Joti Sharma, MD (Host): Hello everyone. And welcome back to another edition of Neonatology Review, Isolette to Crib. I'm Dr. Joti Sharma, and I will be your host for this episode. The purpose of this podcast is to review high yield common topics in neonatology. While our focus is geared towards perinatal and neonatal boards, anyone learning or studying neonatology will find this podcast useful. For this episode, our guest is Dr. Dianne Lee. Dr. Lee is a Neonatologist with us here at Children's Mercy Hospital in Kansas City. And her area of interest is the care of the extremely low birth weight infants. She is one of our Neonatologists on our small baby unit team. Good afternoon, Dr. Lee, how are you doing today and welcome.

Dianne Lee, DO, MBA (Guest): Hi, Dr. Sharma. I'm doing great. And thank you so much for inviting me. I'm super excited to be here today. I also wanted to say hi to all of our listeners.

Host: Great, Dr. Lee is joining us today to talk about neonatal listeriosis with a focus on the epidemiology, pathogenesis and management of neonatal listeria infection. Dr. Lee, let's talk about listeriosis in general, what exactly it is and why should we be concerned about it?

Dr. Lee: Yes, Dr. Sharma. So listeriosis is a foodborne illness that remains a major public health concern due to its ability to cause severe invasive disease with high case fatality. Because of these concerns, the CDC, in 2001 classified listeriosis as a mandatory reportable disease. However, listeria outbreaks from food transmission continues to occur.

Host: You mentioned listeriosis is a food-borne infection. So, are there specific foods that are more likely to have a listeria?

Dr. Lee: Yes, Dr. Sharma. The most common food sources for listeria are unpasteurized milk and soft cheeses, deli and ready to eat meats such as poultry. And it's also important to remember that it's not only cheeses and deli meats, but also contaminated fruits and vegetables can also be a source of listeria.

Host: I know we generally concentrate on soft cheeses and deli meat, but as you noted, it's important to remember that fruits and vegetables can be sources of listeria. Especially the pre-packaged ones. I guess all the more reason to have a backyard vegetable garden. Well I digressed on that, but back to our topic. So, let's talk about the incidence and epidemiology of listeriosis. What can you tell us about that?

Dr. Lee: Yes, so the actual incidence of listeriosis is unknown because mild cases may go undetected and unreported. It's very interesting, but in 1985, the largest epidemic occurred in North America, which affected mostly pregnant women and their newborns. And in this epidemic, the combined fetal and early neonatal mortality rate was 63%, which was a very specific. Having said that, the more recent data from the CDC, since the year 2000 shows a generally stable incidence of total listeria infections in the United States, which is about 0.24 cases per hundred thousand population.

Host: So, what I'm hearing is while there was a significant epidemic in 1985, mostly affecting women and newborns, the more recent data shows there has actually been a decrease in cases. What do you think is responsible for this decrease?

Dr. Lee: That is an excellent question. Two important factors that have played a role in the decrease in the incidence of listeriosis. The first one is regulation around food preparation and handling. So, the regulatory agencies have developed and enforced rigorous screening guidelines for listeria in processed foods and better detection, to identify contaminated foods. And secondly, public awareness of foods that have increased risk for contamination and especially avoidance of these in high risk populations such as pregnant women, have led to the decrease in listeriosis cases.

Host: Dr. Lee, before we move on, can you just talk about the mortality more specifically with regards to neonatal mortality of listeria infection?

Dr. Lee: Yes. The overall mortality rates range from 10 to 15% for non-pregnant individuals, but can go up to 20% for fetal and neonatal deaths.

Host: Thanks for providing a good summary of the incidence and the impact of listeriosis in general. Can you talk about the predisposing factors of listeriosis infection or the populations that are at high risk?

Dr. Lee: Of course Dr. Sharma. It does have a significant impact on our neonatal population. And that's why we are discussing it here in our neonatal board review podcast, right Dr. Sharma?

Host: Yes, you are correct actually.

Dr. Lee: So, predisposing condition for listeriosis infection, the first one, and the important one to remember is that pregnant women and their fetuses are particularly susceptible to listeria infection and pregnant women are actually 10 times more likely to be infected than other groups and not only are they more likely to be infected, they are also at increased risk for having more severe invasive listeria infection.

Other populations at risk for infection include neonates, those over the age of 65 years old. And also those with impaired immunity from underlying illnesses, such as malignancies, organ transplants, AIDS, or those on chronic suppressive medications, such as steroids.

Host: Dr. Lee, can we move on and talk about the microbiology and the pathogenesis of listeria infections? What can you tell us about that?

Dr. Lee: Yes Dr. Sharma. So listeriosis is caused by a bacteria called listeria monocytogenes, which is a gram-positive bacterial organism and microscopically it occurs either singularly or in short chains. And it is actually important to remember that listeria may resemble other bacteria, such as pneumococci which are diplococci, diptheroids such as corynebacterium or variable shape species such as the haemophilus species. Listeria itself is an intracellular bacteria and actually has a predelectation for placental and fetal tissue. But the mechanism is not well understood for that reason. Fetal infection, generally results from transplacental transmission following maternal infection and bacteremia and other more rare mechanisms of transmission include inhalation of infected amniotic fluid, and ascending infection from the maternal vaginal infection.

