Clinic Rev Allerg Immunol (2008) 34:250259

DOI 10.1007/s12016-007-8037-y

Pediatric Angioedema
Anita Krishnamurthy & Stanley M. Naguwa &
M. Eric Gershwin

Published online: 18 September 2007

# Humana Press Inc. 2007

Abstract Angioedema is a self-limited nonpitting edema

generally affecting the deeper layers of the skin and mucous
membranes. It is the result of increased vascular permeability causing the leakage of fluid into the skin in response
to potent vasodilators released by immunologic mediators.
Two main pathways are thought to be implicated in
angioedema. The mast cell pathway in which preformed
mediators, such as histamine, rapidly formed mediators,
leukotrienes and prostaglandins, are released from mast
cells through IgE or direct activation. This is the most
common pathway among children, with food, medications,
and infections commonly implicated. The second pathway
is the kinin pathway, most notably affected by angiotensinconverting enzyme (ACE) inhibitors and hereditary forms
of angioedema, which ultimately results in the formation of
bradykinin, a potent vasodilator. Angioedema is being
encountered with increasing frequency, particularly among
children and is important to recognize and treat for its lifethreatening associated manifestations such as anaphylaxis
and airway obstruction. Although angioedema is still not
fully understood, we have broadened our understanding of
the possible causes and clinical course of angioedema. An
understanding of these potential causes and mechanisms by
which angioedema can occur may guide the clinician in
determining the need for diagnostic testing and the extent of
treatment.

Introduction
Angioedema is a commonly encountered disease that can
occur as the sole clinical finding or with associated
urticaria. Prevalence in the United States is noted to be
between 14% and 25% [1] with a large proportion of cases
among children. Angioedema is an immunologic process
causing a nonpitting edema in the deeper layers of the skin
and mucous membranes. Two main immunologic pathways
are implicated in angioedemamast cell degranulation and
the kinin pathway activation, both of which result in the
release of potent vasodilators, which increase vascular
permeability and result in capillary leakage with resultant
tissue edema.
Although most cases require solely supportive treatment
or removal of offending agents, angioedema is a potentially
life-threatening condition that may be associated with
anaphylaxis or airway compromise, and therefore necessitates prompt evaluation and treatment. Aside from
hereditary angioedema, which remains rare but is often
discussed in association with pediatric angioedema, manifestations and causes of angioedema among children is not
comprehensively discussed in the literature. An understanding of the various causes of angioedema and the potential
mechanisms by which angioedema may occur dictates the
need for further diagnostic testing and guides for therapy.

Keywords Bradykinin . ACE inhibitors . Vasodilation .

Immunopathology . NSAIDs

Definition

A. Krishnamurthy : S. M. Naguwa : M. E. Gershwin (*)

Division of Rheumatology, Allergy and Clinical Immunology,
University of California at Davis School of Medicine,
451 E. Health Sciences Drive, Suite 6510,
Davis, CA 95616, USA
e-mail: megershwin@ucdavis.edu

Angioedema is a self-limited, nonpitting edema occurring

in the deeper layers of the skin and the mucous membranes.
It results from an increase in permeability of the capillaries
and venules from inflammatory mediators causing extravasation of fluid into the interstitium. The process is similar

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to that which occurs with urticaria, although in the case of

angioedema, the pathway occurs at the level of the deeper
dermis and subcutaneous tissues. Angioedema therefore has
swelling as the prominent manifestation, whereas the
superficial appearance of the skin itself may remain normal.
As opposed to edema, which occurs in dependant areas in a
symmetric fashion, angioedema is typically asymmetric
occurring in nondependant areas and characterized by its
rapid onset and transient nature. Angioedema typically
affects the lips, face, hands, feet, bowel, and genital areas
and develops over minutes to hours with resolution in 24 to
48 h. Associated symptoms may include pain, warmth, or
erythema. Pruritis is generally absent unless urticaria is
present (Table 1).

small fraction of the cases of angioedema. The majority of

angioedema seen among children is usually secondary to
precipitating factors such as infection, food hypersensitivity, physical factors, or medications. One study of urticaria
and angioedema among 54 children found that the most
common etiology was infection, which was diagnosed in
58% of the children studied [1]. Although the hereditary
forms of angioedema remain rare, they are important for
their life-threatening implications and recurrent nature.
Laryngeal edema occurs frequently in this population with
a lifetime incidence estimated at approximately 70% and a
mortality rate estimated at 3040% from obstruction of the
upper airway [4]. For this reason, early recognition and
treatment is essential.

