Recurrent Fever Syndromes – PediaCast 588

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Description

Dr Shoghik Akoghlanian visits the studio as we consider recurrent fever syndromes in children. Tune in as we explore typical fevers… and more concerning ones. Learn about PFAPA and Familial Mediterranean Fever. We hope you can join us!

Topics

Recurrent Fever Syndromes
PFAPA: Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis
FMF: Familial Mediterranean Fever

Guest

Dr Shoghik Akoghlanian
Pediatric Rheumatology
Nationwide Children’s Hospital

Links

Rheumatology at Nationwide Children’s Hospital
Autoinflammatory Alliance
Syndrome of Periodic Fever, Pharyngitis, and Aphthous Stomatitis
Autoinflammatory Diseases with Periodic Fevers
Classification Criteria for Autoinflammatory Recurrent Fevers
Consensus Treatment Plans for PFAPA
Common Genetic Susceptibility for PFAPA, Behcet’s Disease, and Recurrent Stomatitis
Syndrome of Undifferentiated Recurrent Fever

Episode Transcript

[Dr Mike Patrick]
This episode of PediaCast is brought to you by Pediatric Rheumatology at Nationwide Children's Hospital. 

Music

Hello, everyone, and welcome once again to PediaCast. We are a pediatric podcast for moms and dads.

This is Dr. Mike coming to you from the campus of Nationwide Children's Hospital. We're in Columbus, Ohio. It's episode 588.

We're calling this one Recurrent Fever Syndromes. I want to welcome all of you to the program. As you know, if you are a parent, fevers are a very common part of childhood, and most of the time they are caused by infections and go away on their own, especially viral infections.

We see a lot of those over the course of every winter. But what happens when the fevers keep coming back, often without a clear cause? Well, today we are diving into the world of Recurrent Fever Syndromes, what they are, how we tell the difference between typical fevers and those that are more concerning.

We'll explore some conditions that cause repeated spikes in temperature. Things like PFAPA, which stands for periodic fever, aphthous stomatitis, pharyngitis, adenitis, which is the most common recurrent fever syndrome in kids. Of course, that's a mouthful.

Periodic fever, aphthous stomatitis, pharyngitis, adenitis, which is why we call it PFAPA. Let's break that down though here really quick. Periodic fever just means it's a recurrent fever.

It's like clockwork. You get it on a set schedule rather than just hit or miss. Aphthous stomatitis, those are just little mouth ulcers.

Pharyngitis means you have a sore throat, and adenitis means that you have some swollen lymph nodes, in this case, often in the neck. PFAPA is fever, mouth ulcers, sore throat, and swelling in the neck. But of course, there are lots of viruses that can cause those same symptoms.

How do you tell the difference? That's what we're really going to dive into today. There's also another one called Familial Mediterranean Fever, or FMF.

That's another cause of recurrent fever spikes, temperature spikes. We'll talk a lot more about that one as well. And of course, in our usual PediaCast fashion, we have a terrific guest joining us for the conversation.

Dr. Shoghik Akoghlanian is a pediatric rheumatologist at Nationwide Children's Hospital. She's going to share expert insights and practical guidance for families. It's an important conversation that we hope will bring peace of mind and a clear path forward for parents dealing with recurrent fevers, again, ones that sort of come and go like clockwork.

Our discussion is coming up, but before we dive in, I do want to remind you the information in every episode of our podcast is for general educational purposes only. We do not diagnose medical conditions or formulate treatment plans for specific individuals. If you're concerned about your child's health, be sure to call your healthcare provider.

Also, your use of this audio program is subject to the PediaCast Terms of Use Agreement, which you can find at pediacast.org. So, let's take a quick break. We'll get Dr. Shoghik Akoghlanian settled into the studio, and then we will be back to talk about recurrent fever syndromes in kids. It's coming up right after this. 

Music

Dr. Shoghik Akoghlanian is a pediatric rheumatologist at Nationwide Children's Hospital and an assistant professor of pediatrics at The Ohio State University College of Medicine. She has a passion for supporting children and families impacted by recurrent fever syndromes.

What exactly are these? What causes recurrent fevers? And how are they diagnosed and treated?

Answers to these questions and more are coming your way. But first, let's offer a warm PediaCast welcome to our guest, Dr. Shoghik Akoghlanian. Thank you so much for visiting with us today.

[Dr Shoghik Akoghlanian]
Thank you. Thank you for having me.

[Dr Mike Patrick]
Yeah, we're really excited to talk about this because it's a thing that as pediatricians, you know, we learn about these, and we do see some kids here and there with them. For parents, when it happens, they're really caught off guard in our understanding. And so, we really want to get the word out and raise awareness about what these things are.

So first, what exactly qualifies as a fever for one? And then why do some high temperatures not necessarily count as a true fever that's indicative of like an infection?

[Dr Shoghik Akoghlanian]
Sure. So, as you said, it's definitely catches them off guard and it's definitely scary because anytime your child has a temperature, they look miserable, and you don't know what to do for them. So, we typically call normal temperature anywhere between 97.2 to 99.5. And that's like normal temperature. So often I hear patient coming in and saying like, oh, my child has a temperature of 99 and that's kind of like a high temperature, but it is not still counted as a fever. So, for fever, we say anything above 100.4 Fahrenheit is a fever. And that's what I usually when I see these patients, I say, OK, please do not give any antipyretic medication.

So, no ibuprofen, no Tylenol. Just let's see if this temperature is going to get higher to the point that we actually do call it a fever. Therefore, there is a whole lot of investigation needs to be done.

