**4. Diagnosis**

Low awareness of the disease among both doctors and the public can lead to more than a 10‐ year delay in the diagnosis and also result in a misdiagnosis such as allergies, systemic lupus erythematosus, and appendicitis [30–32]. HAE patients usually have a typical medical history with episodes of angioedema without urticarial plaques on their skin and/or abdominal pain attacks without inflammatory signals. Such a clinical presentation accompanied by a family history is highly suggestive of the diagnosis, but laboratory tests are recommended to confirm the diagnosis [9]. Serum C4 level is the screening test for HAE, which is decreased both dur‐ ing and between episodes in almost all of patients (98%). Interestingly, C4 can seldom be observed at a normal level between episodes [20]. Serum C1 and C3 levels are not affected by the disease. If C4 levels are normal during an episode, the diagnosis of type I, type II HAE, and acquired angioedema is excluded. After measuring C4, C1‐inh must be measured in the serum to accurately diagnose the HAE type. In type I HAE, both serum C1‐inh and C4 levels are detected below the normal ranges (the reference range of C4 is 15**–**50 mg/dl and of C1‐inh is 16**–**33 mg/dl), whereas in type II HAE serum C1‐inh is normal but the function of C1‐inh is impaired. These tests can indicate a false negative in children younger than one, so the tests must be repeated to confirm the diagnosis [9]. In the third HAE type, HAE with normal C1‐ inh, serum C4‐ and C1‐inh levels are normal and the diagnosis is challenging. Its diagnosis depends on recurrent angioedema attacks without urticaria or abdominal pain attacks and possibly a family history. However, clinical presentation is highly variable, which often leads to a misdiagnosis, and genetic tests including FXII mutations rarely support the diagnosis [33]. In **Table 1**, differential diagnoses of angioedema including both hereditary and sporadic diseases based on laboratory are shown.


ACEI, angiotensin‐converting enzyme inhibitor; ACID, acquired angioedema due to C1‐inh deficiency; HAE‐1, hereditary angioedema type I (due to C1‐inh deficiency); HAE‐2, hereditary angioedema type II (due to C1‐inh defect); C1‐inh, C1 inhibitor.

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a Nonclassified implies that no cause has been identified [34]. http://dx.doi.org/10.1016/j.anai.2012.10.008

**Table 1.** Differential diagnosis of angioedema according to laboratory results [34].

#### **5. Management**

of the mutations in type II HAE are missense at or near the active site causing the production of a defective protein, which cannot act properly [10]. In patients with HAE with normal C1‐inh, the SERPING1 gene is not mutated, but in some of these patients mutations on the FXII gene, which is located on the fifth chromosome, can be detected. The pathomechanism of angioedema in these patients is not well defined. One of the detected mutations on factor XII leads to a gain of function, which is thought to cause the increase in the production of bradykinin [28]. However, this hypothesis was not confirmed in another study [29]. Since bradykinin antagonist drugs are effective in uncontrolled patients, it can be assumed that

**Figure 1.** The role of C1‐inh in the plasma cascade and complement pathway and the pathogenesis of the HAE [14].

Low awareness of the disease among both doctors and the public can lead to more than a 10‐ year delay in the diagnosis and also result in a misdiagnosis such as allergies, systemic lupus erythematosus, and appendicitis [30–32]. HAE patients usually have a typical medical history with episodes of angioedema without urticarial plaques on their skin and/or abdominal pain attacks without inflammatory signals. Such a clinical presentation accompanied by a family history is highly suggestive of the diagnosis, but laboratory tests are recommended to confirm

this type of angioedema is also bradykinin mediated [10].

(With permission from Massachusetts Medical Society).

136 A Comprehensive Review of Urticaria and Angioedema

**4. Diagnosis**

Angioedema and abdominal pain episodes do not respond to antihistamines, corticosteroids, and epinephrine, which are effectively used in histaminergic angioedema. The manage‐ ment of HAE comprises prophylaxis and treatment of acute attacks [35]. Moreover, patients should be educated about their disease and some preventive measures must be taken, such as avoiding known triggering factors like estrogen‐containing pills and ACEI [30]. All patients are at risk for life‐threatening episodes independent from their previous attacks. Therefore, all patients should have a written action plan that includes what to do in a severe attack [21].

#### **5.1. Treatment of acute attacks (on‐demand treatment)**

For the treatment of acute attacks, C1 inhibitor concentrates, B2 receptor antagonist, icatibant, and an inhibitor of kallikrein synthesis, ecallantide, are used (**Table 2**, **Figure 1**) [34].

