Drs. Sarah May Johnson and Fani Ladomenou discuss a case of neonatal HSV in the fourth case of the Febrile “Curious Congenital Conundrums” series

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Hi everyone.

Welcome to Febrile, a cultured podcast about all things infectious disease.

We use consult questions to dive into ID clinical reasoning, diagnostics, and anti-microbial management.

I'm your host, Sara Dong, a combined adult and pediatric ID fellow.

Here on Febrile, we use patient cases and consult questions to learn about high yield ID topics.

We'll present pieces of the story of a patient's case, and then pause along the way to hear from our guest consultant.

Welcome to the final episode of our Curious Congenital Conundrum series.

I'm excited to introduce our guests today.

Our host is Dr.

Sarah May Johnson.

She is a pediatric registrar of infectious diseases, immunology and bone marrow transplant at Great Ormond Street Hospital in London.

She is also interested in global health and has completed a diploma from the London School of Hygiene and Tropical Medicine.

And she has also been awarded a Wellcome Trust global health research fellowship to explore adolescent tuberculosis.

Our guest discussant today is Dr.

Fani Ladomenou.

She is a consultant in Pediatric ID at the Venizeleion General Hospital in Crete, Greece.

She was previously a fellow in pediatric ID and immunology in the UK, and has worked as a consultant in pediatric immunology and ID also at Great Ormond Street Hospital.

Since then she's been caring for children in Greece and has been responsible for the pediatric ID and immunology service since 2012.

And she's focused her previous research efforts on various pediatric ID topics.

In addition, she has previously served as a Young Board Representative for ESPID or the European Society for Pediatric Infectious Diseases between 2018 and 2021.

Thank you for joining us today.

Thanks.

Thank you.

I'm glad I'm here too.

So before we jump into the case today, which is super interesting, we always like to ask one nonmedical question.

We wanted to see if you'd be willing to share a little piece of culture or something that you have enjoyed recently.

I'm a big knitter.

So I spent most of my life knitting and for the second time ever, I'm actually knitting a pair of socks because I normally like to do more complex knitwear.

Um, but my boyfriend's been wearing my grandpa's socks around the house and they are eaten to pieces.

So now I'm knitting him some socks and they're literally like that.

It's like a World War II style socks that go up to the knees, kind of like Wellington boots.

Uh, well, I've only been able to knit a scarf, but never quite moved into anything tubular yet.

So that'll be my next step.

Um, what about you Fani?

I will talk about, um, it's an old book.

It's a not, it's not a new one, but, it's about place where I'm working and living at the moment, about Crete, the Southwest part of Greece in Europe, an island.

Uh, so the book is, uh, is named Island from Victoria Hislop.

I don't know if you have read it or not and it deals with a small place, very small, um, even smaller from Crete island, um, next to Crete where people with Hansen's disease were kept a century ago.

So if you haven't read the book, you should do it.

It's a very interesting.

Great.

Excellent.

Well, thank you both for sharing.

So moving us forward, today's consult question is about a mom and baby pair who have both become acutely ill.

So I hand it over to Sarah, take it away

On with the next consult.

After a busy day on the ward, you're called by your obstetrics colleagues from the hospital across town about a curious conundrum that they have been dealing with in conjunction with neonatal colleagues at the hospital.

The case involves a mother and neonatal pair whom are both fall acutely ill.

The baby boy is born approximately 24 hours back to 32 year old, gravida one para zero mom who has become acutely unwell with peripartum fever and gastrointestinal symptoms.

She has prominent abdominal pain and blood stricken loose stools.

The antepartum course was otherwise uneventful.

The baby was born at 39+4 weeks without any initial concerns, although since fallen ill with fever and suspicion for sepsis and has been transferred to NICU for ongoing care.

The mother has also been transferred to ICU due to suspicion of sepsis.

The mother was previously healthy with no significant past medical history.

She was born in the Philippines, but has been living in the UK for four years.