[Dr Mike Patrick]
Yeah. Yeah. And so, 100.4 and higher is really our definition of a true fever, because, you know, sometimes folks will say, well, they were 99 and then they call a low-grade fever. But that's really not a thing, right? It's either you have a fever, or you don't have a fever. And 100.4 or higher is the definition of what we would consider to be a fever. Correct. Yes. OK.

And of course, this is really, really common for kids to have fevers. I mean, we see this every day in pediatric practices and emergency departments and urgent cares, like literally many, many children every single day in every community have a fever. So, when are we worried about fevers and not worried about fevers?

And I guess we have to look at the things that cause the fevers to understand whether we're worried or not. So, kind of what are the general things that lead to fever in children?

[Dr Shoghik Akoghlanian]
Yeah. So, as you said, it's extremely common. So pretty much any child, you know, like, yes, at some point in time they have a fever and, you know, as like common things are common, a vital infection, bacterial infection can cause are the most common things.

And often this is important to, you know, to talk to our patients, especially if these younger ones, they just start to school or start to preschool, daycares. It's extremely common for them to have some like infections. Typically, these are the infections that they are on its course.

Sometimes it's frustrating for parents when they take their kids to the primary care doctors and then like they say, OK, well, your child doesn't have any back any signs to suggest bacterial infection and it's only vital infection. It needs to run its course. And it's my job sometimes is when I see these patients with recurrent fever to actually reassure them and tell them, like, you know, up to 14 independent infections for a kid who just started daycare, it's it can be completely normal.

And sometimes that's a frustrating for the parents.

[Dr Mike Patrick]
Yeah, yeah, absolutely. And we see this every single winter. And folks who work in pediatrics and take care of kids in terms of health and wellness understand exactly what I'm talking about.

But as you said, kids can have, you know, as many as 14 infections a year. And those often are kind of compressed into the school year because that's when kids are around each other and sharing their germs in the classroom. And the way that our immune systems work is that we have to get sick with the virus the first time it comes around.

It's training our immune system to fight that particular virus off the next time it comes around so that we're not quite as sick the next time. And of course, there are literally hundreds and hundreds of different viruses and virus strains out there. So as a young kid, every time you get exposed to a new one or a new strain, you're going to get sick.

Whereas an adult, you've had all of these viruses when you were a kid. And so, you have hopefully built-up immunity against them. Vaccines are another way that we build up immunity against more dangerous infections.

And so, if you're looking at 14 viral infections and each of them can last one to two weeks and then you compress that into the school year, you really can have a situation where it just seems like your kiddo is sick all the time. And that doesn't necessarily mean something is wrong. On the other hand, we are talking today about recurrent fever syndromes.

So, there is a sort of a different disease process that causes recurrent fevers that's not associated with these viral infections. And so, if recurrent fevers are so common during the school year, then how do you tell the difference between fevers that are just virus and it's OK and recurrent fevers that, hey, there's something else going on? How do you tell the difference between those two things?

[Dr Shoghik Akoghlanian]
So, the first few episodes of when the child kind of presenting with recurrent fever, it is definitely important to get checked at the primary care doctor. Urgent care depends on how sick the child is. Very often is like, you know, first thing again, common things are common.

They cannot probably not do a whole lot of testing. But when this happens again and again in a very like in a pattern where all the symptoms seem to be happening again and again. And then let's say primary care doctors and urgent care doctors, they're going to kind of investigate a little bit more.

That's why it's really important to look at the history. So, yes, you they are maybe there once or maybe the uncle doctor are looking at them and they're like, OK, well, we'll treat this as a viral infection. Often, actually, parents bring this up to say, oh, you know, like we were just here and then it seems like Johnny had exactly the same symptoms last month.

And then let's say sometimes we take it a step further where actually they do further tests. Maybe they do like a nasal pharyngeal swab looking for viruses. Of course, even if that's negative, this doesn't mean that they don't have a virus.

But if this continues to happen, often these kids actually present with a sore throat. So, kind of what it looks like a strep. But often I see like they get swabbed for strep for a rapid strep testing.

And then often it comes back negative. And honestly, I see this all the time where parents actually get frustrated. So, they actually stop going to the doctor.

And I'm like, you know, why does that happen? Because they're like, every time we go, it's just like nothing to do. And they tell me it's a virus and go home.

I cannot tell you how often I see that.

[Dr Mike Patrick]
Yeah, yeah. And that is frustrating not only for parents, but it’s also frustrating for physicians because we want to get the right diagnosis and tell the family what we think is going on. But hopefully we are not feeling so rushed in exam rooms that we're not taking time to really get a good history because these viruses, of course, are often going to be associated with some other very common symptoms like runny nose, congestion, cough.

You might have vomiting or diarrhea. So, if those things are present with the virus and especially if there's all you know, it's wintertime, there's other kids in the house with very similar symptoms and that all points toward viral infection. But when you have a fever with really not much else and no one else is sick and it keeps happening and maybe even in the summer it's happening, then that does start to raise your radar a little bit that there might be something else going on.

Right.

[Dr Shoghik Akoghlanian]
Absolutely. Actually, that's a good point. So just to give you an example, so a few years ago when we got hit with a pandemic, that was a time that we saw a whole lot of referrals actually for recurrent fever syndrome because, you know, everybody was on a lockdown.

Everybody was, you know, mask outside. The kids are not in school. Everybody's, you know, zooming through the school.

So not much contact. And that's when the kids with recurrent fever showed up. Like, you know, Johnny is sick, but actually, well, nobody else is sick.

And we have not been exposed to anything or anybody who was sick. And then that's exactly when we got like this big spike in the referrals for recurrent fever.

