Program faculty Dr. Jonathan Bernstein and Dr. John Anderson are available for Q&A by teleconference. The duration for each teleconference is 30 minutes. Please note that faculty will only provide educational and informational input in response to your questions.

Please email info@p2psyncro.com to schedule. This is provided at no cost.

Disease

Hereditary angioedema (HAE) is an autosomal dominant disease that involves recurrent attacks of swelling in various parts of the body. The first attack typically occurs in childhood or adolescence. Most patients have a genetic defect that causes a deficiency of C1-inhibitor (HAE Type 1&2). Some patients have normal C1-inhibitor but other genetic defects.

Symptoms

Recurrent episodes of swelling in the hands, feet, genitals, bowel, face, and/or throat can last 2 to 5 days. The frequency and severity of attacks may vary dramatically in HAE patients, even those in the same family. Many HAE patients also experience a flat, non-itching red rash that occurs before or during an HAE attack. It is often mistaken for urticaria.

Triggers

While some attacks appear to be spontaneous, some have triggers that include anxiety, emotional stress, minor trauma, surgery, and ailments such as colds/flu/viral infections. HAE patients have also reported swelling in extremities following typing, prolonged writing, hammering, shoveling, and other physical activities.

Source: US Hereditary Angioedema Association. https://www.haea.org accessed 5/28/2022

Diagnostic delay of at least 8 years in HAE has been reported consistently across studies. Misdiagnosis is common.

In children with HAE, bowel wall edema with resultant severe abdominal pain and nausea/vomiting/diarrhea is a frequent initial symptom. It mimics other common pediatric gastrointestinal disorders, most notably appendicitis. Unnecessary surgical procedures such as appendectomy were often performed.

Allergic angioedema is another common misdiagnosis in children. Allergic angioedema and HAE share similar clinical features as described in the tables below. The prodromal nonpruritic rash in HAE is often mistaken for urticaria. In HAE, neither epinephrine, antihistamines, nor corticosteroids are effective.

US Hereditary Angioedema Association (www.haea.org) provides information on how to find physicians treating HAE.

What should be asked when evaluating an undiagnosed HAE patient with angioedema or acute abdomen or recurrent abdominal pain in the ER?

[Dr. Bernstein] Taking a very good family history is important, although 25% of the time there may not be a family history and it may be a spontaneous mutation. I think C4 test in these situations is appropriate, provided if it's not an infant less than one year of age. As a screening test, C4 comes back fairly quickly. It's not very costly and it's accurate in about 70% of cases. If C4 comes back low or if there's a high suspicion, those individuals should be referred to a specialist. I'm not convinced that every patient who comes in the ER with angioedema should have a full HAE workup. The tests for full work-up are not going to come back when the patient is in the ER.

Should any treatment be started while the patient is in the ER?

[Dr. Anderson] So first, if we start with the patient who has a confirmed diagnosis, then I would say yes that C1 esterase inhibitor can and ought to be administered. Sometimes a child might have HAE, but that doesn't mean that he or she doesn't have other medical conditions that can cause abdominal pain or an acute abdomen. So certainly a quick administration of esterase inhibitor is part of that differential workup. If symptoms are improving, then that kind of helps steer you out of the woods. But afterwards, I do think it's very important to consider pursuing the rest of the workup, especially if the patient is not responding well to therapy.

Now, if you have a patient who's not diagnosed and you're wrestling with decision about when to utilize treatment with on formulary esterase inhibitor or other like product, that becomes a more complicated decision. I will say that there have been occasions when I have advocated for the use of these products. But that should be kind of a rare event and standard of care approaches are first line for treating abdominal and airway issues. But certainly, if a child is not responding to first line therapy, differential diagnosis needs to be opened and alternative treatments and tests should be considered.

Any workup should be done by primary care pediatricians before making referrals to a specialist?

[Dr. Bernstein] I've seen many times where patients sent to me for a diagnosis of HAE when they have clearly urticaria and angioedema. They've ordered all these tests. There's a lot more into it than just ordering the tests. I would say a primary care doctor who has suspicion can get a C4 level, but they should refer the patient to the specialists for additional workup. I think we're seeing a lot of unnecessary testing for cases that are low likelihood of having HAE.

[Dr. Anderson] Yeah, I certainly agree. If a physician is suspecting HAE, that's already a win in my book because either they will draw labs or they will refer. I think both are appropriate options. I think part of that might deal with the comfort level that the physician has. If you choose to order merely C4 or if it's a bundled panel, I think it's really a question of interpretation of the test. If there's any question of that, reaching out to your allergy colleagues would be essential.