The faster intervention leads to a quicker response; therefore, patients should be treated as early as possible in attacks [21]. If these drugs cannot be provided in a health‐care facility, fresh‐frozen plasma can be substituted. However, it can possibly worsen an attack because of the presence of bradykinin in the plasma [36]. Furthermore, symptomatic treatment including intravenous fluid replacement, anti‐emetics, and analgesics can be effective in relieving the symptoms [14]. Patients experiencing angioedema in the oropharyngeal or laryngeal region should be closely observed for the possibility of the impairment of the air passage since tra‐ cheostomy or intubation may be needed [21].


EMA, European Medicines Agency; FDA, Food and Drug Administration; IV, intravenous; SC, subcutaneous [34]. http:// dx.doi.org/10.1016/j.anai.2012.10.008.

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**Table 2.** Drugs used for acute attacks in HAE [34].

#### **5.2. C1‐inh concentrates**

avoiding known triggering factors like estrogen‐containing pills and ACEI [30]. All patients are at risk for life‐threatening episodes independent from their previous attacks. Therefore, all patients should have a written action plan that includes what to do in a severe attack [21].

For the treatment of acute attacks, C1 inhibitor concentrates, B2 receptor antagonist, icatibant,

The faster intervention leads to a quicker response; therefore, patients should be treated as early as possible in attacks [21]. If these drugs cannot be provided in a health‐care facility, fresh‐frozen plasma can be substituted. However, it can possibly worsen an attack because of the presence of bradykinin in the plasma [36]. Furthermore, symptomatic treatment including intravenous fluid replacement, anti‐emetics, and analgesics can be effective in relieving the symptoms [14]. Patients experiencing angioedema in the oropharyngeal or laryngeal region should be closely observed for the possibility of the impairment of the air passage since tra‐

1000 U IV every 3–4

Acute attacks 50 U/kg IV Deficiency

mg/ml each)

Icatibant Acute attacks 30 mg SC Bradykinin B2‐

as three injections of 10

EMA, European Medicines Agency; FDA, Food and Drug Administration; IV, intravenous; SC, subcutaneous [34]. http://

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days

**Recommended dosage Mechanism Potential adverse** 

replacement

Deficiency replacement

replacement

Inhibits plasma kallikrein

receptor antagonist

**effects**

Theoretical: transmission of infectious agent

Theoretical: transmission of infectious agent

Uncommon: risk of anaphylaxis in rabbit‐sensitized individuals

Uncommon: antidrug antibodies, injection‐ site reactions, risk of anaphylaxis

Common: injection‐ site reactions

and an inhibitor of kallikrein synthesis, ecallantide, are used (**Table 2**, **Figure 1**) [34].

**5.1. Treatment of acute attacks (on‐demand treatment)**

138 A Comprehensive Review of Urticaria and Angioedema

cheostomy or intubation may be needed [21].

**indications**

prophylaxis in the US and Europe Short‐term prophylaxis and on demand in Europe

Ecallantide Acute attacks 30 mg SC (administered

Berinert‐P® Acute attacks 20 U/kg IV Deficiency

**Drug EMA and FDA** 

Cinryze® Long‐term

dx.doi.org/10.1016/j.anai.2012.10.008.

entID=S1081120612008125&orderBeanReset=true

**Table 2.** Drugs used for acute attacks in HAE [34].

Plasma‐derived nanofiltered C1‐inh

Recombinant human C1‐inh (Rhucin®)

There are three kinds of C1‐inh concentrates: Cinryze® (Shire ViroPharma Inc., Lexington, USA) and Berinert® (CSL Behring GmbH, Marburg, Germany) are both plasma‐derived C1‐ inh, and Ruconest® (Pharming, Leiden, Netherlands) is a recombinant human C1‐inh and was approved in 2014 by the Food and Drug Administration (FDA). Plasma‐derived C1‐inh con‐ centrates have been widely used for many years and carry the potential risk of contamination of pathogens as in the case with other plasma‐derived products [37]. The recombinant human C1‐inh was produced as an alternative and has been used to treat angioedema attacks for a few years in some countries. The studies evaluating the efficacy of this drug in acute attacks of HAE showed that it rapidly improves the episodes and it is well tolerated with headache and nausea as the most common adverse effects [38–41].

In a recently published review, it was observed that weight‐adjusted doses of 20‐U/kg plasma‐ derived C1‐inh concentrates lead to more rapid improvement in symptoms within 15 min than the standard 500‐U dose of the drug that works in 30–45 min. Moreover, approximately 30% of the laryngeal attacks treated with 500‐U plasma‐derived C1‐inh need a second dose while patients with laryngeal edema treated with a 20‐U/kg dose do not require an additional dose. Therefore, a 20‐U/kg‐dosing regimen induces a quicker and more effective response [42].

