September 24, 2021
All providers are familiar with long, dubious allergy lists pointing to a rash around the time a medication was taken. Given the endless list of competing causes for rash, misattribution to medications is wildly common as many studies by pharmacists have shown. The result is “allergy jail”, where angry pop-ups limit our treatment options, impact antibiotic stewardship and often follow a child into adulthood. This week’s case will investigate principles to correctly identify when rashes and other associated symptoms are (and more frequently are not) attributable to a medication taken.
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 Goepford. We have all been there. Is it an allergy? Is it a medication reaction? Or is it something else entirely? On today’s episode of Crack the Case with Dr. Fate, Dr. Fate gives us some tips and tricks for keeping ourselves and our patients out of allergy jail.
Dr. Bryan Fate: Welcome to Crack the Case. I’m Dr. Bryan Fate, a primary care pediatrician at Children’s Minneapolis. Today we’ll be diving into real cases seen at our Minneapolis Continuity Clinic, to highlight medical decision-making, approaches to general pediatrics topics in life and primary care. We’ll also incorporate music written by myself and friends at the end of every episode to highlight teaching points and hopefully engage the emotive side of your brain. With me today is Dr. Robert Becker, and we’ll get to know him a little bit better. When residency life gets tough, is there a song or musician that you turn to?
Dr. Robert Becker: I am a big fan of some good sad music, especially going to the gym and turning on some Phoebe Bridgers or Bon Iver or something. When things are tough, especially, I think that’s great, but I have a pretty wide interest in music in general. I like a good jazzy musician, like Lake Street Dive, which is fun because I live right off Lake street, so they’re named right after the street that I live off of, or like Shakey Graves or something like that. But there’s some curve balls in there. I’m a big Chance the Rapper fan. I don’t know. I’ve got a pretty broad taste.
Dr. Bryan Fate: Yes, I share your sad boy tendencies. And I’m also one to use music to unpack a lot of what you see in medicine that, in the moment, you might not be feeling so as to be able to act and think clearly. I do remember one of the hardest shifts I ever had in the trauma hospital in Seattle. I came home after 26 hours, just kind of numb, I put on a Fruit Bats song, Absolute Loser was the song. And I cried a lot and just started for the first time, felt all the things that were happening throughout that night of car accidents and kids falling out of windows, and just connected me to what I was doing in a way that I couldn’t do in the moment, which has been the magic of music for me, and medicine. So, let’s introduce the case.
*music playing* Gotta Crack the Case with Dr. Fate, Crack the Case with Dr. Fate, Crack the Case with Dr. Fate.
Today’s case we’ll be exploring rashes and reactions in the proximity of medication use. Which are truly caused by medications? Or just something else? What are strategies to help us discern this? All providers are familiar with long, dubious allergy lists pointing to a distant, vague response around the time a medication was given. The result, is allergy jail or angry pop-ups that limit our treatment options, impact antibiotic stewardship and often follow a child into adulthood. Correct attribution is key and misattribution in medications is wildly common, as many studies by pharmacists have shown. And so let’s start the case.
Dr. Robert Becker: So this case is about a three-year-old female who came into clinic after being seen in the emergency department the day before. I’m just going to lay out the background of the case for you guys. Probably ten or eleven days earlier, this young girl had been started on a treatment course of antibiotics, amoxicillin, for treatment of bilateral acute otitis media, and it had all been going well, her symptoms had improved, but two days prior to presentation to the primary care office, she started to develop a rash in the evening. And mom gave some Benadryl because the rash was itchy. The child was able to fall asleep overnight and everything was going okay. But the next day it had gotten worse. And so mom brought the child to urgent care. At urgent care, they said, oh, you know, this could be related to the amoxicillin that you’ve been getting for eight or nine days. Why don’t you stop taking the amoxicillin, your ear infection looks better. They gave her some Benadryl and discharged her to home and said, come back if this gets worse. It did get worse. She presented later that day to a neighboring facility, which was the day before presentation with worsening rash, and she was also feeling a little bit tired at that point. In the emergency department, they said, oh, this rash looks like hives. It’s not like a normal drug reaction rash. We’re really concerned about anaphylaxis. They got some labs and they were notable for a leukocytosis to 19.5, CRP of 6.8, electrolytes which were consistent with some mild dehydration, with a CO2 of 20, and a creatinine of 0.6, and BUN of 23. And they also noted that her temperature was 100.9. Out of an abundance of caution, they said let’s treat for anaphylaxis because we really want to make sure that these hives aren’t going to lead to hypotension or GI symptoms, some of the more severe things that we can see with anaphylaxis and maybe most severe, airway compromise. And so, they gave steroids, epinephrine, phormoradine and diphenhydramine. She did well afterward. And since she didn’t develop any of those other symptoms, they discharged her home to be seen the next day in primary care clinic. And Dr. Fate, what is running through your mind at this point? What are the things on your mind? And how would you approach the case, knowing only what we know based on the ED notes?