How available are the diagnostic tests, what are the limitations, and should the tests be repeated by allergists?

[Bernstein] I think most laboratories do have these assays. These are send-outs typically to one of the national laboratories. There is importance to understand the difference between the chromogenic and enzymatic assays. They have different sensitivity specificities. It is important to recognize the limitations of C4 as a screening tool (> 1 year of age, accurate in 70% cases) and that C1q which should be normal, but can be low and high in up to 30% of cases. None of these tests are 100% other than a very low inhibitor functional (less than 40% is important), which is really the required test. And in fact, if you have a high C1 quantitative and a low functional level, that's what we call Type 2, which makes up about 15% of cases, whereas 85% have low C1 inhibitor functional and quantitative level.

[Dr. Anderson] When the patient is referred, it's very likely that the allergist will do more than merely interpret the previous test. They'll repeat the test in case there was processing error which can happen sometimes in complement studies to cause a test to be falsely low.

[Dr. Bernstein] But if the functional level is low and it comes from a decent lab, I don't think repeating tests is necessary. I think if there is equivocal testing and sometimes indeterminate values, then sure. But it's not a routine where you repeat the test automatically. So I think just talking to you, we're finding out that there are differences in how people would be approaching some of these cases. So, sure, that's medicine, that's health care.

What is your experience in starting preventative therapies in the child who's younger vs. older than 12 years of age and how long should they be treated?

[Dr. Anderson] For those younger than 12 years of age, I am more confident in using C1 esterase inhibitor replacement therapy. I have in the past used more iv product, but with the emergence of subcutaneous esterase inhibitor that has become the treatment that I will reach for most often. It's probably still the number one therapy that I have used for pediatric patients 12 and older as well. Although I do have pediatric patients that are on Lanadelumab and Berotralstat who are older than 12, generally with good results.

[Dr. Bernstein] Yeah, I think that's my experience as well. There's a lot of factors that go in with shared decision making to determine who should get a prophylactic therapy, because once you start them, for the most part, these are sometimes continued for the entire life of the individual. There is a heterogeneity in the frequency of attacks. Once patients are experiencing severe attacks and find out that they get relief from these therapies, they don't really want to come off. But I think we have to monitor and assess these patients over time to determine the need for continued prophylactic therapy and or changing prophylactic therapies to therapies that are easier for them to tolerate or adhere to.

Program faculty Dr. Jonathan Bernstein and Dr. John Anderson are available for Q&A by teleconference. The duration for each teleconference is 30 minutes. Please note that faculty will only provide educational and informational input in response to your questions.

Please email info@p2psyncro.com to schedule. This is provided at no cost.

Disease

Hereditary angioedema (HAE) is an autosomal dominant disease that involves recurrent attacks of swelling in various parts of the body. The first attack typically occurs in childhood or adolescence. Most patients have a genetic defect that causes a deficiency of C1-inhibitor (HAE Type 1&2). Some patients have normal C1-inhibitor but other genetic defects.

Symptoms

Recurrent episodes of swelling in the hands, feet, genitals, bowel, face, and/or throat can last 2 to 5 days. The frequency and severity of attacks may vary dramatically in HAE patients, even those in the same family. Many HAE patients also experience a flat, non-itching red rash that occurs before or during an HAE attack. It is often mistaken for urticaria.

Triggers

While some attacks appear to be spontaneous, some have triggers that include anxiety, emotional stress, minor trauma, surgery, and ailments such as colds/flu/viral infections. HAE patients have also reported swelling in extremities following typing, prolonged writing, hammering, shoveling, and other physical activities.

Source: US Hereditary Angioedema Association. https://www.haea.org accessed 5/28/2022

Diagnostic delay of at least 8 years in HAE has been reported consistently across studies. Misdiagnosis is common.

In children with HAE, bowel wall edema with resultant severe abdominal pain and nausea/vomiting/diarrhea is a frequent initial symptom. It mimics other common pediatric gastrointestinal disorders, most notably appendicitis. Unnecessary surgical procedures such as appendectomy were often performed.

Allergic angioedema is another common misdiagnosis in children. Allergic angioedema and HAE share similar clinical features as described in the tables below. The prodromal nonpruritic rash in HAE is often mistaken for urticaria. In HAE, neither epinephrine, antihistamines, nor corticosteroids are effective.

US Hereditary Angioedema Association (www.haea.org) provides information on how to find physicians treating HAE.

What should be asked when evaluating an undiagnosed HAE patient with angioedema or acute abdomen or recurrent abdominal pain in the ER?

