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™)
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
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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
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–
–
–
–
Cold
Cholinergic
Solar
Vibratory
Pressure
• Other causes
– Some contact reactions
– Systemic diseases (e.g.,
systemic lupus
erythematosis)
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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
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Angioedema develops in 0.1% to 0.5% of those
receiving the drug
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Onset from 1st week of use to 2-3 years of use
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Symptoms resolve with cessation of drug, but may
persist days
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Described with all ACE inhibitors
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Genetic factors may be important
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Subjects with a history of angioedema from other
causes are more susceptible to ACE-induced
angioedema
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Face, lips and tongue most commonly involved but
laryngeal edema reported
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Risk factors include obesity, prior endotracheal
intubation and face and neck surgery
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ACE inhibitors will trigger attacks in those with HAE, so
avoid in these patients
Bradykinin = Arg Pro Pro Gly Phe Ser Pro Phe Arg
ACE
Arg Pro Pro Gly Phe Ser Pro Phe Arg
Bradykinin
Arg Pro Pro Gly Phe Ser Pro + Phe-Arg
ACE
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
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.118:1428-1429, 2005
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1888 – family described by William Osler
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1963 – Donaldson and Evans described the
biochemical defect responsible – absence of C1
inhibitor
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Defective gene located on chromosome 11
Epidemiology
• 1:10,000 – 1:50,000 with no racial or gender predilection
Clinical Presentations
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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
• 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 (p11.2q13)
– 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
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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
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For screening – C4 is cost effective and is low during
attacks and in most people between attacks
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Quantitative and functional assays of C1 inhibitor are
usually indicated
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C2 levels reduced in acute attack
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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
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Lack of C1 inhibitor leads to abnormal activation of
complement pathway, reduced C2 and C4 levels
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Hageman factor induces formation of kallikrein from
prekallikrein
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Bradykinin is released from high molecular weight
kininogen
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Bradykinin binds to the bradykinin receptor resulting in a
marked increase in micro vascular permeability to cause
angioedema
Kaplan JACI 2002
Trace factor XIIa
Prekallikrein
HK
Factor XII
Factor XIIa
surface
surface
HK
HMW Kininogen (HK)
Kallikrein
Bradykinin
Factor XI
Factor XIa
Factor XII
Intrinsic
Coagulation
HK
Factor XIIa
Factor XIIf
Autodigestion
Kallikrein
C1
Inhibited by CĪ INH
CĪ
C4 & C2
Digestion
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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 (50-100 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
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The earlier the patient is treated in an attack with C1
inhibitor the more rapid is the resolution
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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
B Bradykinin Receptor Antagonism
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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
C Kallikrein Inhibition
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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 antiecallantide 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
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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
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Serum lipid levels
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– Blood pressure
– Weight
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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
Short Term Prophylaxis
Minor Manipulations
Major Procedures or Intubation
If plasma-derived C1 inhibitor (pdC1INH)
immediately available:
-No prophylaxis needed
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:
-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
Bowen T, Brosz J, Brosz K, Herbert J, Ritchie B.
Management of hereditary angioedema 2010:
Canadian approach. Allergy Asthma Clinical
Immunology, 2010; 6: 20
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
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
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Newer management strategies aim to address
pathogenesis more specifically
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Medications are being developed to decrease adverse
reactions (for example, avoiding viral contamination of
blood products by using recombinant products)
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Oral bradykinin antagonist is being studied
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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
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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
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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
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Treatment of underlying condition may result in resolution
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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
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Plasmaphoresis may be effective
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Icatibant and ecallantide are also expected to be
effective
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Main treatment is treating the associated lymphoma
Cicardi, publication pending
C4
C1 INH
Concentration
C1 INH
Functional
Activity
C1Q
Type I
Low
Low
Low
Normal
Type II
Low
Normal
Low
Normal
Type III
Normal
Normal
Normal
Normal
Low
Low
Low
Low
AAE
Acquired C1 INH
deficiency - Type I
Acquired C1 INH
deficiency - Type II
C1-INH Function
<30%
<30%
C1-INH Antigen
Low
Low
C1Q
Low
Low
C4
Low
Low
Absent
Present*
C1-INH Antibody
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
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Recurrent angioedema, no recognized exogenous
precipitant, normal C4 levels, may or may not be
associated with urticaria
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Typically: episodes of swelling of lips, cheeks, eyes,
tongue, pharynx, extremities, genitalia
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Sub-types:
– Respond to antihistamines
– Non-responsive to antihistamines. Possible role of
bradykinin?
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Normal Complement – C1, C4, C1 inhibitor protein and
function
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Negative testing for antibody to IgE receptor
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Anti-thyroid antibodies elevated in some; perhaps less
frequently than in chronic urticaria
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No obvious cause on history or exam
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May not respond to antihistamines or corticosteroids if
secondary to bradykinin
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Non-sedating antihistamines (e.g. fexofenadine,
desloratadine, cetirizine, loratidine) – up to 4 times the
doses used for allergic rhinitis
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Diphenhydramine 50 mg (for more severe attacks) –
repeat in 4 hours
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Prednisone 50 mg x 2 doses and stop without any taper
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Epinephrine – if rapidly advancing
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H2 antihistamines and leukotriene modifiers can be
added
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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
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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
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Prophylaxis for HAE is also effective
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ACE-inhibitor induced angioedema is an important cause
of angioedema and is treated with avoidance
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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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