Transcription:
Early Onset Sepsis: Epidemiology and Pathogenesis

Dr. Julie Weiner:  Hello everyone, and welcome back to this edition of Neonatal Review, Isolette to Crib. The purpose again, of this podcast is to review high yield common topics in neonatology. While our focus is geared towards the perinatal neonatal boards, anyone learning or studying neonatology will find this podcast helpful.

I will be one of your hosts for today's podcast. Again, I'm Dr. Julie Weiner, one of the Neonatologists and current Medical Director for the NICU at Children's Mercy Hospital in Kansas City, Missouri. We're located here in the heartland where we have really good barbecue. So, welcome and thank you for joining us.

To help prepare for boards, we have a collection of neonatologists to help us along the way. All have either passed boards, been there, done that, or are currently studying for boards, same boat as you. Today, we are going to be joined again by Dr. Joti Sharma. She will be the other host for today's podcast. She is the current Fellowship Program Director here at Children's Mercy Hospital. Tell everybody hi, Dr. Sharma.

Dr. Joti Sharma: Hi, everyone.

Dr. Julie Weiner: She is joining us to talk about the epidemiology and pathogenesis of early onset neonatal sepsis. Okay. Dr. Sharma let's get started. But before we get to early onset sepsis, can we discuss some aspects of neonatal sepsis in general?

Dr. Joti Sharma: Sure, Dr. Weiner. So let's kind of talk a little bit about neonatal sepsis in general. So, as you know, neonatal sepsis is a systemic infection with isolation of a bacterial pathogen, namely a positive blood culture from the bloodstream in infants who are less than or equal to 28 days of life. Neonatal sepsis is actually an important cause of morbidity and mortality in newborns, especially in very low birth weight infants.

Dr. Julie Weiner: Can you comment on the incidence of neonatal sepsis?

Dr. Joti Sharma: So, the overall incidence of neonatal sepsis is about one to five cases per thousand live births in the US.

Dr. Julie Weiner: Can you shed some light on worldwide neonatal infection epidemiology?

Dr. Joti Sharma: Sure. So, it's important to realize that most global infections are from countries with limited both maternal and child health care, which accounts for about 98% of all neonatal deaths due to infections, globally. Worldwide neonatal sepsis, actually accounts for about a third of all neonatal deaths. The other third is accounted for by prematurity and the rest is birth asphyxia about 20% and congenital anomalies about 10%. So, Dr. Weiner, as you can see, 66% of neonatal deaths worldwide are either due to infection or prematurity. And if we can prevent these, things would be different. And I still do have some hope.

Dr. Julie Weiner: Thank you, Dr. Sharma. Okay. So, neonatal sepsis, as we know is classified generally, into either early onset sepsis or EOS or late onset sepsis, can you help us distinguish these two definitions?

Dr. Joti Sharma: Sure. So, this podcast focuses on early onset sepsis, which is defined by blood and or CSF culture proven infection occurring in newborns who are less than or equal to seven days of life. But there's another definition specifically for hospitalized premature infants, specifically the very low birth weight infants where early onset neonatal sepsis is defined as culture proven infection occurring at less than, or equal to 72 hours of age or up to three days of life.

Dr. Julie Weiner: So, why is there the difference in the definition for very low birth weight infants regarding EOS being only in the first three days of life?

Dr. Joti Sharma: So, the differentiation is due to two reasons. One is the risk for infection in very low birth weight infants after 72 hours of life is primarily derived from the specifics of ongoing neonatal intensive care rather than perinatal factors. And then the second reason is that organisms that cause infection in these babies after 72 hours of life, reflect the nosocomial flora of the NICU, more than dependently acquired maternal flora.

Dr. Julie Weiner: Since this podcast is focusing on EOS neonatal sepsis, can we discuss some of the epidemiology? So, let's start with incidence. Can you comment on the incidence of EOS?

Dr. Joti Sharma: Sure. And some of this information may actually appear on the board exam. So, the overall incidence of culture proven EOS in the US is about 0.7 to 1 per thousand live births. The incidence of EOS is strongly influenced by the gestation age at birth, with sepsis rates increasing with decreasing gestational age. For infants more than or equal to 37 weeks gestation, the incidence is only 0.5 per thousand live births.

