Angioedema

Outline

Angioedema
Classification
Clinical presentation
C1 inhibitor
Hereditary Angioedema
Acquired Angioedema
Idiopathic Angioedema

Angioedema
Localized, transient, episodic edema of the
deeper layers of the dermis and subcutaneuous
tissue or of the mucosa of the GI tract,
respiratory tract
Result of interstitial edema from mediators
affecting capillary and venule permeability
Caused by extravasation of plasma in the
affected areas, which at times is accompanied
by nonspecific, minimal cellular infiltrate
Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

Episodes of angioedema may be classified

in two broad categories:
Acute angioedema (single episode)
Acute recurrent angioedema (three or
more episodes of angioedema within a 3-6
month period)

Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

Classification

Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

Major caused of urticaria and

angioedema
1. Drug reactions
2. Food or food additives
3. Inhalation, ingestion of, or contact with
Ag
4. Transfusion reaction
5. Infection : bacterial, fungal, viral, and
helminthic
Allen P. Kaplan : Middletons Allergy 7 edition

6. Insects (papular urticaria)

7. Collagen vascular diseases
8. Malignancy: angioedema with acquired
C1 and inactivator ( INH) depletion
9. Physical urticarias
10. Urticaria pigmentosa: systemic
mastocytosis
Allen P. Kaplan : Middletons Allergy 7 edition

11. Hereditary diseases

1.
2.
3.
4.

Hereditary angioedema
Familial cold urticaria
C3b inactivator deficiency
Amyloidosis with deafness and urticaria
(Muckle-Wells syndrome)

12. Chronic autoimmune urticaria and

angioedema
13. Chronic idiopathic urticaria and
angioedema
14. Idiopathic angioedema
Allen P. Kaplan : Middletons Allergy 7 edition

M. Bas: Allergy 2007

Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007

Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007

Clinical presentation
Angioedema of the skin is nonpitting, with
ill-defined margins
Skin is swollen, tender, and warm
Frequently a burning sensation is present,
but pruritus is typically uncommon (fewer
mast cell and sensory nerve ending)
Attacks of angioedema may last a few
days and usually resolve spontaneously
Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

 The time from onset of angioedema to

complete obstruction of the upper airway
may vary from minutes to 14 hr
Intestinal obstruction may result from
angioedema of the wall of the GI tract
Nausea, vomiting, and abdominal pain
may be severe at times, mimicking acute
abdomen, rarely diarrhea
Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

 Fever and leukocytosis are unusual in

angioedema
Cases of cerebral angioedema, leading to
migraine and transient ischemic attacks
have been described

Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007

Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007

C1 Inhibitor
Complement regulatory protein
C1 INH is an 2-globulin of 105 kDa and is
synthesized mainly by hepatocytes
Major functions inhibition of autoactivation C1,
bind to C1r and C1s and dissociates the C1
complex (C1r2-C1s2-C1-INH2 complex)
Inactivation of the coagulation factors XIIa, XIIf,
and XIa, direct inhibition of activated kallikrein

Kathleen E. Sullivan: Middletons Allergy 7 edition

Kathleen E. Sullivan: Middletons Allergy 7 edition

Kathleen E. Sullivan: Middletons Allergy 7 edition

Hereditary angioedema
(C1 INHIBITOR DEFICIENCY)

1 in 10,000 to 1 in 150,000
Located in chromosome 11q13.1
Heterozygous, AD but 20-25%
Spontaneous mutation
Mildly increased susceptibility to infection
and increased risk of SLE ( chronic
consumption of C2, C4)
Angioedema not associate with urticaria
Kathleen E. Sullivan: Middletons Allergy 7 edition

 Hx
Involvement airway in the absence of
anaphylaxis
abdominal episodes
a positive family history
angioedema arising after trauma

5% of people who carry a C1 inhibitor

mutation are asymptomatic
Kathleen E. Sullivan: Middletons Allergy 7 edition

 Half of patients have had episodes before

the age of 10 years
Episodes may be as infrequent as 1/year
or as frequent as 1/month and the
frequency and the severity of episodes do
not correlate with laboratory features

Kathleen E. Sullivan: Middletons Allergy 7 edition

 The extremities, face, or genitalia are most

often involved
Involved GI abdominal pain, vomitting,
rarely diarrhea
1/3 of patients with C1 inhibitor deficiency
had undergone an appendectomy or
exploratory laparotomy for abdominal pain

