Global Guidelines for the
Care of Patients with
Hereditary Angioedema
World Allergy Organization
General Advisor
WAO President Ruby Pawankar, Professor, Nippon Medical School, Tokyo
General Advisor
WAO President (Initiator of the guideline development):
Richard Lockey, Professor of Medicine, University of South Florida
Steering Committee Chair:
Timothy Craig, Professor of Medicine and Pediatrics, Penn State University
Members of the Steering committee:
Emel Aygoren-Pursun, Professor of Medicine, University of Frankfurt
Konrad Bork, Professor of Medicine, Johannes Gutenberg University Mainz
Tom Bowen, Professor of Medicine, University of Calgary
Henrik Boysen, Executive Director, HAEi-International Patient Organization
Marco Cicardi, Professor of Medicine, University of Milan
Henriette Farkas, Professor of Medicine, Semmelweis University
Anete Grumach, Faculty of Medicine, University of Sao Paulo
Connie Katelaris, Professor of Medicine, Allergy University of Western Syndney
Hilary Longhurst, Consultant Immunologist, Barts and the London NHS Trust
William R. Lumry, Clinical Professor of Medicine, University of Texas Southwestern
Inmaculada Martinez-Saguer, Professor of Medicine, University of Frankfurt
Marcus Maurer, Professor of Dermatology and Allergy, Charité – Universitätsmedizin Berlin
Bruce Ritchie, Professor of Medicine, University of Alberta
Bruce Zuraw, Professor of Medicine, University of California San Diego
Pharmaceutical Supporters of the
Guidelines in Alphabetical Order
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CSL Behring
Dyax
Shire
Viropharma
World Allergy Organization’s HAE Global
Guidelines
• Objectives:
To develop a global approach for the management of
patients with Hereditary Angioedema (HAE) so as to
improve the quality of care delivered to patients with
HAE
• To increase the global availability of HAE medications
• To encourage all physicians, patients, pharmaceutical
companies and governments to ensure that patients with
HAE are given similar access to appropriate therapies
and care worldwide
HAE Global Guidelines
• Developed by a international group of physicians
selected by the WAO who were considered HAE
specialists
• Evidenced based and rated
• Supported by the literature
• Reviewed by a larger international group of HAE experts
• Approved by the WAO leadership
• Finally, approved by WAO Member Allergy Associations
HAE Global Guidelines
Were developed to be:
• A resource to clinicians for self education
• Document to be a reference while providing clinic care
• Teaching tool for physicians to have access to slides for
educating others
1.0 Background and Introduction
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1.1
1.2
1.3
1.4
1.5
Terminology
Genetics
Pathophysiology
Role of bradykinin
Role of C-1-esterase
2.0 Presentation of HAE
• 2.1 When to suspect HAE
• 2.2 Triggers for HAE
• 2.3 Prodromal symptoms
3.0 Diagnosing HAE
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3.1
3.2
3.3
3.4
When to suspect HAE
Diagnosing HAE
Laboratory tests for HAE
Flow chart for assessing angioedema
4.0 Suggested Future Terminology for
Angioedema
• Deferred to future conference
5.0 Treatment of HAE
• 5.1 Acute treatment of attacks (On Demand)
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5.1.1
5.1.2
5.1.3
5.1.4
5.1.5
5.1.6
C1-INH
rcC1-INH
FFP
Icatibant
Ecallantide
Cost comparison
6.0 Short Term or Event Prophylaxis
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6.0
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
6.9
Purpose of short term prophylaxis
When to use it
Therapies for
Alternatives
Therapies to avoid
Dosing
Androgens
C1-INH
Cost comparison
References
7.0 Long Term Prophylaxis
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7.0 Long term prophylaxis
7.1 Indications
7.2 Antifibrinolytics
7.3.1 Androgens
7.3.2 Children and chronic prophylaxis
7.3.3 Pregnant females and prophylaxis
7.3.4 Dosing for chronic prophylaxis
7.3.5 Adverse effects of androgens for chronic
prophylaxis
7.0 Long Term Prophylaxis
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7.3.6
7.4.1
7.4.2
7.4.3
Monitoring adverse effects of androgens
C-1 Inhibitor- indications for chronic prophylaxis
C1-inhibitor- efficacy
Monitoring safety of C1-inhibitor
8.0 Preventive Medicine and Long Term
Care of the Patient with HAE
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8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
8.9
Trigger avoidance
Drug avoidance
Vaccine
While using C1-INH
While on androgens
While on anti-fibrinolytics
Family screening
Summary table
References
9.0 Caring for the Child with HAE
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9.1 Why is the HAE child unique
9.2 When to test
9.3 Screening for HAE
9.4 Prenatal screening
9.5 Treatment of HAE
9.5.1 Dosing by weight is essential
9.5.2 Need for action plan
9.5.3 Dosing C1-INH for on demand
9.5.4 Prophylaxis
9.6 Pediatric references
10.0 Care of the Pregnant Patient with
HAE
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10.1
10.2
10.3
10.4
10.5
10.6
10.7
Why pregnancy is unique
Diagnosis of HAE during pregnancy
Prenatal diagnosis
In-vitro fertilization
Abortion
Lactation
Family planning
10.0 Care of the pregnant patient with
HAE
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10.8 Treatment during pregnancy
10.8.1 Long term prophylaxis therapy
10.8.2 Short term prophylaxis therapy
10.8.3 On demand therapy
10.9 Post partum care
10.10 Cost comparison in care
10.11 References
11.0 Special Issues in HAE
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11.1
11.2
11.3
11.4
11.5
11.6
11.7
Home and self therapy
Patient support
HAE associations
Databases for HAE
Action plans for HAE
Need for better medications
World wide access to therapies
1.1. As of now angioedema is known to be secondary
to bradykinin and histamine. Histamine induced should
be replaced by mast cell induced angioedema. (90%
agreement)
Mast cell-mediated angioedema:
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Allergic
Idiopathic
Autoimmune
Drug induced
Bradykinin - induced angioedema:
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ACE inhibitor induced
Hereditary with low C1-INH (type-1)
Hereditary with poorly functional C1-INH (type 2)
Hereditary with normal C1-INH (type 3)
Acquired with abnormal C1-INH
Idiopathic
C1INH Null Mice and Vascular Permeability
C1INH gene
B2BKR gene
Evans blue
+/+
+/+
No
C1INH therapy No
+/+
+/+
Yes
No
-/+/+
Yes
No
Adapted from Han ED, et al. J Clin Invest. 2002;109:1057-1063.
-/+/+
Yes
Yes
-/-/Yes
No
In Vivo Generation of Kinins in HAE
From Nussberger J, et al. J Allergy Clin Immunol. 1999;104:1321-1322.
1.2. Genetics of HAE
Type I and II:
• Autosomal dominant
• Penetrance of type I and type II HAE is high
• Large array of different mutations of the SERPING1 gene
• De novo mutation of SERPING1 gene in 25% of cases
Type III:
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Penetrance is variable
A small subset of patients have a mutation in factor XII
Genetic abnormality of most patients has not yet defined
Requires a strong family history of angioedema since genetics
is poorly defined. (90% consensus)
The genetics of Type I and II
Crowder JR, Crowder TR. Five generations of angioneurotic edema. Arch Inter Med 1917;
20:840-52
HAE Is Caused By C1 Inhibitor Mutations
Bissler JJ, et al. Proc Assoc Am Physicians. 1997;109:164-173.
Davis AE 3rd. Annu Rev Immunol. 1988;6:595-628.
Verpy E, et al. Am J Hum Genet. 1996;59:308-319.
Zuraw BL, Herschbach J. J Allergy Clin Immunol. 2000;105:541-546.
C1-INH involved in 3 systems → C1-INH
depletion
Factor XIIa
C1-INH
Factor XII
Contact System C1-INH
Prekallikrein
HMW-K
Kallikrein
Increased vascular
permeability 
ANGIOEDEMA
Complement
System
C1rs
Plasminogen
Bradykinin
C1
Plasmin
Fibrinolytic
System
C4
C2
1.3. Bradykinin is responsible for the
angioedema associated with HAE
• Plasma kallikrein and factor XII are normally inhibited by
C1INH
• Complement and contact plasma proteolytic cascades are
activated with the potential to generate several vasoactive
compounds.
• Plasma kallikrein cleaves high molecular weight kininogen
(HMWK) to generate bradykinin
• Bradykinin is generated through activation of the contact
system
• Bradykinin is the primary mediator of swelling
1.4 C1-esterase inhibitor protein (C1INH)
• Member of the serine protease inhibitor (serpin) superfamily
• “Molecular mousetrap”
• 1:1 stoichiometric relationship between the protease and
C1INH
• Major inhibitor of several complement proteases (C1r, C1s,
and mannose-binding lectin–associated serine protease
[MASP] 1 and 2) and contact-system proteases (plasma
kallikrein and coagulation factor XIIa)
• Relatively minor inhibitor of the fibrinolytic protease plasmin
and the coagulation protease factor XIa.
• C1-INH is deficient (type 1) or abnormal in function (type 2),
but normal in type III HAE
Active
Cleaved: Inactive
1.5 Bradykinin
• Nanopeptide generated by activation of the contact
system.
• Binds to the the B2 bradykinin receptor
• Degradation product, des-Arg-bradykinin, binds to a
separate B1 bradykinin receptor
• Important for normal homeostasis, normal immune
responses, inflammation, vascular tone, and vascular
permeability.
• Angioedema is primarily mediated through the B2
bradykinin receptor causing increase permeability
• Increased vascular permeability is primarily mediated by
down regulation of vascular endothelial cadherin and
increased contraction of the actin cytoskeleton.
Bradykinin Effect on Endothelial Cells
Increased vascular permeability
VE-cadherin
Non stimulated
Stimulated
From Tiruppathi C, et al. Vascul Pharmacol. 2003;39:173-185.
Actin stress fibers
2.0 Clinical Presentation of HAE
• 2.1 When to suspect HAE
• 2.2 Triggers for HAE
• 2.3 Prodromal symptoms
2.1.1. Suspect HAE when a patient presents with
angioedema, especially if free of urticaria, that is
unpredictable in onset, but frequently follows a trigger
such as trauma, and is associated with recurrent
abdominal pain and upper airway swelling. (100%
consensus)
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Estimated prevalence of 1 per 50,000
All ethnicities and males and females equally effected
Recurrent angioedema without urticaria
50% of the patients begin swelling before the age of 10
Recurrent swelling of the extremities, the gastrointestinal
tract, the external genitourinary tract, the face, and the upper
airway often (40%) proceeded by a trigger
• Probability that a given attack will involve the skin or abdomen
is nearly 50% each
• Genitourinary and laryngeal attacks, account for only 3.6% of
attacks
2.1.2. Continued
• Swelling typically increases slowly over approximately 24
hours then resolving even more slowly over the subsequent 2
to 4 days
• Preceded by prodromal symptoms, most classically erythema
marginatum
• Highly variable in individuals and within families.
• Angioedema is often quite severe and unpredictable and
limits productivity
• Swelling of the upper airway can result in mortality
• Abdominal swelling can cause nausea, vomiting and diarrhea
and may result in inappropriate surgery
Common triggers of HAE attacks
Trauma
Menstruation
Angioedem
Angioedema
a attack
Infection
Medications:
Estrogens
ACE-I
Stress
2.3 Prodromal Symptoms Frequently
Proceed an Attack of HAE
Prodromal symptoms include:
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Flu-like feelings
Erythema marginatum
Parathesias
Fatigue
Indigestion
Non-specific rashes
Other non-specific symptoms
The Percentage of Time That Patients Report
Being Able to Predict an Acute HAE Attack
Based on Prodromal Symptoms
100%
of
attacks
6.5%
8.7%
Unable to
predict
25% of
attacks
26.1%
75% of
attacks
50.0%
50% of attacks
8.7%
Prematta M, et al. Allergy and Asthma Proceedings. 2009
Prodromal Symptom (%)
Prodromal Symptoms That Patients Reported
Before Their Last HAE Attack
Percentage of Patients
Prematta M, et al. Allergy and Asthma Proceedings. 2009
Erythema Marginatum before an HAE attack
HAE Attacks can Involve
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Face
Extremities
Upper airways
Gastrointestinal system
Genital-urinary system
Intestinal swelling during an
Abdominal attach
3 Diagnosing HAE
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3.1
3.2
3.3
3.4
When to suspect HAE
Diagnosing HAE
Laboratory tests for HAE
Flow chart for assessing angioedema
3.1. Patients with suspicion of HAE and family
members of patients with HAE should be screened so
that appropriate therapy can be available for treatment,
especially since the first event may be of the upper
airway and potentially may be fatal without appropriate
therapy. (100% consensus)
• In order to be prepared all patients with suspected HAE and
all family members of patients diagnosed with HAE should be
screened by at least a C4
• All patients with HAE should have a treatment action plan.
