Curr Allergy Asthma Rep (2017) 17:60
DOI 10.1007/s11882-017-0729-7
PEDIATRIC ALLERGY AND IMMUNOLOGY (W DOLEN, SECTION EDITOR)
Pediatric Angioedema
Debendra Pattanaik 1 & Jay Adam Lieberman 2
# Springer Science+Business Media, LLC 2017
Abstract
Purpose of Review The aims of this study are to update the
clinician on current understanding of angioedema as it pre-
sents in the pediatric population and to review proper diag-
nostic techniques and treatment modalities for various types of
angioedema.
Recent Findings Angioedema is still best classified by wheth-
er it is likely histaminergic or kinin-mediated. New guidelines
have been published around the world to help diagnose and
treat both forms (urticaria/angioedema and hereditary angio-
edema). The vast majority of the studies on treatment have
been conducted in the adult population; however, there are
data available in the pediatric population. In the realm of he-
reditary angioedema, there are multiple new therapies that
have been studied in the pediatric population (down to 2 years
in some studies) in recent years and offer the clinician options
for treatment.
Summary Angioedema (whether occurring with or without
urticaria) is common in the pediatric population. The majority
of the recent studies has been conducted in hereditary angio-
edema, and now, the clinician should have various options
to treat all forms of angioedema. Many treatment options,
This article is part of the Topical Collection on Pediatric Allergy and
Immunology
* Jay Adam Lieberman
jlieber1@uthsc.edu
1
Department of Internal Medicine, Division of Rheumatology, The
University of Tennessee Health Science Center, 51 North Dunlap,
Suite 400, Memphis, TN 38105, USA
2
Department of Pediatrics, Division of Allergy & Immunology, The
University of Tennessee Health Science Center, 51 North Dunlap,
Suite 400, Memphis, TN 38105, USA
especially for hereditary angioedema, are further being exam-
ined specifically in the pediatric population.
Keywords Angioedema . Pediatric . C1 inhibitor . Urticaria .
Hereditary . Angioedema treatment
Introduction
Angioedema is localized, non-pitting, and transient swelling
of submucosal or subcutaneous region and is distinct from
pitting edema secondary to interstitial fluid accumulation. It
is commonly non-dependent, asymmetric, and non-pruritic,
affecting loose connective tissues such as seen in the tongue,
lip, face, mouth, throat, and extremities [1]. Often, it is a self-
limiting, benign condition but can present as a medical emer-
gency secondary to upper airway obstruction. Clinically, an-
gioedema that is associated with urticaria or pruritus is classi-
cally separated from angioedema not associated with these
findings, as the pathophysiology of urticaria/angioedema is
typically thought of as histamine-mediated, while angioedema
without any urticaria or pruritus points to another etiology
such as the kinin-mediated angioedema seen in hereditary
angioedema (HAE). While pure pediatric studies of angioede-
ma are limited, there have been major advances in the under-
standing of the pathophysiology of angioedema recently,
which have led to improved treatments and outcomes. This
review will discuss angioedema seen in the pediatric popula-
tion and will concentrate on reports within the past few years.
Epidemiology
The exact incidence and prevalence rate of pediatric angioede-
ma is not well known, and any reported rate will clearly vary
60 Page 2 of 8
depending on whether angioedema is considered with or with-
out urticaria, or on a specific cause of the angioedema. Two
nationwide studies (one from Japan and one from Denmark)
reported the lifetime prevalence of non-hereditary angioede-
ma to be 4.9 and 7.4% [2, 3]. Other studies have indicated that
15 to 25% of the population at some time in their life will
suffer from urticaria/angioedema, and children are commonly
affected [4]. If discussing only HAE, reports have estimated
that about 1 in 50,000 individuals is affected with a range of 1
in 10,000–1 in 150,000 worldwide [5]. Subjects of both sexes
and all races are affected.
