Authors: Allen P. Kaplan, USA Connie H. Katelaris, Australia Paul C. Potter, South Africa Timothy J. Craig, USA Updated: June 2011

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First described by Quincke in 1882 Well-demarcated non-pitting edema Often caused by same pathological factors that cause urticaria Reaction occurs deeper in dermis and subcutaneous tissues Face, tongue, lips, eyelids most commonly affected May cause life-threatening respiratory distress

Allergic: Foods, drugs, insect stings/bites Radiocontrast media NSAID and ASA Associated with anaphylaxis Autoimmune Idiopathic: –May be histamine induced or bradykinin induced ACE inhibitors Bradykinin-induced with normal C1-inhibitor (HAE-3) C1 inhibitor deficiency –Hereditary – Types I, II –Acquired

Physical causes –Cold –Cholinergic –Solar –Vibratory –Pressure Other causes –Some contact reactions –Systemic diseases (e.g., systemic lupus erythematosis)

Now most common exogenous cause of angioedema seen in emergency rooms Usually has no associated urticaria Due to increased bradykinin levels because kinin degradation is inhibited Can cause dramatic swelling of tongue, pharynx, or larynx – may require intubation or tracheostomy acutely

Angioedema develops in 0.1% to 0.5% of those receiving the drug Onset from 1 st week of use to 2-3 years of use Symptoms resolve with cessation of drug, but may persist days Described with all ACE inhibitors Genetic factors may be important Subjects with a history of angioedema from other causes are more susceptible to ACE-induced angioedema

Face, lips and tongue most commonly involved but laryngeal edema reported Risk factors include obesity, prior endotracheal intubation and face and neck surgery ACE inhibitors will trigger attacks in those with HAE, so avoid in these patients

Bradykinin = Arg Pro Pro Gly Phe Ser Pro Phe Arg Arg Pro Pro Gly Phe Ser Pro Phe Arg ACE Arg Pro Pro Gly Phe Ser Pro + Phe-Arg Bradykinin Carboxypeptidase N Arg Pro Pro Gly Phe Ser Pro Phe + Arg Arg Pro Pro Gly Phe + Ser Pro Phe ACE Arg Pro Pro Gly Phe + Ser Pro + Phe Arg ACE

Management Stop drug and use other classes of antihypertensive agents ALL ACE inhibitors are to be avoided Management of angioedema depends on site of involvement – securing the airway by intubation may be necessary ARB receptor antagonists are generally considered to be safe Consider off label use of icatibant or ecallantide to treat swelling Johnson SP, Jacobsen J, Monster TBM et al. Am. J.Med.118: , 2005

1888 – family described by William Osler 1963 – Donaldson and Evans described the biochemical defect responsible – absence of C1 inhibitor Defective gene located on chromosome 11

Epidemiology 1:10,000 – 1:50,000 with no racial or gender predilection Clinical Presentations Usually manifests in 2 nd decade May be seen in young children Edema may develop in one or several organs Presentation depends upon site of swelling Attacks last 2-5 days before spontaneous resolution Nzeako Arch Intern Med, 2001

Angioedema may develop in subcutaneous tissues of extremities, genitalia, face, trunk Gastrointestinal tract and upper airway are also potential targets

Symptoms of bowel wall edema can be confused with an acute abdominal emergency –White blood count may be normal or abnormal and symptoms resolve within 72 hours without therapy Submucosal edema of larynx (or, rarely, pharynx) may cause asphyxiation – this may occur on first presentation

Laryngeal Edema Commonest cause of mortality in HAE Time from onset of swelling to death 1-14 hours (mean 7 hours) May be presenting feature Death may occur in those with no previous laryngeal edema episodes Increased risk within certain families Early symptoms: lump in throat, tightness in throat Hoarseness, inspiratory stridor, progressive dyspnoea

