Febrile Neonates: Can We Safely Skip the Lumbar Puncture? – PediaCast CME 121
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Show Notes
Description
Dr Brett Burstein and Dr Nathan Kuppermann visit the studio as we consider febrile neonates ≤28 days of age. Can we skip the lumbar puncture in low-risk babies? What constitutes low risk? And how can we employ shared decision-making with parents of these infants? Tune in for this important conversation!
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Topics
Febrile Neonates
Invasive Bacterial Infections
Bacterial Meningitis
Lumbar Puncture
PECARN Prediction Rule
Presenters
Dr Mike Patrick
PediaCast and PediaCast CME
Nationwide Children’s Hospital
Dr Brett Burstein
Associate Professor of Pediatrics
McGill University Health Center
Montreal Children’s Hospital
Dr Nathan Kuppermann
Professor and Chair of Pediatrics
George Washington University School of Medicine
Children’s National
Learning Objectives
At the end of this activity, participants should be able to:
- Describe the prevalence and clinical significance of invasive bacterial infections in febrile infants ≤28 days.
- Explain the components and diagnostic performance of the PECARN prediction rule.
- Analyze the benefits and limitations of risk stratification in neonatal fever management.
- Apply study findings to clinical decision-making regarding lumbar puncture, antibiotics, and hospitalization.
Links
Prediction of Bacteremia and Bacterial Meningitis Among Febrile Infants Aged 28 Days or Younger (JAMA)
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Episode Transcript
[Dr Mike Patrick]
This episode of PediaCast CME is brought to you by the Pediatric Emergency Care Applied Research Network and by Nationwide Children's Hospital.
[MUSIC]
[Dr Mike Patrick]
Hello everyone, and welcome to another episode of PediaCast CME. We are a pediatric podcast for healthcare providers.
This is Dr. Mike coming to you from the campus of Nationwide Children's Hospital. We're in Columbus, Ohio. It's episode 121.
We're calling this one, Febrile Neonates. Can we safely skip the lumbar puncture? Want to welcome all of you to the program.
We are so happy to have you with us again. You know, fever in the first month of life is one of the most challenging and high stakes workups in pediatric medicine. For decades, our approach has been intentionally cautious, full sepsis evaluations, lumbar punctures, antibiotics, and hospitalization for nearly every single infant.
But what if we could safely identify which babies are truly at low risk? And would it be safe to skip the lumbar puncture in these low-risk infants? Today, we are discussing a large international study evaluating the PCARN prediction rule for bacteremia and bacterial meningitis in febrile infants 28 days or younger and what it might mean for clinical care, shared decision making, and the future of clinical guidelines and pathways.
Of course, in our usual PediaCast CME fashion, we have two terrific guests joining us in the studio to discuss the topic. They are the lead author and senior author of this landmark study. Dr. Brett Burstein is an associate professor of pediatrics at McGill University Health Center and Montreal Children's Hospital. And Dr. Nathan Kuppermann is professor and chair of pediatrics at George Washington University School of Medicine and Children's National Hospital. Don't forget, after listening to this episode, you can claim free category one continuing medical education credit. Really easy to do.
Just head over to the show notes for this episode. That's at pediacastcme.org. You'll find a link to the post-test in the show notes.
Follow that link to Cloud CME, click on the materials tab, take and pass the post-test and the category one credit is yours. And we do offer credit to many pediatric professionals, including doctors, nurse practitioners, physician assistants, nurses, pharmacists, psychologists, social workers, and dentists. And since Nationwide Children's is jointly accredited by all of those professional organizations, it's likely we offer the credits you need to fulfill your state's continuing medical education requirements.
Of course, you want to be sure the content of this episode matches your scope of practice. Complete details are available at pediacastcme.org. Also want to remind you, the information presented in every episode of our podcast is for general educational purposes only.
We do not diagnose medical conditions or formulate treatment plans for specific individuals. Also, your use of this audio program is subject to the PediaCast CME Terms of Use Agreement, which you can find at pediacastcme.org.
So, let's take a quick break. We'll get our guests settled into the studio and then we will be back to talk about febrile neonates. Can we safely skip the lumbar puncture?
It's coming up right after this.
[MUSIC]
[Dr Mike Patrick]
Dr. Brett Burstein is a clinician scientist, associate professor of pediatrics and epidemiology and biostatistics at McGill University in the Montreal Children's Hospital. He is a national and international leader in febrile infant research and the first author of a research paper we will explore today, one that examines risk prediction in neonates with fever.
Dr. Nathan Kuppermann is executive vice president, chief academic officer and chair of pediatrics at Children's National Hospital and George Washington University. He is a true pioneer in pediatric emergency research and senior author of this important study. It's a study that promises to shape how we evaluate febrile infants less than or equal to 28 days of age.
Together, they are helping us rethink one of the most fundamental and cautious areas of pediatric care. Before we dive in, let's offer a warm PediaCast CME welcome to our guests, Dr. Brett Burstein and Dr. Nathan Kuppermann. Thank you both for stopping by the studio today.
[Dr Brett Burstein]
Thanks so much for having us, Mike.
[Dr Nathan Kuppermann]
Great to be here, Mike. Really looking forward to it.
[Dr Mike Patrick]
Yes, I am looking forward to this conversation again. This is a really, really important one, especially for those of us in emergency medicine that take care of kids. Brett, I want to start with you.
What exactly is the clinical problem that you were aiming to address in this particular study?
[Dr Brett Burstein]
So, Mike, as you know, newborns in the first months of life are at increased risk of invasive bacterial infections. That is, bacteremia and bacterial meningitis. And they are presenting to the emergency department frequently.
