September 10, 2021
Caregivers of young infants are instructed to bring babies to the hospital for a fever. Why? On this episode of Talking Pediatrics guest host Dr. Gabi Hester will speak with Dr. Robert Pantell, Professor Emeritus of Pediatrics at the University of California San Francisco and the lead author of the recently published “Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old” guideline from the American Academy of Pediatrics. This guideline has been in the works since 2004 and is chock full of new information about how to best evaluate young babies with fever. Some of the recommendations may surprise you!
Dr. Angela Kade Goepferd: This is Talking Pediatrics, a clinical podcast by Children’s Minnesota, where the complex is our every day. Each week we bring you intriguing stories and relevant pediatric healthcare information. As we partner with you in the care of your patients, our guests, data, ideas, and practical tips will surprise, challenge, and perhaps change how you care for the most amazing people on Earth, kids.
Welcome to Talking Pediatrics. I’m your host, Dr. Angela Kade Goepferd. We all know that we, for years, have recommended that parents and caregivers of young infants bring their babies to the hospital for a fever, but why, and where did those guidelines come from? On this episode of Talking Pediatrics, Dr. Gabi Hester speaks with Dr. Robert Pantell, professor emeritus of pediatrics at the University of California San Francisco, and the lead author of the recently published “Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old” from the American Academy of Pediatrics. This guideline has been in the works for years, and may surprise you with some of the new recommendations.
Speaker: Welcome to Guidelines with Gabi.
Dr. Gabi Hester: Learning how to appropriately manage an infant with fever is a key milestone for all pediatricians, and really everyone who takes care of children. When the last febrile infant guidelines were published in 1993, the world was a very different place. Bill Clinton was sworn in as 42nd president, Michael Jackson played the Superbowl halftime show, and I was earning $3 an hour in my first job as a babysitter. A lot has changed since then for the care of febrile infants as well. Shifts in epidemiology, food safety, new diagnostic tests, and additional studies to help with risk stratification have been published. Today I get to talk with Dr. Robert Pantell, professor emeritus of pediatrics at the University of California San Francisco, and the lead author of the recently published guideline “Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old” from the American Academy of Pediatrics. Thank you so much, Dr. Pantell, for joining me today.
Dr. Robert Pantell: You’re welcome.
Dr. Gabi Hester: Tell me a little bit about which patients you included in the guideline. Obviously you need to have fever, and if you could mention how is that defined, and what age groups are included in this guideline?
Dr. Robert Pantell: Well, we define fever pretty much like everyone has done since they started talking about fever, which is 38 Centigrade, which is 100.4 Fahrenheit. This also applies to children with temperatures taken at home. By temperature taken at home, we need a number. It can’t just be, “She felt really hot,” even from a very experienced parent. We need a number, and while rectal is always preferred, since COVID, everybody seems to have a digital, point-to-the-forehead thermometer. As long as we have a number, that child can, “enter the guideline.” We also decided not to deal with the first seven days for a variety of reasons. That’s kind of the perinatologist’s wheelhouse.
Also, the rate of infection is extraordinarily higher in that first seven-day age group. Remember, it took us 17 years ignoring that age group. We decided to go up to 60 days. Initially we went to 90, but we said, “90 is not very… The third month is not much different than the fourth, fifth, or sixth.” It’s really the first two months where all the action is, and where there’s a rapid decline in the prevalence of the bacteremia and bacterial meningitis. That’s how we decided to go 8 to 60. We also decided that if a child appeared ill, we don’t really want to deal with that group, a sick-appearing child, in this age group there’s high risks of bacteremia and meningitis, sick-appearing children could get the complete sepsis workup.
That’s also backed up by the fact that, when we did that PROS febrile infant study, the single best predictor, by all sorts of fancy statistical tests, were well-appearing versus ill-appearing. So let’s just toss out the ill-appearing, this is what do you do when you’ve got a four week old child. “Gee, the kid looks pretty good but the temperature’s 101. Now, what do I do?” That’s really the group we focused on. Also, we decided just to make it as clean as possible. If there were perinatal infections, if this was a premature infant, all of the things that you would suspect would place the child at higher risk, we decided to keep it out. That leaves basically full-term infants, no infectious complications in the perinatal period, no congenital anomalies, and don’t appear sick. Your basic well child with a fever.
Dr. Gabi Hester: I recently was able to attend a talk that you gave, and I really liked how you called out the idea of what is well-appearing versus ill-appearing. If you’re in a position where you can’t confidently say that the child is well-appearing, you probably should not be applying this guideline to that patient. I like how you guys didn’t go into detail on defining what is a sick patient versus a not sick patient. Really, the idea is that if you can’t reliably say this is a well-child, then this guideline shouldn’t apply. Am I interpreting that correctly?