Booking bloods verbally reported to you over the phone are negative for hepatitis B, HIV, and syphilis.

The baby is started on ben pen (benzylpenicillin) and amikacin, and acyclovir after blood cultures, full blood count, and biochemistry is drawn as per standard neonatal sepsis guidelines in the hospital.

Mother is also started on broad spectrum antibiotics, ceftriaxone, gentamycin, and metronidazole after blood cultures are drawn.

With a differential diagnosis remaining broad, what additional information would you like to gather on the phone?

Would you have done anything different in the management of this child so far?

There are some questions that I would like to ask on the phone.

Uh, I was wondering whether the baby was born by cesarean section or by normal vaginal delivery.

In case he was born by cesarean section, or was there a rupture of membranes before the section?

Was this mother screened for group B strep during pregnancy?

And did she also receive any intrapartum antibiotics in view of the fact that she was Febrile in labor?

She was acutely unwell..

Uh, did the baby have any lumbar puncture or was he very unstable to have that?

And I was also wondering whether the baby had any skin lesions suggestible of HSV infection or whether the mother had any history of orolabial HSV or any genital herpes.

Did this baby having a stigma about other congenital infections, or clinical dissemination, such as for petechiae, blueberry muffin, hepatosplenomegaly, microcephaly, or any other rashes.

And moreover, I would also like to know the results for the full blood count and the biochemistry.

Did the full blood count show any disorders in cell counts or any cytopenias, or were there any abnormal liver function tests.

And regarding the maternal history would also like to have some more information.

Was this mother monogamous or was she having a high risk sexual behavior?

Uh, for example, during pregnancy, was she consuming sushi or rare or raw meat?

Was she consuming unpasteurized milk or cheese?

And did she have any known sick contacts recently?

For example, somebody with tuberculosis or did you have any recent exposure to animals?

These are all the things that they would like to know before going ahead.

At the moment I wouldn't have done anything differently.

As we all know, sepsis is an important cause of morbidity and mortality among newborn infants.

Here, although we still don't have the results of the blood culture back, we believe that we're dealing with an episode of early onset sepsis.

And I'm saying early onset because the onset of symptoms occurred before seven days of age.

This early onset infection is usually due to vertical transmission by ascending contaminated amniotic fluid or during the general delivery from bacteria in the mother's lower genital track.

I mentioned in the questions group B Strep.

Group B strep and E.coli are the most common bacteria, the most common causes of both early and late onset sepsis.

Therefore the empiric antibiotic regimen would include agents active against these pathogens.

Some other less common pathogens include Enterobacter, Enterococcus, Klebsiella, Listeria, Haemophilus influenza, other enteric gram-negative bacilli, Staph aureus, viridans streptococci, so the combination of ampicillin and gentamycin provide empiric coverage for these organisms until the culture results are available.

In our practice, where I'm working in Greece at the moment, we're using ampicillin and gentamicin for early onset sepsis.

If we consider central nervous system infection involvement, we add cefotaxime, a third generation cephalosporin.

In cases we believe that we are dealing with nosocomial infection, which is not the case here, we use meropenem as empiric treatment.

That's for early-onset sepsis.

For late onset sepsis with onset after seven days of life, we use ampicillin and gentamycin or ampicillin and an extended spectrum cephalosporin, like cefotaxime or ceftazidime.

Regarding now, the group B strep screening that I asked earlier during pregnancy.

There are different guidelines in different countries.

Um, regarding the United Kingdom where this baby was born, the Royal College of Obstetricians and Gynecologists doesn't recommend routine screening or testing for GBS colonization with pregnant women, because the clinical and cost effectiveness of this strategy remains unclear.

Uh, therefore I wouldn't expect that this mother was screened during pregnancy.

In Greece, where I'm working, although it's recommended by the national guidelines.

In practice, it is rarely performed by the gynecologist.