This is very, very common in pediatric health care. The problem is that most febrile infants in the first months of life have self-limited viral illnesses. But in the first month in particular, because of their immune immaturity, about 4% have the invasive bacterial infections we worry most about.
So, we call those IBIs. And what this study sought to do was to build on a risk prediction rule that was developed in 2019 by the PCARN group. And Nate will tell you some background about the genesis of that rule.
But this was a pooled analysis of international prospective cohorts to be able to determine the risk of bacterial meningitis and bacteremia among low-risk infants.
[Dr Mike Patrick]
All right. And then, Nathan, can you just briefly review the PCARN prediction rule and what exactly it is and what defines low risk?
[Dr Nathan Kuppermann]
Yeah, thanks, Mike. And yeah, I was the lead investigator of the PCARN febrile infant prediction rule. And we've had two iterations.
The first one was in 2019. It was a rule in which we enrolled 1,800 or so febrile infants younger than 60 days. We divided them into 900 patients to derive a rule, another 900 to validate it.
And it went all the way to age zero. So, zero to 60. And of course, we looked at a number of factors and the software that we used identified three important factors that if you don't have any of them, you have an extremely low risk of having a serious bacterial infection.
And those were, if you have a negative urinalysis, that's good. If your absolute neutral count was less than or equal to 4.09, and then if your procalcitonin was less than 1.71. Now we then validated and both the derivation validation worked quite well with very high sensitivity, and we did not miss any infant with bacterial meningitis. I just want to point out two important things before I pass it back to you, Mike, is that because those cutoffs were not easy to remember cutoffs, we then rounded those thresholds for ANC and procalcitonin just to the point where it didn't really mess with the test characteristics of the rule.
So, the rule we then looked at was an ANC of less than or equal to 4,000 and procalcitonin less than or equal to 0.5. And it just very minorly affected the rule. However, once you modify a rule, you then have to validate it again. So, we subsequently enrolled nearly 1,400 febrile infants, same thing, 0 to 60, now testing that rounded rule.
And the test characteristics were nearly identical and again, never missed bacterial meningitis. And the last thing I'll say, because it's an important part of the genesis of the current study that Brett and I did, was that even though the rule worked all the way to age zero without missing bacterial meningitis, there just weren't enough patients in that youngest cohort for us to feel really comfortable about pushing forward the PCOR rule for that first month of life. For the second month of life, there were, you know, three quarters of the patients and we pushed it hard.
So, we thought, God, you know, we would love to have more patients in that first month of life, but we stopped it there.
[Dr Mike Patrick]
Yeah. Yeah. So I want to just recap my understanding of this to just say it succinctly so that folks, this is just so important that this initial study and then the validation study, which had about 900 babies total from birth, zero days through 60 days of age, and as long, if they had a fever, of course we're talking rectal temperature of 100.4 degrees Fahrenheit or higher. If they had a negative or non-concerning urinalysis, they had a procalcitonin less than or equal to 0.5, and they had an absolute neutrophil count of less than or equal to 4,000, then you would classify them as low risk. And in that initial study, no baby who had those three criteria ended up having bacterial meningitis. That is exactly correct.
[Dr Nathan Kuppermann]
Okay.
[Dr Mike Patrick]
And then you wanted to be extra cautious in those less than or equal to 28 days because the standard of care really is to do a lumbar puncture in all of those babies. And so, then the question becomes, well, if we can validate it in that younger age group, then maybe we could forego doing a lumbar puncture in those babies. And I think, Brett, if you could take it from there, your study was really designed to show that this could be true.
[Dr Brett Burstein]
Yeah, Mike, that's a good synthesis of the evolution. So, after PCARN had derived this rule in 2019, they had built an external validation cohort, as you said, of these three predictors without using lumbar puncture, the urinalysis, procalcitonin equal to or less than 0.5, and absolute neutrophil count equal to or less than 4,000. So, in total, Nate was presenting data from the U.S. with 3,000 infants, zero to 60 days, that had never missed a case of bacterial meningitis. As Nate mentioned, there weren't a lot of them in the first month of life. But when we looked at that data and compared it to ours, but here in Montreal, Canada, we built one of the largest prospective cohorts of febrile infants. And the rule held up here too.
And ultimately, I like telling the story that this work really is the effort of so many investigators that have been in this space and investigating febrile infant management for so many years. So, I approached Nate and said, you know, listen, the only way we're going to solve this definitively is if we work together with our collaborators around the world. And so that's when we reached out to our collaborators from the PERUKI network across the U.K. and Ireland, data from 30 emergency departments there, from our collaborators in Spain and across Europe. And that's what this study is. So, we look to now validate the test characteristics of this updated rule for infants in the first month of life specifically and also focusing on ruling out invasive bacterial infections. So, bacteremia and bacterial meningitis.
And that's important distinction from the initial PCORN studies. When they were initially derived, they looked initially at with the inclusion of ruling out urinary tract infections. But the problem is these are so much more frequent.
They distort the rules. They may distort the rules ability to identify the infections we care the most about. So that was one difference.
This was our primary outcome, ruling out IBIs rather than IBIs and UTIs.
[Dr Mike Patrick]
Yeah. And this is, again, a very large number of babies involved. And it's a prospective study.
So, you're following them along. Just easy to do when you only have 28 days that we are looking at in terms of how all these kids are. But it did include folks from six different countries and really was the largest and most geographically diverse validation to date.
