Evaluation of Febrile Infants 61-90 Days of Age – PediaCast CME 118
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Description
Dr Nathan Kuppermann and Dr Paul Aronson visit the studio as we consider febrile infants between 61 and 90 days of age. This has traditionally been considered a “gray zone,” but new data informs an updated approach. We hope you can join us!
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Topic
Febrile Infants: 61-90 Days of Age
Presenters
Dr Mike Patrick
PediaCast and PediaCast CME
Nationwide Children’s Hospital
Dr Nathan Kuppermann
Pediatric Emergency Medicine
Children’s National Hospital
Dr Paul Aronson
Pediatric Emergency Medicine
Yale School of Medicine
Learning Objectives
At the end of this activity, participants should be able to:
- Describe the risk of invasive bacterial infections in febrile infants who are 61–90 days old.
- Compare risk-stratification strategies with and without blood testing in this age group.
- Interpret sensitivity and specificity data from PECARN-based clinical decision rules.
- Apply evidence-based risk-stratification to clinical decision-making for these febrile infants.
Links
Prediction Rule to Identify Febrile Infants 61–90 Days at Low Risk for Invasive Bacterial Infections (Pediatrics)
Risk of Bacterial Infections in Febrile Infants 61 to 90 Days Old With Respiratory Viruses (Pediatrics)
Managing a Febrile 61-90 Day-Old Infant: A Prediction Rule (PECARN)
A Clinical Prediction Rule to Identify Febrile Infants 60 Days and Younger at Low Risk for Serious Bacterial Infections (JAMA Pediatrics)
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 Nationwide Children's Hospital.
[MUSIC]
[Dr Mike Patrick]
Hello, everyone, and welcome to another episode of PediaCast CME. We are a pediatric podcast for health care providers.
This is Dr. Mike coming to you from the campus of Nationwide Children's Hospital. We're in Columbus, Ohio. It's episode 118.
We're calling this one Evaluation of Febrile Infants 61 to 90 Days of Age. I want to welcome all of you to the program. We are so happy to have you with us.
You know, historically, there have been many studies evaluating the workup and management of infants with fever who are less than or equal to 28 days of age. Fewer studies have looked into febrile infants during the second month of life, but there have been virtually no studies examining infants with fever during the third month of life, so 61 to 90 days of age, well, until now. This is an important consideration because the risk of invasive bacterial infections does not magically decrease at 60 days of age.
And because there have been few studies of these older babies with fever, we have traditionally considered fevers during the third month as sort of a gray zone where provider experience, the clinical scenario, you know, does the kid look sick or not sick? Those sorts of things have prevailed because of a lack of evidence and recommendations. Now, in most cases, this has worked out okay.
However, not in every case. About 2% of these babies do have invasive bacterial infections when they have a fever. Again, we're talking 60 to 90 days of age.
So, they may have bacteremia, they may have meningitis, but again, it's 2%. And we risk missing those kids without an evidence-based plan in place. Today, we are chatting with a couple of researchers who have taken a close look at febrile babies during their third month of life and published their findings in the journal Pediatrics.
Their article is called Prediction Rule to Identify Febrile Infants 61 to 90 Days at Low Risk for Invasive Bacterial Infection. Our guests today are the lead author and the senior author of this paper. We have Dr. Nathan Kuppermann. He is a pediatric emergency medicine physician at Children's National Hospital. And we have Dr. Paul Aronson. He is a pediatric emergency medicine doctor at Yale School of Medicine.
Before we get to them, let's run through a few quick housekeeping items. After listening to this episode, be sure to claim your free category one continuing medical education credit. Really easy to do.
Just head over to the show notes for this episode at pediacastcme.org. You'll find a link to the post-test in the show notes. Follow that link to CloudCME, click on the materials tab, take and pass the post-test, and the category one credit is yours.
And we do offer that credit to physicians, of course, but also nurse practitioners, physician assistants, nurses, pharmacists, psychologists, social workers, and dentists. And it's because 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 the episode matches your scope of practice. Complete details are available over at pediacastcme.org. Also want to remind you, the information presented in 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 Dr. Nathan Kuppermann and Dr. Paul Aronson settled into the studio. And then we will be back to talk about febrile infants between 61 and 90 days of age. It's coming up right after this.
[MUSIC}
[Dr Mike Patrick]
Dr. Nathan Kuppermann is a pediatric emergency medicine physician at Children's National Hospital in Washington, D.C., and a professor of pediatrics at the George Washington University School of Medicine and Health Sciences. He also serves as executive vice president and chief academic officer at Children's National and chair of pediatrics at George Washington University. Dr. Paul Aronson is also a pediatric emergency medicine physician and professor of pediatrics at the Yale School of Medicine, where he also serves as deputy director of the Yale Pediatric Residency Program. Both have a passion for supporting sick and injured children, including babies between two and three months of age who have fevers. That's what we're here to talk about, the evaluation and management of febrile infants between 61 and 90 days of age. Before we dive into our topic, let's offer a warm PediaCast CME welcome to our guests, Dr. Nathan Kuppermann and Dr. Paul Aronson. Thank you both for visiting with us today.
