Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. ANGIOEDEMA Angioedema is a problem that relates to the specialty of otolaryngology because its symptoms manifest most often in the head and neck, often in dramatic form. The term angioedema is used to describe several closely related diseases that manifest by recurrent acute edema of the skin and mucosa. The most serious manifestation of the disease is laryngeal edema which can be fatal. Hereditary angioedema is rare, but knowledge of its mechanism allows diagnosis and initiation of potentially lifesaving therapy. Angiotensin converting enzyme inhibitors account for an increasing proportion of angioedema cases as the popularity of the drug class grows. Angioedema is characterized by subcutaneous edema resulting from increased vascular permeability, dilation of venules and capillaries and separation of collagen bundles. This is in distinction to urticaria which is limited to the superficial dermis. A history of atopy can be elicited in 15% patients. Angioedema may occur anywhere in the body with the periorbital, perioral and oropharyngeal tissues most commonly affected. Women in their third and forth decades are most commonly affected and 94% of patients have head and neck manifestations. All races are affected equally. There are several mechanisms that may produce angioedema. As an immunologic reaction angioedema may be elicited by foods, additives, drugs, transfusions, insect bites and infection. The reaction can be Ig-E mediated or through activation of the bradykinin or complement systems. Activation of the classic or alternative pathway of the complement system can lead to the generation of strong mediator-releasing factors such as C3a and C5a. C5a can release histamine and other mediators from mast cells, which are strong chemotactic agents that attract inflammatory cells to the area. The classic complement pathway can be activated by antigen-antibody interaction, antibody aggregates, the fibrinolytic enzymes and plasmin. Patients with immune complex disease such as lupus can present with angioedema due to this mechanism. The alternative pathway can be activated by complex polysaccharides or lipopolysaccharides such as endotoxin, drugs or dyes with resulting angioedema. The complement system is controlled by certain enzyme inhibitors, the most important of which is C1 esterase inhibitor (C1 INH). Hereditary and acquired deficiencies of C1 INH will cause angioedema by subsequent activation of the complement system. Hereditary angioedema is inherited in an autosomal dominant fashion, and all patients are heterozygous. Most patients have type 1 HAE and have low levels of C1 INH. About 15% of patients have type II HAE with normal levels of C1 INH but with dysfunctional enzyme. Patients with HAE have chronic activation of the complement system brought about by minor tissue trauma. The patients have chronically low levels of C4 and may also have reduced levels of C2 during an acute attack. Measurement of C4 is a good initial screening test. Patients with reduced levels of C4 should have quantitative and functional levels or C1 INH measured. Angiotensin converting enzyme inhibitors have been sited as a cause of acute angioedema in some patients. The etiology of angioedema in these patients is thought due to potentiation of the effects of bradykinin. In most cases the angioedema starts within 48 hours after the medication is begun. The diagnosis of angioedema depends primarily on medical history. When the cause remains unapparent, helpful diagnostic laboratory studies include a complete blood cell count, sedimentation rate, urinalysis, ANA, immune complex measurements, C3 and C4 fractions and C1 INH levels. Skin testing may help identify allergic individuals. Biopsy is used to diagnose underlying vasculitis. Treatment of angioedema associated with ACE inhibitors involves stopping the drug. When the tongue, oropharynx, hypopharynx or larynx is involved airway precautions should be taken. Treatment with diphenhydramine and steroids has been reported. Subcutaneous epinephrine and racemic epinephrine may offer some benefit. Repeated attacks of HAE can be prevented with androgens such as danzol and stanozolol. E-aminocaproic acid and other fibrinolytic agents are often used in children. Prior to invasive procedures; androgens, FFP, and purified C1 INH may be given. Genetic engineering will soon produce CI INH for research availability and gene transplantation will someday make this disease curable. Case Presentation A 57-year-old African-American woman presented to the emergency room with progressive difficulty breathing and a sensation of fullness in her throat. The patient's medical history included noninsulin-dependent diabetes mellitus, hypertension, hypercholesterolemia, coronary artery disease and cerebrovascular disease. The patient denied any known food or drug allergy, recent trauma, or personal or family history of similar episodes in the past. Current medications included Premarin, Lopid, Aldomet, Captopril, Glucotrol and Isordil. Though blood pressure treatment with Captopril had been initiated fourteen months earlier, four days prior to presentation in the emergency room the dose was increased from 25 mg to 50 mg twice daily. Physical examination revealed a women in mild distress with slight facial swelling and pronounced tongue edema. Fiberoptic examination revealed extensive edema of the base of tongue, epiglottis, left aryepiglottic fold and arytenoid. Initial treatment with intravenous Solumedrol and Benadryl resulted in some subjective improvement. The patient was electively intubated through the nose with a 7 mm endotracheal tube and transferred to the medical intensive care unit for assisted ventilation and observation. After treatment with intravenous Solumedrol and Benadryl, all edema had completely resolved within 24 hours and the patient was successfully extubated. The Captopril has subsequently been discontinued and she has experienced no further episodes of edema. Her blood pressure is currently under good control with Diltiazem and Aldomet. Bibliography Barna JS, Frable MS. Life-threatening angioedema. Otolaryngol Head Neck Surg 1990;103:795-798. Bork K, Bitzke G. Long-term prophylaxis with C1-inhibitor concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency. J Allergy Clin Immunol 1989;83:677-682. Cicardi M, Bergamaschini L, Marasinin B, et al. Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci 1982;284:2-9. Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C1-Esterase. Am J Med 1963;35:37-44. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976;84:580-593. Frigas E. Angioedema with acquired deficiency of the C1 inhibitor: a constellation of syndromes. Mayo Clin Proc 1989;64:1269-1275. Fuller RW, Warren JB, McCuster M, et al. Effect of enalapril on the skin response to bradykinin in man. Br J Clin Pharmacol 1987;23:88-90. Gadek JE, Hosea SW, Gelfant JA, et al. Replacement therapy in hereditary angioedema. N Engl J Med 1980;302:542-546. Geha RS, Quinti I, Austen KF, et al. Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. N Engl J Med 1985;312:534-540. Gelfand JA, Boss GR, Conley CL, et al. Acquired C1-Esterase inhibitor deficiency and angioedema: a review. Medicine (Baltimore) 1979;58:321-327. Haddad A, Frenkiel S, Small P. Angioedema of the head and neck. J Otolaryngol 1985;14:14-16. Huston DP, Bressler RB. Urticaria and angioedema. Med Clin North Am 1992;76:805-840. Kaplan AP. The Hageman factor dependent pathways of human plasma. Microvasc Res 1974;8:97-111. Ratnoff OD, Pensky J, Ogston D. The inhibition of plasmin, plasma kallikrein, plasma permeability factor, and the C1r subcomponent of the first component of complement by serum C1-Esterase inhibitor. J Exp Med 1969;129:315-331. Seidman MD, Lewandowski CA, Sarpa JR, et al. Angioedema related to angiotensin-converting enzyme inhibitors. Otolaryngol Head Neck Surg 1990;102:727-731. Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol 1981;68:181-187. Slater EE, Merrill DD, Guess HA, et al. Clinical profile of angioedema associated with angiotensin converting enzyme inhibition. JAMA 1988;260:967-970. Spaulding WB. Methyltesterone therapy for hereditary angioedema. Ann Intern Med 1960;53:739-745. Suarez M, Ho PW, Johnson ES, et al. Angioneurotic edema, agranulocytosis, and fatal septicemia following Captopril therapy. Am J Med 1986;81:336-338. 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