Pathogenesis
Angioedema occurs secondary to vasodilation, increased
tissue permeability, and resultant interstitial edema, which
can occur through two principal pathways. First, mast
cell/basophil degranulation can lead to release of vasoac-
tive substances (e.g., histamine, prostaglandin D2, leuko-
triene C4, D4, and platelet-activating factor) and activation
of the kinin pathway. This can occur through IgE-mediat-
ed, type I hypersensitivity reactions (triggered by foods,
medications, insect stings, etc.) or through direct mast cell
degranulation (triggered by radiocontrast media, opiates,
etc.). The second pathway involves unregulated activation
of the kinin pathway resulting in excess bradykinin.
Bradykinin binds to the bradykinin B2 receptor on vascular
endothelial cells and causes phosphorylation of vascular
endothelial cell cadherin (VE-cadherin) leading to destruction
of VE cadherin. VE-cadherin is the key protein involved in the
formation of endothelial tight junctions and loss of it leads to
water movement from vascular space to extracellular space
causing angioedema [6]. This latter pathway is the pathway
involved in HAE and ACE inhibitor-induced angioedema
discussed below.
Etiology and Classification of Angioedema
Based on the above pathophysiologic pathways, angioedema
can be classified into one of the following categories, which
may aid the clinician in diagnosis and development of a treat-
ment plan. As for timing, classically, angioedema is separated
into chronic if it has occurred for 6 weeks or longer.
Allergic (Histaminergic) Angioedema
Angioedema is more likely to be allergic when it is associated
with urticaria and/or pruritus; however, it can present without
these even when caused by an allergic trigger. For example, in
reports examining successive patients presenting with angio-
edema without urticaria, approximately 10–15% of patients
Curr Allergy Asthma Rep (2017) 17:60
have been reported to have an allergic trigger identified as
the likely cause, and this was consistent in both pediatric
and adult populations [7, 8]. Because the pathophysiology in
these patients is IgE-mediated, the etiologies are thought to
be similar to anaphylaxis with foods, medications, insect
stings being typical triggers and foods being the major cause
in pediatric patients. Aeroallergens have also been reported as
triggers for angioedema alone in pediatric patients [8]. Finally,
it should be noted that allergy to galactose-α-1,3galactose (α-
gal) causing delayed symptoms after ingestion of mammalian
meats has been well described in a large pediatric cohort and
about 1/3 of those patients presented with angioedema [9].
Chronic Spontaneous Urticaria/Angioedema
About 40% patients with chronic urticaria present with both
angioedema and urticaria and 20% present with angioedema
only [10]. While chronic urticaria is more common in adults,
it does present in childhood as well. Like chronic spontaneous
urticaria, chronic angioedema (with or without urticaria) is of-
ten idiopathic. Some patients with chronic urticaria/angioedema
(up to 40% in some cohorts) will have detectable IgG antibod-
ies directed against the α subunit of the IgE receptor (and a few
with antibodies against the α subunit of IgE) and thus can be
classified as autoimmune urticaria/angioedema [11••].
NSAID-Induced Angioedema
Non-steroidal anti-inflammatory drugs can lead to angioedema
through COX-1 inhibition and the generation of various effector
mediators such as cysteinyl leukotrienes or by IgE-mediated
reactions [12]. Various NSAIDs are associated with angioedema
(with aspirin possibly being the most common, but this may be
simply dependent on the commonness of use). In one large
retrospective review of pediatric patients, 4.1% of atopic patients
at one center reported facial angioedema secondary to NSAIDs.
Incidence of angioedema increased with age, and it peaked at
21% in the 16 to 21 years age group (compared to 2% in those
under 5 years old) [13]. In another recent study of pediatric
patients presenting with angioedema without urticaria, 6% were
reported to have NSAID-induced angioedema and all of these
patients were reported to have NSAID-induced cross reactivity
[8]. Finally, angioedema can be the most frequent presenting
symptom and sign in children with NSAID hypersensitivity
[14]. Thus, clinicians should be aware of this and asking about
NSAID use should be done in all patients (pediatric and adult)
presenting with angioedema or urticaria/angioedema.
