00:00 So one of the things we wanted to do in this next section is talk about those ID adjacent conditions where we might get called. As infectious disease providers, you are handling this on the front lines in these situations. So this might range from, abdominal pain to inflammatory conditions that occur after infections or to bone and joint or other rheumatology, abnormalities that occur.

00:25 So that's what this next section is going to look like. And it's my pleasure to introduce for the for the first part of this, doctor Mary Beth Nicholson, Mary Beth Nicholson is associate professor of pediatric gastroenterology at Vanderbilt University Medical Center. Mary Beth and I have worked together for, for many years together now. And she's really expert in things like C difficile and inflammatory bowel disease, but also in evaluating functional abdominal pain.

00:50 And if I can just say, personally, Mary Beth was enormously helpful, even to our own daughter who was experiencing functional abdominal pain. So we're going to talk a little bit about what that looks like to evaluate them and to do well by them. So please help me introduce Mary Beth Nicholson. Come on up. Thank you. You must present perfect.

01:10 Thank you. Good afternoon. It's great to be here. Thank you for the invitation to present to you all today. So I'm going to be discussing, understanding and evaluating both post-infection and functional abdominal pain syndromes in children. And my only disclosure as I write for of today. So in terms of objectives, I hope by the end of this talk you can describe the evaluation of functional abdominal pain disorders, including when you actually need to do an evaluation, which kind of spoiler is not all that often.

01:39 And then also understanding the most common post infectious abdominal disorders. And I always say, if you know a child or maybe if you were once a child, you probably know somebody that has functional abdominal pain. So the prevalence globally is around 11%, which is really just you can imagine exceedingly high, to one and nine children worldwide are affected by a functional abdominal pain disorder.

02:04 And this is actually over 50%. It's pretty much close to 60% of what we see in pediatric GI clinics in the United States. We know that this happens more in girls and boys. But if you thought we were doing kind of bad with this in the United States, this is actually not the highest prevalence place. So Asia has the highest prevalence of functional abdominal pain disorders, followed by Europe and then North America.

02:27 I feel like Canada is probably helping us out here. If I had to guess. So when we think about the term functional abdominal pain disorders, this is truly an umbrella term. And based on the last DSM five, that was put out several years ago in 2016, there's now 33 separate functional abdominal pain disorders in adults and 17 in children.

02:49 Irritable bowel syndrome, whether that's constipation predominant, diarrhea predominant, or not otherwise specified, is the most common of our functional abdominal pain disorders. Functional nausea, which is where patients present primarily with a symptom of functional nausea, is certainly increasing. We see high rates of cyclic vomiting syndrome rumination as well as abdominal migraine. And so there's actually been a name change, based on this last DSM guidance where it's now referred to as disorders of gut brain interaction, I would say within the field, a lot of people still use that functional abdominal pain disorders title.

03:23 But the overall reason for the switch in nomenclature was just to express this high interplay between brain and gut interactions that really lead to a lot of the pathophysiology of this important condition. And so I'm going to use these terms interchangeably. But in general, I describe this to families as there's this known connection in our nervous system, primarily mediated by the vagus nerve that communicates between our brain and our gut.

03:47 And we think about if we have a patient that's more stress, that's communicating to the gut in such a way that increases motility or causes visceral hypersensitivity, then you have more pain that communicates back to the brain, causing anxiety to get worse. We get in this really bad feedback loop. And so it's really important to address both of those areas for optimal healing.

04:05 The one thing I think is interesting in recent years, and as somebody that studies the microbiome, I think is really fascinating, is that we thought a lot of this connection was brain to gut. But now it turns out that probably about 75% of that connection is gut to brain. And some of that is microbial mediated with specific metabolites that are paid by the intestinal microbiome.

04:25 So I think there's a lot more to come here. And but the overall goal of renaming was just to kind of highlight this pathophysiology that seems to be really important okay. So I think you know this has been a challenge with treating these patients. And this is probably something that I felt initially when I was caring for patients.

04:41 And where, you know, we see another kid on our schedule with abdominal pain. They're not going to school. They need school notes. They want to be on homebound. And there's this connotation, oh no, not another one. This is going to take forever. You know, they're not having pain. Just go back to school. You will find me. You have lost weight.

04:57 You know what's the big deal? And then also that that itch in the back of all of our brains is, you know, could it be porphyria? I would say that there was a time in my life I tested for more porphyria than I do now. But I hope, by the end of this talk, we can have a little bit of change in that agenda and understand the functional disability that comes with these, patients and, and that their pain is very real and they need some time and attention.

05:19 And I also want to give you some reassurance when this truly is a disorder of gut brain interaction, and you don't have to continue to do additional testing. Okay. So let's start with a typical case. So this is Sean. He's ten years old. He loves school. He gets really good grades. He's popular. He does well at sports.

05:37 He puts a lot of pressure on himself. His parents describe him as a high achiever. We all know these kids. I'm going to guess in this room. A lot of you are probably this child. So he presents to you, though, because he's been having a lot of abdominal pain. Symptoms started a year ago. He initially had severe vomiting, abdominal pain, and diarrhea.

05:55 They had gone out to eat the night before, so parents thought maybe this was food poisoning, that nobody else was sick. The vomiting resolved, but he continued with a lot of pain and intermittent diarrhea, and he started missing a lot of school related to that, which was really atypical for him. And now his parents are very concerned, very anxious about this as well.

06:12 So you get some more history on his pain and diarrhea. And it's crampy abdominal pain. It's intermittent. He has alternating diarrhea and constipation but no blood, no mucus in stools. He's not waking up during the night related to pain or diarrhea. He does have some bloating or gassy ness. And he does feel that overall, when he has a bowel movement, it will relieve his pain.

06:34 He's also having significant disability associated with this pain. And this is a really important point that I focus on with all of these patients that come for abdominal pain is understanding how their life is really affected. On the day to day. He's missing school. He's not participating in his favorite activities. He missed his basketball tryout. He's also having other pain now.

06:52 He's having muscle pain and headaches. His sleep is disturbed, and mom notes that he's just really anxious. Like he doesn't want to go to a birthday party because he's worried about what if. What if I get pain while I'm there? What if I get pain while I'm at school? And so let's talk about some of the risk factors, some of which Sean had for, the diagnosis of disorder of got pregnant or action.

07:13 And I'm going to focus on the ones here that are most common in our pediatric patients. I mentioned female sex before. This history of gastroenteritis is a really important one. I'm going to talk about that in upcoming slides as well. A lot of our patients will have a history of trauma and abuse or lifetime stress. We know psychological disorders increase the risk of this.

07:31 And how I screen for that in my patients is I think if you ask them if they have anxiety, that's a little bit of a harder question to answer. But I'll say is this is, you know, Sean, a kid that's pretty laid back, really doesn't get bothered or overthink things, or is he a little bit more of the overthinker warrior type?

07:46 And that's when, like the parent looks at the kid and they both make eyes at each other because they're usually an overthinker worrier. And then, somatic symptoms, poor sleep increase the risk of having a functional abdominal pain disorder. But I want to note here is that the ones that matter the most for persistence. So not just whether or not you have functional abdominal pain, but whether or not you continue to have functional abdominal pain is whether or not you have a psychological disorder or significant stress.

08:12 And so that's why it's so important to make sure that we're treating that part of this brain got access. When we care for these patients okay. So these are my personal clues on when this seems like functional domino pain disorders. And so these are the things that I look for in all my patients. And I hope they're helpful for you as well.

08:29 But in general, I know they say like, never say always, but, Perry, umbilical pain is always, almost always constipation or irritable bowel syndrome. Functional bowel pain. And so if they're it's either Perry umbilical or it's multiple locations. They said sometimes it's left lower quadrant, sometimes it's left, sometimes it's epigastric. Those are all much more likely to be a functional abdominal pain disorder if they have no clear pattern.

08:54 So if it's not just with eating, it's not just at the time of their menses. But it can be random different times of the day. That's also a significant clue that this patient has a functional abdominal pain disorder. If they have other somatic complaints, headaches, or in particular very common, and then if they endure anxiety or stress.

09:11 And that can be in both the patient or the parent. And that's why we screened for that and parental family history as well. Okay. So I wanted to give you some warning signs though, that when you know, when this may not be a functional GI disorder and when we may need to work other things up, I'm not going to go through this whole list.

09:27 I think some of those are obvious. Like if somebody has bilious emesis or hematomas or melena, it's probably somebody we need to think a little bit more about and do a little more evaluation. I think weight loss is a really important one for me. That can be the presenting sign of inflammatory bowel disease. So if a patient comes in with weight loss, that somebody that I'm going to do additional workup on, it does not mean that they don't have a functional GI disorder.

09:49 Plenty of these patients will also have an eating disorder overlap. But that just tells me that I need to do additional workup. Family history of IBD is also important, particularly first degree relatives about, patients that have a family history of first degree family history of IBD have a risk of around 10% of having inflammatory bowel disease to significantly increase the risk of that.

10:10 Dysphasia is another big one for me. So that's the sensation that food is getting stuck with swallowing and particularly foods that can happen with drinks as well. In general, patients that have eosinophilic esophagitis will have a lot of belly pain and have some intermittent vomiting. That feels like a functional GI disorder. But the big differentiating factor will be this, report of dysphasia nocturnal symptoms.

