Transcription:
Late Onset Sepsis: Epidemiology and Pathogenesis

Host:  Hello everyone. And welcome back to another edition of Neonatal Review, Isolette to Crib. The purpose 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 this podcast. I am Dr. Julie Weiner, one of the Neonatologists and Medical Director for the NICU at Children's Mercy Hospital in Kansas City, Missouri. We are located here in the Heartland where we're known for our barbecue and fun fact, we are the birthplace of Harry S. Truman, the 33rd President of the United States.

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 joined again by Dr. Joti Sharma the other host for this podcast, who is the Fellowship Program Director here at Children's Mercy Hospital. Tell everyone hi, Dr. Sharma.

Jotishna Sharma, MD (Guest): Hello, everyone.

Host: She is joining us today to talk about late onset sepsis. As you remember, last time we discussed neonatal sepsis and how it's generally classified in early onset sepsis or EOSand late onset sepsis, LOS. Today, we will discuss the epidemiology and pathogenesis of late onset sepsis.

Now, again, in our previous podcast, neonatal sepsis, we discussed early onset and definitions of both early onset and late onset sepsis. Dr Sharma for the sake of our listeners, can you please review the definition of both again?

Dr. Sharma: Sure, Dr. Weiner. As we had discussed previously, the distinction between early onset sepsis and late onset sepsis with regards to the time was seven days. Now it is becoming more acceptable to distinguish the two with time at 72 hours of life, especially in preterm infants. Therefore late onset sepsis is defined by blood and or CSF culture proven infection occurring in the newborn after 72 hours of life. At the same time, we still need to note that some will still distinguish the two at seven days of life.

Host: So, as we get started, let's start with incidence. Can you comment on the incidence of late onset sepsis?

Dr. Sharma: Dr. Weiner, with regards to the incidence of late onset sepsis, it is difficult to ascertain the true overall incidence of culture proven late onset sepsis. This is because as we will discuss later, the incidence is very dependent on the degree of maturity, specifically with regards to both gestational age and birth weight. So, if you look at the larger studies with regards to late onset neonatal sepsis, there is a wide range of study populations. Some studies only look at late onset sepsis in the NICU, others only preterm infants and other studies only study the very low birth weight infant population. The NICHD study that was published in 2002, looked at the very low birth weight population. And in this population, 21% of infants greater than 72 hours of life developed late onset sepsis. There's a more recent publication in 2014, from Taiwan of 5,000 neonates that were admitted to their NICU. And in this population, the incidence of late onset sepsis was 14%. So, as you see, the incidence of late onset sepsis is dependent on the denominator population being studied.

Host: You mentioned the incidence varies based on the population being studied and most incidence of LOS are based on the NICU admission to discharge. Are there any information on incidence of late onset sepsis amongst the larger group of neonates? Because as you know, infants can present with late onset sepsis from home such as with regards to late onset GBS, or even some of the gram negative infections.

Dr. Sharma: Dr. Weiner, what you just said is true. Since as neonatologists, we mostly only deal with late onset sepsis in the NICU and the majority of these infants are preterm, that is what is usually our perspective of late onset sepsis. So, a study that was published in 2019 from Italy, sheds some light on the overall incidence of late onset sepsis. So, this study looked at all babies born in this particular region, and they looked at late onset sepsis from four days of life to 90 days of life. And in this population, the overall incidence of late onset sepsis was 2.3 per thousand live births. And actually a similar study was done in the US, but they looked at NICU admissions greater than 37 weeks from four days of life to 120 days of life. And in this population, the incidence of late onset sepsis was less than 1%.

Host: So, Dr. Sharma, can you talk more about the incidence of late onset sepsis in now the preterm population?

Dr. Sharma: So, in general, the rate of late onset sepsis is inversely related to the birth weight and gestational age. In other words, the more premature the infant, the higher the incidence of late onset sepsis, both with regards to gestational age and birth weight. The incidence of late onset sepsis is about 33% in infants born less than 28 weeks gestation, but the incidence can be as high as 40% in those infants born less than 25 weeks gestation.

Host: So, given what you just told us that the more premature the infant, the higher the risk of late onset sepsis; you would think this would mean that the LOS rates have increased over the years since we are providing NICU care to more and more preterm infants and smaller babies. Is this true?

Dr. Sharma: Dr Weiner, that is what we would expect. But interestingly, the NICHD study showed a decreased incidence of late onset sepsis over the period from 2004 to 2012 in the 24 to 28 weeks gestation patients. While we are providing care to more and more premature infants, I think at the same time, improved NICU practices for infection control, such as the CLABSI bundle and changes in clinical practice, such as decreased utilization of devices and taking them out earlier, as soon as it is not needed, and some other factors, which I will discuss later may contribute to this decrease in late onset sepsis trend, but again, more studies are needed.

Host: Let's shift and talk about how mortality is associated or effected by late onset sepsis.