Hereditary Angioedema
HAE is a rare autosomal dominant disease caused by muta-
tions in the C1-inhibitor (C1-INH) gene (SERPING1), which
leads to decreased C1-INH protein levels (Type 1 HAE) or
Curr Allergy Asthma Rep (2017) 17:60
secretion of dysfunctional protein (Type 2 HAE). Both forms
lead to elevated levels of bradykinin which is thought to be the
major mediator of the angioedema [6]. HAE is rare and is
actually an uncommon cause of angioedema in the pediatric
population. Few reports have examined how often HAE is the
cause of all comers with angioedema in the pediatric popula-
tion specifically. One report out of a tertiary care center in
Turkey showed that out of nearly 100 successive pediatric
patients presenting with angioedema, none were eventually
diagnosed with HAE [8]. Nevertheless, HAE clearly occurs
in children. In fact, the majority of all HAE patients have the
initial swelling episode during the first or second decade of
life, with almost all patients manifesting symptoms by age 18,
and many patients experiencing a worsening of symptoms
around puberty [15, 16]. In one large US cohort, the median
age of first swelling was 11 years [16]. Cohorts reporting these
data typically rely on recall through questionnaires of adult
patients. Pediatric-specific cohorts are rare, although a few
groups have recently reported on their experiences with pedi-
atric HAE, mainly through retrospective studies [17–19].
These are summarized in Table 1.
In pediatric-specific cohorts, the extremities and abdomen
appear to be the two most common sites of attacks [17–19].
Subjects can have prodromal symptoms, most commonly fa-
tigue, nausea, and flu-like symptoms [20]. They can also have
a rash (typically prodromal) that is described as a non-urticar-
ial, erythematous rash with a reticulate and serpentine appear-
ance similar to that of erythema marginatum, which can be
seen in up to 50% of patients [21]. In fact, some newborns
with HAE may present with erythema marginatum within the
first few days of life, which can be a sign of bradykinin activ-
ity and prompt work up for HAE if appropriate [22].
Type III HAE is mainly seen in women, and these patients
have normal levels and functional C1-INH. Some patients
demonstrate activating mutations in the coagulation factor
XII (Hageman factor; HAE-FXII) [23]. Type III is essentially
irrelevant in children and adolescents [24].
Acquired Angioedema
In acquired angioedema, there is thought to be an acquired
deficiency of C1 INH secondary increased consumption in
conditions such as lymphoproliferative disorders like lympho-
ma, leukemia, multiple myeloma, solid cancers, infections,
and autoimmune diseases, e.g., SLE or possibly due to auto-
antibodies against C1INH [25]. This type of angioedema is
quite rare in the pediatric population.
ACE Inhibitor (ACEI)-Induced Angioedema
ACEI-induced angioedema is less common in children than
adults, and only case reports are available [26, 27] and thus
will not be discussed in detail in this review.
Page 3 of 8 60
Miscellaneous Causes
Among children, infections, particularly viral infections, seem
to be a leading trigger for other causes of angioedema. Viruses,
e.g., herpes simplex, coxsackie A and B, hepatitis B, Epstein–
Barr, and other viral illnesses such as upper respiratory tract
infections, may produce circulating immune complex resulting
in anaphylatoxins. Bacterial infections, e.g., otitis media, sinus-
itis, tonsillitis, upper respiratory tract infections, and urinary
tract infections, are also associated with angioedema in chil-
dren. Other etiologies may include hypereosinophilic syn-
drome, urticarial vasculitis, autoimmune disease, and autoim-
mune thyroiditis; although these are not commonly associated
with angioedema alone and are rare in children [7, 8, 28].
Finally, clinicians must be aware that factitious angioedema
can occur in the pediatric patient population (as well as the
adult) and should consider this when evaluating patients, espe-
cially in patients with normal lab findings [29].
Diagnosis
As with most other diseases, the history and physical exami-
nation remain fundamental to making a diagnosis and deter-
mining the etiology of the angioedema. Perhaps the single
most important aspect of the history is whether or not the
angioedema is associated with urticaria or pruritus (or any
other sign/symptom of mast cell-mediated disease), as the
answer to this question should steer the clinician down two
very different diagnostic paths. Other aspects of importance
include the duration of symptoms, the location of swelling,
and any family history of angioedema. Specific inquiry should
also be made about the triggering factors, e.g., foods, medica-
tions including OTCs, insect bites/stings, exposure or contact
with inhalant allergens, exposure to physical agents (pressure,
heat), exercise, emotional stress, and alcohol ingestion. Patients
should be asked about recent viral and bacterial illness or fevers
as infection may trigger angioedema as discussed above. In
addition to asking about medication triggers, the clinician
should ask about the response to medications, specifically
antihistamines and steroids as this can be extremely helpful
(allergic/histaminergic angioedema may respond to these ther-
apies, while non-allergic/bradykininergic angioedema would
not be expected to respond).