[Dr Mike Patrick]
Yeah. Which is a little unsettling because that means that there's probably a lot of kids who do go undiagnosed with these during non-pandemic times when we, you know, when it's more likely just to say, oh, they got a fever because they were at school and around other kids. So, I guess that was one of the silver linings, so to speak, of the pandemic just in terms of it did help to diagnose more of these kids with the with the actual thing that's going on.

And then we can treat them and hopefully improve health outcomes. Right.

[Dr Shoghik Akoghlanian]
Exactly. Exactly. I mean, it's just I think it's going to take longer because, you know, and it might be that they just have infections.

Right. So, it's just going to take longer. So probably a couple of episodes.

[Dr Mike Patrick]
Do these things and we'll talk a little bit more about what exactly causes them, but do they tend to run in families? So, is this something where a parent, you know, if you have a sibling or another child who has been diagnosed with a recurrent fever syndrome, is your kid more likely than to have it or is it not run in families?

[Dr Shoghik Akoghlanian]
Yeah, it can depend on what we're talking about. So, when we talk about really recurrent fever syndrome, it's not like one disease that we're talking about. Actually, we're learning a lot more about these recurrent fever syndromes than the last like probably two decades.

And there's some of them. They are they are genetics, right? Like genetics play a great role in these patients, especially specifically speaking, actually something called familiar Mediterranean fever or FMF.

This is actually about 60 percent of these patients. They have a family history of, you know, somebody in the family has FMF. Therefore, you just present with this recurrent fever.

They present with the classic symptoms that's associated with this syndrome. And then, you know, your diagnosis is pretty much, yeah, actually, you do have FMF. Yes, it does run in the families.

Others are extremely rare diseases. And sometimes people are actually never heard of this. So, yeah, it varies, depends on which specific diagnosis we're talking about.

[Dr Mike Patrick]
And that's familial Mediterranean fever.

[Dr Shoghik Akoghlanian]
Correct.

[Dr Mike Patrick]
Yeah. And then and that is something that is genetic and causes recurrent fevers. Is that through the immune system that the fevers as we think about fever and what causes fever, you know, an invasion from a virus or a bacteria causes our immune system to react and part and a lot of chemicals get released.

And those some of those chemicals are telling white blood cells and other parts of the immune system where to go and what to do. And so, our immune system, one of the sorts of side effects of it is fever. And so, you can have the immune system what we'd call an autoimmune disease where the immune system just there's not an infection there, but it still does what it, you know, it activates.

And so, we get the fever. And then we also have a thermostat basically in our brain that adjusts our body temperature. And if something's wrong with that, that could also cause you to have fevers, too.

Are these the kind of processes that happen in these recurrent fever syndromes, or is it something completely different that I'm not thinking about?

[Dr Shoghik Akoghlanian]
No, actually, you are right. So, these genetic mutations that happen to these patients that they have, this is specific recurrent fever syndrome that actually does cause this immune dysregulation. So often I explain to the families, yes, this is not something you get like that's like a virus or a bacteria, but your body is reacting to these stimuli.

Now, it can be a trigger. This trigger can be a virus. This trigger can be a stress of any sort that actually triggers this immune system that is actually not programmed correctly to release, as you said, these proteins, which we call them these cytokines.

Specifically speaking, there is this like the interleukin one and interleukin six. These are like a fancy fever protein; I would call them. And then that increase of these proteins can actually cause the body to have these fevers.

Yeah.

[Dr Mike Patrick]
So, let's say we have a kiddo that has recurrent fevers. They don't necessarily have viral symptoms with them. And, you know, we're concerned that that they could have a recurrent fever syndrome that's where their immune system is just causing the fever for unknown reasons.

How do you diagnose that? And then how do you treat it?

[Dr Shoghik Akoghlanian]
So, yeah. So, the first thing is actually just keeping track of these fevers. So very often when I see a patient, I tell them, you know, by definition, actually, when we say somebody has recurrent fever syndrome, or actually we didn't talk about this, we also call it just also known as auto-inflammatory syndrome or actually systemic auto-inflammatory syndrome, which stands for like SAID, so again, systemic auto-inflammatory syndromes.

And these are the category of diseases that we're obviously talking about today. And by definition, these are the three or more episodes that happen within the six-month span. So, when I see these patients early, I'm like, well, we need to keep track of what's happening.

So, keeping a diary of all like the symptoms, the fevers, what are the symptoms associated with these fevers, whether it's like sore throat, whether it's like a swelling in the lymph nodes or whether it's abdominal pain or like even eye symptoms, eye swelling, you know, joint pain or even limping sometimes. Rashes are very, very common in recurrent fever syndromes in general. So, I usually tell my patients like, you know, we have phones, we use them for all kinds of, you know, reasons, but it will be extremely important and helpful to actually take pictures.

So, you know, often these patients, when I see them in the clinic, they actually had the fever episode, and they are looking absolutely amazing in the clinic. Their physical exam is completely fine. They don't have any rash, any lymph nodes.

So, a lot of times is the first step to diagnose these kids is actually just keeping a diary for other patients. And I usually hand them a calendar, say like, hey, please keep a track of it. Now, why is that important?

Because as I said, there is over 50 different diseases, specific diseases for recurrent fever syndromes. And then it seems like every one of them have, I would say, specific pattern to it, to like how often these fevers are lasting for, what are the like the specific symptoms that the child present with at the time of a fever and how often these fevers are occurring. So, I think it's important to talk about the most common and benign recurrent fever syndrome, which is actually called PFAPA, which we can definitely talk more about that.

[Dr Mike Patrick]
Yeah, let's do. So PFAPA, P-F-A-P-A, what does that stand for and what is it? Because this is one of the more common ones, correct?