• Patients may be asymptomatic even later in life; however,
preparation is needed to have therapy available for
procedures that can trigger HAE
3.3.1 Complement testing is used for the diagnoses, but is
difficult to work with. As a result repeating the C4 and C1INH
protein and function is important to confirm the diagnosis.
(100% consensus)
• C4- Is the best screening test for HAE and should be
depressed in greater than 90% of patients even between
attacks. A normal C4 during an attack virtually excludes the
diagnosis of HAE 1 or 2
• C1-INH quantitative- low in type 1, normal Type II
• C1-INH functional assay- Should be low in all type 1 and type
2, but the assay is not 100% specific nor sensitive.
• C2- Often depressed during attacks. Not essential for the
diagnosis
• C1q- Should be normal in HAE. Indicated when patient
presents with angioedema after the age of 40 years or if
patient has constitutional symptoms
• CH50- Indicated for complement deficiency, but not HAE
3.3.2. C4 is the single best screening test and repeating
the C4 during an attack increases the probability that a
low C4 will be found; however, C4 is not a definitive
test since neither the sensitivity nor specificity are
absolute. (100% consensus)
• C4 level is an effective screening tool to detect C1INH
deficiency
• Occasional false negatives will be encountered, particularly in
patients on anabolic androgens
• Measurement of the activation product C4d may avoid false
negative results.
• False positives can also be encountered, especially in C4
deficiency.
• C4 level is the best screening test, but alone cannot be relied
upon to make a diagnosis of C1INH deficiency.
3.3.3 Other tests
• Sequencing of the SERPING1 or factor XII genes can be
done to pursue diagnoses of HAE type 1, 2, 3; however
it is rare that this approach is needed.
• Measurement of complement C3 levels OR CH50 is not
useful.
• Many patients with acquired C1INH deficiency have
autoantibodies that recognize C1INH.
3.4 DIAGNOSING HAE
Clinical symptoms + Familial
history
C4
Normal
Low
Confirm C4
during attack
C1INH level
Normal
Low
Normal
Functional
C1INH
Consider HAE
type III or AE
due to
medications
C1q
Normal
Low
Normal
Low
Consider
other causes
of C4
consumption
HAE
type
II
HAE
type I
AAE
References for sections 1, 2 and 3
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Agostoni A, Aygören-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1
esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004 Sep. 1;114(3 Suppl):S51–131
Frank MM, Sergent JS, Kane MA, Alling DW. Epsilon aminocaproic acid
therapy of hereditary angioneurotic edema: a double-blind study. N Engl J Med 1972; 286:808-12
•
Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol: reversal of clinical and biochemical abnormalities. N Engl J Med
1976;295:1444-8
•
Frank MM. Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am 2006;26:653-68
•
Sheffer AL, Austen KF, Rosen FS. Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med 1972;287: 452-4
•
Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin
Immunol 1997;99:194-6
•
Sze AL,Paki G, Varga L, Valentin S, et al. Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema. J Allergy Clin Immunol
2005;115:864-9
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•
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Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: safety of long-term stanozolol therapy. J Allergy Clin Immunol 2007;120:654-8
Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients.
Ann Allergy Asthma Immunol 2008;100:153-61
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Bork K, Pitton M, Harten P, Koch P. Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema. Lancet 1999;353:1066-7
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Farkas H, Varga L, SzeÅLplaki G, Visy B, Harmat G, Bowen T. Management of hereditary angioedema in pediatric patients.Pediatrics 2007;120(3):e713-e722
Cicardi M, Bergamaschini L, Tucci A, Agostoni A, Tornaghi G, Coggi
G, et al. Morphologic evaluation of the liver in hereditary angioedema
patients on long-term treatment with androgen derivatives. J Allergy
Clin Immunol 1983;72:294-8
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•
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Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of
long-term prophylaxis with attenuated androgens in hereditary angioedema:
comparison of treated and untreated patients. J Allergy Clin
Immunol 1997;99:194-6
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•
Zurlo JJ, Frank MM. The long-term safety of danazol in women with
hereditary angioedema. Fertil Steril 1990;54:64-72
References for sections 1, 2 and 3
•
Cicardi M, Bergamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year
experience. J Allergy Clin Immunol 1991;87:768-73
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Lundh B, Laurell AB, Wetterqvist H, White T, Granerus G. A case of
hereditary angioneurotic oedema, successfully treated with epsilon aminocaproic acid: studies on C’1 esterase inhibitor, C’1 activation,
plasminogen level and histamine metabolism. Clin Exp Immunol 1968;
3:733-45
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Bork K, Witzke G. Long-term prophylaxis with C1-inhibitor (C1 INH)
concentrate in patients with recurrent angioedema caused by hereditary
and acquired C1-inhibitor deficiency. J Allergy Clin Immunol 1989;83:
677-82
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Royston D. Blood-Sparing Drugs: Aprotinin, Tranexamic Acid, and Epsilon-Aminocaproic Acid. Int Anesthesiol Clin 1995; 33(1):155-7.
Parish LC. Hereditary angioedema: Diagnosis and management-a perspective for the dermatologist. J Am Acad Dermatol. 2011 May 5. [Epub ahead of print]
Riedl M, Gower RG, Chrvala CA. Current medical management of hereditary angioedema: results from a large survey of US physicians. Ann Allergy Asthma Immunol.
2011 Apr;106(4):316-322.e4. Epub 2011 Feb 5.
Varga L, Füst G, Csuka D, Farkas H. Treatment with C1-inhibitor concentrate does not induce IgM type anti-C1 inhibitor antibodies in patients with hereditary
angioedema. Mol Immunol. 2011 Jan;48(4):572-6. Epub 2010 Dec 15.
Tallroth GA. Long-term prophylaxis of hereditary angioedema with a pasteurized C1 inhibitor concentrate. Int Arch Allergy Immunol. 2011;154(4):356-9. Epub 2010 Oct
26.
Maurer M, Magerl M. Long-term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives. J Dtsch Dermatol Ges. 2011
Feb;9(2):99-107. doi: 10.1111/j.1610-0387.2010.07546.x. Epub 2010 Oct 15.
Bork K, Hardt J. Hereditary angioedema: long-term treatment with one or more injections of C1 inhibitor concentrate per week. Int Arch Allergy Immunol. 2011;154(1):818.
Ebo DG, Verweij MM, De Knop KJ, Hagendorens MM, Bridts CH, De Clerck LS, Stevens WJ. Hereditary angioedema in childhood: an approach to management. Paediatr
Drugs. 2010 Aug 1;12(4):257-68.
Czaller I, Visy B, Csuka D, Füst G, Tóth F, Farkas H. The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during
pregnancy: a long-term survey. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):44-9. Epub 2010 Jun 11.
Farkas H, Czaller I, Csuka D, Vas A, Valentin S, Varga L, Széplaki G, Jakab L, Füst G, Prohászka Z, Harmat G, Visy B, Karádi I. The effect of long-term danazol
prophylaxis on liver function in hereditary angioedema-a longitudinal study. Eur J Clin Pharmacol. 2010 Apr;66(4):419-26. Epub 2009 Dec 19.
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol. 2010 Jul 28;6(1):18.
Zanichelli A, Vacchini R, Badini M, Penna V, Cicardi M. Standard care impact on angioedema because of hereditary C1 inhibitor deficiency: a 21-month prospective study
in a cohort of 103 patients. Allergy. 2011 Feb;66(2):192-6.
Because of the differential diagnosis it is important to
determine the exact diagnosis so that appropriate
therapy for the specific type of angioedema the patient
is manifesting can be utilized. (100%)
Bradykinin Induced
• HAE type 1 (C1-INH
deficiency),
• HAE type 2 (C1INH
dysfunctional),
• HAE type 3 (HAE with
normal C1INH),
• AAE (acquired C1INH
deficiency),
• ACE-I induced, idiopathic
bradykinin induced
angioedema,
Histamine Induced (Mast
cell dependent)
• Idiopathic histamine
induced angioedema
• Allergic angioedema
• Drug induced histamine
dependent angioedema
3.0 Bradykiniin-induced
Angioedema Differential
Frequency
Age of first
symptoms
Pathogenesis
Clinical
Manifestations
Treatment
Angioedema due to ACE
inhibitors
0.1 – 0.5% of the patients
treating with ACE inhibitors
Any period after drug
introduction
Disturbance of bradykinin
metabolism
Facial subcutaneous and
upper airway edema (rarely
gastrointestinal)
Drug removal
HAE
1:10000 - 1:50000 inhabitants
childhood
Functional or quantitative C1INH
Subcutaneous, upper airway
and gastrointestinal edema
androgens, plasmin inhibitors,
C1-INH, icatibant and
ecallantide
Suspect Mast cell Dependent when
• Urticaria coexists with angioedmea
• Majority of cases (Histamine induced disease is far more
common than bradykinin induced so trial of
antihistamines and corticosteroids is indicated until
diagnosis is confirmed).
• Response to antihistamines
• Obvious trigger (i.e. drug, food)
Suspect Acquired Angioedema
• Angioedema similar to HAE, but later onset (over 40
years)
• Constitutional symptoms
• Low C1q
• Lymphoma or monoclonal gammopathy
• Anti-C1INH antibody
Hereditary Angioedema with Normal C1
Inhibitor (HAE type III)
Background:
• In 2000, report on ten families and a further report on one
family with HAE and normal activity of C1-INH in plasma. All
43 patients were women
• In 2006, report of the first men with HAE type III
• In 2006, report of 2 different mutations in exon 9 of the
coagulation factor XII gene (missense mutations)
• In 2006, report that the mutations cause an increased factor
XII activity (gain of function mutation)
• In 2009, investigation in which no increased factor XII activity
in the plasma of patients with HAE-FXII could be found
Hereditary Angioedema with Normal C1
Inhibitor (HAE type III)
Diagnosis
Clinical Presentation:
• Appearance of first clinical symptoms mostly in the second
decade of life
• Relapsing swellings of various organs: skin swellings,
abdominal pain attacks, tongue swellings, laryngeal edema,
pharyngeal edema
• In some women, the onset of symptoms occurs during
pregnancy or after starting estrogen-containing oral
contraceptives or hormonal replacement therapy
• In other women, the symptoms occur exclusively during
pregnancy, the intake of oral contraceptives or hormonal
replacement therapy; however, in others symptoms occur
independently from these time periods
Hereditary Angioedema with Normal C1
Inhibitor (HAE type III)
Assessment and Work Up:
• The diagnosis of “HAE type III” is based on the typical clinical
symptoms in combination with the familial occurrence
• There is no laboratory that can confirm the diagnosis of “HAE
type III”
• A search for one of the mutations in the factor XII gene may
serve to differentiate “Hereditary angioedema with normal C1
inhibitor with a mutation in the factor XII gene (HAE-FXII)”
from “Hereditary angioedema with normal C1 inhibitor without
a mutation in the factor XII gene (HAE-unknown), but a
negative test does not exclude HAE
Hereditary Angioedema with Normal C1
Inhibitor (HAE type III)
Treatment:
• A limited number of patients with HAE type III have been
reported
• Experience with treatments is minimal
• Treatments used for HAE type III attacks include C1 inhibitor
concentrate, ecallantide and icatibant and for prophylaxis
androgens, tranexamic acid, and progesterone
Hereditary Angioedema with Normal C1
Inhibitor (HAE type III)
Prognosis:
• The frequency of acute attacks varies considerably from
patient to patient
• There are many patients with a low clinical disease
expression
• Cases of asphyxiation have been described
4.0 Suggested Terminology for
Angioedema for the Future
Will address this in a future meeting
References
•
•
•
•
•
•
•
•
Cicardi M. Zanichelli A. The acquired deficiency of C1-inhibitor: lymphoproliferation and
angioedema.
Current Molecular Medicine. 10(4):354-60, 2010 Jun. UI: 20455857
Agostoni A. Aygoren-Pursun E. Binkley KE. Blanch A. Bork K. Bouillet L. Bucher C. Castaldo AJ.
Cicardi M. Davis AE. De Carolis C. Drouet C. Duponchel C. Farkas H. Fay K. Fekete B. Fischer B.
Fontana L. Fust G. Giacomelli R. Groner A. Hack CE. Harmat G. Jakenfelds J. Juers M. Kalmar L.
Kaposi PN. Karadi I. Kitzinger A. Kollar T. Kreuz W. Lakatos P. Longhurst HJ. Lopez-Trascasa M.
Martinez-Saguer I. Monnier N. Nagy I. Nemeth E. Nielsen EW. Nuijens JH. O'grady C. Pappalardo
E. Penna V. Perricone C. Perricone R. Rauch U. Roche O. Rusicke E. Spath PJ. Szendei G.
Takacs E. Tordai A. Truedsson L. Varga L. Visy B. Williams K. Zanichelli A. Zingale L. Hereditary
and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor
deficiency workshop and beyond. Journal of Allergy & Clinical Immunology. 114(3 Suppl):S51131, 2004 Sep. UI: 15356535
D'Incan M. Tridon A. Ponard D. Dumestre-Perard C. Ferrier-Le Bouedec M. Betail G. Souteyrand
P. Caillaud D. Acquired angioedema with C1 inhibitor deficiency: is the distinction between type I
and type II still relevant? Dermatology. 199(3):227-30, 1999. UI: 10592402
Bork K. Barnstedt SE. Koch P. Traupe H. Bork K. Barnstedt SE. Koch P. Traupe H. Lancet.