Dr. Sharma: So, once again, with regards to mortality, it is just like the incidence. The mortality for late onset sepsis also depends on the patient population. The more premature the infant, the higher the mortality from late onset sepsis. In the very low birth weight infants, the mortality is about 18%. Going back to the Italian study, the overall mortality in this population, remember they looked at babies from four days to 90 days. The overall mortality in this population was about 7%. And in this population, neonates with hospital acquired late onset sepsis had a worse outcome. Hospital acquired late onset sepsis in this population accounted for 63% of the cases while those that were admitted from home accounted for 35% of cases.

Host: Are there risk factors for late onset sepsis?

Dr. Sharma: Yes. Just like early onset sepsis, both maternal and infant risk factors are associated with late onset sepsis.

Host: Can we first discuss maternal risk factors? I would think this would be pretty close or the same as the maternal risk factors we discussed for early onset sepsis. Is that true?

Dr. Sharma: Yes, Dr. Weiner, you are correct. We had talked about the maternal risk factors for early onset sepsis and they are no different. And with regards to the late onset sepsis during paturation or delivery the infant is colonized with the pathogen, which evolves later into infection. An example of this is the late onset GBS infection.

So, I'm just going to briefly kind of talk about the maternal risk factors, which we should all be aware of by now includes chorioamnionitis, intrapartum maternal temperature greater than 38 degrees Fahrenheit, delivery less than 37 weeks gestation, maternal GBS colonization, rupture membranes more than 18 hours. Of course, we have to think about the maternal immune response, dietary intake of contaminated foods by the mother and procedures during pregnancy. So, if you look at all these risk factors, these risk factors actually predisposed infants, mostly these infants are either term or late preterm infants to GBS, listeria, gram-negative infections, such as e. Coli. Some of these infants are actually readmitted from home with late onset sepsis.

Host: Now that we have discussed maternal risk factors. How about infant risk factors? Can you discuss infant risk factors that increase the risk of LOS? I would think these are more important risk factors for preterm infants and hospital infants versus from home.

Dr. Sharma: Dr. Weiner, as you will see most of the infant risk factors for late onset sepsis are related to hospitalized preterm infants. So, in general, the infant risk factors increase the risk of horizontal transmission. Sometimes, we call this health care related or nosocomial infections.

Host: What are some of the infant risk factors that predispose them to late onset sepsis?

Dr. Sharma: So, there are two main categories of infant risk factors. One is the immaturity of the premature neonatal immune system. As we know most of the IgG are transferred in utero in the third trimester. And since most of these babies are born prematurely, they lose out on this. Therefore this increases the risk of sepsis in infants. Apart from having the low IgG levels, preterm infants also actually have an immature accompliment system and there are opsonization functions also further decrease their natural immune response. The second factor is the disruption of barrier function of the skin and mucous membrane in premature infants. As we all know, the premature skin is still immature, thin and delicate, which is further compromised in these infants by multiple invasive procedures.

Host: You mentioned nosocomial or a healthcare related infections, this is an important risk factor for late onset sepsis, especially in our NICU population. Can you elaborate more on this specifically for our listeners with regards to healthcare related interventions that we do in the NICU?

Dr. Sharma: Yes. So, certain interventions done in the NICU do increase the risk of late onset sepsis. But again, at the same time, it is important to know that many of these are much needed interventions for survival of our sickest and smallest babies. We do have to place invasive devices and sometimes even perform procedures. These include central lines, such as PICC line, umbilical lines, intubation, feeding tubes, even peripheral intravenous lines. These not only further compromise the epithelial barrier, but they are needed for long-term use, which increases the risk of infection.

Host: Apart from central lines that increased the risk for LOS, are there any other factors?

Dr. Sharma: Yes, Dr. Weiner, apart from long-term use of IV catheters, other factors that increase the risk of late onset sepsis include mechanical ventilation. The risk of late onset sepsis is about 50% on patients who are still on the ventilator more than 28 days. The other one is failure of early enteral feeding. The longer the patient is NPO, the higher the risk of late onset sepsis. Prolonged duration of parenteral nutrition is also associated with increased risk of late onset sepsis.

So, in short, the longer these invasive devices and procedures are in place, the higher the risk of late onset sepsis. I do want to mention that there is some data that suggest histamine blocking agents, proton pump inhibitors, and lipid administration may also be risk factors for sepsis. In the end, we do realize the more premature the infant, the more likely the use of invasive devices, all of which increases the risk of infection in these babies.

Host: Now that we have talked about the incidence and risk factors for late onset sepsis in neonates, let's shift a little bit and discuss the causes of late onset sepsis in the neonate. Dr. Sharma, what can you tell us about the causative agents?

Dr. Sharma: So, when we look at the pathogens that are responsible for late onset sepsis, coagulase negative Staph is the most common pathogen that causes late onset sepsis. It accounts for about 35 to 78% of late onset sepsis globally. In the premature population, specifically in the very low birth weight infants, it is responsible for about 48% of cases of late onset sepsis.

Host: So, apart from the coag negative Staph, what are the other pathogens that cause late onset sepsis?

