Disclaimer: This podcast miniseries is supported by a grant from Takeda.

Dr. Kristin Sokol (Host): Despite its rarity, hereditary angioedema has a profound impact on the lives of many patients. As healthcare providers, the ability to recognize and diagnose HAE early, especially in pediatric patients, can make all the difference in improving patient outcomes and quality of life.

However, the challenges of diagnosing HAE, particularly in minority and rural populations, remain significant. The goal of this podcast miniseries, Pediatric Hereditary Angioedema, or HAE, Diagnosis and Management, Challenges, Barriers, Strategies, is to explore how we can overcome barriers from early recognition in childhood to managing long-term care and understanding the genetic and acquired forms of this disease. We'll also discuss the crucial role you play in identifying this condition before it's too late.

Hello, everyone. My name is Dr. Kristin Sokol, and I will be your host for this three-part miniseries entitled Pediatric Hereditary Angioedema Diagnosis and Management, Challenges, Barriers, Strategies. I am a board-certified allergist-immunologist and board-certified pediatrician practicing at Schreiber Allergy in the DC area and currently serving as the Chair of the ACAAI Annual Program Committee.

In this episode, we'll discuss the critical steps in accurately diagnosing HAE, including how to identify key symptoms through clinical history, differentiate between type 1 and type 2 HAE through lab testing, and the role of genetic testing. We'll also explore the unique challenges of diagnosing HAE in pediatric patients, and why early diagnosis is so important.

And in the next two parts, we'll be diving into some real-world challenges of managing patients with HAE. In part two, we'll look at how treatment differs in rural and urban settings, the importance of on-demand therapy, and why shared decision-making is such an important part of our ongoing treatment plan for these patients. Then in part three, we'll get into long-term management strategies, when to start prophylaxis, and how to support pediatric patients with HAE transitioning into adulthood.

I'm excited to be joined by two HAE experts. Our first expert is Dr. Aleena Banerji. Dr. Banerji is a Professor at Harvard Medical School and Clinical Director of the Allergy and Clinical Immunology Unit at Massachusetts General Hospital in Boston, Massachusetts. Dr. Banerji has collaborated with industry on multiple clinical trials, evaluating novel agents for hereditary angioedema, and has published over 50 peer-reviewed manuscripts, including national and international guidelines for the management of hereditary angioedema. She also serves on the medical advisory board for the U.S. Hereditary Angioedema Association. Dr. Banerji, welcome to the podcast.

Dr Aleena Banerji: Thanks, Kristin. I'm happy to be here.

Host: Our second expert is Dr. Timothy Craig. Dr. Craig is a Professor of Medicine, Pediatrics, and Biomedical Sciences, and is a distinguished educator at Pennsylvania State University. He is also a Senior Advisor at Vinmec International Hospital in Times City, Hanoi, Vietnam. He is a Director of the Allergy, Immunology and Respiratory Clinical Research, as well as the PSU Alpha-1 Foundation Clinical Resource Center, and the International Angioedema Resource Center, also known as ACARE. He serves on the Medical Advisory Board for the U.S. Hereditary Angioedema Association. Dr. Craig, thanks so much for joining the podcast.

Dr. Timothy Craig: Thanks so much, Kristin.

Host: All right. So, let's get started. Aleena, let's begin with you, as we know, hereditary angioedema or HAE with C1 inhibitor deficiency is a rare, life-threatening, and lifelong disabling genetic disorder characterized by self-limited tissue swelling that can affect the skin, the upper airway, and the GI tract, and it's caused by a deficiency or dysfunction of the C1 inhibitor gene. Despite HAE being rare, pediatricians and allergists will see patients with this condition in their clinical practice. So, why do you think it's so important to obtain an accurate diagnosis for pediatric HAE?

Dr Aleena Banerji: Thanks, Kristin. I think this is actually a really important part of what we do when we're seeing patients with hereditary angioedema. Obtaining the accurate diagnosis of hereditary angioedema in children is important and critical for several reasons.

First, it allows for the prompt initiation of appropriate treatment and management strategies, which really can improve a child's quality of life. The early diagnosis in the pediatric population also helps to avoid alternate misdiagnoses, unnecessary emergency room visits, unnecessary treatments, especially if they're showing up to the emergency room with recurrent abdominal pain. If we know that the diagnosis is hereditary angioedema, it won't be misdiagnosed. So, this accurate diagnosis early on prevents unnecessary treatments and procedures and ensures that that child actually receives the right treatment for hereditary angioedema.