356(9225):213-7, 2000 Jul 15. UI: 10963200
5.0 Treatment of HAE
• 5.1 Acute treatment of attacks (On Demand)
–
–
–
–
–
5.1.1- C1-INH
5.1.2- rcC1-INH
5.1.3- FFP
5.1.4- Icatibant
5.1.5- Ecallantide
• 5.2 Short Term Prophylaxis (pre-procedural)
• 5.3 Long Term Prophylaxis (Suppression of attacks)
5.1 On Demand Therapies
•
•
•
•
•
Human plasma-derived C1-esterase inhibitor (hpC1-INH)
Recombinant C1-INH (rcC1-INH)
Ecallantide
Icatibant
Fresh Frozen Plasma
5.1.1 Treatment with C1-INH made from
purified human blood eliminates the
underlying cause of HAE by replacing the
deficient protein. (100%)
Its mode of action is physiological:
• It is an endogenous plasma factor,
• Acting on the same targets as patient’s own C1-INH, it inhibits
all cascade systems involved in the production of bradykinin
released during attacks.
References for sections On
Demand Therapy with C1-INH
•
•
•
•
Zuraw BL.Hereditary angioedema. N Engl J Med 2008;359:1027-36.
Cicardi M, Theuse of plasma-derived C1 inhibitor in the treatment of hereditary angioedema.
Expert Opin Pharmacother. 2007 Dec;8(18):3173-81.
Joseph K, Tholanikunnel TE, Kaplan AP. Treatment of episodes of hereditary angioedema with
C1 inhibitor: serial assessment of observed abnormalities of the plasma bradykinin forming
pathway and fibrinolysis. Ann Allergy Asthma Immunol. 2010 Jan;104(1):50-4.
AE Davis, 3rd, F Lu, P Mejia. C1 inhibitor, a multi-functional serine protease inhibitor. Thromb
Haemost 2010; 104(5).
Medicinal Products
Human Plasma-Derived C1-INH Concentrate
• Berinert® P (CSL Behring, Marburg, Germany)
– pasteurization, specific chromatography, nanofiltered
– plasma half-life: 32 to 47 hours
– marketing authorization in 1985; licensed in 2009 in the
USA
• Cetor ® (Sanquin, T Amsterdam, The Netherlands)
– precipitation, pasteurization, nanofiltration,
– plasma half-life: 48±10 hours
– licensed in 1997 in Europe
• Cinryze® (Viropharma, USA)
– licensed currently for prophylaxis in USA and prophylaxis
and on demand therapy in Europe
Medicinal Products
Recombinant C1-INH Concentrate
• Ruconest (Pharming, The Netherlands),
– manufactured from the breast milk of transgenic rabbits
– plasma half-life: approx. 3 hours
– Licensed in EU for on demand therapy
Indications of C1-INH are partially off label and
all plasma derived products can be used in
place of each other (100%)
Berinert®
all types of attacks in adults, children, pregnant women also
during breastfeeding. Dose is 20units/kg
Cinryze ®
all types of attacks in adults, children, pregnant women also
during breastfeeding. Dose is 1000 units
Cetor ®
all types of attacks in adults, children, pregnant women also
during breastfeeding. Dose is 1000 units
Berinert® P
• 20 U/kg body weight (previous, non-placebo-controlled
studies demonstrated the efficacy of doses of 500 to
1000 U/attack.)
• Until further double-blinded data are available 20 units
per kg is the suggested dose for on demand therapy of
C1INH (vote 90%)
Results
Craig et al. JACI 2010
Pasteurized Plasma C1-INH
Concentrate (Berinert)
Pasteurized C1-INH
Bernstein JA, et al. J Allergy Clin Immunol. 2008;121[Abstract
LB16].
Cetor®
• 1000 U should be administered at the first sign of the
onset of an acute attack. Then, if the patient has not
responded adequately after 60 minutes, a second 1000
U dose can be given.
• Previous, non-placebo-controlled studies demonstrated
the efficacy of doses of 500 to 1000 U/attack. (vote-90%)
C1-INH Method of Administration
• intravenously, by slow (1 mL/min) injection or infusion,
by medical professional in the home or hospital setting,
or for self-administration
• storage: 2 to 25 °C- expiration varies by product
• a single, glass vial of 500 U C1-INH concentrate
lympholized powder should be reconstituted with 5 to 10
mL sterile water for injection – it does not contain any
preservative
• Approved dosage:
Berinert® P: 20 U/kg body weight
Cinryze and Cetor ® : 1000 U/attack
When to treat
Subcutaneous Attacks
Recommended:
• Edema of the extremities: if the attack is severe, edema is
extensive, associated with significant pain, or functional
limitations or compromise of blood circulation the person
should be treated.
• Edema of the neck and face, as this can propagate to the
upper airways
• Edema of the trunk, as this can cause breathing difficulty
• Edema of the genitals, as this can cause micturition problems
May be administered:
• To relieve mild edema of the extremities, when the latter
reduces working capacity or interferes with activities of daily
living
Method of Administration
UPPER AIRWAY EDEMA
• in every case – as early as upon the onset of initial symptoms – in
order to prevent progression to a life-threatening condition
• the patient should be monitored until the resolution of symptoms is
complete, at a facility where preconditions for establishing and
maintaining airway patency are guaranteed
Sore, scratchy, itchy throat
‘Something has stuck in my throat’
Lump sensation in the throat
Feeling of tightness
Dysphagia
Voice changes
High-pitched or hoarse voice
Roughness of voice
Resonant, ‘barky’ cough
Stridor
Dyspnea
Fear of suffocation
Aphonia
Inability to breathe, speak or cough
Anxiety and agitation
INITIAL SYMPTOMS
(edema on face and neck)
Use of C1-INH in HAE
Recommendation:
•
•
•
•
The risk versus benefits of C1INH favors benefits.
Few adverse events have been reported.
All 3 products are equal in efficacy and adverse effect profile.
The risk is minimal, but absolute safety cannot be assumed
since it is a human blood product. (100%)
References for C1-INH
•
•
•
•
•
Waytes Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl
J Med, (1996), 334(25): 1630-4., Kunschak, M; Engl, W; Maritsch, F, Et Al.: A randomized,
controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary
angioedema. Transfusion, (1998), 38(6): 540-9.
Craig TJ, Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute
hereditary angioedema attacks. J Allergy Clin Immunol. 2009 Oct;124(4):
Cicardi, M; Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci, (1982), 284(1): 29.
Agostoni, A; Cicardi, M: Hereditary and acquired C1-inhibitor deficiency: biological and clinical
characteristics in 235 patients. Medicine (Baltimore), (1992), 71(4): 206-15.
Bork, K; Barnstedt, S E: Treatment of 193 Episodes of Laryngeal Edema With C1 Inhibitor
Concentrate in Patients With Hereditary Angioedema. Arch Intern Med, (2001), 161(5): 714-718.
Adverse Effects
Allergic Reaction:
• Risk is negligible and has usually resulted from inappropriate
administration (e.g. too rapid infusion of cold solution), or
poorly mixed product.
• Recommendations: Dosage instructions should be
observed. When a hypersensitivity reaction occurs, patient
data and the batch number of the preparation should be
recorded to document a relationship. (100%)
• No reports of transmission of infections or viral pathogens.
Post-marketing experience with Berinert® P (1985-2003)
demonstrates that neither approved, nor off-label use is
associated with transmission of HBV, HCV or HIV-1/-2. (Jurs)
Recommendations: hepatitis A and B vaccine of HAE
patients expected to receive hp-C1INH(100%)
Adverse Events
• Antibody formation against to C1-INH protein
has been documented, but without loss of function
• Overdose
Thrombotic events have occurred in patients receiving high
doses of Berinert off-label (i.e. to relieve capillary leak
syndrome, as well as before, during, or after heart surgery
during the period of extracorporeal circulation)
• Interaction with other medicinal products and other forms
of interaction
None known.
• Tachyphylaxis
Does not occur (Frequent and repetitive use may increase
attack frequency and severity, but does not compromise the
effectiveness of the drug.)
ADVANTAGES of C1-INH
DRAWBACKS
• A natural product
• Inhibits all cascade systems involved in the
generation of bradykinin
• Its half-life is longer than those of other drugs
• it rapidly reaches peak plasma concentration
• Rapid onset of action
• Lack of rebound angioedema
• Effective in all types of attacks
• Safe for children
• Safe for pregnant women
• Safe for home use
• Minimal allergic reaction
• No tachyphylaxis
• Long (over 30 years) clinical experience
• Presently widely available, compared to other
drugs
• Expensive (but its price is not
higher than those of other drugs
for AT)
• Potential risk for the transmission
of other diseases and infective
agents
• Intravenous administration
• Frequent and repetitive use may
influence attack frequency and
severity
• Off label administration of high
doses is associated with
thrombotic events
C1-INH adverse event references
•
•
•
•
•
Zingale, L C; Pappalardo, E; Zanichelli, A, Et Al.: C1 inhibitor concentrate: efficacy and adverse
reactions. Int. Immunopharmacol., (2002), 318(1385 (abs).
De Serres J, Groner A, Linder J. Safety and efficacy of pasteurized C1-inhibitor concentrate
(Berinert P) in hereditary angioedema: a review. Transfus Apheresis Sci. 2003;29:247–254.
Craig TJ, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz D, Obtułowicz K, Reshef A, Ritchie B,
Moldovan D, Shirov T, Grivcheva-Panovska V, Kiessling PC, Keinecke HO, Bernstein JA. Efficacy
of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary
angioedema attacks. J Allergy Clin Immunol. 2009 Oct;124
Farkas H, Jakab L, Temesszentandrási G, Visy B, Harmat G, Füst G, Széplaki G, Fekete B,
Karádi I, Varga L. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J
Allergy Clin Immunol. 2007 Oct;120(4):941-7.
Bork K, Hardt J. Hereditary angioedema: increased number of attacks after frequent treatments
with C1 inhibitor concentrate. Am J Med. 2009 Aug;122(8):780-3.
Recommendation: For on demand therapy
rcC1-INH appears to be equally effective to
plasma derived C1-INH (no vote)
• The mode of action of recombinant human C1-INH
(rhC1-INH) is identical to that of pdC1INH concentrate.
• Administration of a fixed dose of 2100 units restored
functional C1-INH level within the normal range in
approximately 75% of patients.
• Freeze-dried protein, 99% pure, free of preservatives.
• Human plasma protease C1 inhibitor, glycoform-α, N,Oglycosylated recombinant protein secreted in rabbit milk
• Ruconest/Rhucin 1 unit corresponds to the mean
quantity of C1-INH present in 1 ml fresh, normal plasma
5.1.3 Recommendation: For on demand therapy
C1-INH appears to be equally effective to plasma
derived C1-INH
Differences between rcC1-INH and C1-INH
•
•
•
•
rcC1-INH half-life is 3 hours
Contains traces of rabbit antigen
Contraindicated in rabbit allergy
Unique polysaccharides are added to the protein during
production in the rabbit
• No human blood-borne disease associated with it
• Supply potentially endless
Recommendation: Patients with rabbit
allergy should avoid the use of rcC1INH
(100%)
• Ruconest is indicated for the treatment of all types of
HAE attacks in adults.
• Ruconest should not be used in individuals that may be
hypersensitive (allergic) to conestat-alfa or any of the
other ingredients.
• It must not be used in patients with a known or
suspected allergy to rabbit dander.
• If rabbit allergy in question, immunocap or percutaneous
skin test should be performed before administration
Recommendation: The recommended
dose for the routine treatment of acute
attacks is 50 U/kg body weight (100%)
•
•
•
•
•
Test for rabbit antibodies before using the rcC1-INH
Conestat-alfa contains 2100 units per vial
concentration of 150 units/ml
treatment of acute attacks is 50 U/kg body weight
maximum of 4200 U (2 vials) for patients of or over 84kg
body weight
• second injection may be given if the patient does not
improve satisfactorily after the first dose
Efficacy of Recombinant Human
C1-INH
n=13
n=13
Placebo
Placebo
50 u
100 u
Pharming Group NV. www.pharming.com/index.php?act=medi.
50 u
100u
References for rcC1-INH
• RA Hack CE, Haase G, Pijpstra R. Mechanistic
implications from the treatment of acute angioedema
attacks in Hereditary Angioedema (HAE) with
recombinant human C1 inhibitor (rhC1INH) (poster).
XXIII International Complement Workshop 1-5 Aug 2010,
New York.