#### **5.3. Icatibant**

Icatibant is a potent bradykinin B2 receptor antagonist. After application, symptoms begin to resolve within 30–45 min, an improvement of symptoms occurs in an average of 1.16 h, and 7–14% of patients with laryngeal edema need a second dose of the drug [42, 43]. It has some advantages including its subcutaneous application, its ready form, and preservation in room temperature. Therefore, it can be easily carried and taken by the patient. Disadvantages include side effects like pain at the injection site and a short half‐life, which can lead to rebound attacks [9].

#### **5.4. Ecallantide**

Ecallantide is a recombinant protein and a potent kallikrein inhibitor [44]. It effectively improves acute angioedema attacks and is used subcutaneously like icatibant, but it is a frozen product and has a short half‐life. Ecallantide was licensed for patients 16 years old and older at first but recently was approved for those 12 years and older [45]. It leads to an improvement in symptoms within approximately 93 min and 10% of the patients treated with laryngeal edema need a second dose [46]. Although ecallantide is generally well tolerated, anaphylaxis was observed in 4% of the patients, so it is not approved for self‐administration and has a warning sign on its box [47].

#### **5.5. Long‐term prophylaxis**

Determining if patients are in need of long‐term prophylaxis can be a compelling problem for physicians. The decision depends on the frequency, severity, and location of the episodes, the presence of comorbidity, access to emergency medical attention, and the patient's preference. According to a previous consensus report, patients who have attacks more than once a month, who have attacks more than 5 days in a month, and those with a history of obstruction of the respiratory airways should take a long‐term prophylaxis [20]. In the years that followed with the approval for self‐administration of icatibant, the human C1‐inhibitors in some countries provided appropriate control of attacks and less need for long‐term prophylaxis [48].

Anabolic steroids (17α‐alkylated androgens), antifibrinolytics, and C1‐inh concentrates can be utilized for this purpose (**Table 3**).

17α‐alkylated androgens leading to an increase in the serum level of C1‐inh decrease the severity and frequency of episodes in most patients, but they have adverse effects [49, 50]. Both adverse effects and the efficacy of 17α‐alkylated androgens are dose‐dependent; there‐ fore, adjustment of the minimum dose, which is both protective against severe attacks and


a Registration and availability of these drugs differ from country to country. FDA, Food and Drug Administration; HAE, hereditary angioedema [34]. http://dx.doi.org/10.1016/j.anai.2012.10.008

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**Table 3.** Drugs used for long‐term prophylaxis in HAE<sup>a</sup> [34].

cause fewer side effects, is crucial and varies from patient to patient [21]. Treatment with 17α‐alkylated androgens can be started with a high dose that can be reduced to reach the most effective but least harmful dose. The most frequent adverse effects of the 17α‐alkylated androgens are menstrual irregularities, changes in libido, hirsutism, acne, changes in mood, weight gain, myalgia, erythrocytosis, increased blood pressure, and abnormalities in lipid profiles [51, 52]. Less commonly, these drugs can lead to hepatotoxicity involving hepatic adenomas and hepatic carcinoma [53, 54]. Because of these adverse effects, patients should be periodically monitored by blood count, liver enzyme, lipid profiles, and liver ultrasound [14]. Moreover, the attenuated androgens lead to the closure of epiphyseal cartilage prematurely [55]. Stanozolol is used more commonly in some European countries since it was observed to cause fewer side effects and is more effective as well as it is approved for children's use in the US [10, 56]. 17α‐alkylated androgens are relatively contraindicated in patients with prostate or breast cancer, known hepatic dysfunction, children, and pregnant women [57, 58]. Because of these side effects, they are no longer authorized in German‐speaking European countries [48].

Antifibrinolytics including ε‐aminocaproic acid and tranexamic acid are helpful in treating HAE by inhibiting the production of plasmin from plasminogen [55]. Although they have few side effects involving most commonly nausea, vomiting, and diarrhea, which are dose‐depen‐ dent, they are not as effective as androgens. In some earlier studies, antifibrinolytics were observed to decrease the frequency of attacks; however, in a recently published study, no dif‐ ferences were detected between groups with and without antifibrinolytics [59–61]. As a con‐ sequence, they suggested antifibrinolytics for long‐term prophylaxis where plasma‐derived C1‐inh is not accessible and androgens are not suitable for use [55].

