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ACE-inhibitor-related angioedema.

Otolaryngologists are called upon frequently to care for patients with potentially life-threatening angioedema. This condition usually is associated with angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors are among the most commonly prescribed medications worldwide because they are indicated in the management of hypertension, congestive heart failure, myocardial infarction, diabetic nephropathy, and chronic kidney disease. (1,2)

Angioedema is a potentially life-threatening adverse effect of ACE inhibitors, with a reported incidence of 0.1 to 6%. (2-8) ACE-inhibitor-related angioedema is asymmetric, nonpitting, nontender edema that can appear anywhere in the body but commonly affects the head and neck area. (2) Otolaryngologists should be familiar with this drug class and its potential complications.

ACE-inhibitor-related angioedema is not a true allergy but is considered an adverse class effect secondary to the mechanism of action. (2,4,8-10) The proposed pathophysiologic mechanism is the accumulation of bradykinin secondary to the inhibition of ACE. (2,4,8) However, this cannot explain how ACE-inhibitor-related angioedema can occur anytime from hours to decades after a patient has started the medication. (3,4,11-13) About a quarter of patients with ACE-inhibitor-related angioedema present within 1 week of starting the medication. (13) On the other end of the spectrum, approximately half present after having been on the medication for at least a year. (13) This may be explained by the fact that in the setting of ACE inhibition, aminopeptidase P (APP) and dipeptidyl peptidase 4 (DPP4) become responsible for breaking down the vasoactive peptides bradykinin and substance P, respectively. (14) Factors adversely affecting these enzymes may trigger angioedema. (14)

Female gender, African-American descent, and tobacco use are risk factors for the development of ACE-inhibitor-related angioedema. (3,4,6,7,14) Certain atopic diseases, such as seasonal allergies and asthma, may also be risk factors. (5,7,13,14) On the other hand, diabetes mellitus is possibly associated with a decreased risk because diabetic patients appear to have increased DPP4 activity to aid in the breakdown of substance P. (5,14,15)

Currently, no laboratory test exists to confirm the diagnosis of ACE-inhibitor-related angioedema. (13) The diagnosis is made when a patient on an ACE inhibitor presents with nonpruritic, nontender, well-demarcated areas of angioedema and other causes have been ruled out. (13) The differential diagnosis includes the different types of hereditary angioedema, acquired angioedema, medication allergy, food sensitivity, reaction to trauma, and exposure to extreme temperatures. (9)

Patients with ACE-inhibitor-related angioedema can present with varying levels of respiratory distress, with some requiring an airway intervention. Symptoms of dysphagia and voice changes are significant predictors of the presence of laryngeal edema. (13) However, the subjective feeling of shortness of breath is not a good predictor of laryngeal edema. (13) Flexible fiberoptic laryngoscopy is essential for assessment of airway status, with laryngeal edema found in about 30% of patients. (13) The involvement of any one specific anatomic site on the physical exam is not a significant predictor of laryngeal edema on laryngoscopy. (13)

Patients with multiple sites of involvement are not more likely to have laryngeal edema than those with only a single affected site. (13) Involvement of the tongue, floor of the mouth, and larynx are correlated with patients receiving an airway intervention, such as endotracheal intubation, cricothyroidotomy, and tracheostomy. (13) The lips are the most commonly affected site, and their involvement is a significant negative predicator for airway intervention. (13)

In the United States, hospitalization rates for patients diagnosed with angioedema are increasing. (16) Close observation in a monitored setting with serial flexible fiberoptic laryngoscopy examinations is warranted for patients with laryngeal edema on initial evaluation because it may worsen in as many as 25% of such patients despite proper medical management. (13) The ACE inhibitor should be discontinued, and the patient should be started on a different class of antihypertensive medication.

There is debate regarding whether patients who experience ACE-inhibitor-related angioedema can be safely switched to angiotensin receptor blockers (ARBs). Although the estimated cross-reactivity in patients with ACE-inhibitor-related angioedema who receive an ARB is low at 10% or less, because angioedema is potentially life-threatening, the risk-benefit ratio often does not favor the use of an ARB. (17) Patients with ACE-inhibitor-related angioedema are commonly treated with various combinations of epinephrine, a corticosteroid, and [H.sub.1] and [H.sub.2] antagonists. (3,4,5,11,13,18) However, if the proposed pathophysiologic mechanism of bradykinin accumulation or heightened sensitivity to bradykinin is accurate, regimens including these medications theoretically should be ineffective. (3) Although their effectiveness has not been confirmed by randomized, blinded, controlled trials, (13) Grant et al, in a retrospective review, found that intubated angioedema patients who received antihistamines were extubated significantly earlier than patients who did not. (4)

Medications currently used for treating acute episodes of angioedema in patients with hereditary angioedema may be useful in the management of other types of angioedema, including ACE-inhibitor-related angioedema. Icatibant and ecallantide are targeted at the issue of bradykinin accumulation as the cause of angioedema. Icatibant is a selective competitive antagonist of the bradykinin [[beta].sub.2], receptor. (19) Ecallantide is a selective reversible inhibitor of plasma kallikrein and results in reduced production of bradykinin. (20) There are currently no published randomized controlled trials that evaluate the effectiveness of these medications in patients with plasma kallikrein.