[Dr Shoghik Akoghlanian]
Yes, this is actually by far the most common recurrent fever syndrome in childhood. And then this is when, you know, pretty much every primary care doctor or pediatrician should know about and should know like, you know, how to diagnose this and diagnose it and also potentially treat it. Definitely welcome to send a referral if something is atypical.

But what is PFAPA stands for? So, it stands for periodic fever of the stomatitis, that's like the sores in the mouth, pharyngitis, it's kind of usually present with a sore throat and adenitis. That's when the kids have swollen lymph nodes, typically like a cervical lymph node.

So, like in the neck, the swelling, basically, these lymph nodes, it's swollen. And when you think about that, that's somebody who has sore throat, fever and lymph nodes, that's kind of you may think about strep, right? So, these are the kids that I often see that they got like a swab for strep actually a couple of times.

And obviously the rapid strep testing comes back negative.

[Dr Mike Patrick]
And enteroviruses and adenovirus both could also cause similar symptoms as well, absolutely. And those are very common. So, we do see a lot of viral pharyngitis.

And now I'm asking myself, how many times have I diagnosed viral pharyngitis? And it really is PFAPA instead, because it's not the first thing on our mind, especially when we're seeing a whole bunch of sick kids all day long who have very similar symptoms. So that's why I say it's frustrating for both parents and for physicians, too.

[Dr Shoghik Akoghlanian]
Yeah, that's exactly why it's like extreme. And you probably are correct. It's probably a viral infection, but it's just the recurrence of these.

So actually, one of the, you know, almost pathognomonic for PFAPA. So, it's kind of every time I hear this, it's kind of like the PFAPA. It's actually the regular periodicity of these flares.

So, parents come and tell me like, oh, you know, we think Johnny's going to have a fever on September 20th. And I'm like, OK, well, usually you're not going to be able to predict when your son is going to have or your daughter going to have actually an adenovirus. And they had this for a couple of months already that they know and they can predict when this fever is happening.

And typically, that for me, I'm like, I send them home and actually I tell them, hey, please, can you call me if your child actually does have a fever on September 20th? Because that for me.

[Dr Mike Patrick]
Or even a day or two from that is still going to be impressive.

[Dr Shoghik Akoghlanian]
Exactly. So, I'm like, OK, well, this is a probably PFAPA then.

[Dr Mike Patrick]
Yeah. Yeah. And so this is a good case for seeing your regular doctor when you can, because if you go to an urgent care and, you know, as an urgent care and emergency medicine physician myself, I'm not trying to drive away business, but we are much less likely to notice those patterns than your regular doctor, because then all of your visits are with this, hopefully with the same provider and they can start to notice, hey, were you just here a month ago? And wasn't it a month ago before that?

And a month ago. But, you know, so you can start to see that pattern because you're seeing the same provider in your medical home time and time again. And so, if you're able to see your regular doctor when you're sick, you're much more likely for them to be thinking about other things than just the most common things.

[Dr Shoghik Akoghlanian]
Absolutely. Absolutely.

[Dr Mike Patrick]
So then if you do have a kiddo that you determine has PFAPA and you've basically you're thinking in that direction based on their history and the physical exam findings, how do you determine that that really is what's happening? Or is it just a clinical diagnosis? Is there a test or something that you can do to show parents, hey, this is what it is?

[Dr Shoghik Akoghlanian]
No, actually, unfortunately, there is for most of these diseases, there is not really specific tests that we send off. So typically, it's just the symptoms. And there is a bunch of criteria or actually different criteria for every single, you know, auto inflammatory disease.

And it's just like really clinical diagnosis, which makes it really hard because sometimes, you know, like in pediatric rheumatology in general, actually, we don't deal with the like a black and white kind of diagnosis. We have like different shades of gray in between. And sometimes things can overlap, and it can be very tricky to diagnose them with a specific disease.

So, it'd be like I usually tell my patients, it would be like very smart if I tell you like this is what's exactly I suspect is going on. PFAPA is probably the easiest to do so. And as I said, like there is this recurrent like regular periodicity is a big one.

Typically, we do get, you know, I would say one or two sets of blood work for these kiddos. Typically, the inflammatory markers are elevated at the time of the flare. It's extremely important to know that these kids are very well.

They are completely normal in between the episodes of fever. So, they're back to normal playing, growing, doing everything that any child in their age is doing. So, they are completely well between the episodes.

And actually, even if we do repeat the testing, the blood work, I usually get a set of blood work at the time of a fever and another set when they are well. And typically, all these inflammatory markers, I do expect them to be completely normal at the time when they are well.

[Dr Mike Patrick]
Their inflammatory markers when they have the fever, though, would be expected to be high. White blood cell count, is that often high or is that normal when they're having a fever episode or it could go either way?

[Dr Shoghik Akoghlanian]
So, most of them, they are elevated. There are very few ultra rare diseases that yes, you can see low counts. Yeah, typically they are elevated.

And so are all the inflammatory markers. So, we talk about ESR or CRP, like the C-reactive protein. These are usually high at the time of a flare, and they completely get better when the child is well.

[Dr Mike Patrick]
If you don't do anything when the flare happens, how long does that usually last?

[Dr Shoghik Akoghlanian]
So, if we're talking about PFAP, the fever lasts anywhere between three to five days in general. When the child is sick, they are miserable. They have like painful auto ulcers.

And that can actually be very hard because these kids have some decreased fluid intake. Sometimes they end up dehydrated. Sometimes they have very large lymph node and for the first time and they are usually painful.

So, the first, maybe first or second episode, they end up actually in the ER or admitted because they need IV fluids. And you're definitely concerned about like an infection, right, like an infection in the lymph node. So therefore, they end up in the hospital sometimes.

[Dr Mike Patrick]
And then if you do diagnosis, is there something that you can do then at the beginning of the fever? And it's one of the predicted fevers to arrest it, to stop it so they don't have to have the symptoms for the whole three to five days.

