Join the Cribsiders team as we unroof a serious diagnosis that you don’t want to miss. We discuss perinatal prevention, diagnosis, and treatment of herpes simplex virus and how it can affect the newborn with neonatology expert, Dr. Chris Golden. Christopher Golden. MD, is an Associate Professor of Pediatrics at the Johns Hopkins University School of Medicine. He is a neonatologist whose interests include congenital and neonatal infections, neonatal bilirubin metabolism, care of healthy newborns, and pediatric medical student education. And check out the show notes for his marriage-worthy cheesecake recipe!
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Herpes Simplex Virus (HSV) is a double stranded DNA virus. Two types: HSV1 and HSV2, which have different glycoproteins. Primary infection can lead to latent infection, where the virus is dormant in the dorsal root ganglion. Reactivation can occur during times of stress and is when the virus can be transmitted.
The first 30 days of life are a uniquely vulnerable time as neonates have a developing immune system. Neonates exposed to HSV during the first 30 days of life are at high risk of developing infection, however the infection acquired at this time can present up to about 6 weeks of age.
These three well defined manifestations of disease occur as a continuum:
One in 6 adults is seropositive for HSV. This is consistent over time through multiple studies. One 2003 prospective study by Zane Brown et al looked at the incidence of disease in the neonate and found it to be 1/3,200 cases annually. This estimates 1200 – 1500 cases annually in the US.
In pregnant patients who have been appropriately treated with prophylaxis, certain factors can increase and decrease the risk of vertical transmission.
Increased likelihood of vertical transmission:
Decreased likelihood of vertical transmission:
If the pregnant patient has active lesions at the time of delivery, this is an indication for c-section for both primary and recurrent infection. The risk for vertical transmission of HSV is about 40-60% in primary infections and <5% in recurrent infection with active lesions.
Pregnant patients with or without a history of HSV should have a speculum exam at time of presentation to look for vaginal lesions (algorithm based on the Red Book (2018) and the Guidance on management of asymptomatic neonates born to women with active genital herpes lesions). In laboring patients with active lesions during delivery (either vaginal or c-sections), obstetricians should get a swab of the lesion for either PCR or culture assay. PCR is a better test for HSV than culture (faster results) but it is not available at every hospital. Treatment algorithm breaks into 2 trees:
We wait until 24 hours of life in the above cases to obtain cultures because we don’t want the interpretation of results to be confused by the presence of parental secretions at the time of collection (by 24 hours, vernix likely wiped off).
If a pregnant parent has antibodies prior to delivery, there is a possibility of a milder course for neonatal disease. If a patient developed a third trimester infection without time to develop antibodies, there is a risk of more severe disease.
Disease does not always occur in the immediate newborn period! The average onset of neonatal HSV disease (both SEM and disseminated disease) is 10-12 days. The average onset of HSV encephalitis is 16-19 days of age.
In neonates with risk factors, there are no pathognomonic symptoms. For example: there are neonates who get HSV who never develop a rash! In a Kimberlin and colleagues 2001 study, in all patients with symptomatic HSV disease, 68% of neonates had evidence of skin vesicles at the time of presentation, so 32% of children did not have a rash! With the most severe disease (disseminated HSV), 40% may not show any obvious signs of disease except that they are ill-appearing. Babies with HSV can present with fever, lethargy, poor PO intake, tachycardia, and anything that indicates the infant is not well appearing.
Provide anticipatory guidance at the time of discharge: if your child is not eating well, not well appearing, feels hot or cold, is difficult to wake up, has unusual movements, bring them to the emergency room. If that happens, please tell the ED physicians that there is a parental history of HSV and whether or not they were treated for HSV.
In one study from 1997, 1-2% of pregnant patients seroconverted (developed HSV antibodies) during pregnancy. 64% of individuals in that cohort converted asymptomatically, meaning they never knew they had HSV. Known personal history of HSV prior to pregnancy may actually be protective, since the patient would have antibodies during pregnancy to confer protection via placental transfer; whereas asymptomatic seroconversion or third trimester seroconversion actually confers increased risk for neonatal HSV.
HSV1 and HSV2 are equally virulent and able to cause disease in neonates. There has been a change over time in the infection patterns of HSV1 with an increasing frequency of HSV1 genital infections.