Now, as you mentioned, UTIs are way more common. Nate, can you just talk a little bit about the prevalence of these serious infections? So, bacteremia, bacterial meningitis, because we know that if you have something that's not very common, you need a lot larger numbers in order to really feel comfortable in your validation.
[Dr Nathan Kuppermann]
Right. Absolutely, Mike. So, if you look at the big prospective studies, and I do want to highlight something that Brett said.
It's super important. There are not—I wouldn't say plenty but are several other studies that look at febrile infants retrospectively. Brett and I, that's not the course that we have ever moved forward on.
The problem with retrospective studies in this arena, like others, you don't know how the baby looks. And this is not a rule to be applied to ill-appearing infants. We just use our clinical judgment, and they get the evaluation, and they get admitted.
So, I just want to make it clear, Mike, to the listeners that this was a study of non-ill-appearing. How do we know? Because they were prospectively collected, and their appearance was described.
So, I just want to make that point clear, because also it goes to the prevalence of invasive bacterial infections. If you look at the big cohorts of non-ill-appearing febrile infants, 0 to 60 days, their overall rate of UTIs, somewhere around 8 percent. Rate of bacteremia in the ballpark of 1 to 2 percent.
Bacterial meningitis, again, all comers, rules aside, just all comers, somewhere between 0.3 to 0.5 percent.
[Dr Mike Patrick]
Okay. So, these are really, you know, they're rare infections, but ones that can be devastating if we miss. And so, we've always had sort of, you know, wanted to be extra cautious with these babies.
So, Brett, then, in your study, how well did that PCARN rule work? What was the overall performance?
[Dr Brett Burstein]
Mike, thanks for asking. It's really an important question. And as you said, it's about not missing or being able to confidently rule out those infections.
And so historically, the reason the approach we've taken has been so cautious, and that is the recommendation you mentioned for lumbar punctures in all infants in the first month of life. So, if we have a rule that performs with very high negative predictive value, that we can safely say these infants are at very low risk of bacterial meningitis, it could obviate what is the most stressful aspect of care for these infants. So, we're looking for a rule that can safely rule out bacterial meningitis that has a good negative predictive value.
So, we did two analyses. Our primary analysis included the four international cohorts without the original PCARN derivation and validation cohorts. And that was because that could potentially introduce bias into the results.
So, our primary analysis focused on those four cohorts, whereas our secondary analysis now included the two original PCARN cohorts and additional 3,000 total infants, zero to 60 days. What that meant is that that allowed us now to have the most precise estimates available in history, really, on what is the prevalence of bacterial meningitis if you meet low-risk criteria. So, in the primary analysis, we found that the rule performed with very, very good sensitivity.
The rule sensitivity was 94.2, and the negative predictive value was 99.4% for ruling out all IBIs. But importantly, the rule missed no cases of bacterial meningitis. When we look at the secondary analysis now, including all of the infants, now this is a total number that is over 2,500 infants.
We know about 41% of them met low-risk criteria, and among all infants throughout the cohort, there were no cases of missed bacterial meningitis. So, the rule negative predictive value was 99.6% for all IBIs. Now, what we then did is an analysis that used those calculated pooled sensitivity and specificity to say, what then is the negative predictive value for bacterial meningitis specifically across the whole range of possible prevalences?
So, depending on where you work, what your clinical setting is, maybe you're in an area where you think that your risk of bacterial meningitis in that population might be a little higher, might be a little lower, we did an estimate across that whole range. And if we talk about the prevalence of bacterial meningitis in this study, that was 0.7%. At that prevalence, the negative predictive value was 99.96%, better actually even than that. So that is very, very low risk.
You'd have to perform probably in the vicinity of 2,000, 2,500 lumbar punctures. That's the estimate. And in fact, if you look at the confidence interval, you may need to perform infinity.
We don't even know for sure because there were none that were missed. So, our estimates have an upper limit of maybe you need to do infinity lumbar punctures to be able to safely rule out one single case of bacterial meningitis. Given the low rule estimates, right?
[Dr Nathan Kuppermann]
Giving low risk by the rule.
[Dr Mike Patrick]
So, your negative predictive value for bacterial meningitis, as long as the baby looks good, their urine looks good, their ANC is four or less, and their procalcitonin is 0.5 or less, then the negative predictive value was 99.9% for bacterial meningitis. That is just incredible, really. So, it has high sensitivity.
Its specificity is not as great, which is fine. That just means that you're going to have kids that you think, hey, this kid could have bacterial meningitis, and they don't, right?
[Dr Brett Burstein]
Well, we see that in the case of rules designed to rule out, right? So, when you design and derive a rule out rule, you really penalize specificity to be sure that you're being very, very careful and you preferentially are favoring high sensitivity. So that's the most important thing.
And then even the specificity depends a little bit on the pre-test probability and sort of the population. In the PCARN derivations, the specificity was a little higher. It was 60%.
In the international cohort, it's more around 50% taken together. It depends really what setting you're in. But yes, the point is that you're right.
If anything, we would tend to misclassify infants that are in fact low risk as being high-risk and end up erring on the side of caution.
[Dr Nathan Kuppermann]
Dr. David, I'd like to just add on to that because you and Brad both pointed this. Of course, I'm confident about all the data, but the data that I had oversight and control of, that's 3,000 of the patients in the secondary analysis. Those were the PCARN infants.
And in the PCARN-studied infants, I want to point out the specificity. Brad said it was closer to 60%. That's a really big difference than the 40% that report for the pooled study.