[Dr Shoghik Akoghlanian]
Yes, absolutely. Actually, there is. So, we as a pediatric rheumatologist, it's very familiar for us as an organization, actually through North America.

It's called CARA, which is the Childhood Arthritis and Rheumatology Research Alliance. So, CARA, C-A-R-A. And for CARA, there is different or, you know, has a lot of, over actually 82 different sites in the U.S. and some outside. And experts meet. And then we, after a long, long and laborious, you know, meetings and research and data review, we come up with these called like CTP or consensus treatment plan for our diseases. Because as you know, like in pediatric rheumatology, we see a lot of like rare diseases and even ultra rare diseases.

So, for PFAPA, after actually consensus treatment plan was published several years back, and there are different treatment options we do for these kiddos. So, as you mentioned, if this and one of them, actually, as you mentioned, these fevers are predictable. So, for some reason, one single dose of prednisone, which is like the steroids, prednisolone, Orapred, these are all different names for the same thing, basically.

So, one dose of oral steroids at the time of the fever or at the onset of the fever actually may shorten the duration of the episode or maybe it's just completely actually aborted the episode completely. So, the child gets the first dose. Some of the children, they may need a second dose if the fever doesn't resolve completely within 24 hours.

Typically, that's also one of the criteria actually Kira has for PFAPA. So, if the fever resolved, that kind of is another sign for me that actually, yes, this is a PFAPA.

[Dr Mike Patrick]
Yeah, because if it were really a viral illness, you wouldn't expect one or maybe two doses of prednisolone to help them feel better that fast.

[Dr Shoghik Akoghlanian]
Exactly.

[Dr Mike Patrick]
So, it's kind of confirmatory.

[Dr Shoghik Akoghlanian]
Exactly. I actually tell my patients this is like a diagnostic trial, just as much as it is a therapeutic trial.

[Dr Mike Patrick]
Yeah. Now, is there anything that can be done to prevent the fever from happening in the first place? So, like a maintenance sort of thing so that it just doesn't happen.

I suspect that the issue there is that we don't necessarily want to diminish the effectiveness of the immune system in between episodes, you know, because then you may be more prone to other infections. So, it's kind of a balancing act right between you want the immune system to work when you need it to work, but you don't want it to fire up on its own either.

[Dr Shoghik Akoghlanian]
Right. That's kind of like a general rule for all our diseases in rheumatology, where we actually give some immunosuppressive medication, but then we also may decrease the risk for having infections. But for PFAPA specifically, so there are a couple other medications that we can use to prevent fevers from happening.

One of the medications actually called cimetidine, this is a medication for stomach pain or medication similar to actually Pepcid. For some reason, when we give it to these patients, they actually stop having fevers or have less fevers. Another medication actually called colchicine.

Colchicine actually is one of our first go-to medication for most of our recurrent fever syndromes. So even if it's genetic, so for example, familiar Mediterranean fever that we did bring up earlier, it's actually the treatment of choice for that as well. So, it's tricky because these are the, we tell patients like, you know, your child is not having fever every day, but they need to take these medications either once a day for the colchicine or twice a day for the cimetidine to stop actually having fevers.

So, it is going to be a lot of, you know, counseling about compliance because, you know, that's going to become an issue. Actually, there is one other thing I don't think we hit on, but this is extremely important. When we give these steroids, I always warn the family because after we use it for so many, let's say a couple episodes or a couple months, these fevers become irregular and also may become more frequent, which is the challenge, which I feel like most of my patients be like, you know, well, we're not OK with this.

We used to know when Johnny was having a fever, but then now we don't. And these fevers seem to be more often and we're giving them more steroids. And that's why extremely important then to actually talk about different options of treatment.

[Dr Mike Patrick]
Yeah, yeah. And also important, I would think, to have a pediatric rheumatologist involved in your care, because there's going to be a lot of nuance to this. And you are going to see all the different variations because you get kids referred to you.

And so, you see an unusually large number of these kids compared to primary care doctors. And so, you're going to have a better idea of what you have seen that has worked and what has not, what doesn't work as well and how some families may need a different, you know, a different management plan than others, even though they might all have PFAPA.

[Dr Shoghik Akoghlanian]
Exactly. Yeah. Usually, it's kind of like a team decision because, as I said, we do have these consensus treatment plan.

One other treatment we didn't mention about is actually tonsillectomy. So, for some reason we don't understand yet. There are so many studies, you know, going on with it, like just studying the tonsil tissue, but actually taking the tonsils out.

So, getting a tonsillectomy for most of these PFAPA patients, it's curative. So sometimes it's just like a family discussion to, you know, what do we want to do? Do we want to just give, you know, ibuprofen and Tylenol and let it run its course?

Because after all, PFAPA is a disease that kids grow out of. So, it's just a matter of time. As much as, you know, I see patients who are like, we don't want to do anything.

Let's just let it be. And then we give ibuprofen and Tylenol. However, when the kids start going to school, there is, you know, so many school days they're going to miss.

It's a big burden for patients, for parents, even that they're working. You know, I had my kids in the daycare and if they have a fever, you need to go pick them up or even from the school, you have to go pick them up. So, they call in off work and it's just really a big burden for the parents as well.

So sometimes I tell them, you know, we really need to do something about this.

[Dr Mike Patrick]
Yeah. Yeah. Yeah, for sure.

Cause that starts to really interfere with your quality of life and your family's quality of life. When you mentioned the tonsils, that makes me wonder, is there an environmental cause of this, because if something is getting in the mouth, we know the tonsils are sort of the first place that things in the air, what we would call antigens, come into contact with our immune system. And so, if you get rid of the tonsils, then you don't have that contact.