10:33 So I ask all my patients about that. Are you waking up from sleep to have a bowel movement or because you're, you're having abdominal pain? That's a red flag as well. And then finally anemia, particularly in a non menstruating female or in a male patient. Okay. So this is my workup that I do. And I think that's pretty well recommended.

10:52 Within most of the society guidelines, I remember being a first year med student and I had an upper level med student tell me before I did this didactic where you have to come up with differentials. And they said, Marybeth, if you don't know anything to put on the differential, just say lupus, because lupus can cause anything. And I think, celiac disease is kind of the lupus of GI.

11:13 So, celiac disease can cause the classic failure to gain weight, diarrhea, abdominal pain that we think of as a classic celiac patient. But it can also cause constipation. And we have patients that have significant obesity in the setting of celiac disease, just vomiting. And so I think that's something that if you're worried and again, we don't have to do this in everybody.

11:32 This is ones that have some additional red flags where that maybe aren't responding to our classic therapies. I would check a celiac panel. CNP is generally is a screening for kidney disease, liver disease, gallbladder disease, inflammatory markers I check as a loose screening for inflammatory bowel disease. These can be normal in about 10% of the population. So just remember that if you have a patient with weight loss or some other red flags for inflammatory bowel disease, if you have a normal ESR and CRP, that's probably not enough.

11:59 Still, cow protection is the better marker for those patients. So that's a better screen of, inflammation in the bowels, particularly the colon. Some of these patients, I'll get an X-ray and sometimes I'll get an abdominal ultrasound on if I'm concerned about other red flag symptoms. And then if there's a strong family history or exposure history for each pylori, you can check a family.

12:18 And again, those patients probably should be referred to our guest or and our allergist though, because there's a wide, you know, guidelines on, on if they need a scope and how to best treat them. Okay. So I think when we think about Sean, he clearly meets the diagnostic criteria for bowel syndrome. So he has recurrent abdominal pain that's happening at least one time a week.

12:38 It's been chronic, has been going on for over six months. He has it related to defecation. So it improves when he stools. And he's also having a change in both his frequency and form of stool. And so the other thing that I think we want to note about Sean is that his followed what seemed like a classic gastroenteritis.

12:56 And so I would say that Sean has a post infectious IBS, an acute infectious gastritis is one of the strongest risk factors for IBS, so much so that it is felt to account for nearly half of the overall prevalence of IBS. So really just remarkably high symptoms in general will be like Sean's. So they generally happen the more acute symptoms resolve and then they're left with some persistent pain and diarrhea.

13:20 But if you have an acute gastroenterologist, you can develop functional abdominal pain at any point within the six months post-infection is still increased risk period. This is also higher in women. It's higher if there was an antibiotic exposure with this, infectious gastroenteritis and or in patients that have a history of depression and anxiety. Okay. So I am going to talk a little bit more about how we can best treat these patients.

13:45 But I think there is a general misunderstanding about the goals of treatment in our patients with functional GI disorders. I think a lot of times we think the goal is to decrease the abdominal pain and the vomiting first and then restore the function, but it's actually the opposite. We want to restore the function and then the other things get better.

14:02 So we want that patient to get back to their activities to get back to school. And that's the main first priority. And if we can do that, there's been multiple studies saying that if you get them back to school, that abdominal pain is going to get better on its own over time. And so I think we have to remember that that's why we don't do homebound for these patients.

14:19 Okay. So there's things that we think about in terms of coping with pain. And they're all kind of around this volume control metaphor. So basically talk to our patients that they control the messages that go from their brain to their gut and their gut to their brain. And there's ways to do that. The mind is like a stereo.

14:33 So you can turn that volume up or down on the pain signals. So how to turn that pain up is generally stress and excitement. So any kind of nervous system stimulation, we all have these kids that are going to, have pain or vomiting on Christmas and their birthday every year. So it doesn't just have to be negative stress.

14:52 Even positive stress can kind of stimulate the nervous system for this to happen. We also know worry about that pain, particularly this worry that something is being missed with the pain that there's something else going on. And so we do a lot of reassurance in our clinic to address that, and then isolation and inactivity again, while we really try to encourage our patients to get back into their regular activities in school.

15:12 So how do we turn that volume down? So reassurance and education is a lot of this. So not that we do this testing, but it could be something else if you don't get better, if you're not feeling better, we're just keep looking and eventually test for porphyria, but rather that we think that we know what's happening and we know how to treat you and you're going to get better.

15:31 And these are the steps that we can all do to get you there. So it's a lot of eliminating this fear of the unknown. And then we want to validate that these symptoms are real but not dangerous. So the analogy that I use in clinic that I feel like kids with families really well is that functional GI disorders are really similar to a migraine.

15:47 I think everybody is familiar with somebody that has a migraine, which can be really disabling pain. But if we look at MRI's and Cat scans and bloodwork with an MRI, generally they're all pretty normal, right? So disabling a pain normal study is because the pain mechanism is something different. And functional GI disorders are the same kind of process as a migraine, except they're occurring in the belly.

16:05 So these are very real symptoms, but they're not life threatening. And we really want to encourage this return to school. Mind body therapies can also be effective. And we're going to talk about some of those. We're going to talk about some dietary triggers as well as pharmacotherapy. For the last couple of minutes of this talk. So when we think about mind body therapies, the ones that we use the most in our clinic are cognitive behavioral therapy and biofeedback.

16:28 We are very fortunate in our GI clinic to have a psychologist that partners with us to do these visits and do a lot of education. I would say that I know not everybody is so fortunate. But in general, most psychologists are well versed in cognitive behavioral therapy. So identifying a psychologist locally that can see these patients is really helpful.

16:46 We had a fellow that trained in clinical hypnosis and that can also be very effective for patients with abdominal pain syndromes. There's online classes there's online kind of courses that patients can use that can be really helpful. Breathing techniques, mindfulness guided imagery are all kind of in that same grouping. And so identifying what is tailored to the interests of the patient is really important.

17:09 And so when we think about diet, my general approach at this point is to identify some of the most common triggers. And so I would say lactose and fructose are really one and two. And lactose can be a trigger for functional abdominal pain even outside of the setting of classic kind of lactose intolerance. And they'll still have a lot of pain with lactose ingestion.

17:28 So this is the more obvious. So they'll say I had a bowl of cereal with milk and I hurt nearly immediately afterwards. And so I generally do a two week trial of elimination of that to see how much better they feel. And if we need to continue working through other things. Fructose can be a little bit more nebulous, in part because it's in so many different foods.

17:45 So certainly it can be in things like high, high fructose corn sirup, but we can also see it in fruits and vegetables, and it can cause a lot of pain in our, patients that are fructose intolerant. And so I generally will evaluate as food triggers that may be causing them to have more pain that seem to be more fructose oriented.

18:03 And then I would recommend doing elimination with consultation with a dietitian. I again, I'm lucky I have a dietitian who sits next to me in clinic, but, I think these can be really limiting diets, and it's important to kind of work with a dietitian on that as well. I mentioned the low Fodmap diet here. I would say five years ago I was using that more commonly.

18:21 So that is where you do an elimination of many foods. So fermentable oligosaccharides, disaccharides, monosaccharides and polyols, it's highly restrictive. I really don't use it much anymore because I found that it was usually fructose and lactose. And so, I kind of stick with those. Now, classically, the low Fodmap diet, you would take out all of these foods for 4 to 6 weeks, get that patient feeling better, and then slowly reintroduce them to see which ones are tolerated.

18:45 So again, very restrictive. But I think there are patients that this can be helpful for. But again, you need to do is in the consultation with a dietitian. Okay. So let's talk a little bit about medication treatment for these functional GI disorders as well. So and I suppose magicks are kind of one of our first line therapies.

19:04 These are anticholinergics that are really effective at decreasing contractility of the bowels die cycle I mean in high dose the mean are the ones that we use are most widely available. I in general use these as needed in kids that have infrequent pain. But if you have kids that are having almost daily pain, you can schedule these.

19:22 So I schedule them twice a day. They can use a third dose as needed and they can be very effective that way. I don't view these as something forever. It's almost just to get that pain light switch turned back off, break that cycle and then we can go back to as needed. Use the main side effect to watch for in these is constipation.

19:39 So tricyclic antidepressants I also commonly use particularly amitriptyline can be highly effective for our patients with functional GI disorders. We start at a low dose. So I generally start at 0.5 makes per cake nightly. I advise patients that they can have some sedation. At first. There is prolongation that can be associated with amitriptyline. That's generally higher doses. When you get closer to the 1.5 to 2 makes per kilo.

20:02 But I still get a screening EKG prior to starting amitriptyline. Supplements can be really helpful as well. I've had a lot of patients have success with these, particularly IB guard, which is available over the counter, and you ordered on Amazon pharmacies, grocery stores, etc.. It's technically peppermint. I think they add a few extra things to make it more exciting, but peppermint has been shown to decrease the contractility in the bowels and can do that pretty effectively.

20:27 The patients I don't use this center or those that have significant reflux because peppermint can worsen reflux. So that's the one group that I avoid this in. These are capsules that can be opened and sprinkled into applesauce or ones that can't swallow the capsules, and you do them before meals again, I don't use it as a forever. It's almost just let's get this pain cycle stopped and then we can use it just as needed.

20:47 Finally identified triggers. So loperamide we'll use for our patients that have IBS IBS it's diarrhea predominant. Linac lated or the brand name is Linzess or Miralax can be used really effectively for constipation. For those of you that haven't used for nucleotide yet, I really think it is an excellent addition to our arsenal and patients that have constipation predominant IBS.