Kathleen E. Sullivan: Middletons Allergy 7 edition

 Involved airway, upper respiratory tract

swelling leading to respiratory arrest
Mortality rate high as 3040%, is mostly a
result of obstruction of the upper airway
Angioedema typically progresses for 12
days and resolves in another 23 days
Common precipitants are illness, hormonal
fluctuations, trauma, and stress
Kathleen E. Sullivan: Middletons Allergy 7 edition

 C1 inhibitor promoter is androgen responsive,

men have fewer problems in general than
female patients
May also explain the common complaint that
symptoms vary with menstruation
Mechanism underlying the angioedema is not
completely clear but relates to the role of C1
inhibitor as an inhibitor of both the classical
complement pathway activation and as an
inhibitor of the kinin pathway

C1 inhibitor deficiency is
thought to lead to angioedema
through loss of inhibitory
activity for the intrinsic
coagulation pathway
Factor XII (Hageman factor)
activation leads to the
activation of bradykinin, which
is one of the most potent
vasodilators known
bradykinin leads to vascular
leak, and hence, angioedema
cleavage product of C2b, C2kinin is produced by plasmin
Plasmin is itself activated by
factor XII
C2-kinin has some effect on
vasodilation
activation of factor XII is often
due to vascular damage and
collagen expose

 Type I : is a concomitant decrease in

protein levels and function
Type II :is associated with the production
normal but dysfunctional protein ( most
common 85%)
Recommended that both antigenic and
functional levels
Typical functional level is approximately
2540% of normal in both types
Kathleen E. Sullivan: Middletons Allergy 7 edition

 Ideally, the episodes of angioedema are

prevented
Most common strategy for prevention is
the use of attenuated androgens
In children, the use of androgens is
discouraged due to concerns about
closure of the epiphyses and tranexamic
acid is often used
Kathleen E. Sullivan: Middletons Allergy 7 edition

 Short-term prophylaxis for dental

procedures, surgical procedures, or other
situations where significant trauma
Attenuated androgens are typically used,
then FFP is usually given prior to the event
Europe and Austaria, pasteurized C1
inhibitor concentrate is available for both
short-term prophylaxis and treatment and
is very effective
Kathleen E. Sullivan: Middletons Allergy 7 edition

 Episodes also occur in children, pre-adolescent

girls and adolescent girls
may be on an antifibrinolytic agent that is much
less effective than an attenuated androgen
Acute episodes arise in the undiagnosed patient
or in non-compliant patients, corticosteroids,
epinephrine, and antihistamines have no effect
Supportive care and close observation, pharyngeal
swelling can progress to airway compromise in a few
hours
Narcotics are appropriate for abdominal pain
Kathleen E. Sullivan: Middletons Allergy 7 edition

 C1 inhibitor concentrate is best option where

available
Antifibrinolytics to reduce the severity and length
of the episode and attenuated androgens may
do the same (do not begin effect for 24 hr)
FFP and aprotinin have been used for acute
episodes
FFP is thought to provide active substrate to
enhance further edema and is not routinely used
and side effects with aprotinin have limited its
use
Kathleen E. Sullivan: Middletons Allergy 7 edition

 Polycystic ovary syndrome (increased

luteinizing hormone and testosterone are
not seen, Ultrasounds demonstrate
polycystic ovaries and Menstrual
irregularities ) is seen in approximately
one-third of female patients with C1
inhibitor deficiency
attenuated androgen therapy improves the
polycystic ovaries
Kathleen E. Sullivan: Middletons Allergy 7 edition

 Pregnancy poses a particular risk to both

the mother and the fetus
Hormonal shifts of pregnancy lead to an
increased risk of angioedema
Delivery is itself traumatic and an affected
mother has a 50% chance of transmitting
the disorder to her offspring

Kathleen E. Sullivan: Middletons Allergy 7 edition

 Europe, C1 inhibitor is given

prophylactically
USA, low-dose androgens (risks of
androgenization of the baby)
FFP could be administered
prophylactically; however, there are no
data on this strategy

Kathleen E. Sullivan: Middletons Allergy 7 edition

Acquired C1 INH deficiency

Nonhereditary angioedema characterized
by normal C1-INH
Age of onset is after 30 years
Caldwell and colleagues described the first
patient in 1972
Mostly associated with lymphoproliferative
disorders

Lorenza Chiara Zingale: Immunol Allergy Clin N Am

C1-INH or the classic complement pathway

was consumed by the neoplastic lymphatic
tissues

Autoimmune mechanism

 1986, Jackson and colleagues, discovered

an autoreactive immunoglobulin G against
C1-INH
Autoimmune mechanism could be the
cause of acquired C1-INH deficiency
Because the first patients who had
autoantibodies to C1-INH looked
otherwise healthy