So, is there, or do we think there's something in the environment that could be associated with PFAPA? And then, and then it may look like it runs in families if various, if families have the same environment.

[Dr Shoghik Akoghlanian]
Yeah. Yeah, actually that's, that's definitely one of the hypotheses as well. And then there is some new, because we were talking about like, you know, yes, could it be, could PFAPA run in the families?

There is some newer data from National Institute of Health that there is a genetic variant that can actually, of course it's not confirmed yet, but it can be the cause of PFAPA. As for now, as I said, we don't know the reason why there is, why this happens, but there is actually an ongoing trial right now to see if this variant is truly the cause of PFAPA. And this actually is recruiting.

You can find the link for it in clinicaltrials.gov, and then they just need basically a lot of patients, so over a thousand patients to actually confirm this link.

[Dr Mike Patrick]
Yeah. Yeah. There's a lot of overlap in this area with rheumatology and with allergy then too, just to confuse things even more.

[Dr Shoghik Akoghlanian]
We actually care for our patients with, you know, in general with our infectious disease colleagues. So, you know, it's not surprising the kids is getting sick all the time, so they can be referred to immunology because they may think also that there is some immune deficiency of some sort. As I said, the infectious disease colleagues and definitely us in rheumatology, pediatric rheumatology.

Yeah.

[Dr Mike Patrick]
Yeah. Yeah. I tell you, it's quite frustrating for, again, for the families and for us physicians as well.

And when you mentioned there's actually 50 different diseases that can do this, fortunately there's just a handful that are the most common, but it can make it more difficult. And so hopefully families understand that like we're doing our best, but we might not be able to get the right diagnosis immediately, especially when things aren't as common. And then when the symptoms are things that are caused by very common things, that makes it even more difficult.

The other one that you had mentioned, familial Mediterranean fever or FMF, that one is less common than PFAPA, correct?

[Dr Shoghik Akoghlanian]
Yeah. So, this is, so PFAPA is the most common benign recurrent fever syndrome. FMF is the most common genetic, genetically mediated autoinflammatory syndrome.

So, it's actually very common in the area of the world and like around the Mediterranean as the name applied, right? Like it's a very much common, the incidence is significantly higher, but it is the most common monogenic autoinflammatory disease. And we actually with bigger communities with immigrants, we actually, I have many patients with familial Mediterranean fever as well.

[Dr Mike Patrick]
Okay. So, it is also fairly common in your patient population.

[Dr Shoghik Akoghlanian]
Yes. Because we get referrals, as I said, like from, you know, a couple hours away in the nationwide.

[Dr Mike Patrick]
Is this one only fever or are there other symptoms associated with it, like with PFAPA?

[Dr Shoghik Akoghlanian]
So, fevers definitely present, just almost a hundred percent universally present in patients with FMF. The most, the most second symptom actually is abdominal pain. These patients come with severe abdominal pain at the time of a fever.

And then you think of a child you're seeing, cause like a, let's say a 10-year-old with high fevers and severe abdominal pain, you're going to, sometimes even the physical exam suggests that they may have actually surgical abdomen. Many of these patients, they even, you know, again, our providers are very concerned about appendicitis. And the, that's kind of by far one of the most concerning one, but FMF episodes of fever, they are usually short.

So about two to three days and the patient's completely better. They are absolutely miserable in between, or absolutely miserable at the time of a fever, but they're, again, two to three days, they're completely better. Now there is some other symptoms that happen with PFAPA.

So sometimes joint pain. So, we call it, I'm sorry, this is with FMF. I'm sorry.

Yes. Yes. FMF.

Yes. Thank you. So, for patients with FMF, so other symptoms, including like, we call it arthralgia, which is like joint pain or even arthritis.

And then there is a different specific rash that also can happen with FMF patients. So again, keeping track of these episodes. And we actually diagnose almost more than, I would say 90% of these patients in the pediatric ages.

So, like usually the first two decades of life, we diagnose almost 90% of these patients. And as I said, these are the patients that they have a family history of FMF. Or if they come and tell me, you know, for all my patients with, with recurrent fevers, it's extremely important to ask about ethnicity because different ethnic groups have this, the incidence for these diseases are extremely high, so for Female Mediterranean fever, like our patients, Turks, Armenian patients, Ashkenazi, non-Ashkenazi Jews, it's extremely common, so if you see like just fever patterns that suggest FMF and they have background or ethnicity that suggests also FMF, so these are the patients that typically they need Colchicine right away.

[Dr Mike Patrick]
So, this is different than juvenile idiopathic arthritis, which can also have fevers and joint pain and rashes.

[Dr Shoghik Akoghlanian]
That's a completely different game ball, but yes. So, we actually, juvenile idiopathic arthritis, which stands for JIA, so juvenile because it's less than 16 years of age, idiopathic, which means we don't know why it happens, arthritis. So, it's actually, there is, it's one of the most common diseases that we see in rheumatology, so about like roughly 75 to 80% of all our patient populations with JIA, but then there's different types of JIA.

Now, one of them, which is called systemic JIA, is the one that presents with the fever, the rash, and the arthritis. Surely, it's like the triad, right? Like fever, arthritis, and a rash.

But then there is, and this is called systemic JIA. Now we have several other subtypes of JIA and none of the other subtypes actually presents with a fever. So, they just present with arthritis, which typically when I say arthritis, I'm referring to persistent joint swelling and pain or limitation in a joint.

[Dr Mike Patrick]
So how do you diagnose FMF then, especially since there is some overlap with systemic JIA, as we're throwing letters out here, and I'm hoping that families, you know, just understand the complexities of what we're talking about. It's amazing that we understand what we do understand, to be honest.