But the point is, whether it's 40% or 60% or somewhere in between, it means that about half of these infants in the first month of life who we normally routinely do lumbar punctures, we no longer really need to do it. And Brett and I both feel very strongly. We're not telling parents or physicians not to do it, but we feel ethically obliged to at least now we have a good grasp of what the risk is, given if you're low risk by PCARN, to share with parents so they can help make informed decisions.
And as Brett pointed out, the number needed to LP to pick up one case of bacterial meningitis, given that we didn't miss any out of 22 in this huge cohort, is what Brett mentioned, one in 2,000 or one in infinity. So that at least empowers both physicians and families with now really good, rigorous estimates.
[Dr Mike Patrick]
We have a lot of pediatricians who listen to this podcast, but we also have family practice doctors. We have emergency medicine physicians, nurse practitioners. I just wanted to go back to that, does the baby look well, just very quickly.
Nate, can you just describe what does a well-baby versus a sick baby look like so that we know who it's appropriate to apply these rules to?
[Dr Nathan Kuppermann]
Yeah, Mike, I'm so glad you raised that. It's funny, Brett and I just discussed this in the last two days. We were at the Pediatric Academic Society's meeting in Boston, where we were presenting this work.
And it's important to note that this is not a study of well, and the reason I couched that is that, you know, there are various scoring systems around the world to clinically document well or non-well appearance in febrile infants. In PCARM, we use the Yale Observation Score Scale. In Europe, they use the Pediatric Assessment Triangle and others.
So just to be clear, in the PCARM babies, that's 3,000 of this cohort of the secondary analysis. You know, the Yale score, a perfectly well baby is a score of six. That is like the perfect baby.
A normal appearing baby has a score of 10 or less. But to be quite honest, there were many babies in this group that were even higher than a score of 10 in the PCARM cohort. But our exclusion criteria in PCARM, and it highlights the exclusion, were a little bit different in the different cohorts.
For PCARM, you cannot be sick defined by needing pressers, intubated, you know, critically ill. But there was a wide variety of non-ill appearing. Not necessarily well, but non-ill.
And I'll let, you know, Brett can talk about some of how those scoring systems, how our colleagues in other countries use those.
[Dr Brett Burstein]
Dr. Brett Kenney What I would add is that it's a very important point that if a clinician feels an infant is not well-appearing or does not meet the non-ill appearance criteria, really to err on the side of caution. And that would be what we would tell people, particularly those that aren't as comfortable in assessing very young infants. We know that young infants are a challenging physical exam.
They don't have the social cues yet or social smile. It can be a challenge. So, I would say that no matter what, the study had slightly different criteria from within each cohort of how they defined it.
There are a variety of ways to do so, but for any clinician who's not comfortable, they should err on the side of caution. And this is not to say that there's no place for lumbar punctures among infants in the first month of life.
[Dr Nathan Kuppermann]
So, Mike, back to your original question, defining well, it's sort of like, I forget what Supreme Court's justice have said it. Hard to define it, but you sort of know when you see it, but we don't have control over clinicians' experience on how to identify it. So, to Brett's point, any concern, we would say stay conservative, LP, antibiotics, admit.
[Dr Mike Patrick]
Yeah, in general, this is going to be a baby who is, you know, alert. They're not irritable. They're feeding well.
Otherwise, you know, they're acting like a normal baby. But if there's any radar that goes off, then, you know, you should not classify them as low risk and proceed with this prediction rule.
[Dr Nathan Kuppermann]
And, Mike, as you and I have discussed in other of these podcast sessions, this is the reality of all prediction rules. Prediction rules, as I say, are not there to replace your judgment. They're there to empower your judgment.
It empowers it that you go in with prior probabilities that you know the risks are, you know, what they are based on the evidence. However, then there is your clinical judgment that you also have to, of course, pay close attention to. But we're empowering your judgment with good evidence.
[Dr Mike Patrick]
And then, Brett, can you describe how many infants then of the total were classified as low risk based on the prediction rule? Because if you, you know, if you're studying a rule and no one's meeting the requirements, you know, then your numbers aren't going to really be as valid. So, what did that look like in terms of the number of babies that were classified as low risk?
[Dr Brett Burstein]
So, in this study, 41 percent in the primary analysis and 43 percent in the secondary analysis met the criteria for low risk. And essentially, it equates roughly to what the specificity is. And as Nate mentioned, it depends a little bit on which cohort.
In the U.S. cohort, there was approximately 60 percent. In our Canadian cohort, it's about 50 percent. And in the European cohorts, it's a little closer to 40.
So overall, it's about 43 percent we saw in this study that could be classified as low risk. And what we know is that among all of the infants with invasive bacterial infections, those who met low risk criteria, there were a total in this study of five misclassified infants. The rule misclassified five.
So, we highlighted the fact that none of those five had bacterial meningitis, which means that all five had bacteremia. If you look in our paper, the details of the missed cases or delayed diagnoses are all there. And one of them had clinical characteristics that are more likely in keeping with a contaminant.
That was an infant with an E. coli UTI, and then they grew Staph aureus in the blood. So, we used strict criteria.
We called that a missed bacteremia, though probably it's a contaminant, which brings us to four in 2,500 infants that had a delayed diagnosis of bacteremia.
[Dr Mike Patrick]
And so that's something that is going to be important for clinicians. So, a blood culture should probably still be a part of the workup. We're just really, we can feel comfortable that we're not going to miss or it's very unlikely that we're going to miss a bacterial meningitis.
But there is still that tiny number of kids who kind of would look like low risk based on the initial PCARN rule who then did end up having bacteremia. And so, we really do want to get a blood culture on all these babies, so we don't miss any of them. Would you agree with that, Nate?