21:11 It is FDA approved in kids, but it wasn't really not widely approved by insurances or paid for by insurances until the last six months or so. It has some better effects for pain than Miralax does. But mechanism is similar where it's kind of holding in water into the bowels. It's also a capsule. So I think we all struggle with compliance sometimes with miralax, but with Todd, it's easier for these patients to take.

21:35 And then fiber supplements can be helpful too. I much prefer dietary fiber. And when I do use fiber, the one thing we know with patients with functional abdominal pain disorders and, fiber is that it can worsen some pain. So you really want to start low and go slow. Okay. So I want to as an important nod to the infectious disease conference, I want to finish with one final case.

21:57 This is Alex. She's a 14 year old female who presents with four weeks of daily vomiting. This initially started with a stomach bug. She had multiple sex contacts. Kids at school were sick. Family members were sick. A lot of people were having what seemed to be neuro virus. She had two days of fever, diarrhea and significant non bilious, non bloody mass and her diarrhea and fever resolve.

22:21 But she really continues with a lot of non bilious non bloody mass occurring about 1 to 2 times per day. It's generally pretty passive in nature. She'll go back to her activities. She doesn't feel nearly as bad as when she had this initial infection. It's worse in the mornings and it's worse after eating. And so you see her in clinic to get more information.

22:40 She has a really normal, unremarkable exam. She hasn't lost significant amount of weight. And she has normal labs. And so this is really classic for post-viral gastroparesis. And I feel like some of you care for children in a primary care, situation may be seeing increased numbers of these. And I think we're seeing increased rates of this as well.

23:00 And so this is often transient post infectious delayed gastric emptying or accommodation to accommodations kind of how the stomach receives food. And we're certainly seeing higher rates of this across the United States. The symptoms are generally nausea vomiting early satiety, bloating and upper abdominal pain. For these kids. I generally get some lobs, in part because some of the things that can mimic this are pancreatitis or gallstones.

23:25 But I don't do additional imaging. Even though gastroparesis can be formally diagnosed with a gastric emptying study, that's generally about a four hour study to do it. Well, and I find that if I treat these patients, they just get better and I can save them for hours of their life back. So how I treat this is generally with either Cipro heparin, which allows, gastric accommodation.

23:45 The stomach allows it to relax when it receives food or with erythromycin. I like cringe at the thought of recommending a chronic antibiotic at an ID conference, but, it's it's really effective in this scenario. We use it at a much lower dose than classic if you're using it to treat an infection. So generally two makes per kick per dose.

24:05 I generally do it twice a day. I find it's pretty effective that way. And I don't leave it on forever. But I generally find that if you start, these kids feel a lot better within 2 to 3 weeks, and then I usually do them for about 4 to 6 weeks, and I wean them off pretty successfully. I would say I use Cipro have to gene a little bit more commonly in younger patients, or those that have obesity, because in general it stimulates the appetite.

24:28 And so in patients that are obese you can worsen weight. And then erythromycin I've been a little bit more successful in an older population. Or those that have other kind of appetite or weight concerns. Okay. So in summary, the majority of childhood abdominal pain is functional in nature and really doesn't require additional workup. If there's no red flags, few or no diagnostic tests are needed.

24:53 And this treatment is really multi-pronged. And so working with other collaborators is really important to improve the care of these children. IBS and gastroparesis really frequently file infections in children. And so it's something we should all be mindful of. So thank you for your time.

25:20 Never been so excited to hear about poop. That was awesome. Okay. How many of you have been to this meeting before? Raise your hand. Yeah, you're about to get a treat. Member. When Meg Fisher said she wasn't going to do this anymore. Yeah. We cried. I would dare say sobbing occurred. And so this is like Tom Brady coming back to start for the Patriots.

25:42 Again. This is like Peyton Manning saying no I've got a few more in me. Meg is a giant in our field. We love her. For whatever reason. She always takes the hardest possible topics within infectious diseases and makes them clear. And so that's what she's going to do today, because many of you have cared for these children who develop infections, sometimes streptococcal infections, and have neurologic or neuropsychiatric symptoms afterwards.

26:11 So she's going to try to demystify pans and pandas. Meg, thank you for being here. We're so excited that you're here.

26:24 So come on up here. You got your. Oh, yeah. Thanks. Yeah, actually, it's a pleasure to be here. It's, so great to see, all this group again and and to be back here. And I don't even mind that I'm talking about this subject because I think that, as you'll see as I go through it, I can pretty much say what I want to say.

26:48 And there will be an article that says something different, and there will be an article that says something the same. So there's a lot there's not a lot of, consensus exactly about this diagnosis. So let's just get right into it. I do have a financial disclosure. I serve on a vaccine safety monitoring committee for Pfizer vaccine for Lyme disease.

27:08 It has nothing to do about the topic today. So what I'd like you to be able to do by the end of this is diagnose panels, recommend laboratory studies and recommend treatment. So let's start with some terms. I happen to hate acronyms and I hate abbreviations. So pandas is pediatric autoimmune neuropsychiatric disorders associated with Streptococcus. You just can't keep saying that.

27:37 So that's why you end up saying pandas. And then and it was first described by Doctor Guido back in 1998. And then they realized that there were patients who fit the criteria but didn't have an association with group strep. So that's where Doctor Guido really expanded the syndrome to pediatric acute onset neuropsychiatric syndrome. Now, I want to do a little poll here okay.

28:07 So I want to see from the audience how many of you have diagnosed the patients as having either Pans or Pandas. Simple. Yes or no? No. Music.

28:22 I'm bored. I'm. There we go. Oh, single single single. Heavy bag. It could be pretty short. There's no middle speaking. I like your style. Okay? And the. Do I have to click to get the answer up? There we go. So if it pretty interesting. 40%. Yes. And 60% no. So now my next question is to whom are you going to refer the patients with suspected pans or pandas?

28:54 Okay, so so I'm hoping you're taking care of them, but many times you're going to refer them. So who are you referring them to? I see you walking by. Take my hand to my hand. Look me in my eyes. Just like a monkey. I've been dancing my whole life. Are you just begging to see me dance? Just one more, okay.

29:24 And let's see. Okay, so this is fascinating. All right, so what I'm going to tell you is these are psychiatric diagnoses okay. So ideally we would definitely want a psychiatrist involved. These are also neurologic problems. So some neurologists might be interested in being involved as well. And whenever you look at the people who make up the consensus, of what should be done, there's always psychiatry in neurology, infectious disease.

29:57 We have almost no role to play in this diagnosis. Okay. Almost none. But we get to see all of them because you like us. And that's okay. Because we like you guys. Now I'm going to say a word about pans and pandas specialist. And you know this this kind of goes for anyone who's just one disease specialist. So Lyme specialist, pan pandas specialist.

30:24 It's like buddy said, if the only thing in your toolbox is a hammer, everything looks like a nail. So if you're a pan specialist, pretty likely you're going to diagnose pan when the patient comes to you. And Lyme specialists are, in my opinion, the worst. So just saying. All right. So let's get back to the to the real conversation and talk about how we're how we're going to evaluate these patients, how are we going to make the diagnosis and how we're going to manage them.

30:58 So let's start with what the criteria for, for pandas are. So the criteria are sudden onset. And this is really important. It's a sudden dramatic onset of obsessive compulsive behavior and or tics. So it could be just OCD or just tics, but it's sudden onset out of the blue. You didn't have it yesterday. You wake up today and you're different.

31:26 It has to be a pre pubertal onset and it has to have an episodic course. So this is not the patient who's had behavioral problems for their entire childhood. Who now you're coming because they had a strep infection. And maybe their behavior is a little worse. So this has got to be episodic for pandas. It had to be associated with group based strep.

31:50 And during the flare during the time that the patient's having the symptoms, there are neurologic abnormalities. And those are things like tics obviously. So these are mainly motor disorders. So tics hyperactivity or what's called Korea form movements and Korea form movements are different than Korea. So Korea are big major movements. You know big things Korea form movements. You have the patients put their hands out, close their eyes, and it seems like they're playing a piano.

32:25 So they're that little subtle piano playing movements of the hands. And you can bring it out when they close their eyes. So different than the big kind of, more impressive, exciting movements of Korea now pans. So, as I said, doctor Sweden first described pandas and then realized that there wasn't always the association with group strep. So pants kind of expands this group of people.

32:54 So again, there's going to be an abrupt, dramatic onset. And in this case it's either obsessive compulsive disorder or severely restricted food intake. So this is people absolutely refuse to eat. And it's not because they have bulimia or anorexia. Usually, it's because they have an abnormal fear that they're going to choke or they're going to vomit or that the food's contaminated.

33:23 So it really is a psychiatric, a more psychiatric reason for that severely restricted food intake. They also have to have at least two of these neuropsychiatric symptoms. So either anxiety emotional lability or depression, irritability aggression. You can read them yourself. I don't have to read them to you, but you can see it's a real broad spectrum of problems.

33:48 And then there's, you know, in there is sleep disturbances, aneurysms or urinary frequency. And, you know, I don't get the connection, but this is what the observation is. And these things are quite common when you actually get the histories. And then of course, there should be no better explanation for the problem. So for me, the really the what makes a difference between pans or pandas and everything else is this dramatic onset a very short time to peak severity.