It has been suggested that ACE-inhibitor-related angioedema is underdiagnosed because mild symptoms are often ignored or unrecognized until continued use of the medication leads to a more severe event. (10) Although it has the potential to cause airway obstruction, death secondary to this condition is extremely rare. (3,8,11) However, physicians involved in the care of these patients must always be vigilant because of the potential need for urgent intervention to secure the airway. (4,11,13)


(1.) Bicket DP. Using ACE inhibitors appropriately. Am Fam Physician 2002;66(3):461-8.

(2.) Winters ME, Rosenbaum S, Vilke GM, Almazroua FY. Emergency department management of patients with ACE-inhibitor angioedema. J Emerg Med 2013;45(5):775-80.

(3.) Banerji A, Clark S, Blanda M, et al. Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol 2008;100(4):327-32.

(4.) Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema. Otolaryngol Head Neck Surg 2007;137(6):931-5.

(5.) Kostis JB, Kim HJ, Rusnak J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med 2005;165(14): 1637-42.

(6.) Miller DR, Oliveria SA, Berlowitz DR, et al. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension 2008;51(6):1624-30.

(7.) Pare G, Kubo M, Byrd JB, et al. Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics 2013;23(9):470-8.

(8.) Piller LB, Ford CE, Davis BR, et al. ALLHAT Collaborative Research Group. Incidence and predictors of angioedema in elderly hypertensive patients at high risk for cardiovascular disease: A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2006;8(9):649-56.

(9.) Mahoney EJ, Devaiah AK. Angioedema and angiotensin-converting enzyme inhibitors: Are demographics a risk? Otolaryngol Head Neck Surg 2008;139(l):105-8.

(10.) Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother 2000;34(4):526-8.

(11.) Al-Khudari S, Loochtan MJ, Peterson E, Yaremchuk KL. Management of angiotensin-converting enzyme inhibitor-induced angioedema. Laryngoscope 2011;I21(11):2327-34.

(12.) Tai S, Mascaro M, Goldstein NA. Angioedema: A review of 367 episodes presenting to three tertiary care hospitals. Ann Otol Rhinol Laryngol 20I0;119(12):836-41.

(13.) Chan NJ, Soliman AM. Angiotensin converting enzyme inhibitor-related angioedema: Onset, presentation, and management. Ann Otol Rhinol Laryngol 2015;124(2):89-96.

(14.) Woodard-Grice AV, Lucisano AC, Byrd JB, et al. Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics 2010;20(9):532-6.

(15.) Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension 2008;51(l):141-7.

(16.) Lin RY, Levine RJ, Lin H. Adverse drug effects and angioedema hospitalizations in the United States from 2000 to 2009. Allergy Asthma Proc 2013;34(1):65-71.

(17.) Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother 2011;45(4):5204.

(18.) Ishoo E, Shah UK, Grillone GA, et al. Predicting airway risk in angioedema: Staging system based on presentation. Otolaryngol Head Neck Surg 1999;121(3):263-8.

(19.) Cole SW, Lundquist LM. Icatibant for the treatment of hereditary angioedema. Ann Pharmacother 2013;47(l):49-55.

(20.) Sheffer AL, MacGinnitie AJ, Campion M, et al. Outcomes after ecallantide treatment of laryngeal hereditary angioedema attacks. Ann Allergy Asthma Immunol 2013;110(3):184-8.

Norman J. Chan, MD

Senior Resident

Department of Otolaryngology-Head and Neck Surgery

Temple University School of Medicine

Ahmed M.S. Soliman, MD

Professor and Vice Chair

Associate Director Clinical Affairs--Temple

Head and Neck Institute

Department of Otolaryngology-Head and Neck


Temple University School of Medicine

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Title Annotation:GUEST EDITORIAL
Author:Chan, Norman J.; Soliman, Ahmed M.S.
Publication:Ear, Nose and Throat Journal
Article Type:Report
Date:Jun 1, 2015
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