[Dr Nathan Kuppermann]
Yeah, and actually I'd add to that. Absolutely, Mike. And that is why, I mean, again, the purpose of this article was not to make recommendations.
It's to generate evidence to help clinicians. Having said that, you know, I would give my personal recommendation. I think Brett would agree.
In the younger than three weeks, we would, I mean, for all of these babies, as you're saying, Mike, we would certainly get blood cultures, the inflammatory markers. If they're low risk by those inflammatory markers, we would still admit them to the hospital. No LP, no antibiotics observed because there is the slight risk of bacteremia.
And with modern day bacteriologic techniques, the vast majority get picked up in the first 24 hours. So, they mostly would be in the hospital if they were to turn positive. And that is, we think that's pretty conservative.
We're going to admit them, no LP, watch them assuming they're negative by the rule. I will say, and this is actually an area for future research, and Brett and I talk about this a lot. You know, it's interesting.
When historically people started studying febrile infants, we talked about SBI, serious bacterial infection, which was UTI, bacteremia, bacterial meningitis. And then we narrowed it to IBI, bacteremia, bacterial meningitis. We thought UTI, separate animal, you screen the urine and you're good.
But in fact, the reality is all three of these infections are very different. The one that we really cannot miss is bacterial meningitis. That's a killer.
And you cannot miss that. However, it's interesting, you know, missing somebody with bacteremia who's well-appearing, who if their culture is positive, and if they had gone home, you would call them right back, whatnot. There is, we don't have good data about, is that really a super serious miss or not?
As long as you have the phone number, you get them back, whatnot. But for these data, first month of life, we recommend keeping them in the hospital, waiting cultural results.
[Dr Mike Patrick]
Now, Nate, what about the infectious disease folks? So, you know, we could, these kids are coming in through the ER. You know, maybe we'll say, hey, they're low risk.
They look good. They don't need an LP. And we admit them.
And then the ID folks are like, what are these crazy emergency department doctors doing? Has there been some collaboration with the ID folks?
[Dr Nathan Kuppermann]
Yeah, let me talk about it. And then Brett, I know, has his thoughts on this as well. So, first of all, you know, I was a coauthor on the AAP guidelines.
And that was like more than a decade of effort because for two reasons. First of all, the data keep on coming in and you never know when to stop. Okay, use the data that we have and write.
But they kept on coming in. But also, there were three main groups of pediatricians around the table. Pediatric emergency physicians like me, pediatric infectious disease folks, and general pediatricians.
And yes, in general, it's partly the spectrum bias, right? Pediatric infectious disease physicians, they round in the ICU as well and they see serious sepsis and general pediatricians really don't. And PZM, we kind of see a mix.
But there was good collaboration on the AAP group. And we came with that consensus that actually that went down to 22 days that babies, theoretically, could go home. I'll let Brett respond to the first three weeks of life.
All I know is colleagues that have commented. My ID colleagues where I work are very supportive. But I can't comment on the national buy-in on that.
Brett, you can talk about it, I guess, with your guidelines from Canada.
[Dr Brett Burstein]
Dr. Brett D'Alessandro Yeah. So, I led the authorship group for the Canadian Pediatric Society for the Management of Well-Appearing Febrile Infants for the first three months of life. And the American AAP guideline was published in 2021.
And around that time, Nathan was presenting the validation cohort from the PCARN group. And then, you know, combining that with our very large single center cohort, it was, you know, the day was pretty compelling with how well the rule performed. And in Canada, we have other pragmatic considerations as well.
So, as we put that guideline together, which came out in 2023, we were pretty compelled by the data. And we already proposed in that guideline recommendations that are a little different from what the AAP came out with. And so, while the AAP had moved the bar for this routine lumbar puncture down from 28 to 21 days, we really went further than that, actually.
And we said that all infants from zero to 60 days who meet low risk criteria by any validated rule. So, as long as you're using a rule, pick a rule and stick with it. But if infants meet low risk criteria, then even infants in the first month of life, those infants could be admitted, and as Nate mentioned, without lumbar puncture and no antibiotics for observation.
Now, I do want to stress the workup as a whole would still include a blood culture, a urinalysis and urine culture, inflammatory markers. And then we, you know, so our classic partial septic workup. And then from there, we make our decision making based on if they meet low risk criteria.
Now, one of the other aspects in this guideline is that for infants in this first month of life, we went right down to from the whole first month of life, zero to 28 days. And the AAP guideline did something really incredible. They had pooled all the data.
And there is clearly a decreasing risk as infant age increases. So, we know that first month of life definitely has a higher prevalence, a higher pre-test probability. But what this study does really for the first time in history, it really now looks at the post-test probability in a large international sample, allowing us to say, yes, it's true as the AAP said, we do know that they're high risk when they walk in the door, but it turns out that age probably doesn't add any value.
When you're using modern biomarkers like procalcitonin, probably also with CRP, what we see is that modern biomarkers give us more predictive value and it matters more than age. Age isn't really adding anything. So, they definitely are at higher risk upfront, but when we know they meet low risk criteria, that is why our Canadian guideline made this recommendation.
And as Nate knows, we're actually not first in North America to make that recommendation. In Utah, they have a catchment through the Children's Primary Network of 90% of all infants in Utah, of all children in Utah, and their guidelines, they're readily available online, it's from the Intermountain System, have been recommending for about a year as well in Utah that infants who meet low risk criteria right down to three days, actually, could be admitted. They call it their preferred option, admission without LP and without antibiotics for observation.