34:23 So it comes on quickly and it becomes unbearable quickly. So these are children who were high achievers going to school. Everything was great. And now they cannot leave their room because they are. They either have to go through some obsessive compulsive thing or they just are afraid. They have tremendous separation anxiety. This this is a very, a disease that really affects not only the child but their entire family.

34:54 So this is, is a life altering diagnosis. And we really want to be sure that we get it right. And again, the other thing that's distinctive is it's episodic. So how does it happen. What is the likely mechanism. And here's where it gets a little bit murky. So this is where I have to start waving my hands. Because when infectious disease people wave their hands we're making it up okay.

35:19 So the theory is that there's molecular mimicry, but actually there are some animal models that suggest this this, is the likely mechanism. So there are antibodies that are made from an ant from your group, a strep infection that cross react with the basal ganglia. And in an animal model you can take rats and immunize them with group based strep antigen.

35:43 And they will develop motor symptoms and compulsive behavior. And the motor symptoms are kind of cool. They do backflips. So they just do all these backflips. So it's it's kind of it's unique right. And what you can show if you sacrifice those rats is within the brain. There are autoantibodies that are deposited in the striatum the thalamus and the frontal cortex.

36:08 And moreover, if you take immunoglobulin from the affected rats and fuze it into naive rats, you will get the same back flipping behavior. And the the, compulsion. So I would say that, you know, is a pretty good explanation of why this is a pretty good animal model, that there's something going on here. And, you know, there are a lot of people who who really will say, you know, pans and pandas don't exist.

36:36 I don't believe that. I believe they do exist. But I believe that many, many, many of the patients that get referred to infectious disease doctors, it's because someone did an Aso titer and the child has behavioral problems, and it's not the abrupt onset or episodic disease. So I think it's important that we try to make the diagnosis. Now there there are problems with the diagnosis because we don't have a clear cause and we don't have biomarkers.

37:06 We don't even have DMs or DSM five criteria. It's a diagnosis of exclusion. So sometimes you do a lot of other studies to exclude other things. We know that children, all children have multiple infections. And if you now expand this to Pans and say that a whole variety of infections can result in this, I mean, it applies to almost every child.

37:32 And then we also know that anxiety and tics are common. So the the rates for anxiety among our children are 7% of children, suffer from anxiety, 20% develop tics during childhood, and 1 to 3% have obsessive compulsive disorder. So you can see where there's a lot of overlap here. And it's hard to make a definitive diagnosis. So again, what distinguishes this sudden onset set those movements.

38:05 That's not Korea for movements are not part of other things. And then the fact that there's normal cognition. So the other things that can cause neuropsychiatric disease are autoimmune encephalitis. And, you know, true. Other, problems with the brain in almost all those cases, they're seizures and altered awareness. So if they're still normal cognition now, it doesn't mean that there's normal school performance.

38:33 Because if you have all those fears, all that anxiety, all the other neuropsychiatric problems, you're not going to do well in school. So school performance is very, commonly affected. So here are the symptoms. The symptoms are obsession and compulsion and almost 90% anxiety and 78% lability. And depression, and 71% sleep disorders and almost 70% tics and about 62% and these motor abnormalities in 60%.

39:04 And besides the Korea form movements, some patients will have dystonia and some will have faintness and fit into that part, syndrome kind of kind of story. Other symptoms attention deficit and 63% hyperactivity. And 43% half of the people will have, deterioration of their school performance. And I think you can see why because they have all these other things, sensory abnormalities and half irritability or aggressive behavior.

39:35 Some, children actually go into rages, decreased food intake and about 40% pain. That's difficult to, describe in about 38% and then urinary frequency and 44%. So I'm going to talk about evaluation and treatment. And I'm going to base it on the American Academy of Pediatrics. Clinical report, which came out in March. This was supposed to be a clinical guideline, but because the evidence supporting the recommendations was not considered to be of high enough quality, it ended up coming out as a clinical report.

40:14 There's also a three part series by the Pans Research Consortium that was published in 2017, in the Journal of Child and Adolescent. Psychopharmacology. I'm sure you all have copies of that. Your office. And then there's a Nordic pediatric immuno psychiatry group. So this is Denmark, Sweden, Norway and the UK, and they published guidance in 2020. But the main things I'm going to talk about are, are the AAP guidelines.

40:44 And then I'll say where there are differences. So as far as the recommended evaluation you should test for strep. If the patient has pharyngitis that's consistent with strep. So if you think they might have a streptococcal pharyngitis absolutely test them for it. If they have vocal signs or symptoms suggestive of autoimmune encephalitis, you ought to rethink this diagnosis and really be sure that you're not dealing with, psychosis or an encephalitis.

41:16 So if there's psychosis, persistent symptoms, symptoms alter consciousness, cognitive impairment, seizures, Korea dystonia, tremor, clone or ataxia. Your. This is not simple pans. They need a much more of a lab evaluation which should include an EEG, MRI, lumbar puncture, C-reactive protein, said rate, blood counts and look for autoantibodies such as the anti and MDR receptor.

41:50 Okay, what's not recommended. So the AAP does not recommend. Wait, wait a minute. Let me go back for one second and say what's the difference in the other groups? So both the Nordic people and the, Pans research group would do a throw culture on every patient at the beginning of their symptoms. Okay. So that's the the only difference there.

42:16 Now, as far as what the app says not to do, don't do things routinely. Don't look for Azo or anti DNA B. And I would say most of the time that's going to confuse you and not help you. And what all three agree on is the Cunningham panel is not useful. It's an expensive test. And the abnormalities that you find in patients with Pans are exactly the same as the abnormalities you find in otherwise healthy children.

42:43 So it's not a useful test. And then imaging is not recommended. Imaging should only be done if there's suspicion of encephalitis or something other than pans. The treatment part. Everyone agrees that psychiatric interventions for obsessive compulsive disorder, anxiety, tics and avoidant restrictive food intake disorder absolutely should be done as soon as possible. Antibiotic treatment for strep infection, if present, is what the AAP says.

43:19 The other two groups would give you a course of antibiotics for a presumed streptococcal infection at the beginning, at the first time you present, whether you're positive or negative for strep. So I'm not sure why you do the test if you're going to treat anyway, but it's you. I'm telling you, this is when the more you read about this, the more you will be confused.

43:42 And then treatment for underlying neuro inflammatory an autoimmune problems, clearly needs to be done. And it may tell you that you may not have the right diagnosis. Well, what about the psychiatric interventions? What can you do? So for obsessive compulsive disorder the therapy of choice is cognitive behavioral therapy. And SSRI is the combination. If you use both cognitive behavioral therapy and medication, you end up with about a 60% chance that you will have an influence on the OCD.

44:17 If you use just one or just the other, you're only going to see an effect in 20 to 30% of patients. So a little bit a little bit concerning that we don't have a better, better management exposure and response prevention is the specific type of cognitive behavioral therapy that seems to do, the best. The other thing that's been noted, and it's anecdotal, but it seems that children with pans or pandas have an unusual, response to medications, and they sometimes have more adverse effects.

44:53 So it's recommended that you start at low dose and that you increase the dosage very slowly. For separation anxiety, you have to train the parents to get the child back to their normal sleep area and back to school. So just like with functional abdominal pain, the goal is to get them back to what? To to what their normal behavior was.

45:16 But it's not an easy goal. And for tics, there's a comprehensive behavioral intervention that also uses exposure response. Prevention. Well, what about other psychiatric, interventions for other problems for sleep disturbances? Counseling is important. And that I think we you all know as pediatricians that sleep hygiene is absolutely essential. And we all know as pediatricians that if you're deprived of sleep, you get grumpy and you do not do well.

45:47 I don't know how we ever got through residency. Any of us, but I now need a lot more sleep, and I'm a lot happier having gotten so. Sleep hygiene is the only thing you should do in your bed is go to sleep. No screens, no blue lights and, you know, wind down to night time. It is not the time to do your exercise night right before you go to bed, okay?

46:14 And then for the, feeding problem, you really need a medical assessment because these children can be so, hesitant to eat that they can get dehydrated, they can lose massive amounts, and they can require hospitalization. The approach to this, again, is cognitive behavioral treatment. And the ERP expose and response, prevention. And then if a patient has group strep you should give them antibiotics for strep pharyngitis.

46:43 The American Academy does not recommend prophylaxis. The Nordic people do not recommend prophylaxis. But the pans research consortium does recommend prophylaxis for patients who fit the panda's criteria. So I mean, I think you can see why that would make sense. The catch is it has not been proven to be useful. And in fact, in some, studies, it's been shown that that it does it absolutely does not make a difference in the Flair's.

47:15 So I think that one's, up for grabs. But I would agree with the Academy that in general, we certainly should not be, doing antibiotic prophylaxis. And then some people use azithromycin instead of penicillin because of the, the, the, the, the, inflammatory, you know, is it where Mycin is a is an inflammatory mediator? There's not a whole lot of evidence for that.

47:43 The other reason some people use azithromycin is to also take care of mycoplasma. So these are things that the Academy does not recommend doing. So don't treat for Lyme disease. This seems like a no brainer, right? I mean, if you're talking about pans, why are you treating for Lyme disease? For crying out loud. But you know, Lyme disease is the basis for everything that goes wrong in life, so why not?

48:04 But don't do that. That makes no sense. Tonsillectomy and adenoid ectomy have not been shown to be useful in pans or pandas, so they should be avoided in all three groups. I agree with that. And then sinusitis treatment and influenza treatment is not needed unless you have the disease. So obviously if you have sinusitis, yes, you should treat it.