Dr. Julie Weiner: How does the incidence compare in preterm infants?

Dr. Joti Sharma: Dr Weiner, so, when you compare the term infants to preterm infants, among preterm infants, namely less than 37 weeks gestation, the incidence of EOS is about seven times higher at about 3.7 per thousand live births.

Dr. Julie Weiner: Any comment on the incidence for very low birth weight infants?

Dr. Joti Sharma: If we only look at the very low birth weight infants, both the incidence and the mortality is higher   again, which is not unexpected. For example, if you look at babies who are less than a thousand grams, the incidence is about 26 per thousand live births. And those between a thousand to 1500 grams, it's about 8 per 1000 live births.

Dr. Julie Weiner: I think I heard you mentioned mortality. Can you discuss the mortality for early onset sepsis?

Dr. Joti Sharma: Sure, Dr. Weiner, before we talk about mortality, I do want to mention the case fatality of EOS. Basically the case fatality is the proportion of infants that die from EOS and the case fatality for EOS ranges from about 11 to 16%. Of this, more than 90% of the deaths actually occur in the preterm population. Moving to the overall mortality, the overall mortality from EOS has decreased significantly in term infants. And this is thought to be due to two reasons. One, improvement in the neonatal care and the implementation of intrapartum antibiotic prophylaxis for GBS over the last 30 years. Again, as expected, the mortality rates from EOS are higher in preterm infants. I do want to just mention that regarding EOS, the majority of patients typically present with symptoms during their birth hospitalization.

Dr. Julie Weiner: So, let's move on and talk a little bit about risk factors. Are there certain risk factors for EOS?

Dr. Joti Sharma: Yes. So, when we look at the risk factors for early onset neonatal sepsis, we can divide them into two broad categories; the maternal risk factors and the infant risk factors.

Dr. Julie Weiner: Okay. So, first let's discuss the maternal risk factors.

Dr. Joti Sharma: The material risk factors, which honestly, are more important ones includes chorioamnionitis, otherwise known as intrauterine infection. The risk of early onset sepsis in infants delivered to mothers with evidence of chorioamnionitis is about one to 4%.

Dr. Julie Weiner: So, I know we will discuss chorioamnionitis in more detail in a future podcast, but can you briefly discuss some of the risk factors for chorioamnionitis in the setting of EOS?

Dr. Joti Sharma: Certainly, Dr. Weiner. As you mentioned, we'll talk more about this in a future podcast, but some of the maternal factors that are associated with the development of chorioamnionitis include the longer length of labor and rupture of membranes, multiple digital vaginal examinations, placement of internal fetal, or interuterine monitoring devices and meconium stained amniotic fluid.

Dr. Julie Weiner: So, what are the other maternal risk factors for EOS?

Dr. Joti Sharma: The other important maternal risk factors for EOS include intrapartum maternal temperature of more than or equal to 38 degrees Celsius, delivery less than 37 weeks gestation. That is prematurity. Rupture of membranes for greater than or equal to 18 hours. This actually increases the risk of ascending infection by tenfold and lastly, maternal GBS colonization.

Dr. Julie Weiner: Okay, for our listeners out there. GBS is a very important cause of early onset sepsis, which we will discuss in full detail in a different podcast. Does maternal immune system have any effect on EOS?

Dr. Joti Sharma: So, a little bit on the maternal immune system. Yes, an adequate maternal immune system is very important and it is an important risk factor for EOS. One such example is that maternal serum IG antibodies against a specific capsular polysaccharide of GBS have been shown to be protective against infection with relevant GBS strain in their infants. So, mothers who had this particular IgG antibodies, their infants were protected from that strain of GBS infection.

Dr. Julie Weiner: Very interesting. So, what are the risks of early onset sepsis related to the listeria and how does this relate to maternal dietary habits?

Dr. Joti Sharma: Sure we can't discuss early onset sepsis without talking about listeria. So, dietary intake of contaminated food, such as refrigerated foods like deli meats and soft cheeses can result in listeria infection. The interesting thing is that the consumption can occur both before and during labor. The other important differentiation that we need to remember is that early onset listeria infection occurs through transplacental or hematogenous spread of the organism across the placenta. Therefore it is not an ascending infection. Again, this may be an important question on the boards.