[Dr Nathan Kuppermann]
Can I just add one thing? Because this is important for the listeners, and Brett and I, boy, you know, we have thought about this like nobody's business. Echoing Brett's point, our decision on PCARN, it did not identify an age, Brett's did not either.
Clinicians ask me all the time, well, then, Nate, like, how low do we go? I mean, right? And we can't provide that exact answer because if you look at any little cohort, how many babies were there in the first three days of life?
I mean, of course, a very small number, right? So, this is where judgment comes in, right? So, the Utah guidelines, as Brett pointed out, goes down to age three.
I'm just going to tell you personally, if I see a one-day-old with fever that comes into the ED, guess what they're going? They're going right back upstairs, you know? I mean, because in my mind, it's likely the mother probably has bacteremia and the baby has bacteremia.
I mean, this is where clinical judgment overrules the rules, right? So, we don't have a perfect age cutoff, but we don't stress too much on age because the rules have never identified age as important.
[Dr Brett Burstein]
Nathan Levy I would just add, you know, and while I'm completely in agreement with Nate about using your clinical judgment, the truth is offering any specific age would be arbitrary, whether it's three, whether it's seven. We recognize it's arbitrary. I would love if a rule could, you know, clearly say this is the age at which to apply this rule, but actually, every time that there's a statistically derived model, the model doesn't seem to care about the age.
So, when the rule was derived for zero to 60 days, it's a high-performing rule across the full age spectrum.
[Dr Mike Patrick]
Brett Canterbury Yeah, and to your point, if you go up to 60 days, at 61 days, there's nothing magical that happens inside a baby's body, or at 29 days versus 28 days, and those sorts of things. It is going to be important, though, in terms of individual institutions. You know, more and more we have clinical pathways, and we're supposed to follow this.
At individual places, there's going to need to be champions for raising the question of is it time to change what the pathway looks like, because there is pressure on physicians to follow the pathway, you know, so that you feel sort of protected from liability, that you're doing things the way you're supposed to. But this is a big change, you know, as we think of those of us in pediatrics, like it is just, that is like one of the golden rules that babies less than or equal to 28 days are going to get the full workup, including a lumbar puncture, admission, antibiotics, all that, is so ingrained that I feel like it's going to be a little bit of a challenge to translate these findings into actual practice.
[Dr Nathan Kuppermann]
Dr. Michael McKeown Yeah, Mike, let me comment on that. You're absolutely right. And, you know, we're very aware of that.
However, what we, this, you know, you can go back to Catherine DeAngelis, the renowned, she was editor-in-chief of JAMA, pediatrician from Hopkins, who wrote some really sentinel articles about the harm that we do in admission of babies. In other words, this is from the 1980s in JAMA. What everyone has to realize is two important things, I think.
First of all, the LP is the most dreaded thing by parents. Parents put an extremely high value to not do the LP if it's not necessary. Of all these, and, you know, Brett has studied it, Paul Arison has studied it, we've studied it, it is the thing that parents most dread.
And like any procedure in medicine, there's nothing without a risk. And now what we're talking about, again, we are very respectful, back to home meningitis, but we're talking about if you're negative for the rule, the risk may be one in 2,000 or one in infinity. What's the risk of a complication from doing a lumbar puncture?
And we know there are complications. So, you know, it is one of those things about this is not de-implementing an ineffective thing. What happened is we progressed with our biomarkers.
We now have new biomarkers that are really good. So, it's a combination of, yes, I think we do need to de-implement, but it's because we have made tremendous advances in biomarkers and whatnot.
[Dr Mike Patrick]
One piece of the puzzle is the inflammatory markers that you were talking about.
[Dr Nathan Kuppermann]
It's procalcitonin. Procalcitonin has to be available, period. This study was of procalcitonin and absolute neutral count.
If you don't have the procalcitonin, and I'll let Brett talk about it. He has more expertise around the CRP, and we continue to study that. But this rule specifically was around the urine, the ANC, and procalcitonin.
That's where we have the most confidence because that's what we studied in this study. But Brett, why don't you talk a little bit about CRP?
[Dr Brett Burstein]
DR. BRETT PARKER Well, as you guys mentioned, the normative approach that we've taken, this full septic workup, admission, IV antibiotics. We've done this from work that was originally recommended going back as far as really the 1980s. So, at the time, all of those recommendations, and you've heard these names, of course, these are the Rochester, Boston, Philadelphia criteria, things like that.
They were dependent on using white blood cells. What we know is that the white blood cell is not an outstanding marker for IBI. And in fact, it is outperformed by procalcitonin in every head-to-head study, prospective or retrospective.
And so, it was really the development and increased availability of procalcitonin as a biomarker that we're referring to. And CRP, we know, certainly outperforms the white blood cell count, absolute neutrophil count in isolation as well. Exactly how to use CRP is less well-defined right now.
There just isn't a study of this size that yet can be as conclusive. But no, really what we're talking about is the availability of procalcitonin, which actually leads nicely to one of the important limitations of the study. Unfortunately, we recognize that procalcitonin is unfortunately not available to everyone who evaluates infants in the first month of life, and really, it should be.
That's sort of one of the issues. We know it is the best biomarker for this patient population. And so, that's one of the limitations we cite in the paper, and that is that without the availability of procalcitonin, that affects the generalizability of the study.
[Dr Mike Patrick]
So, if you don't have access to procalcitonin, you should not substitute another inflammatory marker like CRP or ESR or the procalcitonin in this rule?