• A Relan, G Haase, E Hack, J Nuijens, B Giannetti, R
Pijpstra. Dose justification for recombinant human
C1INH for the treatment of acute angioedema attacks in
patients with hereditary angioedema. Allergy 2010;
65(s92):S1186. AE Davis, 3rd, F Lu, P Mejia. C1
inhibitor, a multi-functional serine protease inhibitor.
Thromb Haemost 2010; 104(5).
ADVANTAGES of rcC1-INH
• Inhibits all cascade systems involved in the
generation of bradykinin
• Rapid onset of action
• Lack of rebound angioedema
• Effective in all types of attacks
• Safe for children
• Safe for pregnant women
• Minimal allergic reaction
• No tachyphylaxis
• No viral transmission
• Unlimited supply
DRAWBACKS
• Expensive (but its price is not
higher than those of other drugs
for AT)
• Potential risk for anaphylaxis
• Intravenous administration
• Potential, but not described, for
neutralizing antibodies and IgE to
polysaccharide added to the
protein
5.1.3 Recommendation: Fresh Frozen
Plasma should only be used for on-demand
therapy when other medications are not
available (100%)
• action- replaces C1-INH
• indication- not indicated unless no other treatments are
available
• method- 2 units for adults, weight based for children
• adverse events – anaphylaxis, worsening of HAE, viral
transmission
• positives and negatives- negatives out-weigh positives
and FFP should be avoided if other therapies are
available
• Always use solvent treated virus inactivated product
when available
5.1.4 Treatment of HAE: Icatibant
• Recommendation: Icatibant is effective for treatment of
HAE attacks at all locations with a dose of 30 mg SQ
(100%)
• Recommendation: Repeat dosing of icatibant is
sometimes necessary and up to10% require a second
dose and 1% a third dose to treat an HAE attack (not
voted)
5.1.4 Treatment of HAE: Icatibant Mechanism
C1q
Complement system
‘Contact’ system
Immune
complex (AgAb)
C1
I
Negatively charged
surface
Factor X11
Factor X11a
NH
C1qrs
C1INH
• Small 10 AA
peptide
• Competitive
inhibitor of
bradykinin B2
receptor
Factor X11f
C4, C2 and
classical
pathway
activation
C1INH
Prekallikrein
Kallikrein
C1INH
High molecular weight kininogen
Bradykinin
Bradykinin-1 receptor binding
KininaseI
Aminopeptidase
Pain
Des Arg Bradykinin
Bradykinin-2 receptor binding
Angiotensin converting
enzyme (ACE)
Vasodilation
Increased vascular
permeability
Inactive
metabolites
5.1.4 Treatment of HAE: Icatibant Indication
• Treatment of acute HAE
• Any site
• Not licensed for adolescents, children or
pregnant/lactating women due to lack of safety data in
these populations
5.1.4 Treatment of HAE: Icatibant – Trial
Outcomes
Cicardi et al NEJM 2010
5.1.4 Treatment of HAE: Icatibant –
Adverse Events
• Local erythema, swelling and pain at injection site
– almost every patient (97%)
• Systemic events comparable with placebo
• Recurrent swellings
– 10% in FAST I&II open label extension
Positives
• Ease of Use
• Rapid to Administer
• Appear to have good safety profile
•Not immunogenic
• Alternative to C1 inhibitor
• Ideal for self administration
• May address problem of delays in
accessing treatment
• Not Intravenous
Negatives
• Short half life-probably not
suitable for prophylaxis
• Need for repeat dosing
• Not currently
recommended for
pregnant women or
children
• No action on other
systems regulated by C1
inhibitor
• Pain and burning at
injection site
Cicardi et al NEJM 2010
5.1.5 Treatment of HAE: Ecallantide
• Recommendation: Ecallantide at 30 mg SQ can be
used to treat HAE attacks at all locations (100%) in
patients aged 16 and above
• Recommendation: Self injection of ecallantide should
be avoided secondary to a small, but real risk of
anaphylaxis (100%)
Ecallantide (Kalbitor)
• Manufactured by DYAX
• Highly selective, potent, reversible inhibitor of plasma
kallekrein
• 60 amino acid peptide derived from a Kunitz domain
backbone with 7 unique amino acids.
• Kallekrein on rate: 2x106M-1s-1
•
off rate 2x10-5s-1
• Can be administered IV or SQ (30 mg SQ)
Effect of Ecallantide on Treatment Outcome
Score (TOS)
US Food and Drug Administration. www.fda.gov/ohrms/dockets/AC/09/briefing/2009-4413b1-03Dyax.pdf.
Effect of Ecallantide on MSCS in HAE Attacks
placebo
P=0.01
DX88
MSCS Score
US Food and Drug Administration. www.fda.gov/ohrms/dockets/AC/09/briefing/2009-4413b1-03Dyax.pdf.
Ecallantide Safety
• Ecallantide is generally well tolerated
• Most events were mild; similar to placebo
• Related adverse events
– Gastrointestinal (diarrhea, abdominal pain, nausea)
– Upper respiratory infections (colds, cough, pharyngitis)
– Headache, fatigue
– Abnormal results in tests of coagulation
• Known effect on activated partial thromboplastin time
• No patients with clinically significant bleeding
– Anaphylactic/anaphylactoid reactions in some patients
• Role of contaminating Pichia proteins
• Some patients develop anti-drug antibodies (IgG and IgE)
• True anaphylactic reaction on rechallenge has occurred
5.1.5 Treatment of HAE: Ecallantide
• Hypersensitivity reactions occur in approximately 3% of
patients that receive ecallantide.
• IgG and IgE antibodies are produced against ecallantide,
but the IgG does not appear to be neutralizing.
• Approved in the USA to be giving at home by a health
care provider equipped and trained to treat anaphylaxis
How Do the Newer Drugs Compare?
Drug
Advantages
Disadvantages
Best use
Status
Plasmaderived
C1-INH
• Extensive clinical
experience
• Corrects the
fundamental defect
• long half-life
• Infectious risk
• Needs IV access
• Limited supply
• Acute attacks
• Short-term
• Long-term
prophylaxis
• Prodromes
• Berinert P:
approved for attacks
• Cinryze: approved
for prophylaxis and
attacks
• Cetor approved for
attacks
Recombinant
C1-INH
• Corrects the
fundamental defect
• No human virus
risk
• Scalable supply
• Needs IV access
• Short half-life
• Potential for
allergic reactions
• Acute attacks
• Short
prophylaxis?
• Prodrome?
• Rhucin: used for
attacks
Ecallantide
• No infectious risk
• Subcutaneous
administration
• Antibodies may
cause allergic
reaction or
neutralization
• Short half-life
• Acute attacks
in office or by
HCP in home
• Kalbitor approved
for administration
by HCP for
attacks
Icatibant
• No infectious
risk
• Stable at room
temperature
• Subcutaneous
• Short half-life
• Local pain or
irritation
• Self treatment
of acute
attacks
• Firazyr: used for
attacks
6.0 Short-term or Pre-Procedural Therapy
• 6.1 Short term prophylaxis should be considered to
cover periods of high risk for attacks when there is
either:
– increased likelihood of attack
– increased consequence of attack
• [100% consensus. Observational/ case series]
6.1 Short-term or pre-procedural therapy:
Indication
• Prior to some surgeries; especially
– dental/ intraoral surgery
– where intubation is required
– major surgery
• To cover periods of high risk for attacks or very important
events
– increased likelihood of attack
– increased consequence of attack
Evidence limited to case reports, small series and
one controlled study (Bork 2011) –
recommendation based on expert opinion.
6.2 Treatments for short term prophylaxis
• For short term prophylaxis, the following may be used
(best option depends on patient and surgical factors and
should be decided by physician)
– C1 inhibitor (plasma-derived)
– Attenuated androgens (danazol, stanozolol, or
oxandrolone)
• [100% agreement. Observational/ case series]
6.3 Short term prophylaxis for lower risk
procedures
• For lower risk procedures, or where safe prophylactic
agents are not available, prophylaxis may be omitted
• the patient should be aware of the risk of and have a
management plan for attacks, which are more likely to
occur after surgery.
– Two doses of C1 inhibitor, ecallantide or icatibant
should be immediately available.
• [100% agreement. Observational/ case series]
6.3 Short-term or pre-procedural therapy:
on demand in place of short term
prophylaxis
•
•
•
•
Increased risk of swelling 4- 30 hours after surgery
Swellings occur despite prophylaxis
Absolute risk is low
Swelling usually near site of trauma
Decision to treat with prophylaxis depends on patient &
surgical factors
A plan to treat attacks is necessary despite prophylaxis
since breakthrough can occur
6. 4 Therapies not to be used for short
term prophylaxis
• The following are not recommended:
– Plasma (FFP/SDP)*. (only if no other therapies are
available)
– Icatibant
– Ecallantide
– Methyl testosterone
• Probably effective.
– Ruconest/ Rhucin
• [100% agreement except for plasma (75% agreement).
Expert opinion]
6.5 Dosing for short term prophylaxis
• Recommended doses/timings are as follows
– C1 inhibitor (plasma-derived) is a preferred drug for
prophylaxis and should be used as close to the event
as possible at a dose of 20 U/kg or a fixed dose of
1000 units
– Danazol 2.5-10mg/kg//day (for adults or children),
maximum 600 mg* a day or Stanozolol 4-6 mg* a day
for 5 days before and 2 days after procedure
• [75% agreement. Expert opinion]
6.6 Short-term or pre-procedural therapy:
Attenuated Androgens - REGIMEN
Document
Recommendation
Alternative
Children
Duration
UK
Consensus
2005
Danazol 200600 mg
Stanozolol 2-6
mg od
Danazol
300mg od
5 days before,
2 days after
procedure
International
(Canadian/
Hungarian)
Consensus
2010
Danazol 2.510mg/kg//day:
max 600 mg /
Stanozolol 4-6
mg od
Farkas 2010
Danazol
600mg
Doses are expert opinion: not evidence-based
5 days before,
2 days after
procedure
4 days before
and after
procedure
6.6 Short-term or pre-procedural therapy:
Attenuated Androgens - TOXICITY
• menstrual disturbance,
• vaginal dryness or irritation
• emotional labiality
[Danazol USP]
• Blood tests or other safety monitoring is not necessary
[Birjmohun R 2008].
6.6 Androgens as short term prophylaxis
Advantages
Disadvantages
Ease of use
Perceived inferior efficacy to C1 inhibitor
Well tolerated in short term
(usually)
Need to start several days prior to procedure
Concern of side effects, but minimal
Have been used in children
without problem
For children dosage based on weight
Have been used in pregnancy (3rd
trimester) without problem
Not suitable for most pregnant women and
during breast feeding
Low cost
Unavailable in some countries
Availability
6.7 C1-inhibitor for short term
prophylaxis
• There are few reports about the efficacy of a preoperative short-term prophylaxis with C1-INH
concentrate (observational data) (6;17-21).
• Intravenous injection one hour before surgery ensures a
sufficiently high plasma level of C1-INH during critical
time during and after surgery.
• On demand therapy for HAE swelling may still be
required.
6.7 Dosing of C1-inhibitor for short term
prophylaxis
• Retrospective study on 171 patients with 705 sessions
with extraction of one tooth or more teeth.[9] Without
prophylaxis 124 HAE attacks followed 577 (21.5%) tooth
extractions. With a pre-operative prophylaxis with 500 U
C1-INH concentrate 12/75 (16%) tooth extractions were
followed by HAE attacks and with a prophylaxis with
1000 U 4/53 (7.5%). The graded dose-response
relationship was significant at p <0.05. All attacks were
either facial or upper airway swellings or a combination
of both.
• From this best dose is probably between 10 and 20 units
per kg
Bork et al 2011
6.7 Safety of C1-inhibitor for short term
prophylaxis
Safety:
• C1-INH concentrates are well tolerated in the treatment
of attacks of HAE(12) and also when used for preoperative prophylaxis (24)
6.7 Advantages and disadvantages for
C1-inhibitor for short term prophylaxis
Advantages
Disadvantages
Some evidence for efficacy
Good theoretical rationale for use
Intravenous
Well tolerated
Lack of availability in some countries
Treatment of choice in children and
pregnancy
Cost
May give additional doses if swellings
occur
6.8 Cost comparison of drugs for short
term prophylaxis
• Drug
Cost in USD
•
•
•
•
•
•
+++++
+++++
+
+ (not recommended)
variable (cost of on demand)
++
Berinert (20 u/kg)
Cinryze (1000 units)
Androgens
Tranexamic acid
No prophylaxis
FFP
6.9 Short term prophylaxis references
•
•
•
•
•
•
•
•
(1)
Degroote DF, Smith GL, Huttula GS. Acute airway obstruction following tooth extraction in
hereditary angioedema. J Oral Maxillofac Surg 1985 January;43(1):52-4.