Recurrent angioedema without urticaria suggest the possi-
bility of hereditary angioedema (HAE) and work up for this
(discussed below) will be quite different than the work up for
angioedema associated with urticaria/pruritus.
Diagnostic Testing
Diagnostic testing should be selective and based on the history
and physical as above. If the angioedema is associated with
60 Page 4 of 8
Table 1 Findings from pediatric only cohorts with hereditary angioedema
Nanda et al. [18]
Number of patients 21
Gender (% male) 71%
Ethnicity (% White) 95
Family History of HAE 86%
Median age at symptom onset 5.7 years
Median age at diagnosis:
With family history 5.0 years
Without family history 10.0 years
Type of HAE Not reported
Most common site of attack Abdominal
urticaria, this should drive one line of testing. In these in-
stances, if the history suggests it, appropriate skin prick testing
or serum-specific IgE to foods, drugs, or venoms may be
helpful to determine the etiology in acute cases. However, in
cases of chronic urticaria/angioedema, allergy testing is rarely
warranted. There are recent guidelines published from both
US and European organizations to help guide testing for urti-
caria/angioedema, and the authors refer to these guidelines for
a more in-depth discussion for this work up [11••, 30]. Briefly,
typically no testing is warranted in these patients; however,
tests such as a CBC with differential, sedimentation rate (or C-
reactive protein), liver enzymes, thyroid-stimulating hormone,
anti-nuclear antibody, autologous serum skin testing, or auto-
antibodies to the high-affinity IgE receptor may be of use in a
limited number of cases. Many times, in the authors’ experi-
ences, these labs can serve to help soothe and address the fears
of the patient/parent as much as they can add to the decision
making process.
If the angioedema is not associated with urticaria, then this
should lead the clinician down a separate diagnostic pathway.
In patients suspected of having HAE, measuring complement
C4 levels is the best initial screening test to exclude a diagno-
sis of HAE. The vast majority of patients will have low C4 at
baseline, and essentially all patients will have a low C4 level
during an attack [31•]. The next step should be to obtain
C1INH antigenic level and C1INH function. The C1INH
functional level should be less than 50–60% to be compatible
with diagnosis of HAE. Laboratory testing is similar in ac-
quired angioedema. Of special note in the pediatric popula-
tion, complement and C1INH levels can be low physiologi-
cally in neonates, and thus, experts recommend delaying
checking these until 1 year old age if possible (with genetic
testing available if absolutely needed prior to that time) [32•].
One recent report suggests that while this is true for C4, the
C1INH level and functional assessments may be accurate in
patients under 1 year of age however [33] Thus, it may be
reasonable to send these labs even in infants <1 year of age.
Curr Allergy Asthma Rep (2017) 17:60
Bennet et al. [19] Farkas et al. [17]
25 50
48% 46%
Not reported Not reported
84% 84%
7.7 years 5 years
7.2 years 8 years
9.5 years (Data not broken down by family history)
100% Type I 90% Type I
Upper extremity Upper extremity
Type 3 HAE patients have normal laboratory testing but are
exclusively female and have strong family history. Low C1 q
levels point to a diagnosis of acquired angioedema, although
this diagnosis is rare in the pediatric population. These labo-
ratory parameters are normal in idiopathic angioedema, drug-
induced angioedema including ACEI- and NSAID-induced
angioedema, and allergic angioedema.
For drug-induced angioedema, the clinician has to make a
decision whether a drug challenge is warranted to make the
diagnosis (i.e., if the benefits of the challenge outweigh the
risks) and this is likely to be case-dependent.