Dr. Julie Weiner: Yes. I was just going to say, board alert that listeria is spread through the blood and not kind of transvaginal or exposure. So, that will likely be on the boards. Are there any other maternal risk factors that are important to be aware of?

Dr. Joti Sharma: Yes, Dr. Weiner, I do want to mention a more emerging risk factor. So, with the increase in in-utero fetal interventions procedures during pregnancy has become another maternal risk factor for infection. These invasive procedures increase the risk of intraamniotic infection, which can subsequently result in neonatal sepsis. Procedures, such as cervical cerclage, amniocentesis, amnio port or shunt insertion, basically anything that can disrupt the amniotic cavity, increases the risk of intrauterine infection and later, early onset sepsis in the newborn.

Dr. Julie Weiner: So, now that we've discussed maternal risk factors. Let's move on to the infant. So, are there infant risk factors that increase the risk of EOS?

Dr. Joti Sharma: So, with regards to infant risk factors, there are just three important ones that we need to remember. One is the colonization of the infant during the birthing process, leading to invasive infection soon after. The other especially in premature infants, resulting in destruction of the barrier function of skin and mucous membranes through the multiple invasive procedures that we perform on premature infants, such as intravenous access and intubation. And lastly, the immaturity of the premature neonatal immune system, specifically due to lack of transfer of maternal IgG levels to the infant. And this increases the risk of infection in preterm infants.

Dr. Julie Weiner: So, what can you tell us about causative agents, such as bacteria that causes EOS in neonates?

Dr. Joti Sharma: Thanks Dr. Weiner. As you know, there are thousands and thousands of bacteria and viruses out there, but the good thing is that they are only a few of those that you need to remember for early onset neonatal sepsis. And so, I'm just going to briefly kind of discuss some of them. The number one that you have to remember is group B streptococcus. It's the most common cause of early onset sepsis among the term population and it accounts for about 40% of early onset sepsis cases. Interestingly, the incidence of early onset GBS infection has decreased by 87%. In the 1990s, it was about 1.8 case per thousand live births and in 2013, it was down 2.24 case per thousand live births. So, as you can see, preventive strategies have definitely helped. And the preventive measure has been the intrauterine antibiotic prophylaxis.

The other bacteria that you need to remember is the gram negative enteric bacteria. And primarily it is e. Coli. This is the leading cause of early onset sepsis in preterm infants, accounting for more than 38% of early onset sepsis in preterm infants.

Dr. Julie Weiner: If I remember correctly, I think GBS and e. Coli is the most common cause of EOS.

Dr. Joti Sharma: You are correct. Dr. Weiner, GBS and e. Coli account for 70% of cases of early onset sepsis in the newborn.

Dr. Julie Weiner: So, I know the other organism that can cause EOS, we just mentioned, which is listeria, but what are the other bacteria that can cause EOS that we need to know for boards?

Dr. Joti Sharma: Some of the other bacteria that can cause EOS that you need to remember are other streptococci, enterococcus, staph Aureus, and coagulase negative staph.

Dr. Julie Weiner: Since we will cover GBS infection in a separate podcast, we can kind of move on and discuss e. Coli and how it relates to early onset sepsis. Does that sound all right, Dr. Sharma?

Dr. Joti Sharma: Yeah, sure. We will cover GBS in great detail later because it's an important topic on its own. With regards to e. Coli, it is the second most common cause of EOS in all neonates and it accounts for about 24% of all EOS episodes. It occurs in about 81% of cases of EOS in preterm infants. In very low birth weight infants, it's the single most common cause of EOS accounting for 33% of episodes in a large multicenter study. I just want to mention a little bit more about the e. Coli as the bacteria, because this may come as a question, as a multiple choice question on the boards. So, it's a facultative anaerobe. It's a gram negative rod. What is interesting is that as a facultative anaerobe, it can thrive both in aerobic and anaerobic conditions. It's found in the human intestinal tract, in the human vagina and the urinary tract. And there are hundreds of different antigenic types of e. Coli. The one that you need to remember is the K-1 type polysaccharide capsule, because it can sometimes complicates e. Coli meningitis. And it could come on the board exam.