(2)
Bork K, Barnstedt S-E. Laryngeal edema and death by asphyxiation following
tooth extraction in four patients with hereditary angioedema. Am Dent Assoc 2003;134(8):108894.
(3)
Lodi G, Sardella A, Bez C, Demarosi F, Cicardi M, Carrassi A. Dental
experience and self-perceived dental care needs of patients with angioedema. Spec Care Dentist
2001;21(1):27-31.
(4)
Bork K, Hardt J, Staubach-Renz P, Witzke G. Risk of laryngeal edema and
facial swellings after tooth extraction in patients with hereditary angioedema with and without
prophylaxis with C1 inhibitor concentrate: a retrospective study. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2011 July;112(1):58-64.
(5)
Maeda S, Miyawaki T, Nomura S, Yagi T, Shimada M. Management of oral
surgery in patients with hereditary or acquired angioedemas: review and case report. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2003 November;96(5):540-3.
(6)
Maves KK, Weiler JM. Tonsillectomy in a patient with hereditary angioedema
after prophylaxis with C1 inhibitor concentrate. Ann Allergy 1994 November;73(5):435-8.
(7)
Malmstrom HS, Hock JM, Sanford C. Dental management of patients with
hereditary angioedema: report of case. J Am Dent Assoc 1985 December;111(6):957-8.
(8)
Bouillet L, Longhurst H, Boccon-Gibod I, Bork K, Bucher C, Bygum A et al.
Disease expression in women with hereditary angioedema. American Journal of Obsterics and
Gynaecology 2008;199(5):484.
Short term prophylaxis references
•
•
•
•
•
•
•
•
(9)
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma
Clin Immunol 2010 July 28;6(1):18.
(10)
Farkas H, Gyeney L, Gidofalvy E, Fust G, Varga L. The efficacy of short-term
danazol prophylaxis in hereditary angioedema patients undergoing maxillofacial and dental
procedures. Journal of Oral and Maxillofacial Surgery 57[4], 404-408. 1999.
Ref Type: Abstract
(11)
Atkinson JC, Frank MM. Dental management of hereditary angioedema.
Journal of Oral Pathology and Medicine 20, 139-142. 1991.
Ref Type: Abstract
(12)
Marques L, Domingo D, Maravall FJ, Clotet J. Short-term prophylactic
treatment of hereditary angioedema with icatibant. Allergy 2010 January;65(1):137-8.
(13)
Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B et al. 2010
International consensus algorithm for the diagnosis, therapy and management of hereditary
angioedema. Allergy Asthma Clin Immunol 2010 July 28;6(1):24.
(14)
Sheffer AL, Fearon DT, Austen KF. Methyltestosterone therapy in hereditary
angioedema. Ann Intern Med 1977 March;86(3):306-8.
(15)
Longhurst HJ, Farkas H, Craig T, ygoren-Pursun E, Bethune C, Bjorkander J et
al. HAE international home therapy consensus document. Allergy Asthma Clin Immunol 2010 July
28;6(1):22.
(16)
Birjmohun RS, Kees HG, Stroes ES, Hofstra JJ, linga-Thie GM, Meijers JC et
al. Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and
progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary
angioedema. Clin Ther 2008 December;30(12):2314-23.
Short term prophylaxis references
•
•
•
•
•
•
(17) Langton D, Weiner J, Fary W. C1-esterase inhibitor concentrate prevents upper airway
obstruction in hereditary angio-oedema. Med J Aust 1994 March 21;160(6):383-4.
(18)
Lehmann A, Lang J, Boldt J, Saggau W. Successful off-pump coronary artery
bypass graft surgery in a patient with hereditary angioedema. J Cardiothorac Vasc Anesth 2002
August;16(4):473-6.
(19)
Leimgruber A, Jaques WA, Spaeth PJ. Hereditary angioedema: uncomplicated
maxillofacial surgery using short-term C1 inhibitor replacement therapy. Int Arch Allergy Immunol
1993;101(1):107-12.
(20)
Mohr M, Pollok-Kopp B, Gotze O, Burchardi H. [The use of a C1-inhibior
concentrate for short-term preoperative prophylaxis in two patients with hereditary angioedema].
Anaesthesist 1996 July;45(7):626-30.
(21)
Pasto CL, Bordas OJ, Mercadal OG, Perez dl, V, Jodar MR. [Profhylaxis and
treatment of hereditary and acquired angioedema at HUB; use of the C1-esterase inhibitor]. Farm
Hosp 2003 November;27(6):346-52.
(22)
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C et al. C1
inhibitor deficiency: consensus document. Clin Exp Immunol 2005 March;139(3):379-94.
7.0 Chronic Prophylaxis
• Long-term (chronic) prophylaxis refers to the use of
regular medication to prevent episodes of angioedema in
those with confirmed HAE
7.1 Chronic Prophylaxis: Indication
Uniform criteria not established-consider if:
• severe events occur more than once/month
• patient is disabled for more than 3-5 days per month on
average
• patient has frequent and severe attacks
• Patient can not improve their quality of life enough with on
demand therapy
7.1
• Recommendation: The single best recommendation
is chronic prophylaxis is indicated when on demand
therapy fails to significantly improve the quality of life of a
patient with HAE (100%)
7.2 Chronic Prophylaxis: Antifibrinolytics
• Recommendation: Anti-fibrinolytics have little
benefit, have adverse events and are not indicated for
use for prophylaxis of HAE (65%)
• Recommendation: The minority recommended use
in pre-puberty children for HAE prophylaxis (35%)
• Recommendation: Avoid use of anti-fibrinolytics
during pregnancy and lactation (80%)
• Recommendation: The minority recommended use
during pregnancy and lactation (35%)
7.2 Chronic Prophylaxis: Antifibrinolytics
• Anti-fibrinolytics may have a place in the management of
pre-pubertal children when:
- attenuated androgens are relatively contraindicated
- C1-INH is not available and
- on demand therapy is not effective in controlling the disease.
7.2 Chronic Prophylaxis: Antifibrinolytics, Tranexamic acid and
Aminocaproic acid
• Mechanism of action is unclear
• Tranexamic acid has no effect on C1 INH levels
• The dose of Tranexamic acid is 30-50mg/kg daily divided
into 2 or 3 doses (this can result in up to 10 large tablets
per day)
7.2 Chronic Prophylaxis: Antifibrinolytics
Side effects include:
• GI upsets
• myalgia and CK elevation
• theoretical risk of thrombosis
7.2 Chronic Prophylaxis: Antifibrinolytics
Contraindications/precautions
• presence of thrombophilia or increased thrombotic risk
• There is little experience with tranexamic acid in
pregnancy
• Though not contraindicated during breastfeeding there is
little experience with the use of antifibrinolytics during
lactation.
Anti-fibrinolytic use for chronic
prophylaxis
Advantages
Disadvantages
• Inexpensive
• Availability
• Adverse effects
• Few data to support
effectiveness
• Multiple daily dosing
• Unsure of status during
pregnancy, lactation and
pre-puberty
7.3 Chronic Prophylaxis: Androgens
• Recommendation: Androgens are effective to
control the symptoms of HAE, but secondary to the
potential adverse effects the dose should not exceed
Danazol 200 mg a day or an equivalent dose of an
alternate androgen and the dose should be reduced to
the least effective dose (100%)
• Recommendation: Androgens should be avoided
during pregnancy, lactation and in most children before
puberty (100%)
7.3 Use of androgens in long term
prophylaxis
• Recommendation: The aim of treatment is to
minimize the frequency and severity of angioedema
episodes and not necessarily to normalize the
biochemical parameters (100%)
7.3 Chronic Prophylaxis: Androgensfunction
• Androgens increase hepatic synthesis of the C1 INH
protein from the remaining normal C1 gene
• Response is dose-related but the dose required to
suppress angioedema and/or normalize C4 and/or C1
INH levels varies widely between individuals
• Therapy should be titrated by clinical improvement
7.3 Chronic Prophylaxis: Androgens
Androgens e.g. danazol are effective:
• >90% reduction in episode frequency in >70% of
patients
• 95% reduction in the frequency of laryngeal episodes
7.3.2 Use of androgens in long term
prophylaxis in children
• Not recommended for long term prophylaxis in children
but its long term use in children has been reported and in
some cases the benefits outweigh the risks (minority
vote)
7.3.2 Chronic Prophylaxis: Androgens in
Children
• Complicated by potential adverse effects
- risk of androgenization
- premature puberty
- premature closure of epiphyseal plates with limited
growth
- liver disorders
- behavioral problems
• There are few studies of the safety of long term danazol
treatment in children.
7.3.2 Chronic Prophylaxis: Androgens in
Children
• Other attenuated androgens such as stanozolol and
oxandrolone have been used for HAE prophylaxis
• Stanozolol was reported to be better tolerated than
danazol in a retrospective survey but is no longer
available
• Oxandrolone has a lower virilization potential and may be
preferable in children, but this is based only on expert
opinion
7.3.3 Chronic Prophylaxis: Androgens Danazol
In female patients Danazol:
• may inhibit ovulation but cannot be relied upon to prevent
pregnancy and patients should be counseled to use nonestrogen contraception
• not be taken during pregnancy because of the risk of
virilization of the fetus
• safety during breastfeeding has not been established and
they should be avoided
7.3.4 Chronic Prophylaxis: Androgens Danazol
Dosing
• Recommended dosage regimens vary
• commence with a moderate dose (e.g. 100-200mg daily)
• increase or decrease on a monthly basis depending on the
frequency of episodes until satisfactory control is reached
(Budapest protocol)
• maintenance dose required to suppress or substantially
reduce angioedema varies between 100mg qod and 800mg
daily (best 200 mg or less)
• The aim of treatment is to minimize the frequency and
severity of angioedema episodes and not necessarily to
normalize the biochemical parameters
Danazol: Efficacy in Long-Term Prophylaxis
Freedom From HAE Attacks
vs Placebo
88%
98%
100
Attack-Free Courses
Cumulative Freedom From HAE
Attacks at Varying Dosages
75
95%
56%
50
25
0
11%
>1%
Placebo
Danazol
Frank M. Immunol Allergy Clin N Am. 2006;26:653-668.
Gelfand JA, et al. N Engl J Med. 1976;295:1444-1448.
200
300
400
600
Danazol Dosage (mg/d)
7.3.5 Chronic Prophylaxis: Androgens –
Potential Side Effects
• dose related but highly variable
• some patients unable to tolerate even low doses whereas
others including females tolerate surprisingly high doses
for many years without apparent problems
• In a recent survey 79% of patients experienced adverse
effects from danazol but only 25% discontinued
treatment because of these.
7.3.5 Chronic Prophylaxis: Androgens –
Potential Side Effects
General
•
•
•
•
•
•
headaches
nausea
fatigue
constipation
myalgias or muscle cramps
weight gain
7.3.5 Long-Term Danazol Therapy
Increases Atherogenic Indices in
Patients with HAE
A. LDL/HDL Ratio
P<0.0001
8.0
P=0.0013
P=0.8523
6.0
LDL/HDL,
Ratio
4.0
2.0
0.0
Patients Taking
Danazol
Patients Not Taking
Danazol
Healthy
Controls
Szeplaki G et al. J Allergy Clin Immunol. 2005;115:864-869.
7.3.5 Risk of Liver Toxicity Associated
With Long-Term Danazol Therapy
Danazol-associated hepatocellular adenoma in a 69-year-old
female patient on long-term HAE prophylaxis (200 mg/d for 20
years)
Bork K et al. Lancet. 1999;353:1006-1067.
7.3.5 Chronic Prophylaxis: Androgens –
Potential Side Effects
Virilization in females
•
•
•
•
•
•
•
hirsutism
acne
voice changes
decreased breast size
altered libido
menstrual irregularities
Clitoromegaly
• Increase muscle mass
7.3.5 Chronic Prophylaxis: Androgens –
Potential Side Effects
Hepatic
• abnormal liver enzymes, hepatic necrosis, cholestasis,
adenoma, carcinoma
Metabolic
• hypertension, dyslipidemia (but not
hypercholesterolemia), atherogenesis, polycythemia,
hyperglycemia
7.3.6 Monitoring for adverse events when
using androgens for Chronic Prophylaxis
(100%)
Before use and every 6 months:
• Fasting lipid profile
• Liver function studies and biochemistry
• Complete blood cell count
• Urinalysis
• Alfa-fetal protein
Before use and every 12 months:
• abdominal liver ultrasonography
7.4 Use of C1-INH for chronic prophylaxis
• Recommendation: C1-INH that is human plasma
derived can be used at 1000 units IV twice a week to
suppress HAE attacks. Doses as low as 500 units may
be effective in some and others may require greater than
1000 units. (100%- rating A)
• Recommendation: Human derived C1-INH products
should be equally effective, but the shorter half-life of
recombinant C1-INH may limit its use for chronic
prophylaxis (90%)
7.4 C1-INH for chronic prophylaxis
• Recommendation: Dosing may need to be adjusted
since even at 1000 units twice a week acute attacks
occur in the majority of patients. (90%)
• Recommendation: An HAE attack action plan is
necessary despite the use of chronic prophylaxis since
complete suppression of attacks with chronic C1-INH is
unlikely. (100%- A rating)
7.4 C1-INH chronic prophylaxis
• Recommendation: during lactation, pregnancy and
early childhood if on demand therapy is not effective to
control the disease, and chronic prophylaxis is
necessary, C1-INH is the preferred therapy. (100%)
7.4.1 Indications for Chronic Prophylaxis
with C-1-INH
• Angioedema attacks have been frequent and/or
dangerous despite on demand therapy or quality of life is
still significantly compromised despite on demand
therapy
And
• Prophylaxis with attenuated androgens is unsuccessful,
contraindicated or not tolerated
7.4.2 Efficacy of Prophylactic Nanofiltered
Plasma C1-INH Concentrate
Zuwar NEJM 2009
• Reductions are based on results
from a randomized, double-blind,
placebo-controlled, multicenter,
crossover trial designed to establish
the safety and efficacy of routine
prophylaxis with CINRYZE™
Normalized Number of HAE Attacks
Reduction in Number of Attacks
Placebo
Zuwar NEJM 2009
CINRYZE™
Dosing C1-INH for chronic prophylaxis
• The approved dose is 1000 units twice a week.