Dr. Bryan Fate: I want to clarify a couple of definitions first, when we’re thinking about drug reactions. So adverse drug reactions, two types. There’s Type A, which are predictable and dose dependent. So these are not allergies. If you’re taking a blood thinner, this could be bleeding, which is expected. If you’re taking Benadryl, this could be anticholinergic side effects. So these are things we know happen as you take more and more of the medication and they’re not true allergies. And often these can be misattributed as allergies in the kid’s chart. I’m not hearing any of those based on the amoxicillin, which we know can cause GI upset and some other things. Type B reactions are the types that we really want to put on a kid’s medication list. These are unpredictable and dose independent, and there’s a big bucket in this that’s drug hypersensitivity, which would include things like urticaria, hives, anaphylaxis. And we can go through a couple of the other kind of illness scripts that fall into this. That would be clear designations for reasons why we wouldn’t want to give a drug again.
For this child, as they walk into clinic, I would take a look at her skin immediately and be very descriptive about the rash. You want to impress your dermatology friends, because there’s very specific language to describe the different rashes that we see with drug reactions, and you need to be very precise about it. The timeline is essential too. So when was the medication taken? When did the rash happen? In respect to that is really important. Has the rash changed over time? Is important. Have they taken this medication before? If they’ve taken amoxicillin a bunch of times, no reaction, it would be unusual to have a new allergy formed. Have they taken similar medications in similar classes? And if we’re thinking about, does this truly fit a drug reaction that we can attribute to the amoxicillin? Is this a reaction that we know can be attributed to the drug itself? So, knowing each drug profile is really important too, and your pharmacist friends can be helpful, in that regard. That’s where I would start off in terms of digging into whether it’s drug related or not.
Dr. Robert Becker: Just to answer a couple of questions that you had right off the bat that I also wanted to know. This is a medication that this child has had before. She’s had amoxicillin in the past for ear infections. As I mentioned in the background to this case, she did have amoxicillin for eight or nine days prior to the onset of this rash. There were a couple other things that were running through my mind too, when I was reading this ED note. Mostly I also was just thinking, this doesn’t necessarily match my illness script for anaphylaxis. As you pointed out, the timing is really important when we’re thinking about drug reactions and she had been taking this medication for eight or nine days before this all started. So anaphylaxis is not necessarily the first thing that comes to mind, and certainly not the traditional anaphylaxis that happens 20, 30 minutes or a couple hours after taking a medication.
Dr. Bryan Fate: So no wheezing, vomiting, diarrhea, no urticaria plus?
Dr. Robert Becker: Right, she wasn’t meeting any of those other criteria and no hypotension or syncope, things like that.
Dr. Bryan Fate: I agree that I don’t see that she would meet those criteria. So potentially she’s been given an entire regimen of anaphylaxis treatment without necessarily warranting it.
Dr. Robert Becker: We know that early treatment with epinephrine is really important if you’re concerned about anaphylaxis, because it prevents things like hypotension and shock, and earlier treatment is associated with better outcomes in anaphylaxis. But we have to kind of walk that line between caution and providing treatments that may not be indicated.