Dr. Julie Weiner: So, can you comment on EOS incidence and how GBS prophylaxis has affected this?

Dr. Joti Sharma: So, Dr. Weiner, as I discussed earlier, the incidence of EOS has fallen with widespread implementation of the intrapartum antibiotic prophylaxis for the prevention of early onset GBS infection. As I mentioned again earlier, the national incidence has decreased by 87% in the last 30 years. But with the implementation of the intrapartum antibiotic prophylaxis against GBS, concern has been raised regarding increasing incidence of e. Coli specific early onset sepsis, and particularly ampicillin resistant early onset sepsis.

But again, they are conflicting results. But again, in this area, the message is still very conflicting. If you encounter a clinical situation where a critically ill infant has a likelihood, high likelihood of EOS, empiric antibiotic coverage for ampicillin resistant gram negative organism is warranted until blood culture results are known. I just want to mention that we will discuss more on this in the podcast on early onset sepsis treatment.

Dr. Julie Weiner: So, can you briefly, cover listeria since we had mentioned it a little bit earlier, we will again, cover the specific bacterias in a little bit more depth on a different podcast, but let's just briefly go through it now.

Dr. Joti Sharma: Sure. So, listeria is a gram-positive baccilus bacteria, most commonly infecting humans via the ingestion of contaminated food as I mentioned earlier. Again, the interesting thing about listeria is that it can survive in cold temperatures. So, that's why stored refrigerated food is not an uncommon contamination area. It's an intracellular pathogen. Therefore it targets mainly the monocyte macrophage system. It only accounts for about 5% of early onset sepsis in premature infants, and its overall incidence actually is very low. About two to 13 per a hundred thousand live births in the U S.

So, what is important to realize is that apart from causing infection in the newborn, listeria can cause severe illness in the pregnant mother and their fetuses. And as I mentioned earlier, it is transmitted transplacentally. So, the true incidence of listeria infection in pregnancy is difficult to determine because some cases likely go undiagnosed because they result in spontaneous abortions of the previable fetus.

Dr. Julie Weiner: Okay. So, how about other organisms that cause EOS?

Dr. Joti Sharma: The other organisms to be aware of that cause EOS include other gram negative organisms, such as Enterobacter species, Klebsiella, Escherichia. But these are less common causes of early onset sepsis, but more common causes of late onset sepsis, which we will discuss later. The other broad category is the anaerobic bacteria of which bacteroides fragilis is one that can cause neonatal early onset sepsis. The one group of organisms that I want to mentioned and which could be a potential board question is the Citrobacter species and Coronabacter sakazakii, which accounts for about 5% of bacterial sepsis in the very low birth weight infants, but it's important because it can cause meningitis. And with that can result in brain abscesses and subsequent significant neurological sequelae.

Dr. Julie Weiner: Now that we've talked about some bacterial causes, are fungal organisms important causes of EOS?

Dr. Joti Sharma: So, fungal sepsis is very uncommon as a cause for EOS. The one group is the candida infections that can occur in very low birth weight infants as early onset sepsis and is often associated with very prolonged antibiotic exposure to the pregnant mothers before delivery. When I say very prolonged, it is more than 24 hours of antibiotic exposure. So, it's usually in mothers who have preterm labor, who've been on antibiotics for a long time. Their infants are at risk of fungal early onset sepsis from candida.

Dr. Julie Weiner: So, what about staph Aureus and coag negative staph?

Dr. Joti Sharma: The good news is that both MSSA and MRSA remain rare causes of neonatal early onset sepsis. Again, a common cause of late onset sepsis, which we will discuss later. Interestingly in a study of about 5,000 pregnant women who had rectal vaginal screening cultures for GBS, the incidence of MRSA in the swabs was 3.5%, but there were no cases of MRSA neonatal early onset sepsis in their delivered infants. However, as I mentioned, early onset sepsis due to staph Aureus and coag negative staph is rare, but there are case series reports of congenital staph aureus infections where both blood and amniotic fluid cultures were positive. In these patients, the mothers usually had some antenatal invasive procedures, such as amniocentesis or amnio infusions about 24 hours prior to the onset of delivery and infection.

