**2. Classification of bradykinin‐mediated angioedema (BK‐AE)**

BK‐AE comprises several entities (**Table 1**). In recent years, there has been a dramatic increase in knowledge about this condition, particularly on the role of BK as the "final common mediator." The Spanish Study Group for Angioedema due to C1‐inhibitor deficiency was established in 2007 within the Committee of Immunology of the Spanish Society of Allergology and Clinical Immunology (SEAIC). However, such was the progress in the understanding of the pathophysiology of different types of BK‐AE that this group's name quickly changed to "Spanish Study Group on Bradykinin‐Induced Angioedema" (SGBA).

BK‐AE is mainly classified into two subtypes depending on whether or not there is a functional deficiency of C1 esterase inhibitor, better known as C1 inhibitor (C1‐INH) (**Table 1**) [8]. Another common way to classify BK‐AE is hereditary angioedema (HAE) and acquired angioedema (AAE) [8]. There are two forms of AE with C1‐INH deficiency, a hereditary form (C1‐INH‐HAE) and an acquired form (C1‐INH‐AAE).

Among the forms of AE with no functionally active C1‐INH deficiency are hereditary angio‐ edema with normal C1‐INH (nC1‐INH‐HAE), with/without mutation in the *F12* gene that encodes coagulation factor XII (FXII‐HAE/U‐HAE) or acquired AE associated with drugs that inhibit the metabolic pathways of BK, angiotensin‐converting enzyme inhibitors (ACEi‐AAE).

Other drugs that inhibit the catabolism of BK have been implicated in the development of AE. These include dipeptidyl peptidase IV (DPP‐IV) inhibitors, aminopeptidase P (APP) inhibi‐ tors, neutral endopeptidase (NEP) inhibitors, and others.

**1. Introduction: definition of angioedema and differentiation between** 

The term "angioedema" (AE) is defined as localized and transient subcutaneous and/or submucosal swelling (which may affect the gastrointestinal, respiratory, or genitourinary tract) [1, 2]. It occurs when there is vasodilation with consequent increase in capillary

A variety of inflammatory mediators have been described that can lead to this process, such as histamine, prostaglandins, leukotrienes, and bradykinin [4]. The most frequent type of AE is produced by histamine release, as a consequence of mast cell activation, and is called

It includes allergic reactions, but also idiopathic AE in the context of chronic spontaneous urticaria [5]. Histaminergic AE can be associated to urticaria [6], is usually erythematous, warm, and pruritic, and is responsive to treatment with antihistamines [7]. The clinical expression of urticarial lesions is mainly a consequence of inflammation and edema of the upper dermis, whereas swellings are located in the deep dermis and even in the subcutane‐

Another important type of AE is produced by an increase in bradykinin (BK). This AE type is non‐erythematous, non‐pruritic, cold, non‐responsive to antihistamines and urticaria is not

BK‐AE comprises several entities (**Table 1**). In recent years, there has been a dramatic increase in knowledge about this condition, particularly on the role of BK as the "final common mediator." The Spanish Study Group for Angioedema due to C1‐inhibitor deficiency was established in 2007 within the Committee of Immunology of the Spanish Society of Allergology and Clinical Immunology (SEAIC). However, such was the progress in the understanding of the pathophysiology of different types of BK‐AE that this group's name quickly changed to

BK‐AE is mainly classified into two subtypes depending on whether or not there is a functional deficiency of C1 esterase inhibitor, better known as C1 inhibitor (C1‐INH) (**Table 1**) [8]. Another common way to classify BK‐AE is hereditary angioedema (HAE) and acquired angioedema (AAE) [8]. There are two forms of AE with C1‐INH deficiency, a hereditary form

Among the forms of AE with no functionally active C1‐INH deficiency are hereditary angio‐ edema with normal C1‐INH (nC1‐INH‐HAE), with/without mutation in the *F12* gene that encodes coagulation factor XII (FXII‐HAE/U‐HAE) or acquired AE associated with drugs that inhibit the metabolic pathways of BK, angiotensin‐converting enzyme inhibitors

associated [7]. This subgroup is known as bradykininergic angioedema (BK‐AE).

**2. Classification of bradykinin‐mediated angioedema (BK‐AE)**

"Spanish Study Group on Bradykinin‐Induced Angioedema" (SGBA).

(C1‐INH‐HAE) and an acquired form (C1‐INH‐AAE).

**histaminergic and bradykininergic angioedema**

"histaminergic angioedema."

152 A Comprehensive Review of Urticaria and Angioedema

ous tissue.

(ACEi‐AAE).

permeability and extravasation of fluid into the interstitial space [2, 3].

Along with progress in biochemical‐molecular knowledge, much has been learned about the dif‐ ferent pathophysiological mechanisms of the different types of AE. For example, the initial term "HAE type III or oestrogen‐induced" has evolved into the term FXII‐HAE due to the description in some of these patients of mutations in the *F12* gene. Another example would be the recognition of antihypertensives belonging to the group of ACE inhibitors (ACEIs) as producers of AE by increased BK, secondary to the inhibition of its catabolism. This has led to classifications over time by different groups. In order to agree on a common name for all types of AE "without papules" described so far, the HAE International Working Group (HAWK), under the sponsorship of the European Academy of Allergy and Clinical Immunology (EAACI), proposed a classification of AE without wheals as seen in **Figure 1** [7], with four types of AAE and three types of HAE.


**Table 1.** Classification of different types of bradykinin‐mediated AE (modified from SGBA Consensus) [9].

**Figure 1.** Classification of angioedema without wheals [7].

However, this classification has some limitations such as the noninclusion of AE caused by non‐steroidal anti‐inflammatory drugs (NSAIDs), which often occurs without associated urticaria [10]. These drugs act by inhibiting the enzyme cyclooxygenase in the metabolic pathways of arachidonic acid and increasing leukotrienes.

A classification of AE according to endotypes was proposed later [11]. In this classification, three subtypes of AE were included: (1) mast cell and basophil‐driven AE, (2) bradykininergic AE, and (3) idiopathic AE [11]. It has the advantage that NSAIDs induced or exacerbated AE and allergic AE are both included within the mast cell and basophil‐driven AE.
