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GLORIA Module 7: Angioedema. Authors: Allen P. Kaplan, USA Connie H. Katelaris, Australia Paul C. Potter, South Africa Timothy J. Craig, USA. Updated: June 2011. Global Resources in Allergy (GLORIA™).

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gloria module 7 angioedema

GLORIA Module 7:Angioedema


Allen P. Kaplan, USA

Connie H. Katelaris, Australia

Paul C. Potter, South Africa

Timothy J. Craig, USA

Updated: June 2011


Global Resources in Allergy (GLORIA™)

Global Resources In Allergy (GLORIA™) is the flagship program of the World Allergy Organization (WAO). Its curriculum educates medical professionals worldwide through regional and national presentations. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-related patient care.


World Allergy Organization (WAO)

The World Allergy Organization is an international coalition of 89 regional and national allergy and clinical immunology societies.


WAO’s Mission

WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies


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

causes of angioedema
Causes of Angioedema

Allergic: Foods, drugs, insect stings/bites

Radiocontrast media


Associated with anaphylaxis



May be histamine induced or bradykinin induced

ACE inhibitors

Bradykinin-induced with normal C1-inhibitor (HAE-3)

C1 inhibitor deficiency

Hereditary – Types I, II


physical causes of angioedema
Physical Causes of Angioedema

Physical causes






Other causes

Some contact reactions

Systemic diseases (e.g., systemic lupus erythematosis)

angiotensin converting enzyme ace induced angioedema
Angiotensin Converting Enzyme (ACE) – Induced Angioedema

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

ace induced angioedema
ACE-Induced Angioedema

Angioedema develops in 0.1% to 0.5% of those receiving the drug

Onset from 1st 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

ace induced angioedema11
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 degradation site of ace inhibition
Bradykinin Degradation – Site of ACE Inhibition


Arg Pro Pro Gly Phe Ser Pro Phe Arg

Arg Pro Pro Gly Phe Ser Pro + Phe-Arg



Carboxypeptidase N

Arg Pro Pro Gly Phe + Ser Pro + Phe Arg

Arg Pro Pro Gly Phe Ser Pro Phe + Arg

Arg Pro Pro Gly Phe + Ser Pro Phe

Bradykinin = Arg Pro Pro Gly Phe Ser Pro Phe Arg


ace inhibitors and angioedema
ACE Inhibitors and Angioedema


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.118:1428-1429, 2005

hereditary angioedema hae
Hereditary Angioedema (HAE)

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 and clinical presentations of hae
Epidemiology and Clinical Presentations of HAE


1:10,000 – 1:50,000 with no racial or gender predilection

Clinical Presentations

Usually manifests in 2nd 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

hae clinical manifestations
HAE Clinical Manifestations

Angioedema may develop in subcutaneous tissues of extremities, genitalia, face, trunk

Gastrointestinal tract and upper airway are also potential targets

hae clinical manifestations18
HAE Clinical Manifestations

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

hae clinical manifestations19
HAE Clinical Manifestations

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

genetics of hae
Genetics of HAE

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

genetics of hae21
Genetics of HAE

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

diagnosis of hereditary angioedema hae
Diagnosis of Hereditary Angioedema (HAE)

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

pathophysiology of hae
Pathophysiology of HAE

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

pathophysiology of hae 2
Pathophysiology of HAE - 2

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

role of c1 inhibitor in controlling bradykinin formation
Role of C1 Inhibitor in Controlling Bradykinin Formation

Trace factor XIIa



Factor XII



Factor XIIa


HMW Kininogen (HK)



Factor XIa

Factor XI


Factor XIIa

Factor XIIf

Factor XII






Inhibited by CĪ INH

C4 & C2


management of hae general
Management of HAE (General)

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

management of hae


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

Management of HAE

Bowen, Allergy Asthma and Clinical Immunlogy 2010

management of hae28
Management of HAE

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 (50-100 units/kg)

A recombinant C1 esterase inhibitor protein (not FDA


Excellent and prompt response in most patients

Most patients respond well within 2 hours of infusion

Craig, JACI 2009

management of hae29
Management of HAE

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

management of hae30
Management of HAE

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

management of hae31
Management of HAE

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


Cicardi, NEJM 2010

management of hae32
Management of HAE

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

management of hae33
Management of HAE

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

management of hae34
Management of HAE

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


Ultrasound of the liver annually may detect early hepatic adenomas and has been recommended

Craig, Proceedings of Allergy and Asthma 2007

management of hae35
Management of HAE

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


Short Term Prophylaxis

  • 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; 2.5-10 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 (400-800 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

management of hae37
Management of HAE


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

future management considerations
Future Management Considerations

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.

acquired c1 inhibitor deficiency
Acquired C1 Inhibitor Deficiency

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

acquired c1 inhibitor deficiency40
Acquired C1 Inhibitor Deficiency

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

acquired c1 inhibitor deficiency41
Acquired C1 Inhibitor Deficiency

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

c1 inhibitor deficiency hereditary vs acquired
C1 Inhibitor Deficiency – Hereditary vs. Acquired

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

*Bouillet L. Diagnosis and therapy of HAE.Jerini Satellite Symposium Proceedings XXVI EAACI, Goteborg, 2007

idiopathic angioedema
Idiopathic Angioedema

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


Respond to antihistamines

Non-responsive to antihistamines. Possible role of bradykinin?

laboratory features of idiopathic angioedema
Laboratory Features of Idiopathic Angioedema

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

treatment of acute episodes of angioedema
Treatment of Acute Episodes of Angioedema

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

preventive therapy of angioedema
Preventive Therapy of Angioedema

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: 1427-1443

angioedema conclusions
Angioedema - Conclusions

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

angioedema conclusions49
Angioedema - Conclusions

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

world allergy organization wao
World Allergy Organization (WAO)

For more information on the World Allergy Organization (WAO), please visitwww.worldallery.orgor contact the:

WAO Secretariat

555 East Wells Street, Suite 1100

Milwaukee, WI 53202

United States

Tel: +1 414 276 1791

Fax: +1 414 276 3349