The national guidelines in Greece suggest that all pregnant women should be screened for grp B Strep by vaginal and rectal swab between 36 and 38 weeks of pregnancy.

And those found be colonized should receive intrapartum antibiotics in case of a normal vaginal delivery or a Cesarian section with rupture of membranes.

In the mother in our case, probably she wasn't screened but she was febrile in labor.

So I would expect that she was covered within the intrapartum antibiotics.

And the recommended antibiotic regime is ampicillin or penicillin.

This patient has several key features that are consistent with listeria infection.

In an immunocompetent host, injection of food contaminated with Listeria, that's why I asked about unpasteurized milk or cheese, or raw meat.

Typically results in a symptomatic infection or mild febrile gastroenteritis.

However, this mother is at increased risk for, for invasive Listeria infection because she's pregnant.

Moreover, we know that the risk of symptomatic Listeria infection increases over the course of pregnancy, which makes such an infection quite likely in the end of pregnancy like in this case.

Listeria infection in general is usually mild in pregnancy . More or less approximately two thirds of pregnant women with Listeria infection have symptoms.

The most common of these symptoms are fever, influenza like illness, uh, some abdominal pain, headache and vomiting or diarrhea as in our case.

Apart from the bacterial p athogens, we should also consider common nonbacterial agents associated with neonatal sepsis.

These pathogens include herpes simplex virus (HSV), Enterovirus, Parechovirus, or Candida.

I understand that this baby was empirically started on acyclovir for possible HSV infection.

However, my thoughts are that the HSV infection rarely leads to diarrhea and would be unlikely to cause occur in the absence of a rash.

In generally in the absence of skin issues, the diagnosis of neonatal HSV is quite challenging.

In my practice in Greece, we don't usually cover early neonatal sepsis with acyclovir unless there is evidence suggestive of HSV infection, either from the clinical examination or from the history.

For example, when we're dealing with the neonatal sepsis-like syndrome and vesicular lesions or sepsis like syndrome born to mother with active genital HSV lesions or any history of HSV infection.

So these are my thoughts for now, Sarah.

Thank you so much.

That was an interesting overview and also nice to touch base on different practices that we see in different countries.

The next day you are called by our neonatal colleagues from the same hospital.

Uh, you spoke to yesterday with an update on the baby status.

Unfortunately, things have deteriorated.

Baby has been started on dopamine for hypotension, and is now intubated and ventilated.

A 15 minute generalized tonic clonic seizure occurred overnight requiring phenobarbital administration.

Mom's condition is stable.

She remains in the ICU with ongoing gastrointestinal symptoms and imaging findings consistent with frank colitis.

The baby's blood work demonstrates profound liver and kidney injury with an ALT 2,156 units per liter, deranged coagulation, INR of 2.9, requiring administration of FFP and vitamin K.

Creatinine is raised measuring 313 mmol/L.

The full blood count demonstrates an HB of 117 grams per liter and a platelet count of 14 requiring a platelet transfusion overnight.

Full blood count measures, white blood cell count measures 2.1 with an ANC of 1.3 and ALC of 0.7.

The CRP measures 15 milligrams per liter.

The overnight junior doctor noted two small vesicular lesions on the left lower leg, which was swapped for CNS and HSV PCR.

A blood HSV PCR was also obtained.

An LP was deemed unsafe due to their coagulopathy.

In discussion with pharmacy, all medications were adjusted renal clearance.

This morning, the neonatal team were made aware that mum's HSV blood PCR and PCR for stool both returned positive.

She's also been started on acyclovir.

With this in mind, further exposure history was gathered.

The mother has no history of oral labial HSV, or genital herpes.

The father does get recurrent orolabial herpes.

And in fact has a noticeable ulcerating lesion on his upper lip when further history is obtained.

There is no history of genital herpes.

There is a history of orovaginal contact approximately four days prior to delivery, two days after which the father developed the painful ulcerating lesion on his lip.