Host: Dr. Lee, what you just said about transmission is very important. Listeria predominantly is a transplacental infection. As compared to GBS, which is ascending infection, perinatally. This is an important point for board preparation because this question can appear in the board exam. Now let's move to discuss the clinical manifestations of listeria infection during pregnancy. What can you tell us about that?

Dr. Lee: So, it's very interesting, but most pregnant women with listeria infection, can be asymptomatic. Retrospective reports have shown that 65% of pregnant women had a nonspecific prodromal illness, such as with fever, malaise, myalgia, back pain, and occasionally some GI tract symptoms. Another important aspect to note is that pregnancy associated infections are at increased risk for spontaneous abortions, fetal death, preterm delivery, and neonatal illness or death.

Host: So for infants born with intrauterine listeria infection, how may they present in the newborn period?

Dr. Lee: Newborns with intrauterine listeriosis infection, often present with amnionitis with brown staining, amniotic fluid. This is very interesting, as it may be misinterpreted as meconium stained amniotic fluid, which is usually very rare to be seen in preterm deliveries and should be a red flag for an intrauterine infection, if seen.

Host: Dr. Lee, thank you for clarifying that because meconium stained amniotic fluid is rare before 34 weeks of gestation. So, you should think of infection if a preterm infant has amniotic fluid, that is suggestive of meconium. And the two infections that I usually like to think about are listeria, as you mentioned, and e Coli. Now let's move on from intrauterine infection to the clinical manifestations of neonatal listeria infection. Can you talk about the neonatal presentation?

Dr. Lee: So, neonates can present with either early onset or late onset disease. The initial symptoms and signs of neonatal listeriosis are actually indistinguishable from other bacterial infections, such as group B strep. Early onset disease occurs during the first seven days of life and is from transplacental transmission and commonly presents with preterm birth, pneumonia and sepsis.

Also, it's very interesting, but infected neonates with really severe disease can have a unique erythematous rash called granulomatosis infinti septicum, which appears as small pale papules that are histologically characterized as granulomas. And these granulomas can also be seen on internal organs of infants with multi-systemic involvement.

Host: Dr. Lee, it's interesting, you talked about the rash with listeria infection, actually for last week's Cahoot board review for our division, I had a question about listeria with gasper rash. So it's, something that is seen in newborn babies with listeria infection. Before we move to late onset infection due to listeria, do we know the outcome of newborns with early onset listeria infection?

Dr. Lee: Yes. Dr. Sharma the mortality rate is dependent on the degree of illness and can vary from 15 to 55% for early onset listeriosis.

Host: I think the key to early onset infection is to think about listeria as a cause of early neonatal sepsis and treat it empirically, which we will talk about soon. How about moving on to late onset sepsis and what you can tell us about late onset listeria infection?

Dr. Lee: So, late onset infections occur after seven days of age and are usually a result of vertical or environmental transmission. And the most common presentation of late onset infection is meningitis. Usually with an insidious onset and the mortality rate of late onset infection is about 25%.

Host: So we've talked about the clinical manifestation of listeria infection in the newborn. How about let's spend some time and talk about the evaluation. So, what are some of the important aspects of evaluation of a newborn with suspected listeria disease?

Dr. Lee: Like you mentioned earlier Dr. Sharma, any suspected bacterial infection in an ill-appearing neonate warrants a full sepsis workup because listeriosis can present like other common bacterial infections. The full sepsis workup includes a complete blood count, blood culture, cerebrospinal fluid analysis and culture and cultures of any other infected tissue.

Host: I just want to add here, especially for our listeners, we have covered, evaluation of early onset sepsis in the neonate in one of our earlier podcasts that you can listen to if you have not done so already. So we had a patient we thought had listeria infection, patient was evaluated and now let's move on to the management of a neonate with listeria infection. What can you talk about that?

Dr. Lee: So stabilizing a septic and ill-appearing infant is key in the management of these infants. The recommended empiric antibiotic therapy includes ampicillin and gentamycin due to a synergistic effect. It's also interesting but treatment failures have been reported with vancomyocin. And it is also important to remember that cephalosporins are not active against listeria monocytogenes. In addition to antibiotic therapy, supportive care, including ventilatory support, fluid, and electrolyte management, providing hemodynamic stabilization for septic shock may also be necessary for these ill-appearing infants with severe invasive infection.

Host: Dr. Lee, thank you for mentioning about vancomycin and cephalosporins. And they are used in early onset sepsis and how there may be treatment failures if patient has listeria infection. So similar to GBS and e Coli, empiric antibiotic choice is still ampicillin and gentamycin. So what is the length of treatment for listeria infection in the newborn?

Dr. Lee: So the treatment duration for uncomplicated bacteremia is 10 to 14 days. And for listeria monocytogenes meningitis, most experts recommend 14 to 21 days of treatment.

Host: Talking about listeria meningitis, do we repeat the spinal tap while on treatment?