[Dr Nathan Kuppermann]
Yeah. Can I answer that one, Mike? Based on our data, I would say follow our data.
However, I do want to point again to the Utah—and the people from Utah, I know they're writing a paper about their experience. In their rule—and your listeners can go right to the Primary Children's website. They have their febrile infant rule.
It goes all the way down to three days, as Brett mentioned. There, they do mention. They say to use PCT, but if not, to use the CRP.
I personally am not ready to do it just because I don't know their data, and it's a single site there. I'm very confident of the data that Brett and I have put together because, you know, what we've described—big, multicenter, lots of prospective studies. So, I personally think for this age range, it should be PCT-based.
Now, others might differ. And I know in Canada, they might differ. And in Utah, they say that you can substitute CRP for PCT.
I just personally don't know the outcomes of their data.
[Dr Brett Burstein]
Mike, what I would say about this—what we can say is that the AAP guideline, I think with good foresight in 2021, did make recommendations what to do when procalcitonin is not available. So, unfortunately, there wasn't really great data to guide it, and so these were expert consensus recommendations. The recommendations when procalcitonin are not available, they recommended using temperature as an inflammatory marker—that is, for infants to meet low-risk criteria, they'd have to be below 38.5, and they'd have to have a CRP below 20, and an absolute neutrophil count below 5,200. So, that was the recommendation they made back in 2021, what to do when procalcitonin is not available. The problem is that at the time, there was no study that had ever looked at those markers together or at those thresholds. So, we were the first to look at that back in 2022 to see how that performs.
And it probably is safe—at least in our single-center experience, it didn't miss any IBIs, and it had about a specificity, and that's really the problem. The specificity is also about 40%. But again, we're a single center.
We have approximately the same prevalence as what's reported in the U.S., a little bit lower. So, you really want to see that in a more generalizable setting. Those are the recommendations from the American Academy.
They're used widely throughout the U.S. because there's not procalcitonin everywhere, unfortunately, and we see that in the large multi-center work that's coming out of the U.S. So, there is a recommended approach. We just, as Nate said, just don't have the data to say it's exactly how robust it is, and we're working on that.
[Dr Nathan Kuppermann]
Yeah, to tantalize your listeners, Mike, I'm just going to echo the four words that Brett just said. Brett and I, we are working on that with a group of collaborators. So, you'll hear from us at some point in the future again.
[Dr Mike Patrick]
Very good. Very good. Brett, can you just talk a little bit about shared decision-making?
You know, that's really important that we educate our families, that we try to increase health literacy, we explain what we're doing in terms that they can understand. Is there any role for parents having a say in whether their child gets a lumbar puncture or not?
[Dr Brett Burstein]
I'm glad you brought this up, Mike. Shared decision-making is an area that I feel passionately about. I've done a lot of work now with my friend and collaborator who's also a part of this work, Paul Aronson, and we've worked together and interviewed.
We've done, you know, focus groups and countless, countless survey studies with families. We know that, as Nate mentioned, this is a very, very stressful evaluation for their newborn, and shared decision-making is emphasized both by the American Academy of Pediatrics Clinical Practice Guideline and our Canadian Pediatric Society Guideline as well. So, the idea is that parents and physicians will have different risk tolerance, and so we should be able to have a conversation with families and be able to give them the data, and so now we have more precise risk estimates, and that allows us to have shared decision-making.
You know, here in Canada, it's been since about 2023 that we've been having those kinds of conversations, and as I said, both guidelines emphasize that. I would say in practical terms, I've not yet ever once encountered a family that chose lumbar puncture. In part, though, that has a lot to do with the physician's risk tolerance and what they present, and as you mentioned, this is sort of, you know, dogma that's long ingrained.
So, I think it will take time, but as physicians become more comfortable making a more balanced recommendation that's evidence-based and data-driven, I think families can then more comfortably also bring their risk tolerance to the table. The reality is that I don't think any family would ever choose it, particularly when given the data and knowing how rare or how unlikely bacterial meningitis would be, and that a going one step at a time observation approach is really probably safe, but more than that, you know, we probably are avoiding so many harms, so many harms. Resource utilization, the harms associated with the rule-out sepsis evaluation is estimated anywhere from 5% to 20% of all infants that will have some kind of complication or, you know, an uninterpretable or impossible LP, repeat LP, you know, medication errors, near misses.
So, anything we can avoid, you know, and the more we are able to inform parents, the more that decision can, in fact, be shared.
[Dr Nathan Kuppermann]
Rick Habermas And, you know, and even though, of course, this is not our primary focus as we look at the patient and the family in front of us, I will say that I am a bit of a sustainability person as well. And the reality is the number of supplies that we use in, I mean, the thousands and thousands of febrile babies that we're doing this to, if we're not using the evidence, the amount of empirical antibiotics, what we're doing to the microbiome, what we're doing to antibiotic, antimicrobial susceptibility. Again, that's, we don't think about that when there's that one patient in front of us, but from a population and global health point of view, this is another contribution.
[Dr Mike Patrick]
Aaron Powell It seems like it may be important also to have some sort of surveillance that the rule is continuing to work because we know that microorganisms evolve and, you know, certainly could there be a strain of something that could cause bacterial meningitis that in the early days, you know, may meet those low risk factors. Does that make sense?
[Dr Nathan Kuppermann]
Michael O'Hanlon Yeah. Mike, let me comment on that. It's a very insightful observation because, you know, before current era, you know, I've been studying this age group for probably 15 or 20 years.
