#26: Neonatal HSV – Plain and Simplex

May 26, 2021 | By Justin Berk

Summary

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!

Credits

• Producer, Writer, infographic: Martha Brucato, MD, PhD
• Show notes: Martha Brucato, Becca Raymond-Kolker, MD
• Cover Art: Chris Chiu, MD
• Hosts: Justin Berk MD; Chris Chiu MD
• Editor:Justin Berk MD; Clair Morgan of nodderly.com
• Guest(s): Christopher Golden, MD

Neonatal HSV Pearls

1. There are three well defined manifestations of postnatal HSV: mucocutaneous disease (Skin, eye, mouth disease),  encephalitis, and disseminated HSV disease.
2. HSV infection is treated with 20mg/kg acyclovir IV every 8 hours. For SEM disease, treatment course is 14 days. For disseminated disease or meningoencephalitis, treat for 21 days. 
3. After initial treatment, neurodevelopmental outcomes are improved if children are placed on long-term HSV prophylaxis to prevent recurrent disease.
4. The consequences of perinatal HSV can be devastating. It is important to be vigilant for these infections.

SPONSORS: VCU Health CE

We are excited to announce that the Cribsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out cribsiders.vcuhealth.org and create your FREE account!

What is Herpes Simplex Virus?

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. 

Why are we worried about newborns with HSV?

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. 

• 85% of infections arise from exposure during the delivery process
• 10% of infections arise from postnatal exposure (e.g. from kissing the baby with a cold sore or transmission by herpetic whitlow)
• Rarely, can be acquired as an intrauterine infection 

3 Common Manifestations of Postnatal HSV 

These three well defined manifestations of disease occur as a continuum:

1. Mucocutaneous disease (Skin, eye, mouth disease) where findings are only related to the skin, eyes, or mucous membranes (45% of cases)
2. Encephalitis (30% of cases) 
3. Disseminated HSV disease, this is the most severe (25% of cases)

How prevalent is HSV?

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.

Risks Factors for Peripartum Transmission

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:

• Pregnant/delivering patient having active lesions or asymptomatic shedding at the time of delivery (however, no indication from OB literature to routinely screening pregnant patients for shedding at the time of delivery)
• New (primary) HSV infection during pregnancy, especially in the third trimester. This is because of higher viral load and because the pregnant person does not have the ability to transfer protective antibodies to the baby
• Disruption of mucocutaneous barriers (like a fetal scalp electrode) 

Decreased likelihood of vertical transmission:

• C-section has been demonstrated to decrease risk but is not completely protective 

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. 

Caring for Asymptomatic Neonates

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:

1. If the parent had genital HSV prior to pregnancy, we assume lesions represent recurrent infection. The baby does not require a higher level of care and can remain in the newborn nursery or room-in with the parent. If the baby is asymptomatic at 24 hours of age, we obtain surface cultures and/or PCRs and blood PCR. No treatment and we wait on results.
2. If the parent did not have a history of HSV prior to pregnancy, we obtain serologies for HSV1 and HSV2 to help us determine if this is a recurrent or a primary infection. Then (even if asymptomatic), at 24 hours, the baby gets cultures, blood PCR, CSF analysis, serum transaminase analysis. We start the baby on antiviral treatment with acyclovir. 

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).

Natural history of Untreated HSV

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. 

How to counsel parents

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. 

Who’s at highest risk?

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. 

Symptomatic Patients

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: 

• surface testing (cultures or PCR, whichever is available at your institution), swab both eyes, the nose, the mouth, the rectum, and umbilical stump (it’s an open mucosal surface!)
• lumbar puncture for CSF (cell count and diff, glucose, protein, bacterial testing, viral testing; PCR is the best test here if available)
• if any vesicles are present, unroof the vesicle and swab the fluid and base of the vesicle
• blood PCR (though this test does not necessarily differentiate between SEM vs encephalitis vs disseminated disease)
• evaluate any specific symptoms: CXR for respiratory symptoms to eval for pneumonitis or PNA; EEG if any abnormal movements; MRI (best test) or CT or head US; if concern for skin lesions, ophthalmology exam (to look for corneal infection or evidence of chorioretinitis)
• CMP (risk of adrenal insufficiency with disseminated disease—serum sodium and potassium important), AST/ALT (virus has tropism for the liver)

The febrile infant <30 days old

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.

Treatment of HSV infection

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: 

• acyclovir IV infiltrate (it’s a vesicant that can cause tissue necrosis)
• renal toxicity because of crystallization in the distal tubules of the kidney
• bone marrow toxicity resulting in neutropenia 

… but a 2001 study demonstrated a favorable overall safety profile despite these risks.

Monitoring while on acyclovir: 

• CBC (look for neutropenia)
• BMP 1-2x/week (look for increase in creatinine)
• monitor for adequate UOP

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.

After initial treatment of HSV infection

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.)

Health equity

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. 

Takeaway points

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). 

Things to Share

Strange Bedfellows by Ina Park

Dr. Golden’s cheesecake recipe: 

 8 oz softened cream cheese

½ cup plus two tablespoons sugar

1 tablespoon lemon juice

1 tsp vanilla extract

2 eggs

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.

Goals

Listeners will be familiar with the diagnosis and management of neonates potentially or definitely exposed to HSV. 

Learning objectives

After listening to this episode listeners will…

• Recognize the constellation of symptoms and presentations that occur in neonatal HSV (SEM [skin, eyes, and/or mouth] disease, CNS disease, disseminated disease)

• Identify risk factors for neonatal HSV

• Utilize appropriate work-up in the diagnosis of HSV

• Choose evidence-based therapies in the management of asymptomatic and symptomatic neonatal HSV

• Discuss the natural history of treated and untreated neonatal HSV and the spectrum of possible outcomes

• Recommend appropriate follow-up for HSV infected neonates

• Educate parents and have meaningful discussions about the management and prevention of neonatal HSV

Disclosures

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. 

Citation

Brucato M, Golden WC, Chiu C, Berk J. “Neonatal HSV: Plain and Simplex”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ May 26, 2020.