Treatment
In cases of acute angioedema, identification of the trigger and
avoidance of the trigger is the mainstay of therapy. As
discussed however, it is more common than not that a trigger
will not be identified. There are up to date guidelines to aid
clinicians in the treatment of chronic urticaria/angioedema
[11••, 30]. Briefly, non-sedating H1 antihistamines remain
the primary treatment option. Studies have used standard
dosing to up to four times standard dosing with success and
minimal side effects [34•]. However, those caring for pe-
diatric patients should be aware that the majority of these
studies were in adults with some enrolling pediatric pa-
tients down to 12 years of age. To the authors’ knowledge,
there are no trials of four times standard dosing in the
pediatric population specifically. The addition of H2 anti-
histamines, leukotriene receptor antagonists, and sedating
1st generation antihistamines are typically the next step in
management if the patient does not respond to non-sedating
H1 antihistamines.
The addition of immunomodulators is typically withheld
until the patient fails the above measures. In the authors’ prac-
tice, typically pediatric patients are considered failures
after non-response to twice daily dosing of non-sedating
Curr Allergy Asthma Rep (2017) 17:60 Page 5 of 8 60

antihistamines (e.g., cetirizine 5 mg twice daily in children 2–
7 years and 10 mg twice daily in children >7 years) plus an as
needed sedating antihistamine (1 mg/kg hydroxyzine). Of
available immunomodulators, omalizumab and cyclosporine
probably have the most data in the pediatric population
(omalizumab studied down to 12 and cyclosporine down
to 9 years of age for this condition) [35, 36•, 37, 38].
Other immunomodulators (dapsone, hydroxychloroquine,
sulfasalazine, colchicine, and methotrexate) have been report-
ed more often in adults. Oral or systemic corticosteroids are
not recommended, especially for long-term management.
HAE patients do not respond to the above therapies (anti-
histamines, corticosteroids, and immunomodulators) as bra-
dykinin is the primary mediator of the angioedema. The cur-
rent treatment strategies involve either replacement of CINH,
inhibiting the generation of bradykinin, or blocking the action
of bradykinin. There are various medications approved for
treating acute attacks and/or for prophylaxis, and there are
now multiple national and international guidelines on the
treatment of HAE [31•, 39–41]. In addition, a recent US med-
ical advisory board of experts as well as a European consensus
of experts have published recommendations on treatment of
HAE specifically in the pediatric population [24, 32•] While
an in-depth discussion of each of these therapies and their use
in the pediatric population is beyond the scope of this review,
there is a recent review specifically examining C1INH use in
the pediatric population [42]. We outline all of the therapies in
Table 2 and briefly discuss them below.
C1 Inhibitor Replacements
Berinert (CSL Behring, Marlberg, Germany) is a plasma-de-
rived, human C1INH that currently has an FDA-approved
indication for treatment of acute attacks of HAE in the pedi-
atric population. Berinert has been studied in both retrospec-
tive studies and prospective studies (most often for acute at-
tacks, but has been reported for prophylaxis) [17, 43–47]. In
Europe, where it has been available for a longer period of
time, it has been reported on in children down to 2.5 years
of age (fixed dose) [43]. In the US studies, it has been reported
down to 6 years of age (weight-based) [44, 45]. It has been
shown to be safe and effective when administered at home in
the pediatric population [46].
Cinryze (Shire/Viropharma, Lexington, MA) is also a plas-
ma-derived, human C1INH. While it has been studied for
acute attacks in the pediatric population and appears safe
and effective down to 6 years of age [48, 49], currently
Cinryze only has an FDA indication for prophylaxis in ado-
lescents and adults.
Haegarda (CSL Behring, Marlberg, Germany) is a plasma-
derived C1INH that was just recently approved by the FDA

Table 2 Products available for

the treatment of hereditary
angioedema with pediatric focus
Products Route of administration FDA-approved age Indication
C1 inhibitor concentrate
(plasma-derived)
Berinert Intravenous 12 years and above Acute attacks
(reports down to 2 years)
Cinryze Intravenous 12 years and above Prophylaxis
(reports down to 2 years)
Haegarda Subcutaneous 12 years and above Prophylaxis
Recombinant C1 inhibitor
Conestat alfa (Ruconest) Intravenous 18 years and above Acute attacks
(reports down to 14 years)
Bradykinin B2 receptor antagonist
Icatibant (Firazyr) Subcutaneous 18 years and above Acute attacks
(reports down to 2 years)
Kallikrein inhibitor
Ecallantide (Kalbitor) Subcutaneous 12 years and above Acute attacks
(reports down to 10 years)
Fresh frozen plasma Intravenous N/A. Used in all ages Acute attacks
Antifibrinolytic agents
Tranexamic acid Oral Not approved for HAE Prophylaxis
17α-Alkylated androgens
Danazol Oral 18 years and above Prophylaxis
(not recommended for
pediatric population)
60 Page 6 of 8
for prophylaxis and can be administered subcutaneously twice
weekly. It was studied down to 12 years of age [50•].
