Dr. Mike Smith (Host): This is Transformational Pediatrics with Children's Mercy, Kansas City. I'm Dr. Mike. Joining me is Dr. J. Allison Hays, and we'll be discussing histiocytosis. Dr. Hays, welcome to the show.

Dr. Allyson Hays: Thanks so much for having me. I'm really excited.

Host: You know, let's start with some basics. Can you give us a nice review of histiocytosis and how does it present in the pediatric patient?

Dr. Allyson Hays: I'll try to be brief because it is a very big topic. So, histiocytosis is a group of disorders, that includes things like Langerhans cells histiocytosis. And that would present in most kids, the most typical presentation is a skin rash. It can look like anything. It can look like cradle cap. It can look like a diaper rash. It can be those kids who get those ear infections over and over again, and you're treating them the draining ear infections in particular. And they're not getting better. So, it can present as a skin rash, the Langerhans cell histiocytosis or LCH. It can also present as a painless mass, a bump on any bone in the body. And sometimes kids complain of pain overnight in particular. So, it has a wide variety of presentations. It can be something, like I said, as simple as a skin rash, or it can involve lots of different organs and be life-threatening. So, LCH is probably the most common form of histiocytosis that we see.

The second most common form, and this is one that I feel like since I've been doing this has been increasing either in-- I'm not sure if it's increasing in number or increasing in the fact that we recognize it-- is something that it's called hemophagocytic lymphohistiocytosis. We love our long words in histiocytosis, and so we abbreviate that one as HLH. And so, this is one that I'm going to say most people have never heard of. I remember hearing about one case when I was in residency and hearing that it was essentially just, you know, a fatal illness. And I thought to myself, "That just sounds awful." But now, what we know there's a lot of work going on to recognize this disorder and things like that.

I think of HLH as very similar to sepsis that isn't responding to typical treatments. So, sometimes these kids with HLH can be incredibly sick. A lot of times when I meet these patients, they're in the intensive care unit. Sometimes they're quite young. They can be babies, they can be up to teenagers and things like that. And there's two different kinds of HLH. There's what we call primary HLH or like the inherited kind, where there's a gene mutation, that is sometimes recognized that causes the immune system not to function properly. And these kids, like I said, can be critically ill. And eventually, they need some chemotherapy and they need a bone marrow transplant. The secondary form, that's the one that I think is increasing in either frequency or recognition, and that's because, again, it looks like sepsis. And so, when you're treating kids for infections-- and HLH has been associated with almost every infection I can think of. And when you're doing the typical treatments and they're not getting better, that's a time when I think HLH should be considered.

So depending on the severity of that secondary or the infection associated to HLH, sometimes they need, you know, a little bit of steroids. Sometimes they need more serious chemotherapy. Other times, we go all the way to bone marrow transplant based on their responses. So, those are the two most common forms. And again, this is still a rare condition even within Pediatrics. Both of those are very rare.

And then, one other one that I'd just like to mention is something called juvenile xanthogranuloma, or JXG. That is something that it can be a single solitary skin nodule. The color can be anywhere from red to brown. It's not associated with high cholesterol, like this would be in adults. And it usually is a benign condition, not anything that requires chemotherapy or treatment. But sometimes because these lesions can grow, families like to have them removed, or they can be in places like where diapers rub and they, you know, cause a little bleeding and things like that. So, that is another condition that I do tend to follow as well. There's even less common kinds of histiocytosis, but those are probably the three most common ones I see.

Host: Right. And do all types of his osteophytosis at some level affect the immune system? You know, maybe it's a spectrum from some cases not so bad, other cases, like what you've been describing, pretty bad.

Dr. Allyson Hays: It can. Yeah, I would say JXG doesn't really affect the immune system. It's not something that we tend to see a lot of immune dysregulation and things like that. HLH absolutely affects the immune system. And LCH, I would say kind of is in the middle, depending on the severity of the disease. Those kids who have, you know, liver involvement, spleen involvement, bone marrow involvement, those kids can be quite sick and, I would say, fall more in the immune dysregulation category. But those kids who have the single skin rash or a single bone lesion, not necessarily. So, it's frustrating, I think, to many of us because it is so unpredictable and there is such a wide spectrum of diseases. It is not a one-size-fits-all, like so many things in pediatrics. So, it can be quite challenging.