[Dr Shoghik Akoghlanian]
Yes. Yes. And then there is, well, it seems like the more we think that we're understanding more, it seems like we're, we need a lot more.

We kind of realize that, oh, there is a lot more to uncover. So FMF and systemic JIA is completely different things. So, while FMF presents with recurrent fever.

So again, these are episodes of fever. So, the child is sick, has fever, abdominal pain, sometimes rashes, sometimes joint pain or arthritis, and then it gets better and then it happens again. So, for systemic JIA, it's a completely different, you know, symptoms.

So, you have a fever and the joint pain and the rash. Now, sometimes not all of them are present at the same time. Sometimes the fever starts and until a few days later when the rash pops or the arthritis, you know, the swelling comes up.

So, these are, systemic JIA is not recurrent. Okay. So, these are, the kids are sick.

They have high fevers. They're miserable. And typically, systemic JIA patients, they end up in the hospital with a fever of unknown origin, we call it.

So FUO. And then these are the patients that they end up in the, sometimes, very often actually in the infectious disease service because they think it's an infection because, you know, common things are common again. So, we do very, very thorough infectious workup for these patients.

And typically, when everything comes back negative, our colleague in infectious disease, they call us, it's like, hey, you know, we have been, you know, we have, let's say Johnny here and we run so many tests, and everything is negative. We don't think there's any pathogen that causes the disease. These are the patients that are really actually sick.

Sometimes their white count is extremely high. And the one thing we do need to rule out for these patients is actually neoplasm or like malignancy in children. Leukemia or lymphomas because they are also systemic JIA patient, they may have a lot of enlarged lymph nodes.

So sometimes we may need to do like a bone marrow biopsy or a lymph node biopsy because the treatment is completely different, right? Like if they have systemic JIA versus if they have leukemia, we need to get to the diagnosis first before we start any treatment.

[Dr Mike Patrick]
Now with FMF, is the recurrence as regular as it is with PFAPA?

[Dr Shoghik Akoghlanian]
No, actually it's very irregular. It's very irregular. Sometimes the stress can actually trigger the flares, but it's very irregular.

So, it's not predictable.

[Dr Mike Patrick]
Yeah. And that, so that is one, one thing you can, in the clinical history that you can use to differentiate FMF from PFAPA.

[Dr Shoghik Akoghlanian]
Absolutely.

[Dr Mike Patrick]
Now, even though it's Mediterranean and we talk about the, the ethnic groups where it is most common, we still want to keep it in mind for everyone. Correct? Because as, especially, you know, in the melting pot of the United States, we're, there's a lot of sharing of genes.

And so, we don't want to rule something in or rule something out strictly based on ethnicity. Correct?

[Dr Shoghik Akoghlanian]
Absolutely. Absolutely. Yes.

[Dr Mike Patrick]
And then in terms of, you said PFAPA, kids typically outgrow it. What about with FMF? Is that something that also goes away as they get older, or no?

[Dr Shoghik Akoghlanian]
Yeah, no, not really. So, when we talk about FMF, we said it's genetic and typically this is an autosomal recessive, which means we need the two genes for someone from the mother's side, one from the father's side to actually the child present with, with this. And we do have genetic testing to confirm this, this specific disease.

And we send this pen. Also, let's say if the patient comes back positive and the testing becomes diagnostic for FMF, these are the patients that we need to actually treat them for life to actually prevent some of the complications with FMF, something called amyloid doses. And what that is, is basically a result of continuous inflammation.

When this amyloid protein actually gets deposited in different parts of the body. One of the most important ones will be like when it gets deposited in the kidneys and it can cause end-stage renal disease and that sometimes can be irreversible. The problem is these are the patients that they are in their 30s or 40s or even 50s when they end up with dialysis and sometimes, they need renal transplant.

So, these are the patients that we need to treat them. The great news is that colchicine is a medication that works in this group of patients, or let's say most of these patients, and it actually does prevent amyloid doses. They need it every day.

[Dr Mike Patrick]
This has been a really fascinating conversation and it's so interesting. We'll have to have you back at some point and just do JIA, juvenile idiopathic arthritis, because we could easily do an hour on that alone.

[Dr Shoghik Akoghlanian]
Absolutely.

[Dr Mike Patrick]
But what is your take-home message for parents whose kids have fevers frequently? Like, you know, from a parent standpoint, when do I bring this up? When am I concerned?

When do we need to go see a rheumatologist? Kind of break it down for parents. What's the most important message here?

[Dr Shoghik Akoghlanian]
Yeah. Now, keeping track of what's happening is really the most important thing, and when things start, it's extremely important to go and be seen, as you mentioned earlier, better if it is with your primary care doctor, but totally understand that your primary care doctor may not be there all the time. So, and then I would really encourage all the parents to actually bring up and say, yeah, you know, Johnny was sick the last time or last month, we had similar episodes.

I think just keeping track of what's happening and then just bringing their concern that, oh, we think there might be some recurrence here. And that's when the primary is to say, yeah, you know what? Let me just go ahead and, you know, send a deferral to rheumatology.

However, in the meantime, it will be extremely important to keep a diary of all the symptoms. So, when they come to me, at least I'll be able to look through, you know, we said we need six months to diagnose these, right, like by definition. So at least I have a couple months of symptoms so I can look through and say, oh, this looks like PFAPA, or this doesn't look like PFAPA, and we need to investigate more.

I think also being patient is, is helpful because these things take a long time to diagnose. And I see a lot of parents get frustrated. They need answers right now.

