Emerging concepts in the diagnosis and treatment of patients with undifferentiated angioedema

Abstract

Angioedema is a sudden, transient swelling of well-demarcated areas of the dermis, subcutaneous tissue, mucosa, and submucosal tissues that can occur with or without urticaria. Up to 25% of people in the US will experience an episode of urticaria or angioedema during their lifetime, and many will present to the emergency department with an acute attack. Most cases of angioedema are attributable to the vasoactive mediators histamine and bradykinin. Histamine-mediated (allergic) angioedema occurs through a type I hypersensitivity reaction, whereas bradykinin-mediated (non-allergic) angioedema is iatrogenic or hereditary in origin.Although their clinical presentations bear similarities, the treatment algorithm for histamine-mediated angioedema differs significantly from that for bradykinin-mediated angioedema. Corticosteroids, and epinephrine are effective in the management of histamine-mediated angioedema but are ineffective in the management of bradykinin-mediated angioedema. Recent advancements in the understanding of angioedema have yielded pharmacologic treatment options for hereditary angioedema, a rare hereditary form of bradykinin-mediated angioedema. These novel therapies include a kallikrein inhibitor (ecallantide) and a bradykinin β2 receptor antagonist (icatibant). The physician's ability to distinguish between these types of angioedema is critical in optimizing outcomes in the acute care setting with appropriate treatment. This article reviews the pathophysiologic mechanisms, clinical presentations, and diagnostic laboratory evaluation of angioedema, along with acute management strategies for attacks.

Figure 1

Type I hypersensitivity is mediated by IgE and induces mast cell degranulation. FcεRI, high-affinity IgE receptor; IgE, immunoglobulin E; IL-4, interleukin 4; IL-5, interleukin 5; TNF-α, tumor necrosis factor-alpha [4].

Figure 2

Kallikrein-kinin cascade. During an acute HAE attack, reduced activity of C1 esterase inhibitor (C1-INH) results in overactivation of the kallikrein-kinin cascade and subsequent production of bradykinin. Bradykinin is the likely mediator of the vasodilation, edema, and pain that characterize acute HAE attacks. HMWK, high-molecular-weight kininogen; IL, interleukin; MASP, MBP-associated serine protease; MBP, mannose-binding protein; TNF-α, tumor necrosis factor-alpha.

Figure 3

The contact, complement, and fibrinolytic systems. C1-INH, C1 esterase inhibitor. Republished with permission from [37]. [PERMISSION PENDING].

Figure 4

Diagnostic considerations in patients who present with nonallergic angioedema. ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs; C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema; WNL, within normal limits. Modified from [8]; with permission. [PERMISSION PENDING].

Figure 5

International consensus algorithm for the diagnosis of hereditary angioedema. ACE, angiotensin-converting enzyme; C4, complement factor 4; C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema. Modified from [24]; with permission. [PERMISSION PENDING].

Figure 6

Algorithm for the management of patients who present with acute angioedema. C1-INH, C1 esterase inhibitor; CT, computed tomography; ENT, ear, nose, and throat; ICU, intensive care unit; VCD, vocal cord dysfunction. Modified from [8]; with permission [PERMISSION PENDING].