Before that, I studied the 3 to 24-month-old before the introduction of the conjugate pneumococcal vaccine. And as I like to point out to people, you know, people like to talk about occult bacteremia as this, just like we talk about there's something magical about 30 days, 60 days. There, you know, biology does not function the way that we would love it to in simple boxes.
So, for a child with occult, a one-year-old with occult pneumococcal bacteremia, their average white count response, 22,000. For a child with occult salmonella bacteremia, the average white count, 8,000. You can't lump them together, and it's hard to make a rule.
So, your point is an important one that we are going to have to remain vigilant to see what evolves.
[Dr Brett Burstein]
Dr. Griffin I might add two things. What's interesting is that's probably part of why we see differences or, and it's been published by several groups, let's call it poor test characteristics of some of the earlier used risk stratification strategies we talked about. So, Rochester, Boston, Philadelphia that were dependent on the white count, the infectious organisms seen today just don't generate quite the same white count response that some of those other more virulent and more then more prevalent bugs were causing.
So, you're right that over time it's always possible. The second thing I would also comment is that we already had that question and asked it. We wondered how biomarkers would respond even just in the post-COVID era.
And so, we tested the PCARN rule performance in febrile infants basically in the post or let's call it current COVID era. And we saw that it looks like these are still performing just as well as they did before. But this idea of it being a moving target is an excellent one.
And it's definitely true. You know, but the things we know today, we also know that they may not forever hold true.
[Dr Mike Patrick]
Dr. Michael McClendon Nate, I'm going to give you the last word. What should frontline providers, primary care docs, emergency room docs, how should this change the way that we think about things in practice?
[Dr Nathan Kuppermann]
Yeah, Mike, thanks for that. And this is what I would say to the frontline practitioner. First of all, really important, please follow the evidence because evidence is a great equalizer.
We've shown, by the way, in like the head injury rule, if you follow the head injury rule, the PCARN head injury rule, we've been able to mitigate tremendous disparities in CTUs while remaining high fidelity and high accuracy. For the febrile infant, the importance of these predictors is that it allows us to do the necessary tests on the necessary babies, but no more. And what we're talking about really is mitigating an invasive procedure, lumbar punctures, that parents really don't like, physicians don't like and is not a perfect test.
So, what I would say to the clinicians out there for that second month of life, now well tested, well replicated, validated, use the PCARN rule. If it's negative, no antibiotics, no LP, home with close follow-up. In that first month of life, now Brett and I have shown with really big numbers, you can do the same thing with the exception where we're more cautious because we realize there's some missed bacteremia, a little bit more fragile population.
But avoid the LP, just bring them into the hospital, overnight observation, no LP, no antibiotics, you're going to cause a lot of happiness to families while preserving safety of the infant who will be in the hospital.
[Dr Mike Patrick]
Yeah, really important points. Well, this has been a fantastic conversation. Thank you both so much for stopping by.
We are going to have a link to the article, Prediction of Bacteremia and Bacterial Meningitis Among Febrile Infants Aged 28 Days or Younger, that was published in JAMA. We'll have a link to that in the show notes over at PediaCastCME.org. So, folks can take a look at the research article for themselves.
And once again, Dr. Brett Burstein, Associate Professor of Pediatrics at McGill University Health Center and Montreal Children's Hospital. And Dr. Nathan Kuppermann, Professor and Chair of Pediatrics at George Washington University School of Medicine and Children's National Hospital. Thank you both so much for stopping by today.
[Dr Brett Burstein]
Thanks, Mike, for having us.
[Dr Nathan Kuppermann]
Great to chat with you as always, Mike. Thanks so much.
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[Dr Mike Patrick]
We are back with just enough time to say thanks once again to all of you for taking time out of your day and making PediaCast CME a part of it. We really do appreciate your support. Also, thanks again to our guests this week, Dr. Brett Burstein, Associate Professor of Pediatrics at McGill University Health Center and Montreal Children's Hospital. And Dr. Nathan Kuppermann, Professor and Chair of Pediatrics at George Washington University School of Medicine and Children's National Hospital. Don't forget, you can find us wherever podcasts are found. We're in the Apple Podcast app, Spotify, iHeartRadio, Amazon Music, Audible, YouTube, and most other podcast apps for iOS and Android.
Our landing site is PediaCastCME.org. You'll find our entire archive of past programs there, along with show notes for each of the episodes, our CME information, terms of use agreement, and our handy contact page if you would like to suggest a future topic for the program. Or if you just want to say hi, I love hearing from listeners through the contact page.
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Follow that link to Cloud CME, click on the Materials tab, take and pass the post-test, and the Category 1 credit is yours. Super easy, and we do offer, again, credit to many pediatric professionals, not only doctors, but also nurse practitioners, physician assistants, nurses, pharmacists, psychologists, social workers, and dentists. Of course, you want to be sure the content of this episode matches your scope of practice.
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A couple of other podcasts that I host, PediaCast. That's plain PediaCast without the CME. It's an evidence-based podcast for moms and dads. Lots of pediatricians and other medical providers also tune in as we cover pediatric news and we interview pediatric and parenting experts. Shows are available at the landing site for that program, PediaCast.org. Also available wherever podcasts are found. Simply search for PediaCast.
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It's called FAMEcast. So, if you are a teacher in academic medicine or a faculty member in any of the health sciences, then this is a podcast for you. And you can find FAMEcast at famecast.org and wherever podcasts are found by searching for FAMEcast. Thanks again for stopping by.
And until next time, this is Dr. Mike saying, stay informed, keep it evidence-based, and take care of those kids. So long, everybody.
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