Dr. Robert Pantell: Exactly. That’s a very, very important point because when we wrote this guideline, we knew it was not going to be read exclusively by pediatricians. That there would be adult emergency room doctors who were seeing a sick infant, as well as family physicians whose practice maybe had moved into the elderly population. If you’re confident, then you’re good. The other thing that came up is that there’s been some studies from the PECARN emergency department group where they felt that clinical appearance wasn’t that helpful. There’s one flaw, though.
Very, very good studies, but what they did is they used the Yale Observation Score. There’s been at least a dozen papers saying it doesn’t work for infants. People shouldn’t be applying that and then saying, “Gee, we really can’t tell.” We really can tell, but it’s just on a sick or not sick basis. The reason the Yale Observation Score doesn’t work that well is it depends on the social smile, which doesn’t come into play. It’s just going to bomb if you try to use it. If you’ve got experience, and you trust your experience and your judgment, and the child looks sick, the child is sick. If the child looks well, the child looks well.
Dr. Gabi Hester: Your guideline also excludes children with identifiable infections, like a skin or soft tissue infection, or pneumonia for example. Tell me about what infections are you really targeting with this guideline? What are we worried about, and what are we hoping to try to evaluate for?
Dr. Robert Pantell: A lot of the early studies, and even some of the studies being published today, talk about serious bacterial illness. I always thought that was silly. If the child has cellulitis, and you’ve got a red arm, why do you have to include that child in a complicated clinical decision? We know that child has a serious bacterial illness, cellulitis, and there are many other things like that. If you have an easily identifiable infection, omphalitis, cellulitis, treat those infections. Okay? This is really looking for occult infections, looking for bacteremia, looking for meningitis, and urinary tract infections are also occult until you do a urinalysis. Those are the three that we really hope to stop.
Dr. Gabi Hester: I loved in this recent talk that I mentioned where you stated, “RIP WBC.” So rest in peace white blood cells, related to, I think, the poor utility for white blood cells really in the febrile infant workup as far as risk stratification. Can you tell me a little bit more about inflammatory markers, and some of the other ones that you talked about, like absolute neutrophil count, or ANC, as well as procalcitonin, and the role that they should be playing in the workup of infants with fever?
Dr. Robert Pantell: First of all, let me talk about my favorite inflammatory marker because it’s very cheap. It’s universally available. It’s called the temperature, and in numerous studies now, the higher the temperature, the higher the likelihood of bacteremia or meningitis. Let’s not forget about that in risk stratification, but in almost all of these infants, you’re also going to be getting blood work, and you’re going to be looking at a variety of markers. Now, white count is in virtually all of the literature, all of the folks that try to come up with high risk categories and low risk categories. The white count was darn good in the GBS era, but as E. coli has now become the predominant organism for bacteremia, and the number two organism for bacterial meningitis, the total white count just doesn’t fare very well at all.
Many of you may remember back to medical school, or even residency, looking at areas under the Receiver Operational curves, and best number is 1.0. That means 100% sensitive and 100% specific. Worst is 0.5, which is a flip of the coin. When we take a look at all of the markers now, individually, if we look at white count and ANC and then CRP, and then our latest entry, procalcitonin, the areas of occur in roughly 0.5 for white count, not very good. About 0.65 for ANC, much better. About 0.75 for CRP, and about 0.9 to 0.95 for procalcitonin. So as a single predictor, procalcitonin, no doubt about it. Surprisingly though, when recent studies have been done, procalcitonin is very good. It still misses a lot in and of itself. If you only use procalcitonin, you would miss about 30% of the cases in meningitis. I’m saying that first as a reminder that when the procalcitonin salesmen comes around, you might want to buy it, but make sure you have something else on hand as well.
What we did find, though, is that when you combine inflammatory markers, things work out very, very well. The latest studies again from PECARN where they combine a urinalysis, the best predictor. The next best predictor is not procalcitonin. The next best predictor happened to be ANC, or acute neutrophil count. They found the cutoff point was 4,000. If you remember the old studies, it used to be 10,000, but we have better statistical tests, and we have different bacteriology. You shouldn’t be surprised with the shifting bacteriology, shifting a lot of things, that things look differently today. That is the second most important thing. Then the third was the procalcitonin, and procalcitonin was useful in sweeping up some of the cases that the urinalysis missed and that the ANC missed. Putting those together, they did very, very well. As I recall, we got a 95% sensitivity, which is excellent. Also they had a high specificity, which was about 60%, which again is excellent. So it’s a darn good rule.
Dr. Gabi Hester: Thinking about the concept of intentional vagueness, and that’s something that… There were several points in the guideline where I suspect you were being intentionally vague. One point I wanted to just get your insight on was, the guideline talks about using 24 to 36 hours as a range of time for your antibiotics or your hospitalization in certain clinical circumstances. Can you speak a little bit about that intentional vagueness concept, and how a clinician or a family might work together to select 24 versus 36 or somewhere in between?