Can you discuss the approach to management of neonatal HSV, and would you make any changes to the management at this point?

Interesting.

It's obvious now that we are dealing with a disseminated neonatal HSV infection, despite the fact that the initial history of maternal colitis was not suggestive of such an infection.

Herpes simplex should be considered, as mentioned before, as a causative agent in neonates with fever, especially within the first few days of life, a vesicular rash, or abnormal sense of findings.

We didn't have an LP, of course, in this case, especially in the presence of seizures.

Neonatal herpetic infections often are severe with high mortality and morbidity, even when antiviral therapies are administered.

The risk of transmission of HSV to the neonate remain significantly higher with primary maternal infectious acquired closer to the time of delivery, as it obviously happened in our case, compared with recurrent infections.

The percentage, for example, is 50 to 60% with primary infections versus less than 3% for recurrent infection.

Of course, distinguishing between primary and recurrent HSV infections in women by history and the clinical examination, may be impossible.

Maternal type specific serology may be useful.

More than 75% of infants with HSV infection have been born to women with no history or clinical findings, suggestive of active HSV infection during pregnancy.

Regarding now treatment, intravenous acyclovir should be administered at the time of, the diagnosis of HSV is suspected.

It has been described the prompt administration improves outcome.

Of course, there is no place for oral acyclovir in neonatal treatment of acute HSV.

The dose of acyclovir of all forms of neonatal HSV is 60 mg/kg/d, intravenously, divided every eight hours.

The dose of acyclovir must be adjusted to neonates with renal impairment, as in the case of this baby.

The indications for acyclovir therapy include virologically proven HSV disease, clinically suspected HSV disease pending viral studies, asymptomatic but at risk due to exposure, uh, from some of those maternal active genital lesions.

The indications for empiric acyclovir are not standardized.

Uh, most of the experts agree empiric acyclovir is indicated for neonates with clinical features suggestive of HSV infection.

And these features include mucocutaneous vesicles, seizures, lethargy, respiratory distress, thrombocytopenia, coagulopathy, blood losing from intravascular catheter size, hypothermia, sepsis like illness, hepatomegaly, ascites, or even markedly elevated transaminases.

Many experts recommend empiric treatment for ill appearing neonates with fever or aseptic meningitis until results of HSV workup are known.

This is probably what they follow in the UK, where the baby was born.

That's why they started acyclovir from the very beginning.

However, uh, expert opinions differ regarding the relative benefits, risk, and cost-effective, effectiveness of empiric acyclovir before virological confirmation in other clinical situations, such as when we have a CSF pleiocytosis with, uh, a predominance of mononuclear cells in an otherwise well-appearing infant.

When we have persistent or recurrent erythema or crusting at the site of a scalp electrode, or when we have fever without localizing signs and the neonate is less than 21 days of age.

Now neonatal HSV is classified into three main categories for therapeutic and diagnostic considerations-- localized skin, eye and mouth disease; CNS with or without localized disease; and disseminated disease.

Approximately one out of four cases of neonatal HSV manifest as disseminated disease.

30% as CNS disease, and 45% manifest as skin, mouth and eye localized disease.

Of course, there is some overlap in these categories, for instance, approximately two thirds of the neonates with disseminated or CNS disease have skin lesions, but these lesions may not be present at the time of onset of symptoms as in the baby in our case.

The duration now of acyclovir therapy for neonatal infection depends upon the pattern of illness and response to therapy.

We treat localized disease with a minimum of 14 days if disseminated and CNS disease have been excluded.

And disseminated and CNS disease should be treated for a minimum of 21 days.

Because the presence of HSV DNA in the CSF is associated, of course, with poor outcome, lumbar puncture should be repeated near the end of the therapy to ensure that CSF HSV PCR is negative.

For those infants with persistently positive CSF HSV PCR despite 21 days of acyclovir therapy, antiviral treatment should be continued.

And HSV CSF PCR testing should be repeated weekly until negative.