Dr. Lee: Yes. So a repeat lumbar puncture is recommended one to two days after the start of antibiotic therapy to confirm sterilization of the cerebrospinal fluid.

Host: And is there any place for head imaging to assess for abscess or any other brain involvement with listeria meningitis infection?

Dr. Lee: Yes. That is a great question Dr. Sharma. So all neonates with listeriosis should have neuro imaging performed near the end of the anticipated treatment course to evaluate for parenchymal involvement and longer antibiotic courses are necessary for those patients with parencymal brain infection, such as those with brain abscesses or also those with endocarditis.

Host: Are there any other aspects in the management of listeria that you want to discuss?

Dr. Lee: Yes, so a few other important points for our listeners. Iron may enhance the pathogenicity of listeria monocytogenes therefore iron should be withheld while the infant is being treated with antibiotics. And lastly, don't forget that listeriosis is a nationally notifiable disease in the United States. Therefore cases should be reported promptly to the state or local health department to facilitate early recognition and control of common source outcome.

Host: Dr. Lee, thanks for mentioning iron. I have to say I was not aware of that. And I think it's important to remember that, especially if you have late onset listeria infection in our pre-term babies who may be on iron. So, it's important to remember that point. Thank you so much for that. Dr. Lee, you have discussed some very important aspects of listeria infection in the neonate. Can you please summarize the final key points that our listeners will find useful.

Dr. Lee: Some important key points to remember about listeriosis is that it is a foodborne illness that is classified by the CDC as a mandatory reportable disease due to its ability to cause severe invasive disease with high case fatality. Also, pregnant women and their fetuses are particularly susceptible to listeria infection and pregnancy associated infections can result in spontaneous abortions, fetal death, preterm delivery and severe neonatal or illness or death. And any neonate with suspected listeriosis, in fact, warrants a full sepsis workup, including obtaining blood cultures and a lumbar puncture to assess the cerebrospinal fluid for meningitis. And lastly, antibiotic treatment for neonatal listeriosis is a combination of both ampicillin and a aminoglycoside, such as gentamycin for synergy and treatment failures have been reported with vancomycin and cephalosporins are not active against the listeriosis. So, take home point is ampicillin and gentamycin.

Host: Dr. Lee, thank you so much for discussing all the important points of neonatal listeria infection. So, one of the things we like to do at the end of the episode is to have at least one or two questions. Did you come with any questions today?

Dr. Lee: Yes, Dr. Sharma, I have two questions prepared for you and for our listeners. So, the first question is a preterm infant is delivered at 31 weeks gestation after the mother presented in preterm labor, there was meconium stained amniotic fluid reported at delivery. On day of life three, the infant begins having multiple apnea episodes requiring intubation and becomes hypotensive requiring a vasoactive agent. You also notice a new diffuse erythematous rash. You initiate a sepsis workup, including sending a CBC, blood cultures and perform a lumbar puncture. Which anti-microbial agent or agents do you initiate? A. Acyclovir alone. B. Ampicillin and gentamycin. C. Ampicillin and ceftazidime. D. Vancomycin and gentamycin or E. Vancomycin and ceftazidime.

Host: Okay. I'll take a stab at this. You told us vancomycin and a cephalosporin that does not usually cover listeria. C,D, and E are out, A is acyclovir and acyclovir is an antiviral. So the answer is B ampicillin and gentamycin.

Dr. Lee: You are correct Dr. Sharma. And I really liked how you did a process of elimination. So, unique aspects of this case are one, it's a preterm infant delivered for preterm labor with meconium stained, amniotic fluid, which is rare. And it's an ill neonate on day of life three with an erythematous rash. And although many congenital infections may present like this, early onset listeriosis must remain on the differential and as you said, the empiric antibiotic therapy is ampicillin and gentamycin.

Host: Okay. What's your second question?

Dr. Lee: All right, so question two, you are caring for an ill neonate with congenital listeriosis infection. The mother reported being asymptomatic prior to delivery. Upon further questioning, she reports that she had many food cravings during pregnancy. You suspect the source of the infection likely came from which food. A. Honey flavored lemon tea, B. Fried rice, C. Sushi, D. Pasteurized ice cream or E. Tacos?

Host: Okay. Dr. Lee, I have to think about this because I don't usually eat any of these foods. So, you know, you talked about soft cheeses, so I think the answer is eat tacos.

Dr. Lee: Yes, Dr. Sharma. That is correct. So listeria outbreaks and food borne transmission, leading to human infections are commonly from unpasteurized milk and soft cheeses, which includes Mexican style cheeses on tacos, deli, and ready to eat meats, in addition to non-traditional sources, such as fruits and vegetables. For our listeners, the CDC provides recommendations for people at higher risk, such as pregnant women to prevent foodborne listeriosis infection.

Host: Dr. Lee, thank you so much. And to our listeners, thank you for listening. Hopefully we've provided you with a lot of information on perinatal and neonatal listeria infection. Our next two podcasts will focus on perinatal and neonatal CMV infection. Till then, this is Neonatology Review, Isolette to Crib.

And I'm your host, Dr. Joti Sharma signing off. Happy listening.