Epidemiology

Pathophysiology

Angioedema and urticaria are common problems occurring

in as many as 15% to 25% of the population at some time
in their life and frequently encountered among children [2].
Both genders and all racial groups are affected. Acute
angioedema, defined as lasting less than 6 weeks, is thought
to be more common among young people whereas chronic
angioedema more commonly occurs among the 4050 age
group [1]. Angioedema, in general, is more common among
individuals with a history of atopic diseases such as asthma,
food allergy, allergic rhinitis, or atopic dermatitis.
Angioedema may occur in conjunction with urticaria,
but it may also be an isolated finding. In approximately
40% of patients presenting with angioedema, urticaria and
angioedema occur in conjunction. Another 40% of patients
present with urticaria alone whereas 20% of patients have
angioedema but no urticaria [3]. Studies suggest that
patients with both urticaria and angioedema tend to have
more severe and persistent symptoms that those without
this combination.
When evaluating a child with angioedema, the hereditary
forms of the disease must be included in the differential. In
two-thirds of patients, the hereditary forms of angioedema
will manifest during childhood, but it is important to note
that overall hereditary forms are rare and account for only a

Angioedema arises from the release of vasoactive mediators

causing tissue edema. Two main pathways are thought to be
involved: mast cell degranulation and kinin formation. Mast
cell degranulation results in the release of inflammatory
mediators from mast cells such as histamine, leukotriene C
and D, prostaglandin D2, and platelet-activating factor.
These factors have potent vasoactive properties that result
in the dilation of venules, which increases their permeability and causes tissue edema. Many different drugs and
allergens can trigger this process through IgE mechanisms
as detailed below. Certain drugs such as opiates, vancomycin, and radiocontrast media can also trigger mast cell
degranulation directly through direct mechanisms not
involving IgE [2]. The second pathway leading to angioedema involves kinin formation. Kallikrein is an enzyme that
converts kininogen to bradykinin, a vasoactive peptide.
Bradykinin subsequently interacts with bradykinin receptors as a potent vasodilator that increases vascular permeability and causes tissue edema. Angiotensin-converting
enzyme (ACE) inhibitors are the most notable example of
triggering angioedema through this pathway.

Table 1 Classic features of angioedema

Features of angioedema
Nonpitting edema
Lasts 2448 h
Asymmetric
Rapid onset (minutes to hours)
Face, genital areas, extremities, bowel often affected

Classification and Pathogenesis

Classification of angioedema can be thought of in terms of
acute versus chronic and mast cell- versus kinin-mediated.
Acute episodes of angioedema are generally defined as
those occurring within a 6-week period, whereas episodes
occurring over a longer period are designated as chronic.
Clinically, mast cell-mediated angioedema and kininmediated angioedema can often be differentiated by whether
urticaria is present. Mast cell angioedema is associated with
urticaria and/or pruritis in 90% of cases, whereas in the
kinin-mediated responses, urticaria is generally absent.

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Classifying angioedema accordingly can help guide the need

for further diagnostic testing and therapy.

Mast Cell-Mediated Responses

Acute Allergic Angioedema
Acute allergic angioedema occurs within minutes to hours
of exposure to certain foods or drugs. Food allergies in
particular are common among children with symptoms
usually beginning in the first 2 years of life. In food
allergies, a wide spectrum of clinical manifestations may
occur from mild cutaneous involvement to life threatening
anaphylaxis with angioedema being a common clinical
presenting symptom. More than 90% of IgE-mediated food
allergies in children is caused by cows milk, egg, peanuts,
tree nuts, wheat, shellfish, or soy [5]. Substances other than
foods, such as latex and insect stings, can similarly
precipitate acute allergic angioedema. In general, acute
allergic angioedema is most often seen in patients who have
other allergic conditions such as atopic dermatitis, allergic
rhinitis, and asthma, although reactions to food and
medications can occur in any individual (Table 2).
The onset of acute allergic angioedema depends upon
prior sensitization of mast cells. IgE molecules are bound to
dermal mast cells, and exposure to certain antigens for
which the IgE molecules are specific results in the
activation of cellular processes causing mast cell degranulation and release of mediators that increase vascular
Table 2 Causes of acute allergic angioedema
Causes