48:26 But just randomly treating for sinusitis it is what doesn't make sense. And the same for mycoplasma and the same for other infections. Yes, if you have an infection treat it. But don't go looking for for things that may or may not be there. Thinking that you're going to alter the course of pans, the the Academy does not in, recommend invasive therapies, for neuroinflammation and autoimmunity.

48:55 I think the feeling is if you have neuroinflammation, you may, you know, you should probably be looking for a different diagnosis. So the treatments, that are not recommended by the academy are intravenous gamma globulin. We're talking a Mab mycophenolate and plasma exchange. If you go to the Nordic guidelines, they also do not recommend these.

49:21 But the panel's consensus recommendation is that these be used for children with severe disease or for children with persistence, some things that aren't getting better. So I think it's very tough. You have severely affected children. You have some evidence that maybe it'll work. But we should not be using these really outside of a clinical trial. We really need better clinical trials to show us what the right way to go is.

49:53 Now, the ideal place for care of these children is not in an infectious disease office. It's in your medical home, because that's the ideal, site for care in general. And as you all know, it's not a place. It's a way for children and families to receive health care from a primary care pediatrician that they know and trust.

50:16 And so when I get referred these patients, I always send them right back to you. So thank you. These are the references. And they'll be available.

50:38 Thank you. Meg, I told you, I told you she's great. For the last, speaker in this session, it's my privilege to introduce Doctor Jay Mehta. Jay is associate professor of pediatric rheumatology at Children's Hospital of Philadelphia. There, he leads their program, in training fellows in pediatric rheumatology. And he's going to be talking to us a little bit about those rheumatology markers of infectious diseases and to welcome Doctor Jay Mehta to.

51:10 Click on right here. Yep. Right. Thanks for having me. It's really this is my first time at ID conference, so guys seem great. So disclosure I'm not an ID doc, so there is a very good chance I will say something drastically incorrect about infectious diseases. You should feel free to correct me during the Q&A session. I will not, I will learn something from it.

51:34 My other thing is I want to thank Meg, during your polling question, in terms of who to send people to, you didn't put rheumatology up there. I have never met you, but I love you.

51:50 So. All right, so I'm going to, go through I have four cases that I'm going to go through. This is certainly not exhaustive list of, mimics of infectious diseases. But I think at least some of the ones that that may come up and certainly if there are other ones that you have thoughts on or questions about, we can we can discuss it during the Q&A.

52:09 All right. So first case six year old boy who's admitted with daily fevers for the last three weeks, if you're like, if you're at a hospital like mine, any time someone has a fever for more than two days, they consult us. They probably console you guys. And, well, this child's had fever, for longer.

52:28 Fever is typically in the evening. The temperature is actually normal during the day. So this kid actually, like, you go and see him during the day. He looks great. Happy? No. Sort of wonder yourself. Why did they admit this kid? He looks pretty good. But then, as the evening comes around, he starts to become febrile, looks irritable.

52:47 Just really, Doesn't look great. And then he gets this diffuse erythematosus rash. When he has the fever and the fever actually goes away. I'm sorry. The rash goes away when he doesn't have the fever, but as soon as the fever comes on, he gets this rash, and then he's got arthralgia. No, no joint swelling. But his joints hurt, and then he's got lymphadenopathy, all over.

53:09 So as opposed to, you know, CD where you would just get the cervical and then up the he's got a baton up there in lots of places. So this is what his rash looks like. And you can see it's this kind of erythema, this macular, rash that's all over. Really is he can't quite see it, but it's on his face.

53:27 It's on his palms, really everywhere. And this, interestingly, does go away completely when he's a fibro. So they do some labs, and his, he's got an elevated white count with the neutrophil predominance. He's, quite anemic and then play accounts pretty high. His ferritin is, quite elevated. CRP is very high. He's flu B positive.

53:50 And then his RNA is 180 because, you know, it's it's on the differential for rheumatology. So got to do DNA. And then his chest X-ray shows these bilateral pleural fusions. All right. So our poll question, what do you think is going on. So bacterial pneumonia, influenza, leukemia, systemic juvenile arthritis or systemic lupus erythematosus.

54:23 Hey. Oh, hey. Hey, wake up kids. We got a dream. So in addition to never being in an ID conference, I've never been at a conference of musical breaks. And I think that's fantastic. So I'm really, going to try to incorporate that when in our room conferences. So. All right. So systemic juvenile arthritis. There's a rheumatologist speaking at the so I think that was a little bit of a giveaway, but you're right.

54:51 We'll talk. So, a quarter of you, thought lupus, which I think is, is a decent thought. He has a positive and a the and a is kind of an aso of, of rheumatology. It's helpful in the right clinical context if you think a kid has, or suspected lupus or shoguns disease, with parasites or Zika symptoms, dry eyes, dry mouth or scleroderma, tightening of the skin and nodes.

55:16 But, it's not a sort of catch all rheumatology test. People send the RNA quite often, and that's our most common reason for getting consulted. Are people seeing us? But, I think in this case the anti actually wasn't, clinically significant and was at a very low titer. So 1 to 80 is actually the lowest titer that we consider positive.

55:37 All right. So this is systemic che also known as Still's disease. I don't know if in ID there's this whole debate about epidemics. But people are going away from them. And, and moving towards taking the apostrophe s out. But then it would be just still disease, which is awkward. So I think they actually kept it.

55:55 It's still Z's for that reason. So this is an auto inflammatory condition. And what we mean by our inflammatory condition is that there's activation of the innate immune system. And so, you know, two major parts of the immune system, innate and adaptive, innate is the early kind of primitive lizard immune system that every creature has.

56:15 And this is what's overactive in, systemic J or still disease. I'll use those terms interchangeably. They essentially mean the same thing. So this is very different than other types of J. So I think one take, point, that for all of you is that J is is kind of, very broad, umbrella term.

56:33 And most types of J don't actually have fever. They don't have rash. The patients aren't typically systemically ill. And so don't use the absence of fever. If a patient has a swollen joint for ruling out J. But systemic J is the type that has fever. These are patients that will get admitted to the hospital. They're the ones that will both get consulted on, because of this, significant inflammation and fever that they have.

56:57 This, it's characterized by fever. And often the fever is quotidian, and quotidian is Latin for once a day, and typically happens in the evening, and they actually will look quite well when they're febrile, as I mentioned, when I presented the case, they have this evanescent erythema and or to Carroll rash, on the boards, you know, people described as salmon colored.

57:21 I've never heard a rheumatologist use the word salmon to describe the rash, but that is kind of the buzzword, that's used for this. And it's that erythematosus, macular rash. It can look urticaria. It can actually be periodic at times. And then they get diffuse lymphadenopathy. As I mentioned, in the differential for prolonged fever is going to be CD.

57:39 Katie is going to have more isolated or localized lymph than apathy. And then they can have a big liver and spleen as well. And then even though arthritis is in the name, arthritis isn't always present at the diagnosis. And in fact, often the arthritis will come, months later. But by that time we've, we've started treating.

57:59 And so a lot of these patients don't actually ever develop, arthritis. And so it's one of the reasons that some people like to use the term Still's disease more because it doesn't have arthritis in the name. And that can be a little bit confusing if you're looking for the arthritis and it's not there. So these are just some, pictures of the rash, that you might see.

58:18 So again, macular erythematosus, can look sort of coalescence but also can be discrete lesions like in C, you can see in the bottom right. And there you can see it, it's a little bit more res a little bit more vertical. There. So these patients are significantly systemically inflamed. So they have very high sirup levels. They have fare tins that are in the thousands often.

58:42 And this is often a clue to this diagnosis. And so we would recommend sending a ferritin if you, you know, if you get consulted on a patient prolonged see if or you don't think it's infectious. One of the things you can recommend is a ferritin. They have very high white blood cell count, very high platelet count.

58:59 Sometimes in the south, 1000, some millions. And then they can have very elevated 18 levels. And then there's some pretty good data that, 18 levels that are significantly elevated are pretty specific for this diagnosis and can differentiate, in, in patients with prolonged fever, from infection and malignancy. Latinas, at least at Chop is a send out lab.

59:20 It goes to Cincinnati. And so we will send it. I don't I don't certainly expect you all to send it. But if you're if you're thinking about it, you can you can send it. And then we treat this with IL one inhibitor. So I wanted to have been revolutionary for the treatment of this condition. It's one of the reasons that we don't tend to see the really bad prolong, difficult to treat arthritis in the way that we used to, because we're starting to treat these patients with iron when in addition, at the outset, when we make the diagnosis, even if they haven't arthritis yet, if they have the fever, prolonged, a cotillion fever, the rash, high early teen levels, high ferritin levels. We'll start treating on the island. One inhibition. And they dramatically respond. One of the nice things about I wanted to mention is, it actually is quite safe in infection. So as opposed to the rest of our drugs that, are immunosuppressive, I want to repair is actually aren't.

01:00:14 And the data from this came from when I went to Anna. Kendra was being trialed in sepsis, and these, it didn't have any benefit for the treatment of sepsis, but the patients that were on really high doses of Anna can or didn't do worse. And so we do think that, it is quite safe and infection.

01:00:30 So it's one of the things that we're sort of suspecting the diagnosis, but there's still infectious workup pending. We'll start in a Kendra and and see how they do. And often if they respond well, and that's a clue to the diagnosis and then I'll six inhibitors are used as well. This tends to be more in Japan, where they use these at the outset.