In recent guidelines, the importance of quality‐of‐life scores of the patients is more empha‐ sized than the number of attack days for making the decision of long‐term prophylaxis [48]. Cinryze® was approved in 2011 in Europe and in 2008 in the US for the use of long‐term pro‐ phylaxis and its recommended dose for adolescents and adults is 1000 U every 3–4 days [48]. Recombinant human C1‐inh, which is used in the treatment of attacks, was shown to be effec‐ tive for long‐term prophylaxis in preliminary data [62]. A possible side effect of long‐term and high dose of C1‐inh therapy is the undesirable immunization with this protein [48].

#### **5.6. Short‐term prophylaxis**

presence of comorbidity, access to emergency medical attention, and the patient's preference. According to a previous consensus report, patients who have attacks more than once a month, who have attacks more than 5 days in a month, and those with a history of obstruction of the respiratory airways should take a long‐term prophylaxis [20]. In the years that followed with the approval for self‐administration of icatibant, the human C1‐inhibitors in some countries

Anabolic steroids (17α‐alkylated androgens), antifibrinolytics, and C1‐inh concentrates can

17α‐alkylated androgens leading to an increase in the serum level of C1‐inh decrease the severity and frequency of episodes in most patients, but they have adverse effects [49, 50]. Both adverse effects and the efficacy of 17α‐alkylated androgens are dose‐dependent; there‐ fore, adjustment of the minimum dose, which is both protective against severe attacks and

**FDA approved/HAE** 

**Adverse effects**

Common: weight gain, virilization, acne, altered libido, muscle pains, and cramps, headaches, depression, fatigue, nausea, constipation, menstrual abnormalities, and increase in liver enzymes, hypertension, alterations in lipid profile Unusual: decreased growth rate in children, masculinization of the female fetus, cholestatic jaundice, peliosis hepatis, and hepatocellular adenoma

vertigo, diarrhea, postural hypotension, fatigue, muscle cramps with increased muscle enzymes Unusual: enhanced thrombosis

**indication**

Yes/yes

Yes/yes

Yes/no

Yes/no

Yes/no Common: nausea,

provided appropriate control of attacks and less need for long‐term prophylaxis [48].

**Recommended dosage for children (usual,** 

Not recommended; if absolutely necessary do not exceed 2.5 mg/ kg/day (50 mg/week to 200 mg/day)

0.5 mg/day (0.5 mg/ week to 2 mg/day)

0.1 mg/kg/day (2.5 mg/week to 7.5 mg/

0.05 g/kg twice daily (0.02 g/kg twice daily to 0.1 g/kg twice

20 mg/kg twice daily (10 mg/kg twice daily to 25 mg/kg three times daily)

Registration and availability of these drugs differ from country to country. FDA, Food and Drug Administration; HAE,

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day)

daily)

**range)**

be utilized for this purpose (**Table 3**).

140 A Comprehensive Review of Urticaria and Angioedema

**Drug Recommended dosage** 

**range)**

Danazol Minimal effective

Stanozolol Minimal effective

Oxandrolone Minimal effective

Tranexamic acid 1 g twice daily (0.25

2 mg/day

10 mg/day

17‐α alkylated androgens

Antifibrinolytics ε‐Aminocaproic

acid

a

**for adults (usual,** 

dose does not exceed 200 mg/day

dose does not exceed

dose does not exceed

2 g three times daily (1 g twice daily to 4 g three times daily)

g twice daily to 1.5 g twice daily)

**Table 3.** Drugs used for long‐term prophylaxis in HAE<sup>a</sup> [34].

entID=S1081120612008125&orderBeanReset=true

hereditary angioedema [34]. http://dx.doi.org/10.1016/j.anai.2012.10.008

Short‐term prophylactic therapy protects patients with HAE from acute attacks caused by a known triggering factor such as dental, minor, or major surgical interventions [21]. For this pur‐ pose, various prophylactic regimens are used. C1‐inh concentrates between 1000 and 2000 U for adults and 20 U/kg for children or two units of fresh‐frozen plasma for adults and 10 ml/kg for children can be administered before procedures [10]. Another regimen includes a high dose of 17α‐alkylated androgens starting with 6–10 mg/kg/day in divided doses, such as danazol 200 mg three times a day for 5–10 days before and 2 days after the procedure. No studies comparing the efficacy of these prophylactic modalities have been published. Therefore, it must be indi‐ vidualized according to the cost, benefit‐harm ratio, and the patient's preferences. In pregnant patients, C1‐inh administration is preferred [21]. In children, if plasma‐derived C1‐inh is not available, danazol can be used for a short duration [55].