Common examples

Foods

Peanuts, milk, eggs, fish, tree nuts, soy, wheat,

crustaceans, shellfish, mollusks
Foods cross-reacting with latex (i.e., kiwi fruit,
banana, avocado, chestnut)
Penicillin, bactrim, sulfa-derived drugs,
cephalosporins, diuretics, sulfonylurea, dilantin,
oral hypoglycemics, NSAIDs
Fire ants, insect venom
Latex substances, preservatives, formaldehyde,
chemical irritants, flavor enhancers, colorants,
radiocontrast media, opiates
Viral: herpes simplex, hepatitis B, coxsackie A and
B, mononucleosis, upper respiratory infections,
parvovirus
Bacterial: otitis media, sinusitis, dental abscesses,
upper respiratory infections, urinary tract
infections
Parasitic infections: Strongyloides, Ascaris, Filaria,
Echinococcus
Dust mites, pollens, animal dander, molds

Drugs

Insects
Organic
Substances
Infections

Other

permeability. Although angioedema will generally resolve

in 24 to 48 h, repetitive exposure or cross-reactive agents
can result in recurrence. Skin testing may be helpful in
demonstrating specific IgE-mediated hypersensitivity.
There is no minimum age for skin testing, it is widely
available and has a high negative predictive value, although
a relatively low positive predictive value (i.e., a significant
number of patients with a positive result may be asymptomatic). Serum IgE levels to foods (RAST test) or other
possible allergens is an alternative to skin testing, although
values vary among laboratories and it may be more
expensive than skin testing.

NSAID-Induced Angioedema
Nonsteroidal antiinflammatory drugs (NSAIDs) are used
extensively among children as analgesic and antipyretic
agents. Hypersensitivity to NSAIDs can result in acute
angioedema and is being observed with increasing frequency because of the widespread use of NSAIDs, even among
children. Prevalence rates for acute angioedema from
NSAIDs is noted between 0.1% and 0.3% with higher
rates among those who use NSAIDs intermittently, as
opposed to chronic use. One study of the average risk of
urticaria/angioedema in a large cohort of patients was 1.1%
among those who used NSAIDs chronically and 3.6%
among those who used NSAIDs intermittently [6]. Rates
are substantially higher among asthmatics and other
patients with a history of atopy. The incidence of facial
angioedema and NSAID hypersensitivity among atopic
children with asthma or allergic rhinitis was studied in a
10-year retrospective chart review of patients in an allergy
clinic. Among these children, 41 of 1,007 (4.1%) experienced documented facial angioedema secondary to
NSAIDs. The incidence of angioedema among this cohort
was found to increase with age, 2% at less than 5 years of
age compared with 21% in the 16 to 21 age group [7].
Other predisposing factors for the development of angioedema in response to NSAIDs include female sex, family
history, and a history of chronic urticaria.
Although aspirin is the most common agent for causing
angioedema, several of the NSAIDs are known to cause
angioedema. In general, NSAIDs act by inhibiting cyclooxygenase (COX) 1 and 2, which is the pathway resulting
to prostaglandin synthesis from arachidonic acid. This
results in the redirection of arachidonic acid to the
lipoxygenase pathway leading to an increase in cysteinyl
leukotrienes and resultant inflammation [8] (see Fig. 1).
The ultimate result of this inflammatory process is mast cell
degranulation. Whereas COX 1 inhibitors are implicated in
this process, selective COX 2 inhibitors are not and may be
a useful alternative in these patients [911].

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Fig. 1 Arachidonic acid metabolism and action of nonsteroidal