Dr. Robert Pantell: The intentional vagueness is something that was built into AAP guidelines that the committee hated. Rather than intentional vague because that implies, well, we’re not quite sure where it’s going on. We do know what’s going on, it’s just how do we interpret what’s going on? So let’s start with that 24 to 36 hours. What we’ve done to reduce the intentional vagueness is comb the literature and say, “Okay, in 24 hours, what percent of pathogens do you detect?” And you detect 90 to 92%. How comfortable do you feel to discharging at 24 hours if you know there’s still 8% of pathogens that are growing. We did the same with 36 hours, where studies show us anywhere between zero and 8%. So let’s pick 3%. How comfortable do you feel at 36 hours, discharging knowing 3% of the infants might still be positive?
So, we’re really trying to put numbers on it so that both physicians can interpret… and an important part of the guideline is we are in the era of shared decision-making. It’s not just your decision, and I could go on and on, the stories where I thought X, and I’d give the family the number. They’d say, “Oh, it’s only 5%? Ah, I’m out of here.” So those are negotiations that you need to have with families. We’ve done the best we could to come up with the numbers so that you could look at as a physician, and the parents could also weigh in on it. Now, again, you need to do this with some thought. It’s not for every decision. If the child comes in looking horrible and seizing, you’re not going to sit down and start discussing the literature with families, but basically we are promoting to shared decision-making
Dr. Gabi Hester: One of the coauthors of this guideline, Dr. Ken Roberts, also talked a lot about how the decisions should be made in the context that you’re seeing the patient. He used an example of is this 10:00 AM on a Tuesday morning in your office with a patient that you’ve known the family for years, and you know what their follow-up ability is, versus Friday night on a holiday weekend in a busy emergency department. How those different types of contexts can really play into that discussion that you might be having, or the risk tolerance that you might have in that particular situation. Can you talk a little bit about how, for example, an outpatient provider might use this guideline differently than someone like myself, who’s a pediatric hospitalist, versus an emergency medicine physician, for example.
Dr. Robert Pantell: A lot depends on the nature of the follow up. A lot depends as well on how well you know the family and the family’s experience. I think that’s really critical. That’s why literally the first line of this guideline is that we expect individual variation, taking into account individual circumstances. Those are really two perfect examples.
Dr. Gabi Hester: If you had to highlight one thing from this guideline that you just want to make sure everybody knows, what would the one or two things that stand out to you be?
Dr. Robert Pantell: One or two things is, first of all, we’ve made a major change in the fourth week of life. Okay? The way children develop and the way immune system work does not depend on weeks, months, or numbers ending in zero. What we really try to do is look at the decrease in prevalence and say, “At what point in time does it make sense to come up with choices?” as opposed to, “You must do this.” The cut point for us was at 22 to 28 days. I think that one of the big take home messages is we are treating that age group differently. Everything in the past was less than 30 days, or less than a month, you must do this.
The other thing is we’re giving families, particularly in this age group, choices. For example, with this age group, if you did have a negative LP, the risk of the most serious infection was pretty much ruled out. That a child could go home with family that you knew you were going to get good follow-up from. That child could go home at 20 days of age. On the other hand, we also felt that you should not send a child home without having that type of evidence. Again, there might be exceptions, a snow storm in Idaho, an experienced family, so on and so forth. But basically that’s where we had the major shift, is in that period of time we’re giving people choices, we’re sending people home earlier. Again, there are restrictions, but you can send families home the fourth week of life.
Dr. Gabi Hester: Thank you so much, Dr. Pantell. I think we just have learned so much from you, and dedicating 17 years to getting this guideline out, I think it’s well worth it. I’m really excited to begin applying these to my patients. Thanks so much for joining us on the podcast today.
Dr. Robert Pantell: You’re welcome. Thank you for having me. I appreciate it.
Speaker: Take home points.
Dr. Gabi Hester: Number one, new febrile infant guidelines include well-appearing patients age 8 to 60 days of age. Guidelines should not be applied to infants in their first week of life or with other comorbidities outlined in the guideline. Number two, inflammatory markers such as temperature, absolute neutrophil count, and procalcitonin can be helpful in risk stratification of infants with fever. They should be obtained in all patients 22 to 60 days of age. They also may be considered in patients 8 to 21 days of age. However, these patients are already managed more conservatively, regardless of results. Number three, it’s important to recognize ranges of risk tolerance for providers as well as caregivers, and to use shared decision-making when evaluating and managing a young infant with fever.
Dr. Angela Kade Goepferd: Thank you for joining us for Talking Pediatrics. Come back each week for a new episode with our caregivers and experts in pediatric health. Our executive producer and showrunner is Ilze Vogel. Episodes are engineered, produced, and edited by Jake Beaver. Lexi Dingman is our marketing representative. For more information and additional episodes, visit us at childrensmn.org/talkingpediatrics, and to rate and review our show, please go to childrensmn.org/survey.