 1985, Geha and colleagues, mechanism of

complement consumption
Paraproteins had immunoglobulins against the
idiotypic determinants of the M components
Idiotypeanti-idiotype immune complexes fixed
C1q and consumed C1-INH
Direct proof in vivo increased consumption of
C1-INH was provided in 1986 by Melamed and
colleagues (injected patients with radiolabeled
C1-INH and C1q)

Acquired C1-INH deficiency was divided into

two separate forms
type I, paraneoplastic, mainly associated
with lymphatic malignancies or other
diseases
type II, autoimmune, caused by
autoantibodies to C1-INH

 Only 14% of patients with acquired C1 inhibitor

deficiency had no associated medical condition
Lymphoproliferative diseases and acquired C1inhibitor deficiencies
Many from B cell lymphoproliferative diseases
that ranged from monoclonal gammopathies of
undetermined significance (MGUS) to true
malignancies (NHL)
NHL is markedly increased in patients who have
angioedema and acquired C1-INH deficiency

 Variant rarely occurs in association with

malignancies of the rectum, stomach, and
breast; rheumatoid arthritis and systemic
lupus erythematosus; Churg-Strauss
vasculitis; lupus anticoagulant; erythrocyte
sensitization; livedo reticularis; and
infections with human immunodeficiency
virus, hepatitis C and B viruses,
Echinococcus granulosus, and
Helicobacter pylori

 The differences between the two forms are

absence of family history, late onset of
symptoms (after the fourth decade of life), and
response to treatment
C1-INH function and antigen, C4 and C1q
markedly reduced (usually far below 50% of
normal), with a normal C3
C1-INH antigen can be normal, when elevated
amounts of cleaved inactive C1-INH circulate in
plasma

 Autoantibodies to C1-INH may be

detected as immunoglobulins preventing
C1-INH function or binding C1-INH
Alsenz and colleagues developed a solidphase ELISA for detectin immunoglobulins
binding to C1-INH coated to microtiter
plates (simple and highly sensitivity)

 Course of and prognosis for angioedema

with acquired C1-INH deficiency depend
on the underlying disease and the
availability of proper therapy for lifethreatening angioedema
Angioedema attacks usually resolve
without treatment, patients are exposed to
the risk for laryngeal edema

 Successful treatment of the underlying

disease has been shown to resolve
angioedema symptoms
immunosuppressive regimens
(cyclophosphamide, with or without
steroids) have been used for suppressing
the formation of antiC1-INH
autoantibodies in isolated patients who
had acquired C1-INH deficiency

 For long-term prevention of angioedema

recurrences, patients are treated with
attenuated androgens and antifibrinolytic
agents
Acquired C1-INH deficiency are often
resistant to attenuated androgens but
better response to antifibrinolytic agents

Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

M. Bas: Allergy 2007

Treatment

Adult

Pediatric

Comments

Tranexamic acid
(Cyklokapron

13g/day p.o. as
divided doses for
prophylaxis, 1g p.o.
q. 34h until episode
resolves for acute
episodes

2550mg/kg b.i.d.
t.i.d. as prophylaxis,
1.5g/day for acute
episodes (available
as i.v. form)

Not available in the

USA

Epsilon
aminocaproic acid
(Amicar)

1g p.o. t.i.d. as
prophylaxis, 1g/h as
i.v. therapy for acute
attacks

100mg/kg q.46h
not to exceed
30g/day as therapy.
Oral syrup available
for prophylaxis but
established: 6g/day
for children
<11years and
12g/day for children
>11years has been
used successfully

The only
antifibrinolytic
available in the
USA, has modest
efficacy. Cannot be
used in neonates.
Oral dosing has
significant GI side
effects

Kathleen E. Sullivan: Middletons Allergy 7 edition

Treatment

Adult

Pediatric

Comments

Danazol (Danocrine) 200mg p.o. q.d. as a

starting point for
prophylaxis (titrate
to effect), 400
600mg p.o. q.d. for
acute episode or
short-term
prophylaxis

50200mg p.o. q.d.

as a starting point
for prophylaxis
(titrate to effect) and
consider q.o.d. or q.
3 days in preadolescent children;
can use up to
400mg p.o. q.d.as
short-term
prophylaxis