antiinflammatory medications

Membrane Phospholipid

Arachadonic Acid
Lipooxygenase
Aspirin
NSAIDS

Cyclooxygenase
Leukotrienes
Prostaglandins

Inflammatory
Mediators
Mast cell
degranulation

Chronic Angioedema
Chronic angioedema is thought to be secondary to an
autoimmune process in approximately 40% of patients,
whereas the other 60% is considered to be idiopathic [3].
The autoimmune process is thought to be the result of
autoantibodies (IgG) to the IgE receptor on mast cells
causing recurrent attacks of angioedema. These autoantibodies stimulate the release of histamine from basophils
and mast cells. Episodes occur independently of external
triggers and often recur months to years later. Of patients
with chronic angioedema, 75% have symptoms for longer
than a year, 50% have symptoms longer than 5 years,
whereas 20% have symptoms for decades.
Chronic idiopathic angioedema in which recurrent
attacks of angioedema occur without a specific cause is a
diagnosis of exclusion. Idiopathic angioedema with lifethreatening anaphylactic manifestations is termed idiopathic
anaphylaxis. In idiopathic anaphylaxis, recurrent attacks of
anaphylactoid reactions occur without identifiable precipitants. Idiopathic anaphylaxis can be classified into either
idiopathic anaphylaxis generalized or idiopathic anaphylaxis with angioedema. Idiopathic anaphylaxis with angioedema presents with recurrent attacks of angioedema with
upper airway compromise of the larynx, pharynx, or
tongue, but without the other systemic symptoms of
anaphylaxis [12]. Idiopathic angioedema is perhaps the
most common cause of recurrent angioedema. A recent
prospective study of 220 adults found that among adults
with idiopathic angioedema and idiopathic angioedema
with urticaria, 80% and 40.5%, respectively, still had

PGE2

PGF2a

PGA2

PGI2

symptoms after 1 year indicating the recurrent and

persistent nature of the disease [13].
Other Angioedema
Among children, infection is a common cause of angioedema. Viral infections such as herpes simplex, coxsackie A
and B, hepatitis B, EpsteinBarr, and other viral illnesses
such as upper respiratory tract infections, may result in
angioedema and urticaria. The proposed mechanism is a
type 3 immune complex-mediated hypersensitivity process
in which viruses produce circulating immune complex
resulting in anaphylatoxins causing IgE cross-linking
releasing mast cell products. Bacterial infections associated
with angioedema, particularly among children, may include
otitis media, sinusitis, tonsillitis, upper respiratory tract
infections, and urinary tract infections. Parasitic infections,
although less common, should be considered on the
differential including strongyloides, toxocara, and filarial
[14]. Insect bite/stings such as bee stings may also result in
similar reactions.
Angioedema may also occur through nonimmunologic
release of mast cell mediators. Most notably, radiocontrast
media, opiates, and irradiation are thought to have a direct
effect on mast cells resulting in the release of mediators.
Physical factors are implicated in mast cell release,
including heat, cold, pressure, solar, and vibration, and
often results in an urticarial rash. Other medications are
noted to produce reactions either through immunologic or
direct release of mast cell mediators. These include betalactams, sulfonamides, insulin, dilantin and streptokinase.

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Angioedema can also be observed in approximately 15%

of patients with hypereosinophilic syndrome, either through
mediators released from eosinophils that directly result in
angioedema or eosinophil-released products that trigger
mast cell degranulation. Urticarial vasculitis can also
present with angioedema particularly in the low complement form of the disease.

mast cell degranulation. Degradation of bradykinin occurs

most rapidly via ACE located along the pulmonary
endothelium. ACE, also known as kininase II, converts
angiotensin I to angiotensin II and also degrades bradykinin. ACE inhibitors therefore increase bradykinin by
blocking the action of ACE (see Fig. 2). Bradykinin is a
potent vasodilator and results in increased vascular permeability, increased C-GMP, and release of nitric oxide. It is
thought that ACE inhibitor-induced angioedema is primarily
secondary to the increased availability of bradykinin [18].

Kinin-Mediated Responses
Hereditary Angioedema
Angiotensin-converting Enzyme and Angioedema
ACE inhibitors cause angioedema in 0.10.2% of patients
treated with the drug [15]. Given the large number of
patients taking ACE inhibitors, approximately 40 million
patients worldwide, it is the most common cause of acute
angioedema seen in emergency rooms [16]. ACE inhibitorinduced angioedema is more commonly seen among adults,
given the target population of the medication, but occurs
among children taking the medication as well. Half of the
cases occur within a week of starting therapy, but may
occur immediately after starting treatment or months to
years later. All ACE inhibitors are equally likely to cause
angioedema, as it appears to be a class effect, rather than a
drug-specific effect, and is not dependant on the dose
administered. There does appear to be a racial predilection
as African-American patients are five times more likely to
have angioedema from ACE inhibitors than Caucasian
patients [15]. Clinically, angioedema from ACE inhibitors
has a predilection for facial areas, and urticaria is generally
absent [17]. Intestinal edema may also occur, presenting
with symptoms of acute abdominal pain, diarrhea, and/or
vomiting that may mimic an acute abdomen.
The process by which ACE inhibitors induce angioedema is thought to involve the kinin pathway rather than

