVE THERAPY AFTER TREATMENT:-

• Trials on the use of antiviral suppressive therpay after standard treatment of HSV has shown decreased incidence of morbidities and neurological sequale.

• Current recommendation for suppressive therapy is :-

Oral acyclovir : 300mg/m2/dose TID for 6 months

• Absolute neutrophil count should be monitored at 2 and 4 weeks, later on every month.

• Approach to a infant exposed to HSV during maternal genital HSV infection:-

• Recommendations on management of neonate exposed to HSV takes into consideration:-

• maternal serological status

• presence of genital lesions at the time of delivery and

• mode of delivery.

• TESTING OF WOMEN IN LABOR:-

• All women with genital lesions charecteristic of HSV at the time of delivery should be assessed for:

• Status of infection – primary/recurrent

• Maternal serology – HSV1/HSV 2

• PCR for viral culture from genital lesion swabs.

• Management of neonate born to mother with lesions at delivery and a prior history of genital herpes before pregnancy:-

• For women with previous history- the chances of lesions at the time of delivery being recurrent is high ,the risk of transmission to the infant is low.

After 24hrs of delivery,collect surface cultures and blood DNA PCR is done.

If clinically well at 48hrs tests are positive

Negative results

send for

CSF for culture &

Baby can be discharged HSV PCR

Further evaluation only if

There are any signs start iv acyclovir

• CSF culture and PCR

Negative positive

(HSV infection)

Preemptive treatment for treat as neonatal

10 days with i.v acyclovir HSV disease

• Management of a neonate born to mother with lesions at the time of delivery and no prior history of genital herpes:-

• After 24 hrs birth surface cultures and CSF PCR and viral culture is sent as the risk of transmission to infant is high.

• Simultaneous intravenous acyclovir is started.

• If maternal infections are suggestive discontinue

of reurrent infection and acyclovir

neonate asymptomatic re evaluation only if

symptomatic

• If maternal studies are S/O

Primary infection & neonate asymptomatic preempitive

But negative CSF analysis treatment -

10days

i.v acyclovir

• If mother - primary infection

Neonate surface cultures are positive treat as HSV

CSF PCR positive disease

If mother – primary infection

Surface culture positive in neonate treat as HSV

But CSF PCR is negative infection

• Strategies for prevention of neonatal herpes:-

• Caserian delivery:-

• delivery of the baby by C-section in women with active genital lesions can reduce the infant’s risk of acquiring HSV.

• it is more effective if performed before the rupture of membranes.

• However,C-section is not recommened if there are no active lesions or prodromal symptoms at the time of delivery in a women with history prior to pregnancy.

• Antiviral suppressive therapy:-

• In women with active recurrent genital herpes ,antiviral therapy with acyclovir initiated at 36 wks of gestation has been associated with decreased genital lesions at the time of delivery and decreased viral detection by culture or PCR .

• This also thus reduces the need for C-section.

• The use of acyclovir in pregnancy has not been associated with any adverse fetal outcomes or birth defects.

• Study however states that suppressive therpayreduces the risk of genital lesions and viral load ,but the extent to which the therapy prevents neonatal acqusition of disease is still unknown.

• HSV vaccine:-

HSV 2 vaccine has been developed,but its efficacy in previously sero positive individuals is not reported.

Currently no vaccine has proved to be effective.

• Prevention of maternal HSV acquisition during pregnancy:-

To screen all couples for HSV serology at 14 to 18 weeks of gestation.

Abstain from sexual contact in third trimester.

• Prevention of postnatal acquisition:-

• Although most neonatal HSV infections are acquired in the peripartum period,10% of cases are acquired in the postpartum period.

• It is caused due to exposure of virus from open lesions of the care takers.

• It is recommended that infected contacts avoid contact with the newborn.

• KEY POINTS:-

• Three major forms of herpes infections are :-

(1)disseminated disease – 25%

(2)CNS disease – 30%

(3)skin,eye & mouth disease – 45%

• Mortality rate is high in

disseminated(29%) > CNS(4%)

• Disabilities of chronic duration(morbidity) is more in CNS disease(69%) & less in disseminated(17%)

• Neonates with HSV disease should receive oral acyclovir suppressive therapy for 6months after completion of i.vtherapy.

THANK YOU