[Dr. Bernstein] Taking a very good family history is important, although 25% of the time there may not be a family history and it may be a spontaneous mutation. I think C4 test in these situations is appropriate, provided if it's not an infant less than one year of age. As a screening test, C4 comes back fairly quickly. It's not very costly and it's accurate in about 70% of cases. If C4 comes back low or if there's a high suspicion, those individuals should be referred to a specialist. I'm not convinced that every patient who comes in the ER with angioedema should have a full HAE workup. The tests for full work-up are not going to come back when the patient is in the ER.

Should any treatment be started while the patient is in the ER?

[Dr. Anderson] So first, if we start with the patient who has a confirmed diagnosis, then I would say yes that C1 esterase inhibitor can and ought to be administered. Sometimes a child might have HAE, but that doesn't mean that he or she doesn't have other medical conditions that can cause abdominal pain or an acute abdomen. So certainly a quick administration of esterase inhibitor is part of that differential workup. If symptoms are improving, then that kind of helps steer you out of the woods. But afterwards, I do think it's very important to consider pursuing the rest of the workup, especially if the patient is not responding well to therapy.

Now, if you have a patient who's not diagnosed and you're wrestling with decision about when to utilize treatment with on formulary esterase inhibitor or other like product, that becomes a more complicated decision. I will say that there have been occasions when I have advocated for the use of these products. But that should be kind of a rare event and standard of care approaches are first line for treating abdominal and airway issues. But certainly, if a child is not responding to first line therapy, differential diagnosis needs to be opened and alternative treatments and tests should be considered.

Any workup should be done by primary care pediatricians before making referrals to a specialist?

[Dr. Bernstein] I've seen many times where patients sent to me for a diagnosis of HAE when they have clearly urticaria and angioedema. They've ordered all these tests. There's a lot more into it than just ordering the tests. I would say a primary care doctor who has suspicion can get a C4 level, but they should refer the patient to the specialists for additional workup. I think we're seeing a lot of unnecessary testing for cases that are low likelihood of having HAE.

[Dr. Anderson] Yeah, I certainly agree. If a physician is suspecting HAE, that's already a win in my book because either they will draw labs or they will refer. I think both are appropriate options. I think part of that might deal with the comfort level that the physician has. If you choose to order merely C4 or if it's a bundled panel, I think it's really a question of interpretation of the test. If there's any question of that, reaching out to your allergy colleagues would be essential.

How available are the diagnostic tests, what are the limitations, and should the tests be repeated by allergists?

[Bernstein] I think most laboratories do have these assays. These are send-outs typically to one of the national laboratories. There is importance to understand the difference between the chromogenic and enzymatic assays. They have different sensitivity specificities. It is important to recognize the limitations of C4 as a screening tool (> 1 year of age, accurate in 70% cases) and that C1q which should be normal, but can be low and high in up to 30% of cases. None of these tests are 100% other than a very low inhibitor functional (less than 40% is important), which is really the required test. And in fact, if you have a high C1 quantitative and a low functional level, that's what we call Type 2, which makes up about 15% of cases, whereas 85% have low C1 inhibitor functional and quantitative level.

[Dr. Anderson] When the patient is referred, it's very likely that the allergist will do more than merely interpret the previous test. They'll repeat the test in case there was processing error which can happen sometimes in complement studies to cause a test to be falsely low.

[Dr. Bernstein] But if the functional level is low and it comes from a decent lab, I don't think repeating tests is necessary. I think if there is equivocal testing and sometimes indeterminate values, then sure. But it's not a routine where you repeat the test automatically. So I think just talking to you, we're finding out that there are differences in how people would be approaching some of these cases. So, sure, that's medicine, that's health care.

What is your experience in starting preventative therapies in the child who's younger vs. older than 12 years of age and how long should they be treated?

[Dr. Anderson] For those younger than 12 years of age, I am more confident in using C1 esterase inhibitor replacement therapy. I have in the past used more iv product, but with the emergence of subcutaneous esterase inhibitor that has become the treatment that I will reach for most often. It's probably still the number one therapy that I have used for pediatric patients 12 and older as well. Although I do have pediatric patients that are on Lanadelumab and Berotralstat who are older than 12, generally with good results.

[Dr. Bernstein] Yeah, I think that's my experience as well. There's a lot of factors that go in with shared decision making to determine who should get a prophylactic therapy, because once you start them, for the most part, these are sometimes continued for the entire life of the individual. There is a heterogeneity in the frequency of attacks. Once patients are experiencing severe attacks and find out that they get relief from these therapies, they don't really want to come off. But I think we have to monitor and assess these patients over time to determine the need for continued prophylactic therapy and or changing prophylactic therapies to therapies that are easier for them to tolerate or adhere to.