Fig. 2 The reninangiotensin

pathway with inhibitory action
of ACE inhibitors

Hereditary angioedema (HAE) is a rare autosomal dominant disease affecting 1 in 50,000 [12]. HAE reflects 1% of
all angioedema cases. Despite the rarity of hereditary forms
of angioedema, early recognition is important given the
high morbidity and mortality of the disease without
appropriate treatment. Hereditary angioedema is caused by
the deletion, duplication, or mutation in the complement
gene on chromosome 11 resulting in either a reduction in
the C1 esterase inhibitor (C1-INH) concentration or
decreased functional activity of the enzyme. Children
classically present with recurrent episodes of angioedema.
Of patients with HAE, 75% have cutaneous angioedema of
an extremity as the first presenting sign of the disease [4].
Other common symptoms include upper airway obstruction
and dysphagia occurring in approximately 50% of the
patients and recurrent colicky abdominal pain (40%) [19].
The majority of patients have their first attack before the
age of 5. Patients traditionally have milder symptoms in
childhood with more severe presentation in adolescence
after a precipitating event such as mechanical trauma,
stress, exercise, injury, or alcohol consumption that leads to
the diagnosis. Episodes may be less frequent than in
adulthood with intestinal edema perhaps more common
than laryngeal edema [20]. Triggers for angioedema

Angiotensinogen
RENIN
Angiotensin I

Bradykinin
ACE

Angiotensin II

Angiotensin
Receptor
Blockers

Inactive
Fragments
ACE
INHIBITORS

Angiotensin
II Receptor

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episodes include trauma, stress, infection, or medications.

HAE is associated with several autoimmune diseases
including thyroiditis, lupus, and Sjogrens syndrome.
Type I HAE involves a quantitative defect in the C1
esterase inhibitor and occurs in 85% of patients with C1INH levels decreased to 530% of the normal level [21].
Type II involves a functional defect in C1-INH and occurs
in the remaining 15%. C1-INH primarily degrades C1, a
component of the classical complement pathway, to prevent
excessive complement activation. It also inhibits the
generation of other proteins in the fibrinolytic system, in
particular, the enzyme kallikrein that transforms kininogen
to kinins [21]. Thus, a deficiency of this inhibitor results in
increased levels of vasoactive mediators, in particular,
bradykinin. Elevated bradykinin levels is thought to be
the main cause of the swelling seen in HAE [4, 22, 23].
HAE type III clinically resembles the hereditary angioedema disorders but does not have a known C1-INH,
complement, or kinin abnormality. It is described in women
particularly in association with estrogen and pregnancy and
may be an X-linked disorder, although the cause remains
unknown [23, 24].
Acquired Angioedema
Acute attacks of angioedema can also occur as a result of
the acquired form of the disease via an increased destruction or metabolism of C1-INH. Acquired angioedema is
usually clinically apparent after age 4050. These patients
do not have the genetic manifestations of hereditary HAE.
These patients resemble HAE clinically but can be
distinguished from HAE by their depressed C1q levels
(see Table 3).
Type I acquired angioedema occurs often in patients with
rheumatologic diseases and B cell lymphoproliferative
disorders such as chronic lymphoproliferative leukemia
(CLL), multiple myeloma, macroglobulinemia, and most
commonly, lymphoma [25]. Rare associations are also seen
with malignancies of the rectum, stomach, and breast, as
well as some connective tissue diseases and infections [26].
In type I acquired angioedema, the complement system is
thought to be continually activated resulting in the
consumption of complement factors including C1-INH.
Antiidiotypic antibodies against immunoglobulins on B

cells form immune complexes that activate the classical

pathway of the complement system through the activation
of its first component, C1. C1-INH is consumed as it
inactivates the large quantity of continuously activated C1.
When the C1 inhibitor level is lowered via consumption,
the result is an acute attack of angioedema. In type 2
acquired angioedema, autoantibodies against the C1-INH
are produced and ultimately bind the C1 inhibitor resulting
in the inactivation of the C1-INH [4] (Table 4).