Ruconest (Pharming Technologies BV, Leiden, the
Netherlands) is a recombinant C1INH that currently has
FDA-approved indication for treatment of acute attacks in
adults and adolescents (phase III trial enrolled down to
13 years of age), with a very recent open-label extension study
specifically evaluating its safety and efficacy in adolescents
[51, 52].
Other Therapies
Icatibant (Firazyr; Shire, Lexington, Mass) is a bradykinin B2
receptor antagonist that currently has FDA approval for the
treatment of acute attacks in adults only. It has recently been
studied in pediatric patients down to 2 years of age however
with results similar to the adult trials [53].
Ecallantide (Kalbitor Shire, Lexington, MA) is a human
plasma kallikrein inhibitor that has FDA approval for the treat-
ment of acute attacks in patients 12 years of age or older. The
initial efficacy study enrolled subjects 10 years of age and
olderm and there has since been a follow-up study pooling
all pediatric subjects in four efficacy trials, suggesting that
ecallantide is as effective and safe in adolescents as it is in
adults [54, 55].
Avoralstat, an oral inhibitor of the conversion of
prekallikrein to plasma kallikrein, has been studied in adults
[56]. However, it does not appear that this molecule (in
its current form) will proceed through further testing.
Lanadelumab is a fully human monoclonal antibody that in-
hibits kallikrein. Results from the initial study on its use in
adults have now been published [57]. Further studies down to
12 years of age have been conducted with no results published
to date.
Other therapies include Danazol, fresh frozen plasma, and
tranexamic acid. These therapies were used more often prior
to the advent of the more recent therapies discussed above.
Danazol, in particular, is not recommended for children any
longer given its side effect profile and the efficacy of the
newer products.
As most of the newer therapies are effective (typically
working within 1–2 h), and there are no head-to-head trials,
deciding on a therapy for pediatric patients with HAE must
take many factors into account and there is no single best drug
for all patients. Factors to take into account include age, co-
morbidities, ability to self-administer and route of administra-
tion, location of administration (most can be administered
safely at home), cost, access to emergency medical facilities,
patient/parent preference, requirement for prophylactic versus
on-demand therapy, and patient past experiences. Based on
these, as well as other factors, the clinician must decide on
an appropriate therapy for each individual patient.
Curr Allergy Asthma Rep (2017) 17:60
Most experts do agree that no matter the selected treatment,
HAE patients should have a treatment plan in place, attacks
should be treated early, and patients should avoid triggers such
as estrogens and ACE inhibitors. For children, this may mean
discussing with school how attacks need to be managed, wear-
ing medical alert jewelry, having an understanding of where
treatment for an acute attack should be given (local emergency
departments may need to be aware of their treatment and may
not stock their medication, especially in less populated or rural
areas). They should also have a treatment plan in place for
occasions when they are likely to have an attack, such as prior
to surgeries or dental procedures.
Conclusions
Angioedema is a common symptom in the pediatric popula-
tion. Most commonly, this seems to be associated with infec-
tion or allergy (mast cell-mediated) when acute. When chron-
ic, the most common type is idiopathic. When not associated
with pruritus or urticaria, the clinician must consider HAE and
send off diagnostic studies accordingly.
There are now national and international guidelines to aid
the clinician in diagnosing and treating all causes of angioede-
ma with some specific guidelines geared toward the pediatric
patient. In the realm of HAE, there are new therapies available
that have now been studied in both adolescents and pediatric
patients.
Compliance with Ethical Standards
Conflict of Interest The authors declare no conflicts of interest relevant
to this manuscript.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Funding Source None.
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