Thus the baby in our case that was diagnosed with disseminated disease should receive at least 21 days of her IV acyclovir at the proper dose, as mentioned before.

And in this case we don't know if there is CNS involvement, as we didn't have an LP, but, uh, probably there is.

Even though this baby was stable enough, when we suspect HSV, we should have received a comprehensive laboratory evaluation for HSV before initiation of acyclovir therapy.

And this workup should include testing to detect HSV including surface HSV cultures or HSV PCR from the conjunctivae, eye, mouth, nasopharynx, and rectum.

This would also consist of HSV culture or HSV PCR of swabs, scraping some skin and mucous membrane lesions if present, in our case, we have.

CSF HSV PCR, of course, the baby was not safe enough to have one, uh, to have an LP.

Whole blood and plasma HSV PCR and a viral culture or HSV PCR of other specimens that would be available.

For example, tracheal aspirates.

They should also be testing to determine the degree of organ involvement and studies to exclude other diseases that may cause similar symptoms, so we need full blood count, including differential and platelet count.

We need liver transaminases, total and direct bilirubin, ammonia.

Uh, just to point out here that the ammonia should be performed to exclude liver disease and metabolic disease in neonates with elevated liver enzymes and fulminant sepsis.

Um, but it's not necessarily for all of neonates with suspected HSV.

We also need blood urea, creatinine, and urinalysis; CSF cell count and differential, CSF glucose and protein, eye examination, neuro imaging, EEG in neonates suspected to have CNS disease, and chest radiograph for neonates with respiratory distress and blood and CSF cultures, of course, to evaluate for bacterial sepsis.

So, Sarah, this is what I'm thinking at the moment for this baby.

Hm I totally hear all of that, and it's so interesting to think that, of course, the diagnosis is in the history.

Although we so infrequently ask about HSV in pregnancy histories and of the parents that we see until they're symptomatic.

In follow up with the local team two days afterwards, things again, seem to be going in the wrong direction.

The coagulopathy and thrombocytopenia are persistent requiring additional blood products.

The liver function has worsened with an INR 3.7 and the ALT continues to rise and is now 3098 units per liter.

The creatinine remains elevated 329 mmol/L, which is 3.72 mg/dL.

The babies respiratory status has also deteriorated requiring escalation to jet ventilation.

And as such, the decision has been made to transfer the baby to a higher level of NICU at your hospital.

In-house blood HSV PCR is positive at a high copies/ml value.

Six days into the baby's stay in your hospital while still on acyclovir, HSV PCR remains positive without any decline in the quantitative value.

As a result, foscarnet is added to the acyclovir treatment at renal adjusted doses.

Can you comment on dual therapy for persistent viremia , and any thoughts on the management?

Well, it seems that here we have an unusual scenario with a patient not responding to treatment despite being on IV acyclovir for six days.

And it seems like HSV PCR remains positive with no decline in the quantitative value.

My thoughts around this failure is first of all, we may have a potential underlying immune deficiency or possibly there's HSV resistance to acyclovir.

Regarding the immunodeficiency, there is a number of inborn errors associated with susceptibility to HSV such as a severe combined immune deficiency, GATA2 deficiency, DOCK8 deficiency, interleukin 12 receptor deficiency or IFN-gamma receptor deficiency and so on.

However, even in the case we have here, in immunodeficiency in a baby being so acutely unwell, um, we possibly couldn't go for immunological tests because they would be unreliable at this stage.

Regarding my thoughts on HSV resistance to acyclovir, neonatal HSV infections are assumed to result usually from susceptible virus, because it most often follow unappreciated, primary maternal infection, as in our case, or unappreciated reactivation in mothers with prior infection.

In either instance, the likelihood of transmitting acyclovir resistant HSV is very low.

In the first situation, unrecognized maternal infection would be anticipated and maternal HSV wouldn't be exposed to the selective pressure of acyclovir.

