Ann Allergy Asthma Immunol xxx (2016) 1e2

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Letter

Angioedema due to allergy in a patient with hereditary angioedema: all that glitters is not gold A 24-year-old woman presented to the emergency department with lip and throat swelling. She was recently diagnosed as having hereditary angioedema (HAE) type 1 after 2 episodes of angioedema, a strong family history (father and paternal grandmother also affected), and laboratory test results that confirmed a low C1 inhibitor (C1INH) level (8 mg/dL; reference range, 21e39 mg/dL). The week before presentation, she was treated with nitrofurantoin (not previously taken) for a urinary tract infection. The day after completing her antibiotic course, she developed a few hives and swelling of her lower lip. She was admitted overnight to another hospital for treatment with corticosteroids and hydroxyzine. Symptoms stabilized but did not improve. Within hours of discharge the next day, she felt her throat and hands start to swell, and her lips became more swollen. She presented to the emergency department at the University of California, San Diego, where she was noted to have mild lip swelling and generalized urticaria. She received icatibant, a short-term HAE treatment, because of concern for concomitant airway angioedema due to HAE. Six hours after receiving this medication, she had no improvement in her angioedema and worsening of her hives. Additional treatment with corticosteroids and diphenhydramine led to resolution of symptoms within 24 hours, approximately 4 days after symptoms started. HAE due to C1INH deficiency is an autosomal dominant disorder characterized by decreased secretion of functional C1INH. Angioedema in HAE results from dysregulation of the contact system with excessive production of bradykinin.1 C1INH is the major inhibitor of the 2 contact system proteases: activated coagulation factor XII (FXII) and plasma kallikrein. Although the exact mechanisms of activation remain unclear, activated FXII and kallikrein reciprocally activate each other in the absence of sufficient C1INH. When activated, kallikrein digests high-molecular-weight kininogen, releasing bradykinin. Bradykinin binds to the B2 bradykinin receptor and causes angioedema by down-regulation of vascular endothelial cadherin and production of vasodilators, both of which lead to substantially increased vascular permeability.2 Patients with this condition will have intermittent swelling of the face, larynx, extremities, genitalia, and gastrointestinal tract. Attacks can be spontaneous or triggered by a variety of factors, including trauma, stress, infections, or medications. Attacks of HAE are not associated with urticaria, and its presence suggests that the angioedema may be histamine mediated. Erythema marginatum, which can occur with HAE attacks, may appear like urticaria but is more serpiginous and not pruritic. Histamine-mediated angioedema may be allergic, idiopathic, or related to a mast cell disorder. Histamine binds to specific

Disclosures: Authors have nothing to disclose. Funding: This publication was funded by NIH grant T32 AI 007469.

histamine1 G-proteinecoupled receptors and can cause angioedema through mechanisms similar to those described for bradykinin. The cause of histamine release in idiopathic angioedema is not well understood. Histamine-mediated angioedema is less likely to involve the gastrointestinal tract and is typically accompanied by urticaria. Icatibant, a selective, competitive bradykinin B2 receptor antagonist, blocks bradykinin-induced vascular effects, typically improving bradykinin-mediated angioedema within 2 hours.3 Icatibant does not reverse swelling but prevents further edema, allowing normal vascular and lymphatic mechanisms to reabsorb the extravasated fluid. Early treatment, typically by self-administration, leads to shorter and less severe attacks.4,5 Patients will occasionally need additional doses, but typically this is indicated by worsening of symptoms several hours later after initial improvement. Icatibant has no effect on histamine-mediated angioedema. In contrast, antihistamines, systemic corticosteroids and epinephrine are effective for histamine but not bradykinin-mediated angioedema. Given the distinct targeted therapies required to treat allergic (histamine-mediated) and hereditary (bradykinin-mediated) forms of angioedema, it is important to consider allergic conditions in patients with angioedema, even in those with underlying HAE. Icatibant was ultimately used in this patient because of the concern that her underlying illness had spurred an HAE attack, which could have caused her worsening symptoms. When she did not improve despite appropriate therapy, she was treated again with antihistamines and corticosteroids, and her clinical improvement confirmed the original diagnosis of histamine-mediated angioedema. Nitrofurantoin is associated with severe adverse reactions, such as hepatotoxicity, but angioedema and urticaria were also reported in the original efficacy and safety studies.6 Her symptoms were attributed to allergic reaction to nitrofurantoin and/or acute urticaria due to her underlying illness. HAE-specific therapy should not be delayed, but other diagnoses should be considered in the setting of a poor clinical response to effective HAE therapy. Jacqueline Eastman, MD Bruce Zuraw, MD Division of Rheumatology, Allergy, and Immunology University of California San Diego, California [email protected]

References [1] Walford HH, Zuraw BL. Current update on cellular and molecular mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112:413e418. [2] Bouillet L, Mannic T, Arboleas M, et al. Hereditary angioedema: key role for kallikrein and bradykinin in vascular endothelial-cadherin cleavage and edema formation. J Allergy Clin Immunol. 2011;128:232e234.

http://dx.doi.org/10.1016/j.anai.2016.01.020 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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Letter / Ann Allergy Asthma Immunol xxx (2016) 1e2

[3] Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010;363:532e541. [4] Maurer M, Aberer W, Bouillet L, et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One. 2013;8: e53773.

[5] Aberer W, Maurer M, Reshef A, et al. Open-label, multicenter study of selfadministered icatibant for attacks of hereditary angioedema. Allergy. 2014; 69:305e314. [6] Penn RG, Griffin JP. Adverse reactions to nitrofurantoin in the United Kingdom, Sweden, and Holland. Br Med J (Clin Res Ed). 1982;284:1440e1442.

Angioedema due to allergy in a patient with hereditary angioedema: all that glitters is not gold.

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