Dr. Julie Weiner: This information is helpful. Something to keep in mind, given the increased maternal fetal and in-utero procedures that we are starting to see. So, thank you, Dr. Sharma. So, as we kind of go through a summary for EOS epidemiology and pathogenesis, can you kind of summarize what we've just talked about?

Dr. Joti Sharma: Thank you, Dr. Weiner. Yes, I'm going to try to summarize early onset sepsis epidemiology and pathogenesis. So, early onset sepsis is defined by blood and or CSF culture proven infection occurring in infants, occurring in the newborn at less than or equal to seven days of age. For hospitalized premature infants, specifically very low birth weight infants, EOS is defined as culture proven infection occurring at or equal to less than 72 hours of age. The overall incidence of culture proven EOS in the US is about 0.7 to one per thousand live births. The incidence of EOS is strongly influenced by gestational age at birth. The lower the gestational age, the higher the risk of EOS. The most common cause of EOS are GBS and e. Coli.

Maternal risk factors for EOS include chorioamnionitis, maternal temperature, intrapartum temperature above 38 degrees Celsius, premature delivery, less than 37 weeks gestation, maternal GBS colonization, rupture of membranes more than or equal to 18 hours, adequacy of the maternal immune response, dietary intake of contaminated foods, procedures during pregnancy. Infant risk factors include colonization of the infant during the birthing process, disruption of barrier function of the skin and mucous membrane in premature infants and immaturity of the premature neonatal immune system.

Dr. Julie Weiner: Okay, Dr. Sharma, thank you so much for that summary. Let's move on and do a couple of questions just to test our knowledge and what we learned during this podcast.

Dr. Joti Sharma: Yes, I have two questions. And the first one is an infant is born at 25 weeks gestational - an infant is born at 25 weeks gestation after spontaneous preterm labor. A blood culture is obtained in the NICU soon after admission and it yields e. Coli. Which of the following is incorrect regarding EOS? A. E. Coli is the most common organism causing early onset sepsis in very low birth weight infants. B. Listeria early onset sepsis occurs via the hematogenous spread of the organism across the placenta. C. The incidence of EOS has increased with the widespread implementation of intrapartum antibiotic prophylaxis for the prevention of GBS disease and D. Citrobacter species EOS in very low birth weight infants can be a cause of brain abscess. So, which of these is incorrect?

Dr. Julie Weiner: So, if I remember back to what we discussed just a little bit ago, the answer is C. It is not a true statement. The incidence of EOS has not increased has actually decreased with widespread implementation of intrapartum antibiotics for prevention of GBS disease. Do you want to review that Dr. Sharma?

Dr. Joti Sharma: Sure. Yes. Dr. Weiner, you are correct. Statement C is incorrect. It has actually decreased as we mentioned, EOS has decreased with intrapartum prophylaxis. The other statements are all true.

Dr. Julie Weiner: Okay. Do we want to move on to the next question?

Dr. Joti Sharma: So, the next question is the spectrum of microorganisms causing EOS in the era of intrapartum antibiotic prophylaxis is different between term and preterm neonates. Of the following, the most common micro organism attributable to EOS in term neonates is A. The choice is group B streptococcus. B. E. Coli. C. Coagulase negative staph. D. Bacteroides fragilis. E. MRSA. What is the correct answer? So, the most common microorganism that causes early onset sepsis in term neonates.

Dr. Julie Weiner: I think the answer is A. Dr. Sharma, do you want to explain?

Dr. Joti Sharma: So, Dr. Weiner, you are correct. Group B Streptococcus, although the incidence has decreased, it remains the most common cause of early onset sepsis in term neonates.

Dr. Julie Weiner: Thank you, Dr. Sharma. Hopefully this information will give you a better understanding of early onset sepsis epidemiology and pathogenesis. Please join us next time when we will review the management and treatment for early onset sepsis. This is Neonatology Review, Isolette to Crib. I'm Dr. Julie Weiner, and thank you again for listening to this podcast.