Diagnostic Evaluation
A good clinical history including a thorough family history
is the key in the evaluation of angioedema. Associated
symptoms of urticaria, flushing, and pruritus suggest mast
cell degranulation, and the history should be directed to
unveiling possible triggers such as food, medications, or
insect stings. In the absence of such associated symptoms, a
search for hereditary causes is essential. A family history
and/or increased attacks at puberty may be suggestive of an
inherited form of the disease. Chronic and recurrent
angioedema generally requires further laboratory testing.
Chronic angioedema, in particular, necessitates an evaluation for possible underlying autoimmune disorders
(Table 5).
Several other conditions may produce similar clinical
manifestations to angioedema and should be considered in
the differential diagnosis, although angioedema is often
distinguishable based on its rapid onset, distribution, and
transient nature. Allergic contact dermatitis from cosmetics,
topical drugs, or poison ivy can present similarly to
angioedema, afflicting the facial areas with the skin
surrounding the eyes being particularly susceptible [27].
Facial cellulitis may present with facial edema as well,
although there is often fever, very prominent erythema, and
associated pain. Both facial cellulitis and contact dermatitis
may be accompanied by skin peeling upon resolution; this
does not occur in angioedema.
Hypothyroidism can also cause a puffiness of the face
and lips similar to angioedema and in severe hypothyroidism manifesting as myxedema coma, one may see a
generalized nonpitting edema. These conditions are generally not transient and are accompanied by other manifes-

Table 3 Hereditary and acquired angioedemalaboratory comparison

Type
Type
Type
Type

I hereditary angioedema
II hereditary angioedema
I acquired angioedema
II acquired angioedema

C4

C1q

C1-INH quantitative

C1-INH functional

Decreased
Decreased
Decreased
Decreased

Normal
Normal
Decreased
Decreased

Decreased
Normal
Decreased
Normal to mildly decreased

Decreased
Decreased
Decreased
Decreased

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Table 4 Classification of angioedema

Angioedema

Mechanism

Urticaria

Allergic
NSAID
Chronic angioedema
idiopathic or autoimmune
ACE inhibitor
Hereditary angioedema
Acquired C1 inhibitor deficiency
Angioedema with eosinophilia
Infections

IgE/mast cell
Mast cell
Mast cell

Frequently
Frequently
Frequently

Kinin
Kinin
Kinin
Other
Other

No
No
No
Usually
Usually

tations of a hypothyroid state such as cold intolerance, dry

skin, or coarse, brittle hair.
Several connective tissue disorders such as systemic
lupus erythematous, scleroderma, dermatomyositis, and
Sjogrens syndrome can manifest with facial and periorbital
edema. Other cutaneous manifestations such as malar rash,
photosensitivity, or the classic heliotropic (violaceous) rash
in dermatomyositis may be seen.
Tumors of the head and neck, lymphoma, or superior
vena cava syndrome may also cause edema of the face,
neck, and upper extremities, but are usually progressive
swelling rather than transient in nature. Superior vena cava
syndrome is often marked by a ruddy color of the skin
(rubor).
Angioedema of the gastrointestinal tract presents without
cutaneous involvement with symptoms of nausea, vomiting, and abdominal pain that may mimic an acute abdomen.
In children, in particular, this may easily be mistaken for
acute appendicitis. Parasitic infections such as trichinosis
may also present with abdominal pain, diarrhea, vomiting,
and periorbital edema that may mimic angioedema,
although significant myalgias are often present. Other more
unusual conditions include cheilitis granulomatosa, or
Mieschers cheilitis, an idiopathic condition characterized
by recurrent episodes of angioedema with resultant permanent lip enlargement.

Diagnosis
Diagnosis of angioedema is highly dependent on the
clinical history. The initial physical exam and history
should focus on likely agents such as medications,
infections, and foods. A detailed drug history should be
obtained including medications, vitamins, herbs, and over
the counter medications. A food history including the most
common foods that cause allergic reactions such as wheat,
milk, nuts, shellfish, egg, and peanuts should be specifically
discussed. Skin-prick testing or radioallergosorbent testing
(RAST) may be helpful in identifying IgE agonists suspect

triggers. A food diary may be helpful in discovering

offending foods. Laboratory findings may include an
elevated tryptase, a mast cell marker, which may remain
elevated within hours of an anaphylactic event, although a
negative tryptase level does not exclude an anaphylactic
event (Table 6).
Further laboratory testing is generally only needed for
recurrent, unexplained episodes of angioedema, and in
children with a strong family history suggestive of
hereditary angioedema. Workup should include an evaluation for possible lymphoproliferative, connective tissue,
autoimmune, thyroid, and hereditary disorders. An evaluation for a possible connective tissue disorder may include
an erythrocyte sedimentation rate, antinuclear antibody, and
complete blood count. Thyroid function tests and antithyroglobulin and antimicrosomal antibody may also be helpful