Hereditary – Autosomal dominant –85% decreased C1 inhibitor - often gene deletion, insertion, stop codon, frame-shift mutation (Type 1 HAE) in the SERPIN Gene on Chromosome 11 (p11.2- q13) –15 % normal or increased C1 inhibitor protein but decreased function typically due to single nucleotide mutation (Type 2 HAE) –Suppression of the one normal gene product (theoretically should be 50%) to 35% or less causes swelling Zuraw. WAO Journal. Sept 2010

Autosomal dominant; all patients heterozygous Each child of affected patient has a 50% chance of having HAE 20% no prior family history – spontaneous mutations More than 150 different mutations reported Varied clinical pattern may be explained by variable effect of mutations on C1 inhibitor synthesis and secretion as well as differences in Bradykinin metabolism

Clinical presentation is key For screening – C4 is cost effective and is low during attacks and in most people between attacks Quantitative and functional assays of C1 inhibitor are usually indicated C2 levels reduced in acute attack C1 should be normal No role for CH-50 Lunn M, Allergy and Asthma Proceedings 2010

C1 Inhibitor Single chain glycoprotein; 478 amino acids molecular weight 104,000; serine protease family (SERPIN) Important regulatory protein of complement cascade Inactivates C1 esterase complex Regulates coagulation, fibrinolytic, kinin, complement systems Nielson Immunopharmacology 1996

Lack of C1 inhibitor leads to abnormal activation of complement pathway, reduced C2 and C4 levels Hageman factor induces formation of kallikrein from prekallikrein Bradykinin is released from high molecular weight kininogen Bradykinin binds to the bradykinin receptor resulting in a marked increase in micro vascular permeability to cause angioedema Kaplan JACI 2002

Trace factor XIIa Factor XII surface HK surface Prekallikrein Kallikrein Bradykinin Factor XII Factor XIIaFactor XIIf Autodigestion Kallikrein C1 C4 & C2 Digestion Inhibited by CĪ INH Factor XI Factor XIa Intrinsic Coagulation Factor XIIa HMW Kininogen (HK) HK CĪCĪ

No response to steroids or antihistamines Avoid oral contraceptives, ACE inhibitor medications Pre-medicate before procedures including those requiring radiocontrast media or streptokinase as they may decrease C1 inhibitor levels Reassurance; address issues such as ongoing stress Treat infections promptly Genetic counseling and screening Hepatitis B vaccine in anticipation of receiving blood products Influenza vaccine Bowen, Allergy Asthma and Clinical Immunlogy 2010

Principles Action plan for acute episodes Strategy for long term prophylaxis Short term prophylaxis for high risk procedures (e.g. dental work using C1 inhibitor concentrate 20 units /kg right before procedure) Regular follow up for education and monitoring side effects of therapy Bowen, Allergy Asthma and Clinical Immunlogy 2010

Acute Attacks A(i) C1 inhibitor concentrates (a) Berinert 20 units/kg intravenous infusion (FDA approved 2009) (b) Cinryze 1000 units/patient (not FDA approved) (ii)Rhucin ( units/kg) A recombinant C1 esterase inhibitor protein (not FDA approved) Excellent and prompt response in most patients Most patients respond well within 2 hours of infusion Craig, JACI 2009

The earlier the patient is treated in an attack with C1 inhibitor the more rapid is the resolution Home therapy for trained patients using C1 esterase inhibitor concentrate is a safe method for dealing with attacks of angioedema particularly where access to emergency care is difficult Bowen 2010

BBradykinin Receptor Antagonism -Icatibant is a synthetic decapeptide functioning as a potent, selective competitive antagonist of the bradykinin 2 receptor -Given by subcutaneous injection 3ml (30mg), half life 1-2 hours -Approved in Europe, Australia and Brazil (and approval in USA imminent) -Rapid onset usually within an hour, systemic side effects rare and local side effects at site of injection are common but transient Cicardi, NEJM 2010