01:00:49 But you could certainly use these. One of the things, that we need to look out for in patients with, systemic is something called macrophage activation syndrome. This is a systemic cytokine storm where you get macrophages that are, hemo phagocytosis in the bone marrow. So your, the slides on the right, are showing giant macrophages that are human phagocytosis in the marrow.

01:01:15 And you, get subpoenas. You get a falling rate with a very high crp. And the reason for that, the falling rate is if you if you think about what a said rate is, a erythrocyte, erythrocyte sedimentation rate, you take a tube, you put red cells, you see how fall, how fast they fall, how far they fall.

01:01:33 In an hour, millimeters per hour. The reason your rate goes high when you get inflamed is one of your acute phase reactants is fibrinogen. Fibrinogen causes your red cells stick together. They fall faster in the tube. What happens in Mas is you actually get a coagulopathy. You get liver dysfunction, you don't produce fibrinogen or you consume fibrinogen. So actually your set rate drops because you don't have the fibrinogen, causing your red cells to stick together, which causes them to fall faster.

01:01:58 So it's sort of a clue to mass if you have a falling set rate. With the high crp, you get some liver dysfunction. As I mentioned, you get a Co, I go up the you get this very high hyper fair anemia. Sometimes above 10,000. This is this is a clue to this. So I mentioned systemic J.

01:02:14 You can have a high ferritin that's above a thousand in mas. You'll get this. It'll be even higher. And then this can be fatal. And this is similar to infection associated HLA which you may be familiar with EBV. Other viruses can lead to h h. And they're essentially the same condition. There's still a lot of debate about the differences in mass and H.

01:02:38 But I think for most purposes you can think about them the same. All right. So next case, a four year old with six episodes of fever and sore throat every 3 to 4 weeks. The episodes last 3 to 5 days. It's accompanied by this painful anterior cervical lymphadenopathy. Sometimes the patients group strep positive so someone looks in their throat, they see, so our throat, they see pharyngitis.

01:03:03 Swab it. Sometimes they're positive. And then in between these episodes, the child is quite well good growth. Doing fine. Thriving. All good things. All right. So what do you think is going on group strep. Pharyngitis. Primary efficiency, periodic fever at the salsa's. Pharyngitis. And at night is Castleman disease or Kikuchi Fujimoto. Cue the music, please.

01:03:46 All right. Good. The vast majority of you got the diagnosis correct. B Thapa you'll sometimes hear some people call this Thapa actually asked the the the the person that described this. Marshall, I can remember his first name. Yeah. And Garry Marshall, and he said it was fabulous. I feel vindicated because I was one of the Thapa people.

01:04:08 And so anytime anyone says Thapa, I feel very pedantic about, I'm like, it's actually p fab. I ask Garry Marshall. So this is what the throat looks like. And then this on the right is an oral ulcer. So this is the most common acquired fever auto inflammatory syndrome. Some of the other auto inflammatory syndromes, are more genetic.

01:04:32 So familiar. Mediterranean fever. Some of the other ones that we take care of tend to have a gene associated with them. This is one that doesn't typically these patients present at less than five years of age. We don't really know the etiology of it. Maybe there's some immune dysregulation. No real known genetic association. But every once in a while, I have a patient where, the, dad will say, oh, yeah, I had, fevers that they didn't know what the cause of when I was a kid.

01:04:55 And so I think there's probably some genetic, association. We just haven't found it yet. So these are clock like episodes. So sometimes parents can actually look at a calendar and say, oh, yeah, I know what's going to happen on this day four weeks from now. And so it's very, very every 3 or 4 weeks, they typically last 3 to 5 days.

01:05:14 The episodes, the kids are well, in between episodes. And this is a clue you have to ask about this. Make sure if they're not well in between episodes and it's very unlikely to be this, the fever can be quite high. The app. This ulcers don't happen in everyone, so only about 70% of patients. So doesn't if they don't have it doesn't mean that they don't have PIF APA they do have pharyngitis quite often.

01:05:36 The at night is is the most common manifestation. And then they can have some arthralgia belly pain. And then headaches. So these are the classification criteria. So rheumatology is one of the only I think fields that has classification criteria. They're basically used for research purposes to enroll patients and studies. These aren't diagnostic criteria, but they tend to perform pretty well for diagnosis.

01:05:56 So you have to have seven of the eight. So, pharyngeal tonsillitis episodes that are 3 to 6 day cervical. And then I this the periodicity where the patients are well in between episodes and it happens at a certain interval. The lack of diarrhea, chest pain, skin rash and arthritis, these are all things that are associated with some of the other, auto inflammatory syndromes.

01:06:15 And so you shouldn't have these if you have seven of these or eight. Yeah. You get classified as PEF, APA. So they can have elevated inflammatory markers during the episodes. These should normalize in between episodes. If they don't normalize in between episodes, then again that's a clue to one of the other auto inflammatory syndromes. FMF in particular.

01:06:33 Patients can have inter current inflammation. Their set, they can say hi, even when they're well. So in terms of treatment, we tend to do a single dose of prednisone two per kilo at the onset. Sometimes they may need a second dose 12 to 24 hours later if the fever comes back. And that's okay. But ever since I used to start at one per kilo, and over the last few years, I've gone to a single dose of two per kilo at the start.

01:06:58 And ever since I went to two per kilo, I've had very few patients need that second dose, but sometimes they do. A lot of these patients, this will take care of it completely. And this is all they need, not this. They don't need a single dose ever. But they'll need just a single dose at the start of the episode.

01:07:13 And that takes care of it. Sometimes families can start to predict when it's going to happen. The they'll save the patient, you know, their eyes will glaze over, they'll look tired. The downside of prednisone is it may shorten the intervals in between, the episodes. So sometimes if they're going every four weeks, they may go to every three weeks.

01:07:29 Once you start giving the prednisone and maybe going every two weeks. And that's when we need to start to think about one of the other, treatment options. So if the prednisone doesn't work or the episodes are too frequent or the parents just, you know, want you to do something different, there's a lot of fever phobia in schools.

01:07:45 And so, you know, schools won't let a kid come back to school for 24 hours if they've had a fever. It's really problematic if that's happening every month. So some things that we can do is colchicine. Every day. So colchicine is quite safe. It is not immunosuppressive at all and often will take care of the fever.

01:08:02 And then also we can recommend tonsillectomy. And this is often curative. In patients. And then typically you can reassure these families that this tends to go away by the age of ten or after 4 to 5 years.

01:08:17 All right. Next case six year old with the painful swelling over the left thigh and right clavicle. Otherwise, well, with no fever, normal inflammatory markers, MRI of the thigh was done with this T2 enhancing lesion. T1 decreased signal with surrounding soft tissue involvement. This is the X-ray of the clavicle. So you can see in the on the right clavicle there is the bone is larger there.

01:08:43 There's inflammation. There's some sclerosis, over that medial third of the clavicle. And then this is the MRI of the thigh. You can see that there's sclerosis, some lytic areas. And then surrounding soft tissue, inflammation. So the top right is T2. So increased signal in the area of the lesion. And then the bottom right is T1.

01:09:07 So decreased signal in the area of the lesion. So I'm not going to give you the you know, get tell me what the diagnosis is because you then you guess the rheumatology rheumatology diagnosis. And it's really easy I'm gonna ask you what you're going to do next. So do you want to admit for I.V. antibiotics, do a bone biopsy, do a whole body MRI, do more blood work, or do.

01:09:26 Yeah, or begin an anti-inflammatory therapy for this, which I think is even I ha another.

01:09:40 I know I could transform another. Can anyone tell me who's saying that? The great delight. Yes. Groove is in the heart. All right. Good. Okay, so a little bit more of a split. So, some people, thought about bone biopsy. If you thought about this, a blood work, and then anti-inflammatory therapy. So this child, got a whole body MRI, that showed more lesions in the vertebrae, in the pelvis, and then a bone biopsy showed mixed, acute, chronic inflammation.

01:10:17 There were no signs of malignancy. And, the cultures were negative. So this is chronic non bacterial osteomyelitis, also known as chromo or Cremo. Chronic recurrent multifocal osteomyelitis. This is sterile inflammation in the bone and this tends to affect a few different spots the clavicle. And I've highlighted the clavicle because my understanding is that infectious osteo the clavicle is quite rare.

01:10:44 And so if you see isolated ocular osteomyelitis, then, you don't necessarily have to do a bone biopsy. And this is, this is the most common spot for it. And so you can just diagnose, CNO, with isolate clinic velocity myelitis also affects the vertebra. Can affect the pelvis. The mandible causes something called graze osteomyelitis in the mandible and then tends to affect the metastases that we sometimes consider have solutions as well.

01:11:12 So there are some associations with some other conditions. So it is thought to be in the IBD spindle arthritis spectrum. And so there is an association with psoriasis pomo plantar pustular susp, ankylosing spondylitis IBD and then acne for eminence and a lot of lot of family history or personal history of these conditions. So like I said, if you have isolated clavicle disease, you don't necessarily need other workup, but, that's, not the most common situation.

01:11:42 And so when we, if we think that a patient might have CNO or evaluating for it, we tend to do a whole body MRI to look for asymptomatic areas. And what we're specifically looking for here is, high risk vertebral involvement. So patients that have vertebral disease, because the major issue, besides causing pain and swelling, is that the areas that are inflamed can be subject to pathologic, fractures and especially in the vertebrae.