Table 5 Differential diagnosis of angioedema

Syndrome

Distinguishing clinical features

Facial cellulitis

Painful, possible fever, prominent

erythema. Peeling of skin upon
resolution often occurs
Not usually transient. Other
manifestations of hypothyroidism:
Fatigue, weight gain, dry skin, brittle
hair
Not usually transient. Generalized
nonpitting edema. Longstanding
history of thyroid disorder and/or acute
event trigger
Heliotrope rash (violaceous rash)
afflicting eyelids. Proximal muscle
weakness
Pruritis, scaling, pain, burning. May last
longer than 2448 h. Peeling of skin
upon resolution often occurs
Usually associated with rosacea
Edema not transient, exacerbated by
bending forward or lying down. Neck
vein distension. Associated with ruddy
color (rubor)
Progressive swelling, not transient.
Usually unilateral
Involves bilateral hands, Raynauds
phenomenon usually present
Malar rash. Other manifestations
of lupus
Peripheral blood eosinophilia, weight
gain, fever
Recurrent facial edema, fissured tongue,
facial nerve palsy occasionally occurs
Recurrent episodes of angioedema.
Eventual permanent enlargement of lip.
Idiopathic

Hypothyroidism

Myxedema coma

Dermatomyositis

Contact facial dermatitis

Facial lymphoedema
Superior vena cava
syndrome

Tumors (head and neck,

lymphoma)
Systemic sclerosis
Systemic lupus
erythematous
Hypereosinophilia
MelkerssonRosenthal
syndrome
Cheilitis granulomatosa
(Mieschers cheilitis

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Table 6 Laboratory testing in angioedema

Laboratory test

Clinical utility

Comment

Histamine

Confirm anaphylactic event

Tryptase
N-methyl histamine

Confirm anaphylactic event

Confirm anaphylactic event

Serum IgE antibody tests

Skin testing
Complement levels

Acute allergic angioedema

Acute allergic angioedema
Hereditary angioedema

C1 esterase levels
C1q levels
ESR, CBC, ANA,
antithyroglobulin, antimicrosomal

Hereditary angioedema
Acquired angioedema
Chronic angioedema

Elevated within 510 min after mast cell activation.

Elevated 30 min to 1 h
Peaks after 1 h, elevated for up to 6 h
Urinary metabolite of histamineelevated for
several hours
Can be obtained without delay
Delay 4 weeks after anaphylactic event
Useful in patients without urticaria to rule out
hereditary process
Distinguish type I and type II HAE
Distinguish AAE and HAE
Rule out an autoimmune etiology

given the association with thyroid disease and chronic

angioedema [28]. Complement levels are used to determine
if hereditary angioedema is present. Hereditary angioedema
shows a low C4 level during attacks; C1-INH level and
function are used to distinguish type I versus type II HAE
[22]. Acquired angioedema clinically presents similar to
hereditary angioedema and shows low C4 levels. The C1q
levels are used to distinguish acquired angioedema from
HAE. After the diagnosis of acquired angioedema, workup
to rule out an underlying malignancy is needed.

Treatment
Patients presenting with angioedema should first be
evaluated for airway compromise, in particular swelling of
the tongue, uvula, soft palate, or larynx. Such signs
necessitate immediate administration of epinephrine. Diuresis for pulmonary edema and ventilatory support may
Table 7 Pharmacotherapeutic management of chronic angioedema
Management of chronic angioedema
Step 1
Examples
Step 2
Examples
Step 3
Examples
Step 4
Example
Step 5
Example
Step 6

Addition of Second Generation H1

Receptor Antagonist
Cetirizine, Fexofenadine, Loratadine
Addition of First Generation H1 Receptor
Hydroxyzine, Diphenhydramine
Addition of H2 or H1 plus H2 Receptor
Antagonist
Doxepin, Cimetidine, Ranitidine
Add Leukotriene Receptor Modulator
Montelukast
Add oral corticosteroid
Prednisone 1040 mg/day short course
Dermatology and/or allergy consult