[Dr Nathan Kuppermann]
Hey, Mike, thanks for having us. Really happy to be here.
[Dr Paul Aronson]
Yeah, thanks so much. I'm thrilled to be a part of this.
[Dr Mike Patrick]
Yeah, we're really excited about it too, because this is such an important topic and one that often tends to have some gray zone area to it traditionally, but hopefully we are going to change that. So, Nate, why has the focus traditionally been on febrile infants less than 60 days of age? So, you know, that's always been kind of the focus on little babies who have fevers.
If you can just kind of explain what brought us to today and why we are now focusing on the 60-to-90-day age range.
[Dr Nathan Kuppermann]
Yeah, Mike, that's a really nice way to start. And I'm going to just give a very brief historical perspective to your listeners to do just what you asked to get us to this age range. So, you know, I've been in this business of evaluating young febrile children who look pretty well, but you don't know who has a, you know, a cult invasive disease lurking in there.
And the first 10 or 15 years of my career, it was all about the three-month to two-year-old, because in that age range, we had a cult pneumococcal bacteremia. And for me in particular, I was obsessed with the cult meningococcal bacteremia because the adverse outcomes could be so big. So, we studied lots of screening algorithms and how to approach that.
And then we have the wonderful advance of the introduction of the conjugate vaccines, you know, for pneumococcus and actually meningococcus as well. And the screening for that disease really became no longer cost-effective because of the power of these conjugate vaccines. So, then we all kind of turned our focus in the first two months of life.
And there have been generations of investigators before Paul and me, looking at this since the 80s, focused on the first two months of life and screening algorithms there. And we've made a lot of progress there because of new…not because of vaccines per se, given that it's the first two months of life, but because of new age biomarkers and whatnot. But a conundrum always existed in this gap.
This is the shoulder age that is a tad younger than the three-month to two-year group that we always studied. And the first two months of life, and the tricky thing is that they have pathogens from the first two months of life, but they also have pathogens from the older group of life. And as you will hear, we'll describe, each pathogen has its unique characteristic.
So, it's become…it was a challenge to study this group, and nobody really did this prospectively in a really robust fashion. And that's why Paul and I took on this topic.
[Dr Mike Patrick]
Yeah. Yeah. What do we know about the risk of invasive bacterial infections in this age group compared to the less than two months of age?
[Dr Paul Aronson]
In the first two months of age, prevalence of invasive bacterial infection, which we define as bacteremia and or bacterial meningitis, is somewhere around 2%. Kind of depends on the age. But in that second month of life, around 2%.
So, there hasn't been a lot of epidemiological studies in this third month of life isolating it. And so, there was a thought that the risk would be substantially lower. And there's nothing like, I remember being a resident and a child who's 60 days of age would come in at 11.59 p.m., and if we just waited one more minute until they turned 61 days, there would suddenly be zero risk for invasive bacterial infection. But what we know now is that the risk is actually lower, but not dissimilar. Meaning, you know, estimates say the risk is probably around at least 1% of these febrile infants in this third month of life, 61-to-90-day age group, will have an invasive bacterial infection. Predominantly bacteremia.
I think we know the risk of meningitis is probably even lower. So, meaning perhaps 0.1% or even lower. And then, you know, certainly there's still a substantial risk of urinary tract infection, but urinary tract infections will be identified vast majority by a positive urinalysis.
And so, we really wanted to focus on that invasive bacterial infection because the risk is not zero. I think it's sort of a misconception that the risk suddenly magically becomes 0% when they hit 61 days.
[Dr Mike Patrick]
Yeah. Yeah. Yeah.
I think, you know, it's really an important thing to consider because even though it's just 1%, like that 1% is someone's baby. And you know, it's the most important thing to them. And so from the medical side, it does become difficult because when you see 99% of these kids do absolutely fine, you know, you start to think, oh, I don't need to do any screening, especially if the kid's looking good and they're eating and, you know, they just have this fever.
So, I think it is important for physicians to think about, but for families as well. Can you describe, Paul, sort of how you approached this particular study in terms of the questions that you asked and why those questions matter?
[Dr Paul Aronson]
Yeah. So, our aim in this study was to derive and then internally validate a prediction rule specifically for invasive bacterial infection in these febrile infants aged 61 to 90 days. And as I mentioned before, we're focusing on invasive bacterial infection.
And I think, you know, Nate and many others have done some nice work over a number of years, really separating sort of UTIs, which are much more benign from invasive bacterial infections, which again, bacteremia and or meningitis. And so, to conduct that study, we felt that given that risk of maybe 1% at the most 2% risk of invasive bacterial infection, that we needed a large sample. And to do that prospectively would take years and years and years and millions and millions of dollars that I at least don't have.