01:12:09 And so vertebral, chronic noninfectious, osteo can can lead to pathologic fractures there. And so that's what we're looking for. And that the presence of vertebral involvement tends to cause us to escalate therapy. And then the bone biopsy, really importantly, there is nothing that tells you that the patient has CNO on the biopsy. You're doing it to rule out malignancy.

01:12:29 So bone lymphoma, other malignancies, and then to rule out weird infections that might be causing multifocal osteomyelitis. But again you want to see acute and chronic inflammation and then no, nothing that looks like malignancy. And then culture is negative. But again there's nothing that says specifically this is, you know, all right. So how do we treat these patients if they have a low risk lesion.

01:12:51 So again, if they don't have vertebral lesions, we may start with NSAIDs or go to bisphosphonates. So parmigiani or XL under rock acid or TNF inhibitors. We like for these but if they do have high risk or symptomatic lesions. And so if we put them on NSAIDs, and they're not responding or the lesions are especially painful, then we'll do bisphosphonates and or TNF inhibitors.

01:13:13 And then again, the long term risk with these are the pathologic fractures. But the natural history of these is, is healing. All right. So the last case, a 15 year old with three months of fatigue, intermittent fever, cough, and diffuse lymphadenopathy. Ooh, there was some stuff missing there. Let's go back. Oh, she's got. Yeah, she's got a painful rash on her shins, chest.

01:13:43 Bilateral high lymphatic apathy and some nodular lesions. And then she went on this great trip where she went to India, Kentucky and Arizona was like the trip of a lifetime. Yeah. So what do you think's going on Cork city on my coast is to plasma is tuberculosis or sarcoidosis.

01:14:12 It's.

01:14:18 Can I control exam?

01:14:25 All right. So half of you thought sarcoidosis. Even though there's rheumatologists standing up here and I don't know I. Well now I know how his plasma blast and psychosis and the other one that was talked about it earlier, talk. Hopefully, Paul, if it's not in the room and, listening to me do this. So this is, what, an on optimal logic exam.

01:14:48 This is, these findings are, granulomatous uveitis. And so there's a certain, they call it mutton fat precipitate, even though no one's eating mutton and, like, I don't know, 150 years. And then the skin biopsy on the right shows, these, well, non necrotic granulomas, so epithelium granulomas and what the epithelium term means is that the history of sites look like epithelial cells.

01:15:18 And so you're seeing these really well formed granulomas. They're so this is sarcoidosis. So that the presence of the non necrotizing granulomas is your clue there. So there are two types of sarcoidosis. So there's early onset sarcoidosis also known as Blough syndrome. This is a triad of arthritis dermatitis and uveitis. It is related to mutations in the nod to gene and tends to present in early childhood first couple of years of life.

01:15:47 And then there's the late onset, adult sarcoid is adult type sarcoidosis that tends to be more in teens, where they get fever, constitutional symptoms, interstitial lung disease than let that not the special level lymphadenopathy. So the histologic hallmark like I said of sarcoidosis is these non-coding non necrotic epithelial granulomas. And these granulomas are thought to be some exaggerated immune response to an unidentified antigen.

01:16:13 And so for example, not far from here in the World Trade Center, World Trade workers had a high risk of sarcoidosis and it was thought to be some antigen within the dust. That led to this. But in general, it's, you know, when we see these granulomas at some, I don't know, unidentified engine.

01:16:31 So organs that can be involved, so you can see cutaneous disease. So, like, was shown by Doctor Wood during the, in my courses talk lots of erythema and no dose. There can be some erythema as mackerels, papules and plaques. Like I said, there can be granulomatous uveitis. And that's a specific finding that the optimal ophthalmologist will tell you they can have some CNS disease.

01:16:53 So cranial nerve palsy, especially cranial nerve seven can be some seizures. And then conduction defects. So these patients should get, EKGs. If you are diagnosing Sarcoid. Oops. So this is that, the rash of, the dermatitis, a blouse syndrome. So the early onset sarcoidosis. And then this is the arthritis that you can see with, blouse syndrome, early onset sarcoid.

01:17:23 And so, you can see on the, on the top left this patient has swollen wrists, and then the fever, the fingers. Look, doctor, lytic, and then on the right, you can see these pretty, exuberant. We call them boggy, boggy Sen Avitus. Because there's a lot of teno synovial involvement. And then actually the bottom right, that's a family of patients with, blouse syndrome all, showing their hands with their contractures, in the fingers.

01:17:51 And then this is these are some of the other rashes that you can see. This is more with late onset sarcoid. So actually not dissimilar to the blastoma, this, rash that was shown, earlier on the left and then, this is another rash in the middle, and then the erythema had some rash on the right.

01:18:09 They can see a sarcoid.

01:18:14 So treatment for sarcoid, for mild disease, cutaneous, disease, arthritis or mild lung disease, you might do methotrexate, but more, moderate to severe disease. A patient as I or CNS involvement. We usually use TAF inhibitors and specifically the monoclonal antibodies as opposed to a tan or SEPs, infliximab or alum. So other overlaps in the last couple minutes I have between room and ID.

01:18:37 So this is during this. So just to think about immuno deficiencies we talked a little bit about Stat1 earlier. But if you have antibody deficiencies that can lead to those can be associated with lupus arthritis, other granulomatous disease.

01:18:59 Combined immunodeficiency can lead to site apenas and then granulomas. So, we can see that in Covid.

01:19:11 Complement deficiencies can lead to lupus like disease as well as infection. It's.

01:19:22 Even is know what's going on.

01:19:34 And then CGD can be associated with IBD. All right. So some takeaways. So prolonged quotidien fever evanescent rash. Think about systemic j send a ferritin and then watch for mas. So following cell counts the patient looks sicker. The ferritin will go up.

01:19:54 Repeated episodes of fever or pharyngitis. Think about pe fap. You all were on that one. And if you diagnose it, try a single dose of prednisone. It's not unusual for a patient to come to me from ID and, the ID doc has already started, prednisone, which is great. And then chronic osteomyelitis, especially involving the clavicle.

01:20:13 Think about C, you know, chronic noninfectious and or non bacterial osteo. Think about a whole body MRI. Call your favorite author pod for a bone biopsy. And then non necrotizing granulomas. Think about sarcoidosis. And then you want to send them to the doctor and then do screening AKG to look for conduction defects. All right. Thank you all.

01:20:33 And I think we have Q&A now.

01:20:51 And Meredith is everybody is coming up. I want to mention a couple of things. You guys are doing great with questions. And it's on the app. It's on the, the polling and questions I think is the is the portion, on the screen that you tap and you got to kind of work your way in to be able to leave questions.

01:21:08 In addition, under the agenda, as either currently there slides associated or as slides are added into the system, you will have access to all these slides as well through the app. And that you go into the agenda and then into each, particular talk. And you can, you can see this, the slides there as well. I'll also mention that after the break.

01:21:30 And this is don't we're not breaking to see how we're going to Q&A. But after the break, as we come back for the challenging calls session, we'll do an auction of a red book, a 2024 Red book, and of the latest lungs Principles and Practice of Pediatric Infectious Diseases. We've done this for the last few years, and we have one copy of each.

01:21:48 And so we're generating a list, a random list. And we'll go through that and whichever name we get to first set the that'll, that'll be for one of those books. So so come back after the break and we'll start in on that. Jay, you first of all, I had loved the APA. Part of this study, and I had a, heated conversation.

01:22:09 And the reason I want to buddy up here is because you seem to have some additional opinions on this. And I will say that Gary Marshall was at Vanderbilt with Kathy Edwards when they discovered her first wrote. This is awesome. And I wouldn't do this if Jay weren't awesome. In the 1989 paper, Gary freaking Marshall himself said, prefixing a silent P for periodic to the abbreviation would therefore seem appropriate.

01:22:33 Gary has given me like three different pronunciations over the years. We at Vanderbilt call it foreplay. Some people call it Sapa, I call it P faba, and that makes me emotional every single time. So this group, this group for the next 24 hours, because Jay's talk was incredible. You get P APA for like 24 more hours but then activate my legacy.

01:22:55 Yeah I think after that we got to do something. Yeah. But then he got delight out it for for groove is in the heart. So I think you really get 48 hours. Yeah, I think that's perfect. And while we're on P for a detail, Kathy Edwards was here. Had to be pre-pandemic five, six years ago, and she gave a talk on it.

01:23:13 And my recollection is that she reluctantly was endorsing tonsillectomy buddy. Is that is that where she would still stand if you were here channeling Kathy or. Yeah, we only do it in those families who are really riddled by it. And I bet that's your situation too, because between Cimetidine Daily that works in, what, 25 or 30% of kids and, intermittent steroid dosing for a few years, the kids do fine.

01:23:37 But if there's another reason to take the tonsils out, she would say, yeah, take it out for OSR or something like that. Is that what you guys do? I so when I, when I see a patient, I will start them on a board of prednisone and then like I said, if that's not working or what, for whatever reason, then I'll give them the option of colchicine, or I don't I don't use cimetidine.

01:23:56 Not for any good reason, except it just doesn't make sense to me why H2 it's one of the HS, blocker would work. I mean, H is there are now, probably at least 12. And so I use colchicine because I know how it works. And so that makes more sense to me. But I do have colleagues at other places that actually will will bring up tonsillectomy on the first visit.