also become necessary in this setting. Intravenous corticosteroids have become the mainstay of treatment with
adjunctive antihistamines, such as Benadryl, used to reduce
pruritis and inflammation (Table 7).
Children with airway symptoms show rapid improvement with intravenous corticosteroids and histamines when
compared to adults [29]. It is unclear whether children are
simply more responsive to such treatments or whether they
have a slower progression of angioedema. More likely it is
because of the causes of angioedema, which in children is
usually because of food or other mast cell processes that
respond better to steroid and antihistamine treatment,
whereas in adults, medications are the most common cause,
which generally responds to cessation of the drug.
In most cases of angioedema, avoidance of triggers may
be the only treatment needed. The mainstay of medical
treatment for outpatient management of angioedema is
antihistamines. First generation H1 receptor blockers such
as diphenhydramine are often used for their rapid onset of
action. Second generation H1 receptor antagonists include
loratadine and fexofenadine, and are generally preferred
secondary to their nonsedating effects and less frequent
dosing. If the H1 receptor blocker or second generation H1
receptor antagonists are not adequate for the control of
symptoms, the addition of an H2 receptor antagonist such
as cimetidine or doxepin, a tricyclic antidepressant with
potent H1 and H2 blocking ability, may be helpful [30, 31].
Leukotriene modulators such as montelukast may be
helpful in certain patients in terms of reducing swelling
and hives and may have a role in the prevention of attacks
in the chronic setting [3, 32]. Patients unresponsive to
antihistamine treatment may require a short term of low
dose oral corticosteroids. Children with a history of
urticaria and angioedema should be prescribed and parents
taught to use an epinephrine autoinjector. Patients should

258

also be instructed to wear a medical alert bracelet, as well

as educated that they may experience recurrent symptoms
and instructed on the action to take in such situations.
The efficacy of antihistamines and steroids that are used
in mast cell-associated angioedema has not been documented to be effective in angioedema caused by kininmediated processes such as ACE-induced angioedema. In
ACE inhibitor-induced angioedema, for example, cessation
of medication use is crucial, as recurrence with continuation
has been well documented. With discontinuation of the
drug, symptoms generally resolve within 24 to 48 h.
Angiotensin receptor blockers do not affect bradykinin
and theoretically should not result in angioedema; they may
serve as a good alternative to ACE inhibitors.
In HAE, treatment involves treating acute edematous
attacks, short-term prophylaxis, and long-term prophylaxis.
In an emergency situation, acute attacks are optimally
treated with C1-INH concentrate or fresh frozen plasma,
which contains C1-INH concentrate. Prophylactic treatment
is via androgens or antifibrinolytics. In pediatric patients,
antifibrinolytic agents are the first choice for long-term
prophylaxis given the more favorable safety profile when
compared to androgens [33]. If antifibrinolytics are ineffective, then attenuated androgens such as danazol and
stanazol can be used. The mechanism by which attenuated
androgens act is not fully understood although the efficacy
in relieving symptoms has been well established. Among
adults, danazol reduced the risk of at least one acute
episode from 94% to 2.2% over a 28-day period and
reduced the frequency of attacks from monthly to one every
10 months [20]. These androgen derivatives notably
increase the levels of C4, but they likely have other
additional effects as some patients respond before their C4
levels have normalized [34]. Androgens are noted to cause
side effects such as weight gain, menstrual irregularities,
headaches, hirsutism, tremor, and libido changes. Of
particular concern in children are the effects on linear
growth, virilization, delay of menarche, and effects on the
liver. To limit potential adverse effects, the lowest effective
dose should be used. Short-term prophylaxis is needed for
procedures such as head and neck surgeries, most notably
dental procedures or tonsillectomy in children. Antifibrinolytic agents or attenuated androgens in higher doses may be
used; alternatively, C1-INH concentrate may be necessary
in a patient with severe attacks in prior situations.

Summary
Angioedema is encountered with increasing frequency
particularly among children, and it is important to
recognize and treat to prevent life-threatening manifestations such as airway obstruction or anaphylaxis. The

Clinic Rev Allerg Immunol (2008) 34:250259

most common forms of angioedema in children are

secondary to mass cell degranulating processes and are
self limiting, requiring only a thorough history and
possible skin-prick testing to discover external triggers
such as food, infection, or medications. There is likely a
genetic basis to at least some forms of angioedema but,
unlike autoimmune disease, these have not been mapped.
In addition, the role of subpopulations of immune cells
in the inflammatory response is also poorly described,
again, unlike autoimmunity [3543].
More comprehensive laboratory testing is necessary only
for recurrent unexplained episodes of angioedema or in
children with a family history of the disease. Although
angioedema is still not fully understood, we have made
advances in our understanding of the possible causes and
clinical course of angioedema. An understanding of these
potential mechanisms by which angioedema can occur as
well as the chronicity of the angioedema can help guide the
clinician in determining the extent of diagnostic testing and
the need for acute and prophylactic treatment.

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