Host: So, Children's Mercy is one of the few centers in the region treating histiocytosis from what I understand. So, what makes your approach so unique?

Dr. Allyson Hays: I've been interested in histiocytosis, really-- I mean, well, now, it's been 17 years that I've been here at Children's Mercy running this program and things like that. So, I got interested in this when I was a fellow in Dallas and decided that it was something that I didn't fully understand. And I felt like it was something I wanted to look into more. And so, I got involved in what's called the Histiocyte Society, which is the only organization that focuses on histiocytosis. Many of our other organizations that treat children's cancer and things like that, like Children's Oncology group, they historically have not involved kids with LCH and HLH in clinical trials and things like that.

The Histiocyte Society is the only organization that's done that. So, I've been active with them. We have a global meeting once a year, where basic scientists, clinicians, all the people that are invested in this disease come either in person or now there's a virtual option to really discuss this and learn more about it. So since it is such a rare condition, it is not uncommon for kids to have a delay in getting that diagnosis. So, I felt like this was an important and rare condition, something that I thought I could make a difference in. And so, we started this Histiocytosis Program at Children's Mercy. I think that we really focus on treating not just our patient, but also supporting the family at the same time. And we've tried to incorporate some of the newer trials, newer agents, and kind of holistic way of looking at histiocytosis here at Children's Mercy.

Host: That's great. Can you walk us through a typical journey for a child suspected of having histiocytosis. You already mentioned there can be delays in diagnosis, but once they're with you, once they're at Children's, what kind of journey can they expect? Can the family expect?

Dr. Allyson Hays: So, I would say for the kids that have HLH, unless there's a family history, where we know to look for it and things like that, it usually is kids who are admitted to the hospital for some kind of an infection. Epstein-Barr virus or EBV is a very common agent that kind of triggers that secondary HLH and things like that. And a lot of times, I'll get consults from the infectious disease colleagues or the general pediatrics teams or the intensive care team asking me to look and help them think through if this child could meet the criteria for HLH and things like that. There's genetic criteria. And then, in addition, there's also criteria for clinical criteria including blood counts, spleen and liver size, and some send-out labs that we do and everything like that. So for those patients, I would say a lot of times with HLH, we make that diagnosis fairly fast, because these kids are so critically ill. And really, it's kind of all hands on deck thinking about how to intervene and improve this child's health and things like that.

For the kids with LCH, just like everything with LCH, there's definitely a spectrum. There are some times where a child will have a skin rash, and see either Dermatology or Plastics, to have a skin biopsy. And then, the pathologist or the dermatologist will reach out to me and let me know that they have a patient that they'd like for me to see and things like that.

Other times, again, it can be kids who are in the hospital for failure to thrive, or like a secondary skin infection, because this rash could be so widespread. And a lot of times kids with LCH, especially when it's more extensive, they can have a lot of inflammation in their body and just be very uncomfortable. And so, sometimes I can meet them in the clinic, other times I can meet them in the hospital. It just kind of depends on each and every presentation.

Host: So, definitely a lot of challenges in managing LCH, HLH, medically speaking. What about the emotional side of it, the emotional side for the child, for the family?

Dr. Allyson Hays: I would like to say that we have unlimited resources and things like that, but I think no one can really say that. And so, because this is a rare condition and because a lot of the resources that we have in our Oncology Department are focused on specific diagnoses like leukemias and solid tumors and things like that. Histiocytosis, it's underrepresented and it's something that we don't have as many financial resources and things like that. I think we've improved dramatically in being able to qualify kids for resources like Make-A-Wish and other resources that could help them.