Dr. Bryan Fate: Yes, and I think with her fever, you said, and her high white count, there’s definitely inflammation happening. Again, does not necessarily have to be drug related. So this could be an infection of many different kinds. It could be new onset, rheumatologic, presentation, but if we’re going to dig into the drug reactions, I think it’s really helpful to have a good illness script of the drug hypersensitivity reactions that we kind of have a good understanding of with pharmacy. So we can do a quick lay of the land. You mentioned the urticarial reaction. That’s well-known, happens usually pretty quickly, but it can be delayed, so hours to days. It’s really important to truly identify them as urticaria, so these kind of itchy wheels that kind of pop up, come and go like fireworks almost, they don’t stay in one place, they’re really transient and go to new places. And so if she truly has that, we’d want to confirm that on skin exam.
Another category would be the exanthematous drug reactions that we know so well from medical school. So those like morbilliform rashes where you have speckling of red, almost like Pollock, like tiny speckles of paint all over you, that we’ve seen with amoxicillin with EBV responses, in addition to scarlatina form rash, which are those kind of sandpapery, itchy things. So you can have fever with that, you can have itchiness, you can have desquamation, and the differential always is difficult there because viruses cause those rashes all the time, too. So viral symptoms always on the differential.
The fixed drug reactions are really interesting. Those are those violaceous, which is a fun word, they almost look like bruises. So NAT sometimes on the differential. They start off dusky red violet, always in the same place and they can kind of turn into this bruise looking rash. And interestingly, if you give the drug again, it’s always going to come back in the same place. So fixed drug reactions. Then you have the photo-sensitivity reactions where any amount of skin that’s exposed to sunlight. It only happens when you take the medicine, can often resemble a sunburn. The other things we think about are serum sickness like reactions. These kids have a delayed reaction at times, like one to three weeks. Can have fever, can have urticaria actually, so there’s an overlap, joint pains, itchiness. And then finally are the really nasty, severe cutaneous adverse drug reactions, which anaphylaxis is one. And then we think of the really scary like mucosal reactions, where you’re sloughing your skin from eyes, mouth, you are very sick, multi-system involvement, fevers. It is like an immediate admission, and you’re essentially treated as a burn patient because you lose so much of your skin. And the most important thing with those is to stop those medications immediately.
So if we’re thinking about drug reactions, I think it could fit a potentially exanthematous drug reaction, it could fit a serum sickness like illness. And then we talked about a lot of other alternatives with infection. And I think that’s the hardest thing is there’s so many rashes that are caused by viruses, and there are so many rashes that are caused by a lot of other things, like urticaria. You can have cold urticaria when you’re exposed to cold, pressure urticaria. So pinning it on the drug is kind of like a subtle complex thing, but we’ll talk about some strategies for that.
Dr. Robert Becker: Vital signs, her temperature in clinic was 97.1, blood pressure was 89/38, pulse was 111, and respiratory rate was 22. On exam she was pretty well appearing, maybe a little bit fussy or tired. Mom said she hadn’t been sleeping the best in the last couple of days, but otherwise she was pretty well appearing. As far as her skin goes, she had these kinds of flat, red macules that were pretty well circumscribed or clearly, sharply demarcated. And they were mostly in these circle shapes, kind of overlapping like polycyclic. So some of the borders looked irregular where those circles overlapped. And then there were kind of these satellite lesions too, which were also circular. And interestingly, some of the lesions also had almost a central clearing type appearance and maybe a little bit of targetoid, not targetoid like in erythema multiforme with the diffuse borders and then the nice ring of central clearing, but almost like a really thin ring of central clearing and another ring inside of it.
Yeah, it was kind of interesting. And then I had to convince myself a little bit, but I think I saw on the toes, if you were to picture looking up at someone’s feet under a glass board or something, where the skin meets the glass board, there was a little bit of erythema and kind of rough looking rash at that part, like where the sole of the foot skin meets like the normal skin, which was just on a couple toes on one foot.