Additionally, early diagnosis really allows for the development of a comprehensive management plan for that child. And this includes education about potential triggers, preventive measures, emergency preparedness, and access to specialized care. That confirmed diagnosis of hereditary angioedema also provides that family with further clarity about the symptoms, the unpredictable nature of hereditary angioedema, and what to do when symptoms occur. This knowledge and this early diagnosis really empowers not only that child, but also the patient's family to take proactive steps in managing the condition and seeking appropriate support.

Host: Yes, Aleena, everything you said is so on point and so important. I mean, we really have to have an accurate diagnosis and, as pediatric specialists and allergists, we are going to see this. So in a large series of actually C1 inhibitor HAE patients, they reported the illness had a mean onset of age at about 11 years old, with almost 90% of patients experiencing their onset of symptoms by age 20. And in another early U.S. report, nearly half of patients had symptoms by age 6. So as allergist-immunologists who care for pediatric patients, we should obviously be aware of the presentation of this condition. So Tim, can you go through some of the symptoms that your patients report with HAE? What are some clues in the history that point you to work up this disease?

Dr. Timothy Craig: Yeah, Kristin. So, it's really a good history, so important in the diagnosis. So, first of all, these people don't get hives. They can get a rash that's very similar to hives, and by chance alone they may have hives,. But usually if their swelling and the hives always occur together, that kind of makes this diagnosis go away, but they not only have swelling, which can occur in any skin surface, but they also have abdominal pain. And that's where the diagnosis becomes really difficult, especially in young children. A lot of parents think, "Oh, they just have colic or whatever." And it's so important to really try to hone in on the diagnosis very early for that reason, so that if it is hereditary angioedema, something can be done about it.

In addition, it can affect the upper airway and that is key because that could lead to asphyxia and death. So when you see that triad, fortunately, the upper airway is rarely affected. But when you see two of them, the abdominal pain and swelling together without hives, that's what really makes you think of the diagnosis. And that's when you should begin in the biochemical test to confirm the diagnosis. And I try to do that very early in life in the first year to confirm whether or not someone has HAE. So that way, I can be prepared in case they start having symptoms at a very early age.

Host: That's so helpful, Tim. Yes, and we'll get into the genetics a little bit later. But yeah, what you said about the GI symptoms is really important, because the GI symptoms can be masked as so many other conditions. So, really important to take that good history, see how long the attacks last, right? Because in HAE, a swelling lasts for several days, like two to five days, which is different than some other conditions.

Dr. Timothy Craig: Yeah, you're right there. So, they can be shorter. But you're right, textbook-wise, it's two to five days and that is another key as you point out.

Host: So as established at the genetic level, several types of HAE have been described. For the purposes of this discussion, we'll only focus on types 1 and 2. So Aleena, can you tell me about the differences between type 1 and type 2 HAE?

Dr Aleena Banerji: Sure, Kristin. When we're talking about type 1 and type 2 hereditary angioedema, we're really focused on hereditary angioedema with C1 inhibitor deficiency. We know that type 1 hereditary angioedema is the most common form and accounts for about 80-85% of the cases. And in type 1, we have a low C1 inhibitor protein because it's not produced, and consequently a low C1 inhibitor function.

And so in type 1, the lab testing shows not only a low C1 inhibitor level, but also the low C1 inhibitor function. In type 2 hereditary angioedema, which is less common, so about 15-20% of cases, patients do produce the C1 inhibitor protein, but the protein itself is dysfunctional, which means that when you're looking at the labs, they may actually have a normal C1 inhibitor level, but they will have a low C1 inhibitor function.

So, it's really important to check the C1 inhibitor function to make the accurate diagnosis with type 1 or type 2 hereditary angioedema. Clinically, however, both type 1 and type 2 hereditary angioedema present very similar clinically, and you can't really differentiate what type they have based on symptoms, and it actually may not make that much difference when we're evaluating treatment options for patients.

Host: Yeah, everything you said is so important. And that brings us to kind of the next question. You mentioned, you know, that we can't really tell the difference sometimes. So Tim, is there a role for more testing in pediatric HAE, like genetic testing? Do you think this could be helpful for distinguishing between type 1 and type 2 or any other reasons?