And actually, what's even more frustrating that let's say we are seeing a patient that's not PFAPA, that's not FMF, but it's one of these ultra rare different diseases that we have that they cause recurrent fever syndromes, and we need to send the genetic testing. The genetic testing takes about, you know, four to six weeks, sometimes eight weeks to come back. But the tricky part is about 40% of the time, sometimes 50% of the times, the genetic comes back, genetic testing comes back.

That's not diagnostic. We actually see many of these, you know, different variant of unknown significance, we call them. So, it's called BUSs that basically, you know, they don't really diagnose the child with anything, but then unfortunately they don't give me a specific diagnosis for why they actually have recurrent fever syndromes.

We actually do call these patients N-specified systemic autoinflammatory diseases. So, and sometimes not, you know, all parents are open to say, yeah, you know, I definitely need a name for it. I'm like, well, they kind of do have a name.

It's just N-specified yet. And I'll tell you, like, I have patients that I cared for over like a decade. And after that, we were able to actually find out to what specific new diagnosis they have.

So, it's fascinating. Although the treatment sometimes it's still the same. We still treat them.

In rheumatology, we seem to deal with many of these diseases that they are like unknown, and we still treat them. We still have different, you know, like the art of medicine for pediatric rheumatology is definitely a thing. And we try them, we'll treat them with the most appropriate medication and get them feeling comfortable, take care of their inflammation, stop the fevers from happening, et cetera.

But we may not have a name for it.

[Dr Mike Patrick]
Yeah. Yeah. But we might in five years, or we might in 10 years as we continue to understand genetics and are able to diagnose genetic conditions.

[Dr Shoghik Akoghlanian]
Absolutely.

[Dr Mike Patrick]
So patients, that is, that is a, that is a good, and I think hopefully we've done a good job over the course of this episode of really shining a light on how complex this can be and why patience is needed all around, but at the end of the day, everyone has your child's best interests in mind and really wants to get to the bottom of what's happening and get the correct diagnosis and the right treatment so that we can have the best outcomes.

It's just, unfortunately, unlike other things where we have a real quick test with these, we don't often have a clear test to say yes or no. It's great. As you said, gray area where the, where the rheumatologists live are the gray area, the gray zone.

[Dr Shoghik Akoghlanian]
We have our genetics department. We have like in the recurrent fever clinic, we have our genetics and a genetic, a genetics doctor and then genetic counselor, which help us out. And in nationwide, we're doing absolutely amazing job where we can even, if the initial genetic testing comes back negative, we usually start with a, like a smaller panel and then sometimes we dig even more, I usually tell my patients, it's just looking at the stars with your own eyes versus looking at the stars with a telescope versus looking at the stars from like NASA.

So, it's, we get to like different testing, depends on how, you know, we think the child is doing or how much concerns we have that, yes, this is actually a genetic disease to our geneticists are absolutely amazing at Children's to, to help us out.

[Dr Mike Patrick]
Yeah. Yeah, absolutely. Well, we are going to have lots of supporting links in the show notes, both for parents.

Also, if you're a pediatric provider who is listening, we are going to have a lot of sciency resources for you as well in the show notes. So be sure to head over to pdacast.org. This is episode 588 and you'll find all of those resources.

Some of them we have talked about the classification criteria for auto inflammatory recurrent fevers, the consensus treatment plans for PFAPA. We have the syndrome of undifferentiated recurrent fever, just lots of articles for folks to explore. So, if you want to learn more about this, we'll definitely have something for you over in the show notes.

So once again, Dr. Shoghik Akoghlanian, pediatric rheumatologist at Nationwide Children's Hospital. Thank you so much for visiting with us today.

[Dr Shoghik Akoghlanian]
Absolutely. Thank you so much for having me.

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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 a part of it, really do appreciate that. Also, thanks again to our guests this week, Dr. Shoghik Akoghlanian, pediatric rheumatologist at Nationwide Children's Hospital. Don't forget, you can find us wherever podcasts are found, or in the Apple Podcast app, Spotify, iHeartRadio, Amazon Music, Audible, YouTube, and most other podcast apps for iOS and Android.

Our landing site is pdacast.org. You'll find our entire archive of past programs there, along with show notes for each of the episodes, our terms of use agreement, and the handy contact page, if you would like to suggest a future topic for the program. Reviews are also helpful wherever you get your podcasts.

We always appreciate when you share your thoughts about the show, and we love connecting with you on social media. You'll find us on Facebook, Instagram threads, LinkedIn, X, and BlueSky. Simply search for PediaCast.

We have a couple of other podcasts I want to tell you about. If you are a pediatric provider, we do have a podcast for you. It's called PediaCast CME.

That stands for Continuing Medical Education, and it is similar to this program, we do turn the science up a couple notches, and we offer free CME and CE credit for those who listen. And that's not only for doctors, 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 that we can offer the credits you need to fulfill your state's continuing medical education requirements. Shows and details are available at the landing site for that program, PediacastCME.org.

You can also listen wherever podcasts are found. Simply search for PediaCast CME. And then one more podcast that I host, because two's not enough.

Everything comes in threes. This one is a faculty development podcast. So, if you are a medical faculty in any specialty, does not have to be pediatrics, just any medical faculty.

So, if you teach medical students and residents and you are a faculty member at an academic institution, then we have a podcast for you. It's actually from the Center for Faculty Advancement, Mentoring, and Engagement at the Ohio State University College of Medicine. It's called FAMEcast.

So, if you are a teacher in academic medicine or a faculty member in any of the health sciences, then this is a podcast for you. You can find FAMEcast at FameCast.org and wherever podcasts are found by searching for FAMEcast, F-A-M-E-C-A-S-T. Thanks again for stopping by.

And until next time, this is Dr. Mike saying, stay safe, stay healthy, and stay involved with your kids. So long, everybody.

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