And I think most of us don't. And so, we used the PCARN registry, which is a registry that includes 17 emergency departments at 10 health systems. And we looked at around a 12-year period from 2012 to April 2024.
And this registry is nice. It's sort of retrospective data on steroids in a way in the sense that there's data uploaded monthly on a continuous basis from all emergency department visits. And so, you really have access to not just laboratory values, vital signs, but actually charts.
And if you're able to use techniques like natural language processing, you can really get more data from this registry. And so that's what we sort of had the aim to derive this prediction rule using this very, very large data registry.
[Dr Mike Patrick]
And then what were your inclusion and exclusion criteria? How did you determine which infants that you could include?
[Dr Paul Aronson]
Yeah, so we sort of several inclusion criteria. So, one is we of course required fever, and we use the same temperature threshold that's used in the younger infants at 38 degrees Celsius or 100.4 degrees Fahrenheit. Now from the registry, it's easy to determine that from ED vital signs.
But with the expertise of Bob Grunmeier and the EMSC data coordinating center, they're able to use natural language processing to identify infants who had fever at home, but not in the emergency department to really sort of get the whole sort of cohort of febrile infants. We also require them, and this is really important, to have had a blood culture sent because a blood culture is required to, you know, evaluate for invasive bacterial infection and to have a urinalysis sent since an abnormal urinalysis or a positive urinalysis is a risk factor for invasive bacterial infection in younger febrile infants. And then we excluded infants similar to the sort of p-carbon prediction rule for infants in the first two months of life, excluded those with critical illness.
Those who were premature, we use a cutoff of 32 weeks so they could have a corrected gestational age of 40 weeks or more. Those with skin or soft tissue infections, significant pre-existing conditions, or those who were on antibiotics at the time of the visit, and then the rare child who died in the emergency department because you don't need a prediction rule to identify a child who's critically ill or who died. And I don't know if Nate sort of, Nate, you know, talk a little bit more about some of that sort of nuance there.
Dr. Nelson.
[Dr Nathan Kuppermann]
Let me, if I could just add one thing, Mike, to Paul's nice description there, the listeners might be thinking, well, did you require LPs because how can you tell if they have bacterial meningitis? Well, no, we actually didn't very, very mindfully and purposefully because first of all, performing a lumbar puncture in a febrile infant two to three months of age is not the standard of care. And we don't want to even imply that.
And frankly, as you'll hear, we're not implying that even getting blood tests is necessarily the standard of care. That's what the study sort of aimed to do, to try to help figure out who does need blood tests. But to determine whether a child had bacterial meningitis or missed bacterial meningitis, we certainly relied on the electronic medical record for identifying those in the ED.
But also, we had this registry where patients sort of returned to these hospitals and we counted on representation with worsening illness for the diagnosis of missed bacterial meningitis. Yeah.
[Dr Mike Patrick]
Yeah. So important. Tell me in terms of those particular tests, so the urine, the blood culture, and then of course the degree of their temperature, in your analysis, just using those things, were you able to sort of start to make a prediction that who's at higher risk before we add other tests to the group?
[Dr Paul Aronson]
Yeah. So, for our primary analysis, we included just under 5,000 infants with the aforementioned inclusion criteria. So, we didn't require blood tests for that inclusion.
And we use recursive partitioning analysis, which Nate has derived many prediction rules in various diseases and contexts using the same statistical technique. And so that rule identified urinalysis and height of temperature as the two predictors of invasive bacterial infection that were selected. So, meaning if a child had a negative urinalysis and a maximum temperature less than 39 degrees Celsius, that child was considered low risk by this sort of primary analysis prediction rule.
But when we say maximum temperature, what we included in that was either a temperature at home, a clinic, or the first recorded in the ED, since a clinician is going to make decisions based on that temperature, not necessarily the temperature the child had right before discharge or at the end of the visit. So that was our prediction rule. And I can talk about some of the performance characteristics in a moment if of interest.
[Dr Nathan Kuppermann]
Can I add, Paul, to that? Because I think this was an important component. It highlights the limitations, but also the power of the study.
When we did that initial search for the cohort, we were looking for febrile infants two to three months of age in this large PCARN data registry with millions of pediatric visits. Well, we identified 20,000 febrile infants, to be clear, in that age range meeting criteria. But only 5,000 of them had our requirements was a urinalysis and the blood culture.
Again, as Paul said, so we could document the outcome measure, right? So already, that's only 25%. So, we realized that even in this first analysis that Paul just nicely described, it's a subset.
And we're mindful of that when we discuss that in our discussion and limitations. But I can turn it back over to you, Mike and Paul, to talk about the next analysis.