CKallikrein Inhibition -Ecallantide -Approved by FDA (Dec 2009) for acute attacks -60 amino acid with high affinity to kallikrein -Subcutaneous injection 30mg (three10mg injections) -Significant clinical improvement reported within 4 hours of injection -2.7% risk of anaphylaxis within 60 minutes (good response to medical treatment in all reported cases) -12% develop anti-ecallantide antibodies including anti- ecallantide IgG and IgE, but IgG does not neutralize effect Cicardi, NEJM 2010

Acute attacks when C1 inhibitor concentrate, ecallantide or icatibant are not available: –Intubation and respiratory support may be necessary when laryngeal edema present –Fresh frozen plasma (FFP) has been used successfully for acute attacks. Exacerbation of symptoms by supplying more kallikrein substrate is a consideration and is occasionally seen Prematta, Annals of Allergy Asthma and Immunology 2008

Long Term Prophylaxis – Adults 20% of patients have attacks sufficiently frequent or severe that prophylaxis is needed using attenuated androgens (danazol, stanozolol, oxandrin) C1 inhibitor concentrate, e.g. Cinryze, 1000 units intravenously twice a week with 50% reduction of attacks may be used in those unable to tolerate androgens May substitute Berinert, but it is not approved for this indication Higher doses of C1-INH may be necessary * Zuraw NEJM 2010

When using androgens titrate to lowest effective dose to control attacks – for danazol it may be possible to reduce to 200 mg every second day, and in some patients to 50 mg every second day Use the lowest effective dose, to reduce side effects Regular monitoring of liver enzymes Serum lipid levels –Blood pressure –Weight Ultrasound of the liver annually may detect early hepatic adenomas and has been recommended Craig, Proceedings of Allergy and Asthma 2007

Long Term - Children Anti-fibrinolytic agents, e.g. tranexamic acid and aminocaproic acid have been used as first line prophylaxis, but the latter is poorly tolerated Low dose danazol in selected patients C1-inhibtor dosed by weight 20 units per kg (Berinert) is off label indication for children For adolescents 1000 units twice a week is approved (Cinryze) Nzeako, Arch Intern Med 2001

Minor Manipulations If plasma-derived C1 inhibitor (pdC1INH) immediately available: -No prophylaxis needed If pdC1INH not available: -Prophylaxis for five days before and two to 5 days post event -Danazol (avoid during fist two trimesters of pregnancy; mg/kg/day, maximum 600 mg daily) -Stanozolol 4-6 mg/day Major Procedures or Intubation Plasma-derived C1 inhibitor (pdC1INH): -Give one to six hours before procedure* (optimum dose not yet established – see text). -Second dose of pdC1INH should be immediately available If pdC1INH not available: -Danazol prophylaxis as per minor and Solvent/detergent treated plasma (SDP; if not available, then fresh frozen/frozen plasma but less safe than SDP) one to six hours before procedure* -10 ml/kg; 2-4 units ( ml) for an adult *as close to procedure as feasible Bowen T, Brosz J, Brosz K, Herbert J, Ritchie B. Management of hereditary angioedema 2010: Canadian approach. Allergy Asthma Clinical Immunology, 2010; 6: 20 Short Term Prophylaxis

Pregnancy Avoid attenuated androgens Concentrates of C1 esterase inhibitor should be available and used to treat attacks In severe cases chronic use of C1-INH twice a week at doses 1000 to 1500 units IV FFP can be used with caution for attacks Bowen T, Brosz J, Brosz K, Herbert J, Ritchie B. Management of hereditary angioedema 2010: Canadian approach. Allergy Asthma Clinical Immunology, 2010; 6: 20

Newer management strategies aim to address pathogenesis more specifically Medications are being developed to decrease adverse reactions (for example, avoiding viral contamination of blood products by using recombinant products) Oral bradykinin antagonist is being studied Depot subcutaneous C1-INH is being developed to eliminate need for IV infusion Frank M. WAO Journal, 2010 Recombinant C1 inhibitor for the treatment of hereditary angioedema.