I would say that it is very isolating since this is such a rare condition. And there is a lot of information about different kinds of cancer and things like that out there. I think it can be especially challenging. The Histiocyte Society has a wonderful website called histo.org that I refer to on a regular basis. They've got disease information sheets for families, that I think are really helpful. They've got a database that recommends, if you're going to be moving to another place, or if you live in a place where Children's Mercy is not nearby or not accessible, that you could find somebody who specializes in histiocytosis to treat your child or to at least evaluate your child for something like this.

So, it is quite challenging. And just like many things in pediatrics, it's not just the short term that we're thinking about, it's also the long term. So, we do have a lot of my patients that have received chemotherapy for histiocytosis, they do go on to attend our long-term survivors clinic, Survive and Thrive here at Children's Mercy, to look for long-term effects of both their chemotherapy and their disease, and help them navigate the healthcare system as they age out of the pediatric system.

Host: Right. So, you've been treating patients with histiocytosis for, I think, you said 17 years. Is that right?

Dr. Allyson Hays: Yeah, longer than I'd like to admit, but yes.

Host: Great. So when you look at the future of histiocytosis treatment, or not just treatment, even early intervention or a better diagnosis, whatever it is, what kind of research is going on that's really exciting?

Dr. Allyson Hays: Lot of things that are really exciting. I think one of the biggest things is, I guess it was about 10 years ago now, there was a mutation that was associated that was identified in about half of patients that have longer hand cell two cytosis. And due to that, there are some oral agents, some oral chemotherapy agents that can actually target that mutation and help to treat patients so they don't necessarily have all of the same side effects that we associate with typical chemotherapy. Those, I tend to reserve for patients that have had refractory disease. So, they've gotten typical chemotherapy and have either progressed or it's come back, because of my hesitancy with some of the late effects, and we don't know the long-term effects of these agents.

And so, I generally do prefer to focus on more established agents in the beginning, but I think having those options for those patients that have recurrent or refractory disease. There's also a lot of work trying to look at other agents. There's a lot more understanding about the growth pathway that's associated with LCH in particular. And so, using some other Chemotherapy with differing side effects, that might be better tolerated, some oral agents and things like that. There's a lot of information going on about the inflammatory cascade and how we could intervene earlier in it for those kids with HLH. I think it was about five or so years ago, the first and only chemotherapy specifically approved for HLH was brought out and it's called Gamifant or emapalumab. And I've used it with great success in a few patients here at Children's Mercy. So, there's never been a time where there's been as much interest or where research going on in histiocytosis. And so, it is really an exciting time.

Host: Wow, that is a lot going on. You know, to wrap up, what would you like to say to community pediatricians when encountering potential histiocytosis cases?

Dr. Allyson Hays: I think, I would say I would keep LCH on the differential if you have a kid with a rash, that just isn't responding to typical treatments, like I said before, the diaper rash, the kids with cradle cap, that you do all the things that normally work and it's not getting better. Those kids who have those chronically draining ears and you're kind of at the end of your rope with antibiotics and things like that. So, I would say consider LCH for those patients.

For the HLH patients, like I said, unless there's a family history, it can really present at any age. So, I'd like to say those inherited kids only present in infancy. But unfortunately there are some patients that are quite a bit older that present with it. So, I would say, if you have a kid that is refractory to typical treatment you would think of for infection and things like that, I think thinking about that immune dysregulation associated with HLH would be important.

LCH has gone by many different names. You might have heard of it as eosinophilic granuloma, histiocytosis X. There's been many, many names, but I would say that now we try to use that Langerhans cell histiocytosis term, and then define if it is what we call a single system or multi-system.

So, I would say it's something to consider. It's not something I think many people are going to see often. So if you haven't seen a case of it, it's totally understandable. And if you have, it probably made an impact on you because they're usually pretty impressive and pretty surprising.

Host: That was fantastic, Dr. Hays. Thank you so much. What great information.

Dr. Allyson Hays: My pleasure.

Host: For more information, you can go to cmkc.link/histiocytosis. If you enjoyed this podcast, please share it on your social channels and check out the entire podcast library for topics of interest to you. This is Transformational Pediatrics. I'm Dr. Mike. Thanks for listening.