[Dr Mike Patrick]
Yeah, yeah. Well, before we move on to the next one, I just wanted to point out that based on a negative urinalysis and that temperature of 102 degrees or higher, then the sensitivity that you found was about 86%. So, 14 out of 100 occult infections were missed because we weren't sensitive enough.
The specificity, we don't really care as much about that because if you accidentally call a kid that they have a bacterial infection and they don't, it's unlikely that you cause much harm. But at the same time, we don't want to put kids through more than they need to be put through and spend more money than we need to spend. So that sensitivity of 86% just really is, and when we're talking, you know, the risk is only 1% and then we're, you know, only catching 86% of that 1%, you know, those aren't great numbers.
So, we definitely want to add some more data points to really try to focus in on who's really at risk. So, take it from there, Paul, in terms of what your next steps were.
[Dr Paul Aronson]
Yeah, so I'll just add, and this is a really important point, and I will say in our sort of analysis, 2% of the included infants actually had invasive bacterial infection. And that actually relates to what Nate's point was about the requirement for blood culture in particular, that we definitely have a little bit of a sicker spectrum, meaning that if the overall, if you studied all febrile infants, all those 20,000, the risk of invasive bacterial infection might be closer to 1%. Ours was higher because we, these are infants who someone, a clinician, decided to do a blood culture on.
So, with that, you're right, it missed 14 out of our, misclassified 14 out of 100. Initially, the negative predictive value, as it often is, is 99.5% because so many of these febrile infants don't actually have an invasive bacterial infection. But I think the way we sort of view that is that one, if you're going to apply this rule without doing blood tests, just beware that it's going to miss, perhaps misclassify some infants with bacteremia.
There was one misclassified infant with meningitis. This is really important. Though that infant was, got a lumbar puncture and was hospitalized from the emergency department, which is very uncommon at this age group, indicating that trial may have been ill-appearing.
We're not able to, you know, exclude that. So, we sort of then said, well, what about if we then limited our cohort to the 1,200 infants who had both a procalcitonin and an absolute neutrophil count obtained? And that aligns with the PCARM prediction rule for febrile infants in the first two months of life, which is highly sensitive and specific, but incorporated into the AAP guideline.
And so, in that secondary analysis, again, using recursive partitioning, we had 27 infants with invasive bacterial infection. The prediction rule includes PCT or procalcitonin, PCT, less than or equal to 0.24, and then ANC, less than or equal to 10,710. So, meaning if you had values in those two sorts of areas, less than 0.24 and less than 10,700, the infant was considered low risk. This rule had a sensitivity of 100%. So, it didn't misclassify any of the 27 infants with invasive bacterial infection. The specificity was reasonably high for this type of prediction rule and sort of the mid-60s, around 65%.
The caveat being, as sort of Nate alluded to, is now we're gone from a sample of 20,000 down to 5,000 down to 1,200 who got both these tests. And so, this is a subset of the overall febrile infants in this age group who present. And Nate, I don't know if you wanted to add anything.
[Dr Nathan Kuppermann]
So yeah, that was kind of, Paul, that was a nice summary. But it's one other added point that, Mike, I think is really a key for the listeners because, you know, we're all taught about, you know, bacteremia, nonbacteremic, and clinicians tend to lump them all together. Oh, it's just bacteremia or not.
But in fact, different bacteria behave very differently. And that's important because the rule, the secondary rule that Paul described, which is really, you know, nice. I mean, it's perfectly sensitive.
You notice that the ANC threshold is 10,000. Well, the PCOR rule for the first two months of life, the threshold is only 4,000. And the procalcitonin values differ as well.
People ask us, well, why is that? Well, if you look at the pathogens of those two age groups, I need to point out something really important. In the younger age group, zero to two months, the most important bacterial pathogen, E.
coli, it does not give you a big white count ANC. And group B strep is the other one. In the older age group, the one that we started, you know, studying decades ago, the three months to 24-month-old, it's pneumococcus.
Pneumococcus elicits a super-high white count and super-high ANC. And what we found in this group is a blending of those two sorts of pathogens. So that higher ANC really reflects that we had a lot of pneumococci in there.
But I also would say, if people just forgot and they just applied the PCOR rule for that group, it would still be perfectly sensitive because it's even a lower threshold for ANC to call a patient positive, but the specificity would go down substantially, Mike, to what you were talking about. So, I just want to highlight that that's the likely reason why we see different thresholds of those biomarkers as positive. Just, you know, the original PCOR rule, the zero to two-month-old, that's now been validated in a lot of, you know, we just had a publication in JAMA about two months ago validating in the first month of life, which we knew already it worked.