The rash at the time that I saw it was primarily on the trunk. So mostly upper abdomen and lower chest, as well as the back, kind of mid back, and on the forehead above each of the eyebrows. No mucosal involvement. And the rash, actually it had been distributed more generally. It was on the arms and legs as well. It was definitely improving from the previous day.
Dr. Bryan Fate: Was she tachycardic?
Dr. Robert Becker: She was not tachycardic.
Dr. Bryan Fate: Okay.
Dr. Robert Becker: Not when I saw her.
Dr. Bryan Fate: And no fever?
Dr. Robert Becker: Not when I saw her, but the previous day she did have a fever.
Dr. Bryan Fate: Any other pains like gate changes, joint involvement?
Dr. Robert Becker: Not any changes on exam that I saw. But another element of the history that they didn’t ask about at the emergency department was that this child actually did have some joint pain the day before, had complained of knee and ankle pain. And mom thought that they might have been a little bit swollen. I clarified, did it look like the toes were swollen, like edema? And she said, no, like the knees and ankles, but the toes looked fine.
Dr. Bryan Fate: Otherwise normal exam.
Dr. Robert Becker: Otherwise pretty normal exam, yes.
Dr. Bryan Fate: Going back into thinking about amoxicillin as a precipitant for this rash, and describing the rash, you mentioned erythema multiforme, and I tend to think of three distinct color zones and kind of a blistering in the center with those. So it doesn’t sound like it met that criteria per se. And then with joint pain, fever, you always want to think about migraines and Lyme disease too, is something not to miss, which would not be drug related. We talked about the possibility of other kinds of infections and I don’t know exactly what they did for the work up there. So, thinking about swabbing for things like COVID, et cetera, for unusual presentations, I might also consider repeating her labs to make sure her inflammatory markers are improving over time, her white count’s improving over time, you mentioned electrolyte derangements.
Dr. Robert Becker: To me, there were two things that I think were at the top of my differential among maybe a couple other things that are definitely worth considering. The thing that I think it fits most closely with is actually a serum sickness like reaction, which is a more rare type of drug reaction. I think it fits really well with this diagnosis though, because we tend to see these onset five to ten days after the start of an antibiotic. Amoxicillin and other beta lactams are also drugs that we know cause serum sickness like reactions. It’s interesting, cause it’s a little different than actual serum sickness because serum sicknesses is that type three hypersensitivity reaction where we see those antigen-antibody complexes deposit and serum sickness like reactions, aren’t quite the same. They have different drugs that cause the similar symptoms. And we don’t quite understand the mechanism, but they cause a lot of the same symptoms. This urticarial rash, the fevers, you can see leukopenia or leukocytosis and maybe most convincing for why it falls into this category and not a different category for this child is the arthralgias and joint swelling.
Dr. Bryan Fate: It does fit a disease script. It does fit the timing. It fits a known profile of the drug. Just thinking about strategies we have to truly attribute this to the drug itself. And then I would stress that it’s very important to tap your allergy and pharmacist friends, to truly confirm that this is what’s happening. So don’t be afraid to reach out to your pharmacist who knows all these profiles like the back of their hand, because the lists are long and not committed to memory. And there are great tests they can do in the allergy clinic, like skin testing, and then I think the biggest question is, if you think this is not a true allergy for a kid, trying to reintroduce the drug, because that’s a scary thing, because there’s lots of things that yell at you on your computer screen. You don’t want to be the reason a kid gets sick and has another reaction. So I think that the comfort level with trying to reintroduce, because that’s the real test, are they going to respond again? And so many studies have shown us that for a lot of things that’ve been attributed to drugs almost, of the vast majority, if you give it again, nothing happens. So I think 10% of kids who are given antibiotic based on an old vision of the article will have a cutaneous adverse reaction. But the majority of them, when given the medication again, don’t actually have a reaction. So it’s not drug itself. If it doesn’t fit for you and you don’t feel comfortable trying it again, please reach out to the allergist and the pharmacist.