The immune system in preterm infants is immature and they have a decreased immune response. Preterm infants also have less effective barriers (skin and lung) to protect against pathogens. For example, preterm infants have skin that is not yet normally keratinized and is very gelatinous. Prematurity is a risk factor for more invasive disease because (1) preterm infants have a decreased immune response and (2) pregnant patients are not routinely started on valacyclovir suppression until 36 weeks gestation.
In the case of a symptomatic infant (trouble latching, hypothermic, irritable) prior to 24 hours of life: start evaluation for HSV and for bacterial infections (Group B strep, E.coli, listeria—always consider these in the differential even if the parent has a history of HSV and we’re suspicious for HSV infection).
Evaluation for a sick infant consists of:
Now we have a different patient: a 21 day old febrile infant who is ill-appearing and who is being admitted for sepsis work-up.
In Dr. Golden’s expert opinion, if a child is ill appearing and presenting within the first 30 days of life, he would keep HSV on the differential and start acyclovir empirically while awaiting testing. In one cohort of 5817 neonates presenting to a hospital in Houston, HSV was as common as bacterial meningitis. Keep HSV in your differential for the febrile neonate, especially in the presence of mononuclear CSF pleocytosis. HSV infection should also be considered in neonates with hypothermia and a sepsis-like syndrome.
HSV infection is treated with 20mg/kg acyclovir IV every 8 hours. For SEM disease (negative CSF, AST/ALT), treatment course is 14 days. For disseminated disease or meningoencephalitis, treat for 21 days. There is no oral option for treatment; oral acyclovir is poorly bioavailable, so we need to use IV acyclovir for the full treatment course.
Risks of treatment:
… but a 2001 study demonstrated a favorable overall safety profile despite these risks.
Monitoring while on acyclovir:
If you have HSV on the differential, in Dr. Golden’s expert opinion you should initiate treatment—there is evidence that delayed treatment of HSV infection increases the risk of in-hospital mortality.
What’s next after completing a treatment course? Acyclovir prophylaxis for 6 months improves the neurodevelopmental outcomes of children who had neonatal HSV infection. The strategy of using acyclovir prophylaxis was based on data showing that children with >3 recurrences in the first 6 months of age have a risk of long term neurodevelopmental outcomes. Prophylaxis (not treatment!) can be with oral acyclovir. If there is a recurrence of active infection despite ppx, would re-treat with a course of IV acyclovir.
We don’t know if valacyclovir (oral or IV) can safely be used in neonates for treatment or prophylaxis, but clinical trials are in the works! (See https://clinicaltrials.gov/ct2/show/NCT04448392.)
Racial disparities exist in the prevalence of HSV infection, with increased prevalence of HSV seropositivity in individuals who identify as women and non-Hispanic Black individuals. Equity in this case would look like increased access to routine screening for STIs (including HSV) for minoritized populations.
While neonatal HSV is not as common as other conditions in the newborn, the consequences can be devastating. It is important to be vigilant for these infections.
Be aware that the USPSTF does not recommend screening for genital herpes in adults and adolescents, including pregnant people. We need better testing for HSV with improved positive predictive values before we can routinely screen populations (see this 2016 editorial about next steps).
Dr. Golden’s cheesecake recipe:
8 oz softened cream cheese
½ cup plus two tablespoons sugar
1 tablespoon lemon juice
1 tsp vanilla extract
1 cup sour cream
1 graham cracker crust
-Beat cream cheese with hand mixer until fluffy
Add ½ cup sugar, lemon juice, and half of the vanilla extract, beating well.
Add eggs individually, then pour into the crust.
Bake at 325 degrees for 30 minutes.
While first layer is baking, mix sour cream and remaining vanilla and sugar.
When first layer is done, remove from the oven and layer sour cream mixture on top.
Bake for an additional 10 minutes.
Cool for at least 4-6 hours.
Top with your choice of fruit or fruit filling.
Listeners will be familiar with the diagnosis and management of neonates potentially or definitely exposed to HSV.
After listening to this episode listeners will…
Dr. Golden received an honorarium for his work with MJH Life Sciences, Wolters Kluwer, and the National Board of Medical Examiners Editorial Advisory Board. The Cribsiders report no relevant financial disclosures.
Brucato M, Golden WC, Chiu C, Berk J. “Neonatal HSV: Plain and Simplex”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ May 26, 2020.
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