Now we had big numbers. A negative PCOR rule is given your temperature, you know, to get in, you have to have 38 or higher, but fever was no longer part of that rule. It's just a negative urinalysis, an ANC of less than 4,000, and a procalcitonin of less than 1.5. If you're negative for all those, we don't ever miss bacterial meningitis, and, you know, we miss an occasional bacteremia. Interestingly, some of those bacteremias that we quote-unquote miss turned out to be things like staph aureus and repeat cultures are negative, and, you know, we call them miss bacteremias. We want to be conservative, but the rule might even be better than as publicized.
[Dr Mike Patrick]
And then adding the procalcitonin and then changing that ANC requirement to less than 10,000, how do you recommend that clinicians use that information in their management of kids in the ED?
[Dr Paul Aronson]
Yeah, so I think this is the million-dollar question in regard to this, because I think, as Nate, you know, pointed out, so many of these infants did not undergo blood culture and urinalysis to begin with. Now, the urinalysis piece is interesting. I think Nate and I are very aligned in this, is that, you know, the prevalence of urinary tract infections in this third month of life is at least around 5%, probably, and so we think that urinalysis in most of these infants is beneficial as screened for UTI.
But what we don't want this rule to be applied is to increase blood testing. And so, we feel that this rule is not, this procalcitonin-based rule in particular, is not intended to say every febrile infant in this age group should have a bit more, when the clinician makes a decision to obtain blood testing, which could be based on various factors. Certainly, risk tolerance plays into this, but I would say height of temperature.
I think, you know, thinking about height of temperature, a temperature of 39 and above probably has a higher risk, as we identify in the first rule of invasive bacterial infection. If the infant isn't the most well-appearing, for example, perhaps an infant who has no respiratory symptoms, we weren't able to assess respiratory viral testing as a predictor because of missing data that we know from prior work that we and others have done that the risk of invasive bacterial infection in the setting of a positive respiratory viral test is lower. So, we think if the clinician is obtaining blood testing, they should apply evidence.
And then, so to us, we would apply this rule in that setting. So, they've made the decision to obtain blood testing on various factors, and then we would suggest using these cutoffs and these lab tests, procalcitonin A and C. And I think also a piece, one of my favorite topics is shared decision-making.
I think it's a good opportunity there. We're talking about, as you already said, Mike, risks of about 1%, which can seem low. But when you're thinking about bacteremia or, of course, worst-case scenario, meningitis, I think it's also important, depending on the practice setting, to engage parents in that decision-making as well.
So, we think shared decision-making plays into this. But I'll see if, I think Nate and I are aligned with this, and Nate probably can extrapolate further.
[Dr Nathan Kuppermann]
Nate Kelly Yeah, no, no. And I'll comment, and Paul and I have been sort of mind-melding over this for many years, but I will tell you how it affects my practice directly in the ED, going a bit beyond what Paul said, is that one of the beautiful things about these two rules, for me, they're very intuitive, and they kind of validate what I would do anyway. That is, in that 2- to 3-month-old age range, I do not normally obtain blood tests.
I always do put a urine bag. Oh, my God, it's the simplest thing to do. Just get a bag, dip the urine.
If it's negative, you're done. I mean, it's so simple. So, I always get a urine, and, of course, the rule suggested to do that.
And when I decide to get blood tests in that, you know, month 2 to 3, they have to look not just not perfectly well, or I am swayed by the height of fever, because even though, you know, it's interesting, like I said, like in the PCARN rule, fever did not play a factor. Well, the reason why it doesn't play a factor is we got really great biomarkers, and they're better than fever. But if you're on a desert island with a febrile baby, and all you have is the height of fever, guess what?
It's an almost linear relationship with increasing height of fever, increasing risk of bacteremia. So, with that being said, if a child has a high fever or looks at me funny, I am going to get blood tests. And now I know the blood tests that I'm going to get will be, besides the blood culture, of course, is the ANC and PCT with the thresholds that Paul described.
[Dr Mike Patrick]
Yeah, yeah, yeah. A couple of things come to mind that I know weren't part of your study, but we have two experts on infant fevers, and I just wanted to ask real quickly, because these are things that are in the minds of physicians in the ED for sure, does whether a boy is circumcised or not circumcised play into this decision at all?
[Dr Paul Aronson]
So, this is, it's a great question, because I think that we, you know, I think we know that the prevalence of UTIs in the first two months of life is high enough, regardless of male, female circumcision status to obtain a UTI. The question is, at what age do you start applying sort of more the UTI guidelines, you know, which the American Academy of Pediatrics has sort of, you know, revising over time, and there's sort of different predictors, including being a circumcised male, or do you lump this age group, this third month life in with the first two months of life? I think from my practice, and I think probably for many, I lean more towards this as a febrile infant, meaning sort of regardless of circumcision status, I would sort of put them into that sort of similar UTI risk, maybe slightly lower, but still substantial enough at like 5% to do a urine, regardless of circumcision status.