Dr. Timothy Craig: That's always a good question and actually the guidelines differ on the advice they give us for genetic testing. The American guidelines kind of state that in the first year of life, the functional assay is diagnostic still. The international guidelines say that that's not true, that during the first year of life, since people don't make as much C1 inhibitor, or babies, that sometimes you can get the wrong idea about the diagnosis.

And so, the international guidelines do say that maybe genetic testing in the first year of life may be important to do if you want to really distinguish whether a person has HAE or not. The other time it's helpful later in life if someone has late onset angioedema like in their 40s or 50s, that could be acquired angioedema or that could be late onset hereditary angioedema.

And one of the ways to distinguishing that is getting a C1q and acquired angioedema with low C1 inhibitor, and about 75% of cases has a low C1q. But in the other 25%, they don't. And again, that's a time when genetic testing may help you determine whether it is really a late-onset hereditary angioedema or acquired angioedema with a low C1 inhibitor.

The other time is in utero diagnosis. If you wanted to have that test done, I think, you know, in a one-child policy in China, and when you had no medications available for your child, that was something that people often sought, was to make a diagnosis in utero so that you can maybe prevent that pregnancy. But outside of those three things, those three times in life, there really is minimal need for genetic testing because the biochemical testing is so accurate.

Host: Thank you so much, Tim. And Aleena, this question is for you, and Tim kind of mentioned or touched on this prior, but is there anything specific we need to be aware of when diagnosing this condition in very young patients, like infants? And once we've established a diagnosis in a very young patient, is there a role of testing family members?

Dr Aleena Banerji: Sure. Yeah, I'll add on to a little bit of what Tim mentioned. We know that hereditary angioedema is a genetic autosomal dominant condition, which essentially means that a parent has a 50% chance of passing hereditary angioedema on to their child. And so, in general, the guidelines do recommend that the child of any parent with hereditary angioedema should have lab testing. And this lab testing includes looking at a C4 level, a C1 inhibitor level, and a C1 inhibitor function.

And what we know is when you test, especially the C1 inhibitor level and function before before they hit one year of age, there's a lot of fluctuation of the C1 inhibitor levels. And so, it may not accurately reflect their true baseline. So, we will recommend waiting after one year of age to really allow for more stable, reliable test results.

In addition, you know, once a child is diagnosed with hereditary angioedema, we would recommend testing the family members. So, for example, if the child is the first person to be diagnosed with hereditary angioedema, it would be important to test all of the family members. But to remember that in 25% of cases, we do see new mutations, so it's possible that that child may be the first person in that family to have hereditary angioedema. But either way, an early and accurate diagnosis still allows us to focus on appropriate care, set up management plans, give them the right treatment, and avoid any complications which can happen, especially when a child is undiagnosed.

Dr. Timothy Craig: Yeah. Could I add on to that, Kristin, too? And I think Aleena's idea is so key. So even in the first year of life, even if they've never had any symptoms yet, to give them medication is so important to be available. Because remember, most hospitals don't have these medications, right? And so, if you go to the emergency room, you may not be able to get therapy for HAE.

So, I think at the first year of life, you test them, you give them a prophylactic medication, and also you give them a rescue medication, and the prophylactic medication is not long term, but short term in case they need a surgical procedure or they have trauma or they have something else going on in their life that causes an attack. So very early on in life, give them medication that's available even though they might not use it until the age of six or eleven like you mentioned, when most people were starting to have symptoms. So in case they do, the parents can be prepared.

Host: Thank you so much, Tim, and thank you so much, Aleena, both of our experts, for sharing their valuable insights today. It's clear that early and accurate diagnosis of hereditary angioedema is critical to improving patient outcomes, especially in our young pediatric cases. We hope this discussion has provided our listeners with practical guidance to recognize and manage HAE in your patients.

This concludes part one of our three-part miniseries, Pediatric Hereditary Angioedema Diagnosis and Management, Challenges, Barriers, Strategies from the ACAAI. Be sure to tune in to part two when we cover HAE treatment strategies and overcoming barriers to care.

For other interesting podcast episodes and to claim CME for this episode, please visit education.acaai.org. I'm Kristin Sokol for the American College of Allergy, Asthma, and Immunology. I hope you have a wonderful day.