Type I: Seen most commonly with B cell lymphoma or monoclonal gammopathy. Rare cases may occur with autoimmune disorders with B cell hyperreactivity Type II: Most commonly due to IgG antibody to C1 inhibitor which prevents its ability to inactivate enzymes such as plasma kallikrein and factor Xlla. The monoclonal proteins are antibody directed to C1 inhibitor There is an overlap in the two types, since most cases with lymphoma also have anti-C1 INH Cicardi, Publication pending

Decreased C1q levels distinguish AAE from HAE (C1q should be normal in HAE): C1 q is low in about 70% of those with acquired C1 INH deficiency and is very helpful but not totally reliable in distinguishing between HAE and acquired forms Treatment of underlying condition may result in resolution For acute attacks, C1 inhibitor concentrate, where available, should be used, but may require very large doses secondary to high titer of anti-C1-INH Cicardi, publication pending

Attenuated androgens, antifibrinolytics and/or immunosuppression therapy Plasmaphoresis may be effective Icatibant and ecallantide are also expected to be effective Main treatment is treating the associated lymphoma Cicardi, publication pending

C4 C1 INH Concentration C1 INH Functional Activity C1Q Type ILow Normal Type IILowNormalLowNormal Type III AAE Normal Low Normal Low Normal Low Normal Low

Type II acquired C1 inhibitor deficiency (IgG C1 inhibitor) has a decrease in C1 inhibitor size on SDS gel electrophoresis from 105 Kd to 95 Kd Acquired C1 INH deficiency - Type I Acquired C1 INH deficiency - Type II C1-INH Function<30% C1-INH AntigenLow C1QLow C4Low C1-INH AntibodyAbsentPresent* *Bouillet L. Diagnosis and therapy of HAE. Jerini Satellite Symposium Proceedings XXVI EAACI, Goteborg, 2007

Recurrent angioedema, no recognized exogenous precipitant, normal C4 levels, may or may not be associated with urticaria Typically: episodes of swelling of lips, cheeks, eyes, tongue, pharynx, extremities, genitalia Sub-types: –Respond to antihistamines –Non-responsive to antihistamines. Possible role of bradykinin?

Normal Complement – C1, C4, C1 inhibitor protein and function Negative testing for antibody to IgE receptor Anti-thyroid antibodies elevated in some; perhaps less frequently than in chronic urticaria No obvious cause on history or exam May not respond to antihistamines or corticosteroids if secondary to bradykinin

Non-sedating antihistamines (e.g. fexofenadine, desloratadine, cetirizine, loratidine) – up to 4 times the doses used for allergic rhinitis Diphenhydramine 50 mg (for more severe attacks) – repeat in 4 hours Prednisone 50 mg x 2 doses and stop without any taper Epinephrine – if rapidly advancing H2 antihistamines and leukotriene modifiers can be added

A non-sedating antihistamine; possible to use up to 4 times the usual dose for allergic rhinitis Add H2-antagonist high dose BID May try leukotriene modifier If ineffective, diphenhydramine or hydroxizine at 50 mg QID If antihistamines alone are ineffective, try corticosteroids Rarely, corticosteroid sparing agents such as cyclosporine may be tried Avoid known triggers Zuberbier T, Asero R, Bindslev-Jensen C. Allergy, 2009; 64:

Most often occurs in association with urticaria When angioedema occurs alone, consider idiopathic angioedema, ACE inhibitors, hereditary and acquired C1 inhibitor deficiencies HAE is a rare disease, but must be identified as it can be life-threatening New treatments for attacks of HAE, e.g. purified inhibitor, bradykinin antagonists and kallikrein inhibitor offer quick resolution of angioedema

Prophylaxis for HAE is also effective ACE-inhibitor induced angioedema is an important cause of angioedema and is treated with avoidance Acute cases of ACE-inhibitor induced angioedema may respond to icatibant or ecallantide Patients with acquired angioedema should be referred to the appropriate specialist for ongoing management

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