I think certainly if there was hesitation, I think certainly an uncircumcised male, we know from a number of studies has a higher risk, but I think the younger you are, I think you really, I think even the circumcised male, while the risk is certainly lower, I think for many of us, at least for me, the testing threshold is still low enough that I would do the urine regardless of circumcision status.
[Dr Nathan Kuppermann]
And if I could, Mike, if I could just add one thing, and I also find this a really important point, you know, PCAR, and we've been studying febrile infants for, I mean, I think two decades now, and in very rigorous prospective measures, really important because prospectively, you assess the appearance, we give them an appearance score, all these things that are hard to do retrospectively, right? So, we've been doing this, you know, for a long time, and one of the studies we did is how sensitive is the urinalysis for picking up a UTI? And we looked at whether, you know, it was bagged or cath or whatever, and the truth is, first of all, the urinalysis is exquisitely sensitive, about 95%, and for bacteremic UTIs, it's about 100%.
And you know what? That's just a bag. So, to Paul's point, when I have a test that's very non-invasive, very low expense, I can pick up an important disease like a UTI, I use it.
So, I guess the point is, is that I do the same as Paul, first three months of age, regardless of circumcision status, I screen them, but I only screen them with the bag. Now, of course, if the bag is positive, then you can't, as we all know, you can't send that bag, specimen for culture, then you need a cath, you can confirm the UA and send the culture, but that's part of my decision-making there.
[Dr Mike Patrick]
What criteria do you use for your urine dipstick? Because, you know, a lot of them come back, oh, there's a trace of leukocyte estuaries, or there's a small or moderate, like, how, when do you get concerned?
[Dr Nathan Kuppermann]
Yeah, well, okay, so let me go after this. I'm like, okay, see, now we're getting deep into the weeds, right? Yeah, but these are important weeds.
It is totally important. And I have to tell you, so we looked at this in our PECORN article, but just for you and the listeners to know, to be PECORN positive on the urine side, it's basically anything, positive LE, positive nitrite, or five or more cells, okay? So, any of those were considered positive.
I would have to go back to the data to see how many of them are positive, just by, like, a dip of, you know, trace LE, and how sensitive was that for, or were there anybody with UTIs? I just can't answer that right now because I don't have the data in front of me. Yeah.
[Dr Mike Patrick]
And then what about if the child has upper respiratory infection symptoms? So, you know, they have congestion. Maybe there was someone in the house who recently had a runny nose and a fever.
Does that play into your decision-making?
[Dr Paul Aronson]
Yeah. And I think this is where I think you'll certainly see some variation amongst clinicians, because, you know, while your respiratory viral testing now, certainly in the sort of COVID-19 era, I would say, the post-pandemic period, you know, almost every ED or most have that rapidly available, you know, flu, COVID, RSV test, so you can get resulted in an hour or two. And we know from data that studies that we've done, a prior study we've done, and others that the risk of things like invasive bacterial infection is certainly lower, you know, significantly lower with a positive test.
The question, though, is the test also has expense to it, and there's a time component to it as well, and so is the test even necessary? If you look at, you know, I mentioned that the Spanish investigative group who did the step-by-step approach for febrile infants, in their studies, they don't even include infants who have, like, copious URI symptoms because they consider that a source. So, I would say, I think, to me, personally, I not uncommonly may do a viral test, though I think if everyone, if the kid clearly has a cold, everyone in the house has a cold, one could just argue, you know, this kid clearly has a virus, and so that is, regardless of a viral test, because the kid could have paraflu or metapneumovirus or a virus if you don't have rapidly available, that you don't even need to do the test. So, I would say to me, I do the test sometimes, depending on context and perhaps parent preferences, I still do a urine. I think the risk of a UTI is even the setting of a positive RSV test, for example, in this third month of life, is high enough that meets my threshold, but I, unless the child looks ill, I am highly unlikely to probably do blood testing in a child who clearly has multiple sick contacts, viral illness, but again, I will do a urine test, and that's at least my practice, and I think, you know, Nate and I have gone back and forth on the benefit of viral testing, and I think Nate, as I'll turn over to him, will point out that, you know, also, you don't even need to do the test if you know the child has a virus, but Nate, what are your thoughts?
[Dr Nathan Kuppermann]
Dr. Kahneman Yeah, you know, it's interesting, and actually, I think, Paul, both, you know, you and I in the PCARN setting have looked at this, and we actually have a manuscript almost ready to submit, so I won't give all the details, but the question really is, the fundamental one is, first of all, it's your, you go in with Bayesian thinking, your prior probability. If I see a smiling six-week-old, 38.1, and a runny nose, I'm just putting a bag on, and I'm going to leave that child alone, okay? Now, having said that, if you were going to compare head-to-head viral testing versus ProCal and ANC on which is better for ruling out bacteremia, you know what wins?
It's the blood testing. It always wins. So, I guess it really depends on your threshold and your level of suspicion, because if it's a little bit high, I'm going with the blood.