• At this dose breakthrough attacks are not infrequent
• Higher doses and more frequent dosing may be
necessary to improve a patients quality of liufe.
• Optimal dosing of C1-INH for chronic use has not yet be
determined
7.4.2 Chronic Prophylaxis: C-1-INH
• The mechanism of action, effects/side effects and
monitoring have been discussed under previous
sections. Please see section 5.1.
• All marketed C1-inhibitor is nano-filtered and can be
used interchangeably
7.4.3 Use of C1-INH for chronic
prophylaxis
• Recommendation: Before starting C1-INH hepatitis
B, C, HIV and parvovirus titers should be obtained and
monitored on a yearly basis (100%)
• Recommendation: Because of the risk of thrombosis
with central lines indwelling central lines and catheters
should be avoided when administered C1-INH for
chronic prophylaxis (100%)
7.4.3 Use of C1-INH for chronic
prophylaxis
• Because C1-INH is human plasma-derived Hepatitis B
and A vaccine should be administered when starting C1INH. (no vote)
7.4.3 Use of C1-INH for chronic
prophylaxis
Benefits
• Effective
• Few adverse events
• Long safety record from
over 3 decades use in the
EU
Disadvantages
• Dose ranging studies are
lacking
• Human plasma derived
• Breakthrough attacks
occur despite 1000 units
twice a week
• Intravenous dosing
necessary
• Very expensive
7.4.4 Chronic Prophylaxis: Summary
7.4.5 Summary of therapies for chronic
prophylaxis
Drug
Recommendation
Efficacy
Cost
Antifibrinolytics
limited indication
poor
+
Androgens
Recommended with Very effective
precautions
Contraindicated in
certain populations
+
C1-inhibitor
Recommended
+++++
Effective
References for chronic prophylaxis
•
•
•
•
•
•
•
•
(1)
Degroote DF, Smith GL, Huttula GS. Acute airway obstruction following tooth
extraction in hereditary angioedema. J Oral Maxillofac Surg 1985 January;43(1):52-4.
(2)
Bork K, Barnstedt S-E. Laryngeal edema and death by asphyxiation following
tooth extraction in four patients with hereditary angioedema. Am Dent Assoc 2003;134(8):108894.
(3)
Lodi G, Sardella A, Bez C, Demarosi F, Cicardi M, Carrassi A. Dental
experience and self-perceived dental care needs of patients with angioedema. Spec Care Dentist
2001;21(1):27-31.
(4)
Bork K, Hardt J, Staubach-Renz P, Witzke G. Risk of laryngeal edema and
facial swellings after tooth extraction in patients with hereditary angioedema with and without
prophylaxis with C1 inhibitor concentrate: a retrospective study. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2011 July;112(1):58-64.
(5)
Maeda S, Miyawaki T, Nomura S, Yagi T, Shimada M. Management of oral
surgery in patients with hereditary or acquired angioedemas: review and case report. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2003 November;96(5):540-3.
(6)
Maves KK, Weiler JM. Tonsillectomy in a patient with hereditary angioedema
after prophylaxis with C1 inhibitor concentrate. Ann Allergy 1994 November;73(5):435-8.
(7)
Malmstrom HS, Hock JM, Sanford C. Dental management of patients with
hereditary angioedema: report of case. J Am Dent Assoc 1985 December;111(6):957-8.
(8)
Bouillet L, Longhurst H, Boccon-Gibod I, Bork K, Bucher C, Bygum A et al.
Disease expression in women with hereditary angioedema. American Journal of Obsterics and
Gynaecology 2008;199(5):484.
References for chronic prophylaxis
•
•
•
•
•
•
•
•
(9)
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency.
Allergy Asthma Clin Immunol 2010 July 28;6(1):18.
(10)
Farkas H, Gyeney L, Gidofalvy E, Fust G, Varga L. The efficacy of short-term
danazol prophylaxis in hereditary angioedema patients undergoing maxillofacial and dental
procedures. Journal of Oral and Maxillofacial Surgery 57[4], 404-408. 1999.
Ref Type: Abstract
(11)
Atkinson JC, Frank MM. Dental management of hereditary angioedema.
Journal of Oral Pathology and Medicine 20, 139-142. 1991.
Ref Type: Abstract
(12)
Marques L, Domingo D, Maravall FJ, Clotet J. Short-term prophylactic
treatment of hereditary angioedema with icatibant. Allergy 2010 January;65(1):137-8.
(13)
Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B et al. 2010
International consensus algorithm for the diagnosis, therapy and management of hereditary
angioedema. Allergy Asthma Clin Immunol 2010 July 28;6(1):24.
(14)
Sheffer AL, Fearon DT, Austen KF. Methyltestosterone therapy in hereditary
angioedema. Ann Intern Med 1977 March;86(3):306-8.
(15)
Longhurst HJ, Farkas H, Craig T, ygoren-Pursun E, Bethune C, Bjorkander J et
al. HAE international home therapy consensus document. Allergy Asthma Clin Immunol 2010 July
28;6(1):22.
(16)
Birjmohun RS, Kees HG, Stroes ES, Hofstra JJ, linga-Thie GM, Meijers JC et
al. Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and
progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary
angioedema. Clin Ther 2008 December;30(12):2314-23.
References for chronic prophylaxis
•
•
•
•
•
•
(17) Langton D, Weiner J, Fary W. C1-esterase inhibitor concentrate prevents upper airway
obstruction in hereditary angio-oedema. Med J Aust 1994 March 21;160(6):383-4.
(18)
Lehmann A, Lang J, Boldt J, Saggau W. Successful off-pump coronary artery
bypass graft surgery in a patient with hereditary angioedema. J Cardiothorac Vasc Anesth 2002
August;16(4):473-6.
(19)
Leimgruber A, Jaques WA, Spaeth PJ. Hereditary angioedema: uncomplicated
maxillofacial surgery using short-term C1 inhibitor replacement therapy. Int Arch Allergy Immunol
1993;101(1):107-12.
(20)
Mohr M, Pollok-Kopp B, Gotze O, Burchardi H. [The use of a C1-inhibior
concentrate for short-term preoperative prophylaxis in two patients with hereditary angioedema].
Anaesthesist 1996 July;45(7):626-30.
(21)
Pasto CL, Bordas OJ, Mercadal OG, Perez dl, V, Jodar MR. [Profhylaxis and
treatment of hereditary and acquired angioedema at HUB; use of the C1-esterase inhibitor]. Farm
Hosp 2003 November;27(6):346-52.
(22)
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C et al. C1
inhibitor deficiency: consensus document. Clin Exp Immunol 2005 March;139(3):379-94.
8.0 Preventive and long term care of the
patient with HAE
• Recommendation: All patients with HAE should
have an action plan and product available to treat an
attack of HAE. (100%)
8.0 Preventive and long term care of the
patient with HAE
• Recommendation: All patients with HAE should
have at least an annual assessment by an HAE
specialist. (100%)
8.0 Preventive and long term care of the
patient with HAE
• Recommendations: During pregnancy and lactation
C1INH is considered the preferred therapy. During the
third term of pregnancy androgens can be used for short
term prophylaxis, but is a second line therapy. (100%)
• Androgens, antifibrinolytics, ecallantide and icatibant
may be safe during lactation and pregnancy, but use
should be discouraged until more safety data are
available. (no vote)
8.0 Preventive and long term care of the
patient with HAE
• All HAE patients have a potential for receiving human
blood products. Because of this all HAE patients should
be screened as early as possible for Hepatitis B and C
and HIV.
• In addition, vaccination for Hepatitis B and possibly A
should be stressed.
• Annual assessment for infections with hepatitis and HIV
are suggested. (100%)
8.0 Follow-up appointments
• Newly diagnosed patients and those on long term
prophylaxis should be seen at 3 month initially and then
twice to once a year.
• Evaluation at visits should include recording of type and
frequency and severity of symptoms, frequency of use
and effectiveness of treatments. A comprehensive
history, physical examination and appropriate laboratory
evaluation should be conducted.
• Action plan should be updated and reviewed
8.1 Triggers and trigger avoidance
• Triggers of attacks include medication (estrogen
contraceptives, estrogen-containing hormone
replacement therapy, ACE-Inhibitors), dental work /
minor surgery / local anesthesia, stress, infections,
menstrual cycle, alcohol.
• EVIDENCE LEVELS: C / case series, extrapolation from
retrospective studies
• Trigger avoidance may reduce number and/or severity of
attacks.
• EVIDENCE LEVELS: D / expert opinion
8.2 Drugs to avoid in HAE
• Estrogen birth control
• Estrogen hormone replacement
• ACE-inhibitors for blood pressure, CHF and other
diseases
• Agreement: 100%
8.3 Vaccines
• Recommendation: All patients with HAE should
receive Hepatitis B vaccine and Hepatitis A vaccine
since the chances of receiving blood products is very
high
• (100% agreement) LEVEL OF EVIDENCE: D / expert
opinion
• All other vaccines for the general public should be given
as indicated
• Annual influenza vaccine is indicated since URI can
trigger upper airway swelling
8.4 When using C1-INH
• Recommendation: Because of the risk of thrombosis
with central lines indwelling central lines and catheters
should be avoided when administered C1-INH for
chronic prophylaxis (100%)
8.5 Monitoring while receiving
treatment with Androgens
Before
Follow up
Liver Functional Tests
Every 6 months
Lipid profile
Every 6 months
Urine analysis
Every 6 months
Abdominal ultrasound
Once/year
Alpha fetoprotein
Every 6 months
CBC
Every 6 months
8.6 Care while on treatment with
Plasmin Inhibitors (anti-fibrinolytics)
Before
Follow up
Liver Functional Tests
Every 6 months
Renal function
Every 6 months
CPK
Every 6 months
Eye pressure
Annual
Tests for thrombophilia
Before starting
8.8 summary of screening tests for drug safety
Tests
Androgens
Plasmin
inhibitors
Liver Functional Tests
Q 6 mth
Q 6 mth
Lipid profile
Q 6 mth
Renal function
Q 6 mth
Urine analysis
Q 6 mth
Abdominal ultrasound
Q 12 mth
Alpha fetoprotein
Q 6 mth
Q 6 mth
CPK
Q 6 mth
Eye pressure
Q 6 mth
Thrombophilia tests?
At start of
therapy
Serology for HIV,
hepatitis B, C, E,
Parvovirus
Plasma
derived
C1INH/
Plasma
Start of therapy
and every year
8.7 Family Screening
• Screening of all siblings, parents, and children in
immediate and extended family with a C4 is
recommended. If suspicion is high or C4 screening is
abnormal then C1INH protein and function should also
be done. If C4 is normal during asymptomatic period,
repeating when in an attack may be helpful because of
the increase sensitivity.
• EVIDENCE LEVELS: D / expert opinion
• 100%
8.9 References for preventive therapy
•
•
•
•
•
•
•
•
•
Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its
management. Ann Intern Med 1976;84:580-93.
Bowen T, Cicardi M, Farkas H. 2010 International consensus algorithm for the diagnosis, therapy
and management of hereditary angioedema Allergy, Asthma & Clinical Immunology 2010, 6:24.
Gargnano Consensus (? will this be available for reference by publication date?
Bork K, Staubach P, Eckardt AJ, Hardt J. Symptoms, course, and complications of abdominal
attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol. 2006;619–
27.
Bork K, Ressel N. Sudden upper airway obstruction in patients with hereditary angioedema.
Transfus Apheresis Sci. 2003;29:235–238.
Bowen T, Cicardi M, Farkas H. 2010 International consensus algorithm for the diagnosis, therapy
and management of hereditary angioedema Allergy, Asthma & Clinical Immunology 2010, 6:24.