Dr. Sharma: So, the other pathogens that are responsible for late onset sepsis include the gram-positive bacteria of which staph Aureus is associated usually with vascular access catheters, giving rise to CLABSI, enterococcus, and of course GBS, which is not an uncommon cause of late onset sepsis. The other pathogens are the gram negative bacilli, which includes e. Coli, Klebsiella, enterobacter, pseudomonas and Serratia. And then fungi specifically Candida and parapsilosis are also responsible for a fair amount of late onset sepsis, especially in premature infants.

Host: Does the pathogen of LOS have any impact on the mortality and long-term outcomes?

Dr. Sharma: So, this is interesting. While coagulase negative Staph is the most common cause of late onset sepsis, it is the gram negative organisms and fungal late onset sepsis that is more likely to result in death. And this is likely related to the virulence of the pathogens, the gram-negative and fungi being more virulent than coagulase negative Staph. But while coagulase negative Staph, late onset infection has a lower rate of short-term complications and mortality, the long-term complications with regards to the neurodevelopmental outcome is not pathogen dependent in extremely low birth weight infants.

Host: So Dr. Sharma, as you mentioned, most of what we know about causative agents are in a NICU population, which happens to be mainly younger infants or preterm infants. Is there any information on causative agents with regards to kind of those late preterm or term infants?

Dr. Sharma: So, Dr. Weiner, for this, I would go back to study I had mentioned earlier from Italy, because again, this is the study that encompasses all infants and in this study, GBS and e. Coli are the prominent pathogens in infants that were admitted from home. And they considered this community acquired. This group of patients were either late preterm or term infants. The GBS and e. Coli in these patients is actually a reflection of colonization at birth and presenting with late onset sepsis, as opposed to hospital acquired, who remained in the NICU from birth. Interestingly, the leading cause of meningitis in this study was GBS.

Host: So, Dr. Sharma that has all been very great information. Can you give us a summary on the late onset sepsis epidemiology and pathogenesis?

Dr. Sharma: So, in summary, late onset sepsis is defined by blood and or CSF culture proven infection occurring in newborns greater than 72 hours of life. The overall incidence is around 2.3 per thousand live births. The incidence is strongly influenced by gestational age and birth weight. The lower the gestational age at birth, the higher the incidence of late onset sepsis.

The most common cause of late onset sepsis is coagulase negative Staph. The routes of transmission of the microorganisms include vertical transmission through maternal colonization during delivery and horizontal transmission. This includes nosocomial or hospital care related infections, secondary to invasive procedures and devices needed to provide medical care to the immunocompromised mainly preterm infants. Risk factors for healthcare-related late onset sepsis or nosocomial infection in the NICU include lower gestational age, lower birth weight, invasive devices and procedures, longer duration of central lines in place, prolonged parenteral nutrition, delayed enteral feedings, longer time to attain full enteral feeds and prolonged mechanical ventilation.

Host: Thank you for that summary. To conclude Dr. Sharma, did you bring any questions to test our listeners?

Dr. Sharma: Yes. I always come prepared with questions. So, today I have two questions and the first question is you are attending the delivery of a 24 weeks gestation infant with your resident. You are discussing the NICU morbidities likely encountered in this patient, including risk for late onset sepsis. So, the question is all of the following factors increase the risk of late onset sepsis in this patient, except. Choices are A. Intubation and mechanical ventilation for a month. B. Full parenteral nutrition for a month. C. Surfactant therapy. D. Patient being NPO for greater than three weeks. E. Having an umbilical venous catheter and umbilical arterial catheter in place for 10 days.

So, doctor, Weiner, what is the answer? Which of this following is not a risk factor.

Host: So, because I was paying attention to what you were talking about, the answer that is not a risk for late onset sepsis is surfactant therapy. Is that correct Dr. Sharma?

Dr. Sharma: Yes, you are correct. Surfactant therapy in studies has not shown to be a risk factor. I just want to point out if you look at it prolonged parenteral nutrition is not good for our babies and keeping our babies NPO for longer time is also not good. And that is why early enteral nutrition is always encouraged.

Host: Okay, let's move on to the second question.

Dr. Sharma: So, the second question is, the following are correct regarding late onset neonatal sepsis except. So again, all of them are correct regarding late onset sepsis, except. Choices are A. Initial neonatal colonization that evolves into later infection. Approximately one third of neonates less than 28 weeks gestation develop late onset sepsis. C. The most common cause of late onset sepsis is methicillin sensitive staph Aureous. D. The rate of late onset sepsis is inversely related to the birth weight and gestation age, and E. In extremely low birth weight infants gram-negative infections have higher mortality compared to coagulase negative Staph sepsis. So, which of these is not true?

Host: I'm going to say C, that the most common cause of late onset sepsis is MSSA. I remember you saying the most common cause is coag negative Staph.

Dr. Sharma: Yes, you are correct. It is not MSSA. All the others are true of late onset sepsis. And as you mentioned, the most common cause of late onset sepsis is actually coagulase negative Staph. I think that's all I have today.

Host: Thank you, Dr. Sharma. Hopefully this information will give you a better understanding of late onset sepsis, the epidemiology and pathogenesis. This is Neonatology Review. Isolette to Crib. I'm Dr. Julie Weiner. Thank you for listening and please join us on our next podcast where we will discuss the evaluation and treatment of late onset sepsis.