If it's low, I'm going with either no testing or, and by the way, just so you know, when I do the viral testing, I'm just doing the rapid, you know, COVID, RSV, influenza, no disrespect to fancy panel testing, but that's a lot of money, and I'm not doing that.
[Dr Mike Patrick]
Yeah, yeah. I think a lot of us would agree with that, and that's how we practice. I mean, those panels, you know, are several hundred dollars, close to a thousand bucks, you know, each, and that certainly, when you think about all these babies with fever, that's going to add up pretty quickly, and you're only going to, you know, again, we're talking one to two percent of these kids having the bacterial, at least a bacterial infection.
[Dr Paul Aronson]
And in full disclosure, my mom is a virologist who sort of runs the clinical lab testing here at Yale, and so we have plenty of conversations about the utility of viral testing. So, I have a, you know, not a financial disclosure, but I will say yes, in agreement to that the tests are expensive, and I think really send them if it's going to change your management. If it's not, then I think that if you're already going to sort of send the child home without blood testing, then it probably doesn't need the test.
[Dr Nathan Kuppermann]
Dave Oh, my God. And I'm going to reveal something on your show here, Mike, okay? I don't know, you can cut this out afterwards, but first of all, Paul, I never knew that about your mother.
And the other thing, Paul, you and I have never talked about, but I have a daughter who's mid-20s who's a budding Broadway singer-dancer. Paul has a brother who is a very well-known composer in Broadway. And you know what?
I've never talked about that either, Paul. I need to like; I want to pair them up at some point.
[Dr Mike Patrick]
Mike You guys need to connect on this. For sure. Let's boil all of this down for the listeners.
So, we have an infant who is between 60 and 90 days of age who comes in with a fever. You know, first we're going to get our clinical gestalt, you know, does this kid look sick, not sick? We're going to ask about upper respiratory, just we want to know that.
We want to know if they've been exposed to anything. But then you're saying the urine is going to be really important to do, and a bagged urine is fine as long as you understand you can't use that for the culture. So, if you do find evidence of a urinary tract infection on the bagged urine, you're going to need to cath them.
And that may be all that we need to do, but if we're still, you know, something, you know, we got that little voice in our head, you know, then the next steps are going to be the procalcitonin and the CBC and figure out what the ANC is.
[Dr Paul Aronson]
Paul Yep. And I think the thing I'll add, too, is I think the question comes up, because our specificity of this rule was around, you know, 65%, which is, you know, good for a prediction rule, but it means it will be, quote, false positives, you know, especially thinking about meningitis. So, we think about a child whose procalcitonin is above that 0.24 threshold or the ANC is above that 10,710 threshold, does that mean that child needs a lumbar puncture?
I think that's also where that sort of voice in your head goes. I think we would be in agreement, meningitis is very rare in this age group, 0.1% or lower. The child looks ill appearing, then, of course, that supersedes any blood test.
But I think the way I would sort of approach the abnormal blood test, I think if it's negative, you can feel pretty confident the child is low risk and can go home. But if it's positive, I think it doesn't, I think we also don't want to give the impression that it means do a lumbar puncture necessarily, but I think, think about the child's practice setting you in, follow-up ability, options include admitting off antibiotics. So, I think, again, we don't want to increase lumbar punctures either because they're pretty uncommon, but more that child may be at higher risk for bacteremia if their labs are abnormal.
I think, then, again, I think you have to make a decision at that point, which includes several options, but does not automatically mean fail the rule, so to speak, equals lumbar puncture.
[Dr Mike Patrick]
Yeah, but blood culture is going to be important and at least a dose of IV antibiotic with close follow-up the next day at a minimum if you're, you know, if those are positive, correct?
[Dr Nathan Kuppermann]
Yeah, let me, Paul, let me jump in. Paul and I, we agree on this and this would be my spinner, and I give it the historical comparison again with the PCARD rule for the first two months of life because in that rule, if you're positive for ANC or you're positive for ProCal, this is the first two months of life we recommend an LP because the risk of meningitis is higher as opposed to what we're talking about now, months two to three of life, and Paul described it nicely. I have a higher threshold because the teaching, and I'm a believer in this, is that in that age range, bacterial meningitis manifests clinically, you know, much more likely than in the first two months of life. So, if those thresholds are breached, that is the ANC or PC2, Mike, I do just what you said.
My personal practice would be blood culture, antibiotics, follow-up with their clinician, again, assuming they're well-appearing. I don't use the lab tests to decide about lumbar puncture in the third month of life. I use those just for the blood culture antibiotics.
To do the lumbar puncture, there has to be, for me, something more, looking not well, something else triggering, but to Paul's point, we're not suggesting that use those lab thresholds to decide on LP.
[Dr Mike Patrick]
And then, Paul, what are the next steps for research in this area?