Waytes AT, Rosen FS, Frank MM: Treatment of hereditary angioedema with a vapor-heated C1
inhibitor concentrate. N Engl J Med 1996, 334:1630-1634.
Kunschak M, Engl W, Maritsch F, Rosen FS, Eder G, Zerlauth G, Schwarz HP: A randomized,
controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary
angioedema. Transfusion 1998, 38:540-9.
8.9 References for preventive therapy
•
•
•
•
•
•
•
Craig TJ, Levy RJ, Wasserman RL: Efficacy of human C1 esterase inhibitor concentrate
compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009,
124:801-8.
Zuraw B, Cicardi M, Levy RJ: Recombinant human C1-inhibitor for the treatment of acute
angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol. 2010
Oct;126(4):821-827.e14.
Cicardi M, LevyR, McNeil D: Ecallantide for the Treatment of Acute Attacks in Hereditary
Angioedema. N Engl J Med 2010 N Engl J Med 2010;363:523-31.
Sheffer AL, Campion M, Levy RJ: Ecallantide (DX-88) for acute hereditary angioedema attacks:
integrated analysis of 2 double-blind, phase 3 studies. J Allergy Clin Immunol. 2011
Jul;128(1):153-159.e4. Epub 2011 Apr 9.
Cicardi M, Banerji A, Bracho F. Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary
Angioedema. N Engl J Med 2010 363;6.
Lumry WR, Li H, LevyRJ: Randomized placebo-controlled trial of the bradykinin B2 receptor
antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial,
Ann Allergy Clin Immunology, 2011 In Press.
Aygoeren-Puersuen E, Martinez-Saguer I, Rusicke E, Kreuz W: On demand treatment and home
therapy of hereditary angioedema in Germany - the Frankfurt experience. Allergy Asthma Clin
Immunol 2010, 6:21.
8.9 References for preventive therapy
•
•
•
•
•
•
•
•
Bygum A, Andersen KE, Mikkelsen CS: Self-administration of intravenous C1-inhibitor therapy for
hereditary angioedema and associated quality of life benefits. Eur J Dermatol 2009, 19:147-51.
Levi M, Choi G, Picavet C, Hack E: Self-administration of C1-inhibitor concentrate in patients with
hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol
2006, 117:904-8.
Longhurst HJ, Farkas H, Craig T. HAE international home therapy consensus document. Allergy
Asthma Clin Immunol 2010, 6:22.
Bouillet L, Hereditary angioedema in women. Allergy, Asthma and Clin. Immun. 2010;6(17).
Bork K, Meng G, Staubach P, Hardt J: Hereditary angioedema: new findings concerning
symptoms, affected organs, and course. Am J Med 2006, 119:267-74.
Cicardi M, Bergamaschini L, Cugno M, et al. Pathogenetic and clinical aspects of C1 inhibitor
deficiency. Immunobiology. 1998;199:366–376., Frank MM: Hereditary angioedema. J Allergy Clin
Immunol 2008, 121: S398-401.
Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, Hurewitz D, Jacobs J, Kalfus I:
When is prophylaxis for hereditary angioedema necessary? Ann Allergy Asthma Immunol 2009,
102:366-372.
Szema AM, Paz G, Merriam L: Modern preoperative and intraoperative management of hereditary
angioedema. Allergy Asthma Proc 2009, 30:338-42.
8.9 References for preventive therapy
•
•
•
•
•
•
•
•
Wall RT, Frank MM, Hahn M: A review of 25 patients with hereditary angioedema requiring
surgery (see comments). Anesthesiology 1989, 71:309-11.
Atkinson JC, Frank MM: Oral manifestations and dental management of patients with hereditary
angioedema. J Oral Pathology & Medicine 1991, 20:139-142.
26. Farkas H: The efficacy of short-term danazol prophylaxis in hereditary angioedema patients
undergoing maxillofacial and dental procedures. J Oral Maxillofac Surg. 1999 Apr;57(4):404-8.
Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of
hereditary angioedema. N Engl J Med. 2010a;363:513-522.
DeSerres J, Groner A, Lindner J. Safety and efficacy of pasteurized C1 inhibitor concentrate
(Berinert P) in hereditary angioedema: a review. Transfus Apheresis Sci. 2003;29:247–25.
Bowen T, Cicardi M, Bork K: Hereditary angioedema: a current state-of-the-art review, VII:
Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and
Management of Hereditary Angioedema. Ann Allergy Asthma Immunol 2008, 100(Suppl 2):S3040.
Lumry WR, Castaldo AJ, Vernon MK, et al. The humanistic burden of hereditary angioedema:
impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc.
2010;31:407-414.
31. Bork K, Bygum A, Hardt J: Benefits and risks of danazol in hereditary
angioedema: a
long-term survey of 118 patients. Ann Allergy Asthma Immunol
2008, 100:153-61.
8.9 References for preventive therapy
•
•
•
•
•
•
•
•
32. Chen JG, Parkin DM, Chen QG, Lu JH, Shen QJ, Zhang BC, Zhu YR:
Screening for liver cancer: results of a randomized controlled trial in
Qidong, China. J Med Screen 2003, 10:204-209. 58.
33. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial of screening
for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004, 130:417-422.
34. Lunn M, Santos C, Craig TJ. Is there a need for clinical guidelines in the United
States for
the diagnosis of hereditary angioedema and the screening of family
members of affected
patients? Ann Allergy Asthma Immunol. 2010 Mar;104(3):
211-14.
35. Zuraw BL. Hereditary Angioedema. NEJM. 2008;359(10):1029.
36. Riedl M, Gower RG, Chrvala CA. Current medical management of
hereditary
angioedema: results from a large survey of US physicians. Ann Allergy
Asthma
Immunol. 2011;106:316-322.
9.1 Why Children with HAE are Unique
Family History

Positive family history (in 75-85% of cases) may assist early diagnosis,
before the onset of characteristic symptoms.
Complement Testing



Complement levels are influenced by age, birth weight, and gestational age.
Antigenic and functional C1 inhibitor levels correspond to 70% and 61.8% of
adult values initially and increase to the normal level by the age of 6 months
to one year.
Initial screening should be done after one year.
Genetic Testing
•
•
•
Not routinely used in clinical practice (uncertain cases, prenatal
diagnostics).
It is expensive and available in a few health care centers only.
No mutation of the C1-INH gene can be detected in 8 to 10 per cent of
cases.
In children, the possibility of C1 INH deficiency should never be ruled out
until the final diagnosis is established.
9.1 Why Children with HAE are Unique
Initial Symptoms
• usually occur between 5 and 11 years with 50% have symptoms during
•
•
•
childhood
extremely uncommon during infancy
the frequency and severity of symptoms may increase during adolescence
especially around puberty
the earlier the onset of symptoms, the more likely the HAE will be severe
during life
Subcutaneous Edema
• the most common and the earliest symptom
• erythema marginatum is more frequent and is often mistaken for
urticaria
Upper Airway Edema
• Asphyxia may ensue more rapidly in children, because of smaller airway
diameter. The earliest occurrence was described in a 3-years-old infant. It
rarely is an initial manifestation.
9.1 Why Children with HAE are Unique
Gastrointestinal Edema


It can mimic an ‘acute abdominal catastrophe’.
Estimating the prevalence of GI edema in the pediatric population is difficult,
because ‘belly ache’ is a common symptom – especially in infants.
Differential Diagnostic Candidates



Acute appendicitis, mesenteric lymphadenitis, intestinal invagination,
strangulation ileus (intestinal torsion), perforated Meckel’s diverticle, ovarian
torsion, etc.
Abdominal ultrasound is a sensitive, rapid, and non-invasive differential
diagnostic method, especially in children.
CT has risk of irradiation, but may be necessary to exclude acute surgical
abdomen
9.1 Why Children with HAE are Unique

Teachers and health care personnel responsible for the child
at school should be informed in writing of the diagnosis.

Special medication and an action plan for emergency
treatment should be made available at home, at school, and
field trips.

A proportion of attacks can be prevented through appropriate
counseling and lifestyle modifications aimed at eliminating
triggering factors.

Stigmatization by peers is more frequent in children, than in
adults.
9.1 Why Children with HAE are Unique
Identification and – when possible – elimination of the
following:
Triggering Factors
•
•
•
•
•
•
The incidence of these factors differs slightly in pediatric and
in adult patients.
Infection and mechanical trauma are more common during
childhood. Compulsory and recommended vaccinations for
children are safe and the prevention of infections may reduce
the frequency of edematous attacks.
Treatment with ACEI is less often necessary during childhood;
however, should be avoided.
Early initiation of oral contraceptive use is increasingly
common. but should be avoided in HAE.
The use of estrogens to treat acne is contraindicated in HAE
Good dental hygiene is indicated to prevent unnecessary
dental procdures
9.1 Treatment of HAE attacks in Children
Drugs and the indications for their use in children.
• The majority of children do not require long-term prophylaxis (LTP).
• Anti-fibrinolytics have minimal benefit
• Androgens can cause significant adverse events in children and
should be used only in severe cases uncontrolled by other therapies
because of adverse events that include:
–
–
–
–
–
–
liver damage
proatherogenic
Masculinization
hypogonadism and menstruation irregularities
effects on psychic functions and behavior
reduction in ultimate body height may occur owing to the premature closure
of epiphyseal plates
9.1 Treatment of HAE attacks in Children
Drugs and the indications for their use are the same as in adults.
Short-Term Prophylaxis (STP)
•
•
•
Short term use of androgens is tolerated well.
Preferred pre-procedural treatment is with C1-inhibitor.
FFP can be utilized, but only in cases C1-inhibitor is not available.
Chronic Prophylaxis
• In severe cases uncontrolled by on “demand therapy of acute attacks”
chronic prophylaxis may be necessary
• C1-inhibitor prophylaxis is preferred in children
• Androgens can be used, but toxicity often exceeds benefits and should
be reserved only in severe uncontrolled cases where other therapies are
not available.
• Anti-fibrinolytics have minimal efficacy, but may be tried in children
9.1 Treatment of HAE attacks in Children
•
C1-INH concentrate is effective and safe.
•
Probably the best dose should be based on 20 units/kg since
other weight based dosing is not available
•
No significant experience is available with the use of
ecallantide, icatibant or rcC1-INH in the pediatric population
and these drugs should be avoided until more data are
available or if benefit outweighs risk.
9.1 Children should be encouraged to
have home and self therapy
• It is the treatment with the quickest possible action.
• It eliminates delays in intervening, as well as the removal of
the child from the comforting home environment.
• Medication is best administered at home to reduce
absenteeism from school
• Models from the hemophiliac communities suggest self
administration of therapy by children at 8 years and above is
effective and safe after appropriate training
9.2 Children with recurrent swelling or
abdominal pain
• Recommendation: Patients with isolated
angioedema, especially if associated with abdominal
pain, should be tested to determine if HAE accounts for
their symptoms. If confirmed the family should also be
tested. (100%)
9.3 Screening for HAE in children
• Recommendation: Screening children for HAE
should be deferred until after the age of 12 months.
(100%)
9.4 Prenatal Diagnosis
• Prenatal diagnosis is not recommended because: (75%
agreement)
– Prediction of severity of disease based on genotyping
is not possible.
– Many new interventions will allow a much better
quality of life
– Genetic testing is not absolute
– Appropriate reference levels of C4 for fetuses is not
known
9.5.1 Treating children
• Recommendation:
• For children therapy should be based upon weight in
HAE
• Pharmaceutical companies developing drugs to treat
HAE should be encouraged to develop trials for pediatric
dosing
• At this time, the preferred therapy for children is C1INH.
In adolescents androgens can be used, but are second
or third line therapeutic options. (100%- expert opinion)
9.5.2 Children need action plans
• Recommendation: Similar to adults all children need a
treatment action plan, on demand therapy and in rare
cases may need prophylaxis. (100%)
9.5.3 Dosing on demand C1-inhibitor
• Recommendation: The preferred therapy for ondemand therapy is C1INH dose at 20 units per kg (75%)
• Minority opinion suggested 500 unit dosing with repeated
dosing as necessary
9.5.4 Chronic Prophylaxis in children
• The majority of children do not require long-term
prophylaxis
• Aminocaproic acid is dosed 20 to 40 mg/kg, but efficacy
is questionable
• Androgens have significant adverse effects in children.
Dose is 2.5 mg/kg of danazol, but dose should not
exceed 200 mg a day
• Dose for C1-INH should be 20 units/kg twice a week and
is the preferred prophylactic therapy
9.5.5 Pediatric references
•
•
•
•
Gompels MM, Lock RJ, Abinun M et al. C1 inhibitor deficiency: consensus document. Clin Exp
Immunol 2005; 139(3):379-94.