Concern about
androgenization and
premature closure of
the epiphyses limits
the use of
attenuated
androgens in
children. Titration to
desired effect is
recommended
rather than to
laboratory criteria

Oxandrolone
(Oxandrin)

0.1mg/kg per day as Has less

prophylaxis. Not
androgenizing
effects than Danazol
proven as shortterm prophylaxis or
treatment in a formal
clinical trial

2.520mg p.o. t.i.d.

as prophylaxis
(titrate to effect). Not
proven as shortterm prophylaxis or
treatment

Kathleen E. Sullivan: Middletons Allergy 7 edition

Bruce L:Immunol Allergy Clin N Am

Treatment

Adult

Pediatric

Comments

Fresh frozen plasma

(FFP)

1000U as treatment

1030U/kg as
treatment (up to
5001000U total

Very rapid effect,

especially useful in
pregnancy

C1 inhibitor
concentrate

1000U as treatment

1030U/kg as
treatment (up to
5001000U total)

Very rapid effect,

especially useful in
pregnancy

Icatibant

Bradykinin receptor
antagonist; awaiting
trial results

DX-88

Kallikrein inhibitor,
has shown efficacy
in early trials; could
be available later in
2007

Kathleen E. Sullivan: Middletons Allergy 7 edition

Bruce L:Immunol Allergy Clin N Am

 ACE inhibitors, estrogen replacement

therapy, and oral contraceptives should be
avoided in patients with either HAE or AAE

Idiopathic recurrent Angioedema

Three or more episodes of angioedema
have occurred within a period of 6 months
to 1 year without any cause being
identified
Diagnosis is made after a comprehensive
evaluation has ruled out the known causes
of angioedema

Evangelo Frigas:Immunol Allergy Clin N Am

 Women are affected slightly more often

than men, and at presentation 50% of
patients are found to have both urticaria
and angioedema
Angioedema alone in chonic urticaria and
angioedema, 20%

Evangelo Frigas:Immunol Allergy Clin N Am

 Excessive production or decreased

catabolization of molecules that increase
vascular permeability
Histamine, tryptase, prostaglandin F2
from mast cells, and bradykinin from
inappropriate and excessive activation of
the complement and kallikrein systems

Evangelo Frigas:Immunol Allergy Clin N Am

 Food allergens (especially shellfish, nuts, and

peanuts), latex, and insect venoms as well as
several medications can release histamine from
sensitized mast cells and may produce
angioedema on an IgE-mediated basis
Some medications (narcotics, polymyxin, dtubocurarine) may cause angioedema owing to
their ability to cause direct mast cell
degranulation in the absence of IgE antibodies
against the drug

 Pathogenesis of idiopathic recurrent

angioedema with or without urticaria is not
known

 Initial work-up includes the following

laboratory tests: complement C4, C1q,
CH50, C1 esterase inhibitor by functional
and quantitative assays, and a panel for
mast cell-mediator screening, which
includes measurements of tryptase and
calcitonin in the serum and histamine, Nmethylhistamine, and prostaglandin F2 in
a 24-hour urine collection.

 CBC, chemistry group, serum protein

electrophoresis, total serum IgE, ESR, and
a thyroid cascade, which includes testing
for antithyroid antibodies
Allergy skin tests or specific IgE blood
tests are performed to rule out latex and
food allergy

 Devided into histaminergic and nonhistaminergic depend on response or lack

respons to antihistamine
Isolated elevation of prostaglandin F2 in
the urine but normal levels of the other
mediators, patients may benefit from
treatment with aspirin

 step 1, we usually start with a nonsedating

or less-sedating antihistamine, such as
fexofenadine, cetirizine, loratadine, or
desloratadine, taken during the daytime
step 2 by adding a sedating antihistamine
such as doxepin, hydroxyzine, or
diphenhydramine, usually taken at
bedtime
step 3, cyclosporine, nifedipine,
methotrexate, androgens, warfarin

 treatment trials for 2 to 4 months with

either colchicine 0.6 mg once or twice
daily or dapsone 25 mg twice daily and
titrated up to 100 mg twice daily, or
sulfasalazine 500 mg once or twice daily
recombinant interferon , ASA
Systemic glucocorticoids, although very
effective for the majority of patients with
recurrent angioedema

 prednisone 20 mg for 5 to 7 days usually

without tapering
Omalizumab (case report 3 case hige IgE)

Summery

Classification Angioedema
C1 INH
HAE
AAE
Idiopathic angioedema
Treatmeant