[Dr Paul Aronson]
Yeah, so I think, and they and I have discussed this as well, we're actively talking about it, as long as, and I just want to give a shout out to our collaborators, especially Prashant Mahajan, as well as sort of the EDC team, as well, and Bob Grummeyer, who worked on the study, but the ideal always is a prospective external validation. This is a pretty narrow age group of one month, and to get enough numbers of invasive bacterial infections would take, you know, even, for example, we had 5,000 infants who got blood culture and urinalysis, and 100 had invasive bacterial infection. That was over 12 years and a number of EDs.
And so, I think we would, of course, need, you know, a large sum of money and prospective validation would be ideal, but very, very hard to do. Retrospective validation is a sort of possibility, but the question is, does that provide enough evidence? Even, you know, we suspect the rule will hopefully perform similarly, but it's, so I think, to be honest, right now, it's going to be some time before I think there's a prospective external validation of this.
I'm sure someone at some point will sort of retrospectively, you know, validate it, probably with not as large a sample size. And I think those studies help, but don't necessarily get people over the hump of prospective. So I think for now, I think this is probably the sort of best sort of evidence we'll have around this rule for at least the time being, sort of pending, you know, some further study, which would be great, but it'll be a number of years, at least, just for the logistics of having to be able to do that type of study.
[Dr Nathan Kuppermann]
And, you know, and I'd take that just one step further because I think for this age range, given what Paul said, and we're totally aligned with that, given that I think this is the best evidence that we have, and it'll be a multi-planet, multi-billion-dollar prospective study to validate, I actually think this is ready to implement in the course of implementing how to approach the febrile infant in the first three months of life. That is, I'm comfortable that we have enough data here.
It's not the best. It's not perfect. I mean, it's not perfect, but it's the best we have that I actually think it could be bundled into an implementation strategy for clinicians around the country.
And that's something that Paul and I are thinking about very closely, along with our colleague, Prashant Mahajan.
[Dr Mike Patrick]
This has been a fascinating conversation, and an important one, and an enlightening one. We are going to have lots of support in the show notes. We'll have links for you there.
So, if you head over to pdacastcme.org, look for the show notes for this particular episode, and you'll find the article that really describes this study. So, if you really want to dive deeper into it, you'll be able to do that. So, prediction rule to identify febrile infants 61 to 90 days at low risk for invasive bacterial infection, published in Pediatrics.
Also, risk of bacterial infections in febrile infants 61 to 90 days old with respiratory viruses. That was also published in Pediatrics. And then, of course, the PCARN rule, managing a febrile 61 to 90-day-old infant.
Prediction rule, we'll have links to all of those things. As we think about younger infants, again, that now less than two months of age, we're also going to have a link to JAMA Pediatrics, where we have a clinical prediction rule to identify febrile infants 60 days and younger at low risk for serious bacterial infection. And just as a preview for an episode that we have planned next month, we are going to talk more about febrile infants 28 days and younger on that episode, because there's also a new article out in JAMA, a prediction of bacteremia and bacterial meningitis among febrile infants aged 28 days or younger.
So, lots of resources and information for you to dive deeper in the show notes, again, over at pediacastcme.org. So, once again, Dr. Nathan Kuppermann and Dr. Paul Aronson, both pediatric emergency medicine physicians. Nathan's at Children's National Hospital and Paul's at Yale School of Medicine.
Thank you both so much for stopping by today.
[Dr Nathan Kuppermann]
Hey, thanks so much, Mike. Really been fun to chat with you and always fun to chat with my buddy, Paul.
[Dr Paul Aronson]
Yeah, thanks so much. It was great to be here with you. A lot of fun.
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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. Nathan Kuppermann with Children's National Hospital and Dr. Paul Aronson with the Yale School of Medicine. 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.
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So, you have listened to the podcast. Now be sure to claim your free category one continuing medical education credit. Really easy to do.
Just head over to the show notes for this episode 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 taken past the post-test, and the category one credit is yours.
It's all free, by the way. You will need to sign up for a Cloud CME account if you don't already have one, but again, that is completely free of charge. Super easy, right?
And again, we offer credit to physicians, but also nurse practitioners, physician assistants, nurses, pharmacists, psychologists, social workers, and dentists. You'll just want to be sure the content of this episode matches your scope of practice. And again, complete details are available over at pediacastcme.org.
A couple of other podcasts that I want to tell you about. We do have an evidence-based podcast for moms and dads called PediaCast. Lots of pediatricians and other medical providers also tune into that one as we cover pediatric news and interview pediatric and parenting experts.
Shows are available at the landing site for that program, pediacast.org. Also available wherever podcasts are found. Again, just search for PediaCast.
And then finally, I also host a faculty development podcast called FAMEcast. This one's from the Center for Faculty Advancement, Mentoring, and Engagement at The Ohio State University College of Medicine. 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 simply 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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