When it's due to reactivation, the frequency of resistant HSV is very, very low.

Obviously the mother in our case had no prior history of genital HSV or acyclovir treatment, despite that, uh, I would suggest HSV isolates should be studied for antiviral susceptibility by enzyme immunoassay measuring antigen reduction.

Then they could continue dual therapy with the acyclovir and foscarnet.

All very good points.

10 days into admission at the transferring hospital with further deterioration in ICU, the difficult decision was made by the parents and the medical team to take a comfort care approach, and the baby passed away in the parents' arms.

After 12 days of antiviral therapy, the blood PCR quantitative viral load remained unchanged.

Retrospective resistance testing did not reveal any acyclovir resistant mutations.

Are there any additional pearls about the case or clinical pearls regarding HSV in the neonatal period?

Unfortunately.

Neonatal HSV is a serious infection, as I mentioned earlier, with high morbidity and mortality.

Even in cases with prompt treatment with IV acyclovir as in this baby.

Uh, it has been noticed that the one year mortality rate for disseminated diseases is 29%, which means one out of three babies will die even if they get the proper treatment.

The risk of mortality is increased in infants with lethargy, severe hepatitis, acute liver failure, pneumonia, at the time of presentation, disseminated, vascular coagulopathy, prematurity, pneumonitis.

It is important to remember that HSV infection is lifelong, even with the appropriate therapy.

Even in those neonates that survive, recurrence of mucocutaneous lesions, eye disease, or even CNS disease may occur.

Following for entire treatment for all forms of neonatal HSV in that form and the doses that we mentioned earlier, we suggest suppressive therapy with oral acyclovir 300 milligram per meter squared per dose two times per day for six months.

Of course the dose should be adjusted each month to account for growth.

Uh, these recommendation I mentioned is based on a randomized clinical trial in which suppressive therapy reduced cutaneous recurrences and was associated with the improved neurological outcomes in infants with CNS disease.

Moreover if HSV eye disease is present, many experts suggest also pushing for up to one year, not just six months.

In case now of recurrences, uh, even when on suppression therapy, the ultimate optimal management of cutaneous recurrence is not established, however, uh, treatment doses of oral acyclovir, 10-20 mg/kg/dose two times per day for young infants, or 10 to 15 mg/kg/dose four to five times a day for older infants and children, may be administered early at the time of each recurrence to reduce discomfort and shedding associated with these lesions, or preemptively for a brief period for one or two weeks when a cutaneous recurrence is anticipated, which is quite usual at times of high stress or exposure to sunlight.

When patients have frequent cutaneous recurrences that are painful or cause disturbance in daily life, long term oral suppression may be of benefit.

These are my thoughts, Sarah, for this case, very interesting case, unfortunately, with not a very good course.

Yeah.

I think one thing that is interesting, we didn't really talk about it as much because our goal was to focus on baby, but it sounds like mom was quite ill and I think it's a good reminder that mothers can have really fulminant hepatitis from HSV in pregnancy and have pretty high morbidity and mortality.

So I think it was, this is really nice because we talked through baby, but also just taking a big picture step back, I think thinking about the mom who didn't necessarily have lesions, but clearly it was unwell is also a good, good thing to remember

Obviously her colitis was a bit misleading.

That's why it was more consistent with Listeria, something similar, and not HSV.

Well that does it for today.

Thank you so much to Sarah and Fani for joining us.

Thank you, Sara.

Thank you.

Thank you.

Thank you.

If you haven't already, please make sure to check out the other episodes from the rest of our Curious Congenital Conundrum series.

I'll just mention our quick usual disclaimer, that all presented patients on this podcast are inspired by patient experiences, but cases are constructed or significantly altered and de-identified for learning purposes.

If you haven't checked it out or are new to Febrile, please visit our website, febrilepodcast.com for more information, and to find the Consult Notes, which are written complements to the show with links to references as well as the library of ID infographics.

Thanks for listening.