01:24:20 Because they say it is burdensome for families and so to have these monthly fevers and so they want them, you know, shared decision making, present all the options. So I don't think it's wrong to to, you know, recommend or consider tonsillectomy. The first is if it's just not my practice. And when you do use steroids, do you do it with every single one or just on if they're going to Disneyworld or something like that.

01:24:42 Every. Yeah, every single one. I will do it because if we don't, then, you know, you're sitting with a fever for 3 to 5 days when we could have done something about it. All right. Okay. And another question for each of y'all, because it's it's fascinating to me. Ferritin. I don't honestly remember checking ferritin ten, 15 years ago.

01:25:01 For but but it's it's almost a screening diagnostic now. And so we've got multiple, you know, specialties represented here. I'm just curious on each of y'all's perspective on on checking ferritin in workups of patients, not necessarily to follow HLA to macrophage activation syndrome and start with whoever you thought That that's why he's a rheumatologist. I don't use ferret ins either.

01:25:31 How about in GI anything? I mean, just for their iron purposes, but not as an inflammatory marker. It's, So, so the principle behind it is IL six. Drives, it helps website in which then interacts with the ferritin pathway. And so that's why we get these super high ferritin levels in our inflammatory diseases. And so it is actually a really nice screen for our conditions.

01:25:57 We used to think that like Ms. was the only thing that gave you ferritin that were in the 50,000. We we now know that like really bad liver disease can do that. Patients malignancies can give you really ferritin. So it's not it's Ms. isn't the only thing that gives you super sky vergence. But it is if we're suspicious or, you know, worried about a mass and then we'll definitely send it.

01:26:17 But it's like I said, it's also high in a lot of our other inflammatory diseases. Okay. Mary Beth, is is functional abdominal pain the same as inflammatory bowel syndrome? I think we just use those interchangeably. Alright. So irritable bowel syndrome is the most common type of functional abdominal pain disorders. But you can have non. So I want to say this right.

01:26:42 You can if you have IBS you definitely have a functional abdominal pain disorder. But if you have an a functional abdominal pain disorder you don't definitely have IBS. That makes sense. It's a type of functional abdominal pain disorders, but it is the most common one. And do they resolve over time inflammatory bowel syndrome. Yeah. So in general irritable bowel syndrome will I mean irritable improve with time.

01:27:04 What they've seen with long term follow up studies is that about 75% of kids that have irritable bowel syndrome will ultimately be diagnosed with anxiety or depression. So it can be a marker for other, conditions later in life. But in general, the thought is that at least in the majority, over 50%, the pain processes will result.

01:27:29 And then you I think you mentioned, I believe it was your talk about, help to define what's the mechanism of action. How does it work? So super happy has a couple different mechanisms. When we think about it. For gastroparesis, we say gastric accommodation because it, allows the stomach to relax when we kind of receive food.

01:27:49 And that's because it, it, has effects on the serotonin receptors. So serotonin generally is kind of pro stimulatory to the stomach, causes it to, to contract. And so it blocks that serotonin receptor in the stomach and allows the stomach to relax and kind of receive food in a more physiologic way. And these patients that are having challenges.

01:28:09 So it's not a propulsive kind of thing. So erythromycin will do that. That will stimulate contraction. Adding it's more kind of relaxation to come in, but they both seem to work kind of for similar processes. Okay. Meg, you mentioned, I think in one of your slides, a Cunningham panel. What is that? Well, I'm, I we're not as I don't want anyone to use.

01:28:33 It's it's a bunch of, autoimmune antibody studies, against different neuronal, antigens. All right. Do you want it with with pans or pandas? Do you want to comment on serial testing for strep? I know you mentioned about if there's symptoms, but is there is there any role for, for for periodic testing of, for the strep pathogen bacterium.

01:29:01 So my opinion and that the AAP there's no reason to test for strep unless you have signs of streptococcal pharyngitis. The however the consortium, the Pans research consortium, feels fairly strongly that every time there's a flare, you should look for strep, but not randomly. And you know, so there's not there's not uniform agreement on this, but I think, you know, I'm going to quote Kathy D'Angelo's here.

01:29:35 If you're going to do a test, you know, test ordering lab test is like picking your nose in public. You better know what you're going to do. The result is you.

01:29:49 Nuff said.

01:29:52 We're just going to let that one sit for so you know. What is this, the Pans Research Consortium or these, it's a group of. Now, remember, the name of the disease is neuropsychiatric. So it's a group of neurologists, psych psychiatrist. I can't remember if they're I'm sure there's some infectious disease people on it, but probably not many.

01:30:18 But it's mainly neurologists, psychologists, psychotherapists, occupational therapists. It's people who who describe this so sweet. Oh, sweet O's on it. And a number of other, people. Like, if you look at the the authors on those papers, there's 12 to 15 on each one. And they're from very respectable, reliable, appropriate university. Stanford. NIH. It's it's a group of people who have looked at pans and pandas for a very long time.

01:30:49 And come to, to to these opinions. I think most of us are not used to reading the psycho pharmaceutical journals. So all of this stuff, if you look at the the references, it's all published in in journals of psychiatrists and their ologist.

01:31:11 And I think, you know, in terms of watching the interactions that led to the clinical report, the interactions within the AAP, tell me if you would agree or disagree with this. My my perception from the ID perspective, was that we kind of wanted to stay as far away from it as we could and that it the main hills that we were ready to die on were serial testing for strep.

01:31:36 Didn't like that. And prolonged prophylactic use of antibiotics didn't like that. The remainder probably as a disorder. It definitely can be disruptive for families. And, and neurobehavioral interventions or the most appropriate approach. Would that be a summary that you would agree with? Absolutely. And and I absolutely believe that it is a it absolutely occurs. I just think it's not nearly as common as the number of referrals that used to get.

01:32:04 All right. And it's terrible when it happens. Jay, you mentioned about with systemic Jia or Still's disease, about a very elevated IL 18. Is that diagnostic for systemic GI yeah. I it's I think it's as good as, it's as good of a diagnostic test as anything that we have in any of our conditions. In, in the setting of prolonged fever.

01:32:30 Right. So when, you know, like I said, when you have prolonged fever or you're thinking about infection, you're thinking about malignancy, and, and our conditions. And so in isolating, and this is not one that's just a little bit above normal, but this is one that's like significantly elevated, like we'll get values. And, you know, I think normal is maybe like up to a couple thousand.

01:32:52 And we'll get values that are ten, 20, 30, 50,000. And if we have that, that we feel pretty good that that's diagnostic for systemic GI. And then why is going to show my ignorance with, with some of the cytokine cascades. Why block IO one or IL six if it's IL 18 that's so elevated. Yeah. So great question.

01:33:14 So, the so we all have something called the inflammasome, which is basically this sort of part of the innate immune system that triggers inflammation. So when you get a fever that, that triggers the inflammasome, to produce IL one and Latino IL one is ingest pathogen goes to the hypothalamus, raises your temperature, cause fever. And so in systemic J and some of our auto inflammatory syndromes there's dysregulation of the inflammasome.

01:33:39 So you get lots of IL one and IL 18 production. And so we so there are 18 drugs being developed now. But we but the principle behind it is that IO1 is, is driving a lot of the inflammation. And similarly IL six is driving a lot of the inflammation, in the disease.

01:34:02 We just and so to then the follow up to that is that L1 levels are really hard to measure in the serum. And so that's why we don't we don't rely on those in the same way that we do IL 18 levels. In in pans. The couple of questions about treatment. One with pans and pandas.

01:34:19 How long are the SSRI is used for two. Is there is there a standard duration or is it type treated per person? I honestly have no idea. I hope it's titrated per person. I mean that would make the most sense, but I don't know the answer to the question. And anybody have any any any ideas? I don't know.

01:34:39 There. And then for colchicine and for what's, what's the like, how do you dose that and for how long? So that is we will depending on the, the how big the child is. So the max dose of colchicine is 0.05 per kilo. Colchicine has got a huge therapeutic range. So if it's a little kid, I'd say, you know, anyone less than, 4 or 5, I'll do half a tablet, which is 0.3, and then I'll just dose it up to, you know, to response and side effects.

01:35:12 The big side effects with colchicine are, gi upset. Make can induce a lactose intolerance. So I'll tell patients when our families when I start start at that. It may cause some stomach upset if that happens, then going lactose free can help with that. But as long as they're tolerating it and if they're still having fevers, then I'll just keep going up on it.

01:35:32 And then in terms of how long to keep it on, it's hard to say. You know, like I said, it lasts on average 4 to 5 years. Some patients it's shorter. Usually I'll do two years or so and then stop. And I'll abruptly stop and see how goes some patients tolerate that and don't have another fever or some patients.

01:35:52 The fever comes back pretty quickly. Colchicine is quick on so we can restart it and it and it works pretty well. But it's it's a question that families have all the time. And I don't have a great answer. I just say, well, you know, we'll try it for a couple of years and then and stop. So it's not a taper, it's a you just stop it altogether.

01:36:06 Yeah. And the pattern when that recurs, if it recurs after that pattern resumes the same old pattern. Yeah. Yeah. Typically sometimes it might be a little bit milder than, than before. I tend to see like a tapering off, of the disease. When as, as kids get older. And so if they're older, you know, they're going to be a couple years older than when they started.

01:36:26 So it might be a little less severe than, than when we start the colchicine. If it does come back. All right I want to thank the panel. Thank you guys very much.