So to summarize, we have a previously healthy three-year-old who started taking amoxicillin, about ten to eleven days into the course for otitis media, developed a rash, which was apparently urticarial, there was an outside facility, had fever, some systemic symptoms, maybe some joint pain, signs of inflammation and elevated white count and CRP, maybe some dehydration, received the full kitchen sink for anaphylaxis, though we’re not convinced that she truly had anaphylaxis. And has now come in with this kind of irregular rash, which is a little bit harder for us to define, but it doesn’t seem like erythema multiforme, maybe urticarial, probably urticarial…
Dr. Robert Becker: I would say so.
Dr. Bryan Fate: But overall feeling better, no further systemic symptoms, no fever in clinic, no signs of her immune system being revved up. And so I think in terms of maybe a top three, we have talked about anaphylaxis, which we’ve nixed. We’ve talked about a serum sickness like reaction, if we’re going to attribute to the drug that fits the illness script the best. We’ve also talked about a host of other things that could potentially cause it like Lyme disease, like any kind of viral infection with exanthem, and it doesn’t seem like there’s any other bacterial process for seeing, and if she’s getting better, most likely not a rheumatologic process or an oncologic process. So why don’t you tell us what happened there on? What was the diagnosis and what happened with the kid?
Dr. Robert Becker: So it was a serum sickness like reaction.
Dr. Bryan Fate: Wow.
Dr. Robert Becker: Yes. The treatment for serum sickness like reactions is conservative. There’s really not a lot you need to do other than withdrawing the offending agent, the long-term prognosis is really excellent. There’s not a whole lot of long-term effects from the serum sickness like reaction. There are times when serum sickness and serum sickness like reactions can have some kidney involvement. And so, especially if you’ve got a DMI, I think it would be prudent to get your analysis to make sure they’re not spilling protein in their urine. And certainly if they are, getting our nephrologist friends involved, because there’s all these other tests with compliment proteins and things like that that they’ll want to look at and potentially follow if there’s significant kidney involvement, but that’s much more common in serum sickness than serum sickness like reactions.
Dr. Bryan Fate: If we had two take-home messages for our viewers that you want them to leave with, what would you say those are?
Dr. Robert Becker: One thing is that in a world where rashes are so frequent, how can we determine if our rash is truly due to a drug or not? And I think a lot of that comes down to, as you mentioned, having almost an illness script for each type of these drug reactions and paying really close attention to the chronology and what features are associated with it, and what drug reactions we know to be associated with specific medications, because we know which drug associations are associated with which drugs for the most part.
Dr. Bryan Fate: So if you had a serum sickness like reaction to vitamin D…
Dr. Robert Becker: You’d probably be backing up.
And I’d also recommend, if we’re not sure if something is truly an allergy, sending them to an allergy specialist to try to help determine which drugs can we or can’t we give, particularly for kids with these long drug allergy lists, because oftentimes those are also kids who are going to be more vulnerable to other health problems in the future and need antibiotics again. And to not have our full repertoire of tools, could be potentially dangerous or at least not up to the highest quality of care that we could potentially provide for kids. So if we can expand that range of tools that we have, it’ll serve our kids better.
Dr. Bryan Fate: Thank you so much for your insight today, Dr. Becker, until it’s time to crack another case, an original musical number to help solidify our key concepts and hopefully tug at your heartstrings.
*guitar music playing*
Help me out I’m stuck in an allergy jail
Had a rash one time and they put me here
Can’t take the same medicines
Pathogens more resistant
I’m using my one phone call
To call an allergist
And talk to the pharmacist
*voice on phone speaker* This is pharmacy, how can I help you?
What medicine were you taking, and how long were you takin’ it
Use your derm-y nomenclature when describing the rash
Were there other symptoms, have you had the drug before?
Does it fit into a pattern that in pharm is understood?
And if doesn’t equate
You got two roads to take
One is to re-challenge if you’re sure
Two, if there’s doubt open the door
To your friend the allergist
She’s got all kind of tests
To put the question to rest
And finally break the shackles of that
Allergy jail, allergy jail, allergy jail
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 Ilza Vogel. Episodes are engineered, produced and edited by Jake Beaver. Lexi Dingman is our marketing representative.