Farkas H, Varga L, Szeplaki G, Visy B, Harmat G, Bowen T. Management of hereditary
angioedema in pediatric patients. Pediatrics 2007; 120(3):e713-22.
Farkas H, Jakab L, Temesszentandrasi G et al. Hereditary angioedema: a decade of human C1inhibitor concentrate therapy. J Allergy Clin Immunol 2007; 120(4):941-7. Martinez-Saguer I,
Rusicke E, Aygören-Pürsün E, Kreuz W. Clinical surveillance program of pediatric hereditary
angioedema (HAE) patients undergoing home treatment AAAAAI 2009. Washington, DC, United
States, 2009.)
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin
Immunol. 2010 Jul 28;6(1):18.)
10.1 Why Pregnancy is Unique
• Anatomical and physiological – primarily hormonal – changes
during pregnancy may:
• influence the manifestations of HAE,
• interfere with the diagnosis of HAE.
• Affect the response to therapy.
• The range of medicinal products available for safe therapy is
narrow, owing to the need for avoiding neonatal undesirable
effects.
References:
- limited
- case reports,
- retrospective studies involving a small
number of patients and pregnancies,
reviews, consensus documents
10.1 Why Pregnancy is Unique
Pregnancy
• It can mitigate, aggravate HAE – or have no impact whatsoever.
• Attacks are the most severe during the 1st trimester and occur
with the highest frequency in the 3rd trimester; however,
decreased attack rates have also been reported during the 2nd
and 3rd trimesters.
• Attack frequency observed during previous pregnancies does
not predict HAE events during any subsequent pregnancy.
• Fewer symptoms can occur during the 3rd trimester, if
menstruation has been a provoking factor previously.
• Early onset of initial symptoms is associated with an increased
frequency and severity of attacks.
• Abdominal attacks occur more frequently.
10.1 Why Pregnancy is Unique
Labor and delivery:
• Delivery only rarely induces an attack, which may occur either
during labor or within 48 hours of delivery.
• The proportion of Caesarean sections is not higher, than in the
general population.
• C section should be avoided if possible
• Intubation should be avoided if possible
10.1 References
•
•
•
•
Agostoni A, Medicine (Baltimore).1992 Jul;71(4):206-15.
Farkas H, Eur J Clin Pharmacol. 2010 Apr;66(4):419-26.
Bork K, Ann Allergy Asthma Immunol. 2008 Feb;100(2):153-61. 1:
Bouillet L. Allergy Asthma Clin Immunol. 2010 Jul 28;6(1):17.
10.2 Diagnosis
During Pregnancy
Infrequently, the manifestations of HAE first occur during
pregnancy.
•
Complement testing
– Plasma C1INH level decreases during pregnancy as a
consequence of the increase of plasma volume.
– In patients with eclampsia and pre-eclampsia, the decrease of
C1INH levels is greater during the third trimester of pregnancy.
– Transitory low C1INH levels return to normal after delivery 
repeated C1INH testing is necessary after delivery to confirm the
diagnosis of HAE.
10.3 Diagnosis
Prenatal Diagnosis
Routine use of prenatal diagnostics is impractical.

No mutation of the C1-INH gene can be detected in 8 to 10
per cent of cases.

Mutation itself is not a valid indication for terminating
pregnancy, because:
– HAE is a manageable disease
– its severity cannot be predicted in advance.
10.4 Diagnosis
Preimplantation Diagnosis
• PGD allows the selection of in vitro fertilized eggs
according to mutational status. Only fertilized eggs
without disease-causing mutations are used for
implantation into the uterus.
• PGD:
– expensive
– requires hormone therapy
– pregnancy rate is low
10.5 Spontaneous Abortion and
Premature Labor
• No increase in incidence of HAE
• Pre-procedural prophylaxis should be administered
and/or on-demand therapy should be available
depending on procedures required.
10.6 Breastfeeding
• May be associated with an increased number of
edematous attacks, but breast feedings should be
encouraged
• Medications selected should be safe for the child. C1inhibitor is presently the medication of first choice during
lactation
10.7
• Contraception
Estrogens should be avoided – as these can worsen the natural
course of HAE. Barrier methods, progesterone and intrauterine device
should be preferred.
• Anti-fibrinolytics should be discontinued several days before
attempting to conceive.
• Androgens
• Should be stopped 2-3 months before attempted conception, owing
to the risk of abnormalities in the sexual differentiation of the fetus.
• If a patient becomes pregnant while taking androgens, the
androgens should be discontinued and the family informed about
the risk of fetal abnormalities
• Male HAE patients planning a family should avoid androgens,
because androgens reduce male fertility (testicular atrophy,
impaired spermiogenesis).
• C1INH concentrate is the perferred on-demand and prophylaxis
therapy during the period of conception
10.8 Treatment during pregnancy
• Recommendation: Because of the lack of safety
data with icatibant and ecallantide and the toxicity of
androgens and antifibrinolytics during pregnancy, C1INH
is the preferred drug during pregnancy and lactation.
• (100% expert opinion)
10.8.1 Management
Prophylaxis
Elimination of Triggering Factors
The measures for non-pregnant females apply.
Drug Prophylaxis
Chronic prophylaxis:
•
•
•
•
Pd C1-INH concentrate is safe and effective during both pregnancy and
lactation.
Anti-fibrinolytics are not recommended to use during pregnancy. AFs
cross the placenta. They are not teratogenic in animals, but are excreted
into breast milk. These drugs are not recommended during breastfeeding.
Androgens are not recommended, as these drugs cross the placenta. They
cause masculinization of the female fetus, placental insufficiency, and fetal
growth retardation. No mutagenicity has been shown in animal models.
Excretion into breast milk is unknown, but androgens should be avoided
during lactation.
Heat-treated fresh frozen plasma (FFP): Only limited data exist on the
use of FFP during pregnancy. Use only if no C1-inhibitor is available
10.8.2 Management
Prophylaxis
Short-Term
Pd C1-INH is the drug of choice. If this is not available, htFFP
or androgens may be administered
•
•
•
•
Amniocentesis / chorionic villous sampling: pprophylaxis is recommended,
preferably with pd C1INH.
Surgical artificial abortion: prophylaxis is recommended with pd C1INH. Alternatively,
pd C1INH should be administered immediately for signs of an attack. FFP can be used if
C1-INH is not available.
Delivery and puerperium: It is recommended to manage childbirth in the hospital
setting. Routine administration of prophylaxis before uncomplicated natural delivery is
not recommended, but pd C1INH should be immediately available. C1-INH concentrate is
recommended before labor and delivery when HAE is severe, if symptoms have been
recurring frequently during the third trimester, and if the patient’s history contains genital
edema caused by frequent mechanical trauma. Administration of pd C1INH concentrate
is recommended if forceps delivery or vacuum extraction is performed. After vaginal
delivery, patients should be monitored carefully for the initial 48 hours postpartum.
Cesarean section (abdominal delivery): Epidural anesthesia and prophylaxis with pd
C1INH concentrate are recommended.
10.8.3 On-Demand Therapy during
Gestation and Lactation
• C1-inhibitor is the preferred therapy. Presently, until
further information is available the dose would be 20
units/kg (majority). Minority opinion is 500 or 1000 units
for an attack (minority opinion)
• FFP (heat treated) can be substituted if C1-inhibitor is
not available, but risk is greater than with C1-inhibitor
• Anti-fibrinolytics should be avoided
• No data are available for ecallantide or icatibant and
both should be avoided until safety data exists
10.8 References- Prophylaxis during
Pregnancy
•
•
•
•
Obtulowicz K, Porebski G, Bilo B, Stobiecki M, Obtulowicz A. Hereditary angioedema in
pregnancy – case series study. The 6th C1-INH Deficiency Workshop, 22-24 May, Budapest,
abstract book page 58.
Bouillet L Am J Obstet Gynecol. 2008 Nov;199(5):484.e1-4
Czaller Eu J Obstet Gynecol Reprod Biol 2010,
Martinez Am J Obstet Gynecol 2010,
10.10 Cost-Effective Care
• Although pd C1-INH is expensive, this is the only agent
safe for both the mother and the fetus,and as well its
effectiveness is outstanding
10.11 References for Care during Pregnancy
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Martinez Am J Obstet Gynecol 2010,
Greaves MW. J R Soc Med. 1984 Dec;77(12):1046-8.
Farkas H, J Allergy Clin Immunol. 2007 Oct;120(4):941-7.
Czaller Eu J Obstet Gynecol Reprod Biol 2010,
Obtulowicz K, Porebski G, Bilo B, Stobiecki M, Obtulowicz A. Hereditary angioedema in
pregnancy – case series study. The 6th C1-INH Deficiency Workshop, 22-24 May, Budapest,
abstract book page 58.)
Chinniah N, Aust N Z J Obstet Gynaecol. 2009 Feb;49(1):2-5. 41.
Farkas H, J Allergy Clin Immunol. 2007 Oct;120(4):941Bowen T, Ann Allergy Asthma Immunol. 2008 Jan;100(1 Suppl 2):S30-40,
McGlinchey PG,. Ulster Med J. 2000 May;69(1):54-7.
Logan RA, Greaves MW. Hereditary angio-oedema: treatment with C1 esterase inhibitor
concentrate. Acute attack J R Soc Med. 1984 Dec;77(12):1046-8.
Czaller Eu J Obstet Gynecol Reprod Biol 2010,
Gorman PJ. Can Fam Physician. 2008 Mar;54(3):365-6.
Prematta M, Ann Allergy Asthma Immunol. 2007 Apr;98(4):383-8.)
Gompels MM,. Clin Exp Immunol. 2005 Mar;139(3):379-94.
Carbella, Teresa et al. JACI 2011
11.1 Home Therapy
• Recommendation: Patients with HAE should be
encouraged to provide self care and home care to allow
early, effective and cost effective care
• Agreement: 100%
• A evidence
Self-administration: C1 INH 1000 IU
Levi M et al. 20061
1Levi
M et al. J Allergy Clin Immunol 2006;117 (4):904-908
Self-administration: C1 INH 1000 IU
Levi M et al. 20061 Self-admin
Historical control
1Levi
M et al. J Allergy Clin Immunol 2006;117 (4):904-908
Self-administration: Results
Bygum 20091
Dermatology Life Quality Index (DLQI) scores before and after selfadmin of C1 INH
1Bygum
Δ SF36
95%CI
pvalue
Physical component
21.01
15.29-26.73
0.0001
Psychological component
19.91
9.58-30.23
0.0033
A et al. Eur J Dermatol. 2009 Mar-Apr;19(2):147-51.
11.2 Social and Psychiatry Support
• Recommendation: HAE is a physical disease, but
the psychiatric toll of the disease is significant and care
should be holistic and include the social and psychiatric
aspects of the disease. 100% agreement
• Patients with HAE suffer from stress and depression
more often then matched controls. Stress has been
shown to increase severity of disease. Patients may
benefit from stress reduction techniques and therapies to
improve quality of life.
11.3 Patient Support Organizations
• Recommendation: Patients should be encouraged
to join groups such as the International Hereditary
Angioedema Association
• Agreement: 100%
11.4 Database
• Recommendation: International database should be
developed and all patients encouraged to register so that
data are available to help determine the demographics,
expression of the disease and variables that affect the
expression of the disease.
• Agreement: 100%
11.5 Action Plans
• Recommendation: All patients with HAE should
have an acute action plan to include location to acquire
care, therapies available or in possession, dose and
route of administration
• Agreement: 100%
11.6 Need for Better Medications
• Recommendation: Pharmaceutical companies
should be encouraged to develop more effective, less
toxic and easier to take medications.
• Agreement: 100%
11.6 Better medications
• Pharmaceutical companies should be encouraged to
preform pediatric studies to determine appropriate
weight based dosing and side effects of presently
available drugs and future medications.
• 100%
11.7 World Wide Access to Therapies
• Recommendation: Associations, doctors, patients,
health care providers, and pharmaceutical companies
should petition to have therapies available world wide for
all patients with HAE.
• Agreement: 100%
12.0 Future Needs for HAE Include
•
•
•
•
•
•
Prophylaxis therapy that is oral
Dose ranging study for C1INH prophylaxis
Subcutaneous C1INH for long term prophylaxis
Oral therapy for on demand therapy
Pediatric safety studies for icatibant and ecallantide
Weight based therapy for all available treatments for
pediatric use
12.0 Future Needs for HAE Include
• Comparative studies between the treatments for on
demand therapy
• Comparative studies on prophylactic therapies
• Availability of all therapies to all patients around the
world
• Emphasis on self care
• Emphasis on early therapy
• Emphasis on action plans for all patients
• Gene therapy research
13.0 Summary
• We hope this slide set, the abbreviated slide deck and
the manuscript that accompanies these are helpful. All
are intended for the better dissemination of knowledge
about HAE and treatment of patients with HAE. These
slides are available on the WAO website to be used for
self teaching, patient care and teaching of others. Feel
free to use them as you see fit.