1.1.1.2 Angioedema

Idiopathic: 4A00.15; hereditary 4A0014; drug induced EH61.1; others 4A06.1Y

Angioedema is common. However statistical data depend on the subtype. No exact statistical data are available for spontaneous angioedema, which may be allergic or so called pseudoallergic. The prevalence of hereditary angioedemas is about 1:50,000 for type I (85%) and II. Type III is rare, almost always females are affected. The estimated risk of death caused by asphyxia in patients with HAE is about 8.5 % .

Most of the pathogenic causes of angioedemas are of histamine-related allergic or ‘pseudoallergic’ nature, following the course of different types of urticaria. Hereditary forms HAE type I (INH-activity loss) and II (INH-activity partial deficient) are observed where there is no primary urticaria. Type I has an autosomal dominant mutation of the serine protease inhibitor gene 1 (SERPING1). Subtype III has a normal INH-activity and is bradykinin driven. The new Definition, Acronyms, Nomenclature and Classification of Angioedema (DANCE) categorization distinguishes between C1-esterase inhibitor deficiency type I bradykinin-mediated (AE-BK) and type II vascular-endothelial dysfunction-mediated (AE-VE) variants. It often is induced by renin-angiotensin system-related drugs (ACE and dipeptidylpeptidase inhibitors). It may also be a paraneoplastic phenomenon. The gene defect is localized on chromosome 11 subregion q11.2– q13. Kallikrein and factor XIIa cannot be controlled in the acute attack and the bradykinin cascade is activated.

Subcutaneous and mucosal oedema (face, upper and lower airways, esophageal-gastro-intestinal and genital tract) with the sensation of tightness or swelling are the main symptoms. Sometimes it can be itchy or even painful. The velocity of lesion development varies from acute to slowly progressing

See urticaria for diagnostics. Allergic: IgE, specific IgE, histamine, diaminooxidase, tryptase.

In addition: C1-esterase inhibitor analysis and complement C4 (both concentration + activity). C1-INH autoantibodies and C1q.

Edema of the dermal, subcutaneous and submucosal and mucosal tissue without inflammatory infiltrate. Mast cell degranulation. In drug induced urticaria and angioedema eosinophils are sometimes seen.

Depending on acute or slowly developing course. Physical urticaria (pressure, vibration), autoimmune diseases (Lupus erythematosus, dermatomyositis), acute lymphedema, acute phase of herpes zoster and erysipelas, trichinosis. Acute contact dermatitis. Melkersson-Rosenthal syndrome,. Traumatic edema in subcutaneous and muscular tissue.

Preventive: if origin and type of angioedema development in relapsing courses of already known underlying disease are explored, avoidance of trigger factors (histamine or bradykinin provoking agents) and in for example hereditary courses substitution of disease associated drugs.

Acute: depending on the localization and the acuity one would either give systemic antihistamines orally or by injection, systemic corticosteroids and adrenaline i.m. (autoinjector). Since very recently, a one way nasal spray containing 2mg adrenalin is available. Antihistamines and corticosteroids usually do not interrupt attacks of HAE.

For C1-esterase inhibitor deficiency: replacement of C1-esterase inhibitor (if not available, fresh frozen plasma), concentrated C1-inhibitor infusion, Conestat alfa is a recombinant human (rh) C1- Inhibitor, bradykinin - B2 receptor antagonist infusion (icatibant, lanadelumab), recombinant C1 inhibitor. (Danazol or tranexamic acid for long-term prophylaxis only, however, less used currently). An antisense oligonucleotide PKKRx, also known as donidalorsen, which inhibits plasma kallikrein expression at the messenger RNA (mRNA) level will soon be available. Another oral plasmakallekrein inhibitor for acute attacks is Sebelstratat. Garadacimab, a human monoclonal antibody that inhibits activated FXIIa at the early step of the cascade has been recently launched in Europe.

Suspicious drugs as trigger of acute attacks or maintaining symptoms have to be investigated fully and stopped. Before birth delivery prophylactic recombinant C1 inhibitor should be given or stand by procedure.