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Curr Allergy Asthma Rep (2017) 17:60

DOI 10.1007/s11882-017-0729-7


Pediatric Angioedema
Debendra Pattanaik 1 & Jay Adam Lieberman 2

# Springer Science+Business Media, LLC 2017

Abstract especially for hereditary angioedema, are further being exam-

Purpose of Review The aims of this study are to update the ined specifically in the pediatric population.
clinician on current understanding of angioedema as it pre-
sents in the pediatric population and to review proper diag- Keywords Angioedema . Pediatric . C1 inhibitor . Urticaria .
nostic techniques and treatment modalities for various types of Hereditary . Angioedema treatment
Recent Findings Angioedema is still best classified by wheth-
er it is likely histaminergic or kinin-mediated. New guidelines Introduction
have been published around the world to help diagnose and
treat both forms (urticaria/angioedema and hereditary angio- Angioedema is localized, non-pitting, and transient swelling
edema). The vast majority of the studies on treatment have of submucosal or subcutaneous region and is distinct from
been conducted in the adult population; however, there are pitting edema secondary to interstitial fluid accumulation. It
data available in the pediatric population. In the realm of he- is commonly non-dependent, asymmetric, and non-pruritic,
reditary angioedema, there are multiple new therapies that affecting loose connective tissues such as seen in the tongue,
have been studied in the pediatric population (down to 2 years lip, face, mouth, throat, and extremities [1]. Often, it is a self-
in some studies) in recent years and offer the clinician options limiting, benign condition but can present as a medical emer-
for treatment. gency secondary to upper airway obstruction. Clinically, an-
Summary Angioedema (whether occurring with or without gioedema that is associated with urticaria or pruritus is classi-
urticaria) is common in the pediatric population. The majority cally separated from angioedema not associated with these
of the recent studies has been conducted in hereditary angio- findings, as the pathophysiology of urticaria/angioedema is
edema, and now, the clinician should have various options typically thought of as histamine-mediated, while angioedema
to treat all forms of angioedema. Many treatment options, 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-
This article is part of the Topical Collection on Pediatric Allergy and ma are limited, there have been major advances in the under-
Immunology standing of the pathophysiology of angioedema recently,
which have led to improved treatments and outcomes. This
* Jay Adam Lieberman review will discuss angioedema seen in the pediatric popula-
tion and will concentrate on reports within the past few years.
Department of Internal Medicine, Division of Rheumatology, The
University of Tennessee Health Science Center, 51 North Dunlap,
Suite 400, Memphis, TN 38105, USA Epidemiology
Department of Pediatrics, Division of Allergy & Immunology, The
University of Tennessee Health Science Center, 51 North Dunlap, The exact incidence and prevalence rate of pediatric angioede-
Suite 400, Memphis, TN 38105, USA ma is not well known, and any reported rate will clearly vary
60 Page 2 of 8 Curr Allergy Asthma Rep (2017) 17:60

depending on whether angioedema is considered with or with- have been reported to have an allergic trigger identified as
out urticaria, or on a specific cause of the angioedema. Two the likely cause, and this was consistent in both pediatric
nationwide studies (one from Japan and one from Denmark) and adult populations [7, 8]. Because the pathophysiology in
reported the lifetime prevalence of non-hereditary angioede- these patients is IgE-mediated, the etiologies are thought to
ma to be 4.9 and 7.4% [2, 3]. Other studies have indicated that be similar to anaphylaxis with foods, medications, insect
15 to 25% of the population at some time in their life will stings being typical triggers and foods being the major cause
suffer from urticaria/angioedema, and children are commonly in pediatric patients. Aeroallergens have also been reported as
affected [4]. If discussing only HAE, reports have estimated triggers for angioedema alone in pediatric patients [8]. Finally,
that about 1 in 50,000 individuals is affected with a range of 1 it should be noted that allergy to galactose-α-1,3galactose (α-
in 10,000–1 in 150,000 worldwide [5]. Subjects of both sexes gal) causing delayed symptoms after ingestion of mammalian
and all races are affected. meats has been well described in a large pediatric cohort and
about 1/3 of those patients presented with angioedema [9].

Pathogenesis Chronic Spontaneous Urticaria/Angioedema

Angioedema occurs secondary to vasodilation, increased About 40% patients with chronic urticaria present with both
tissue permeability, and resultant interstitial edema, which angioedema and urticaria and 20% present with angioedema
can occur through two principal pathways. First, mast only [10]. While chronic urticaria is more common in adults,
cell/basophil degranulation can lead to release of vasoac- it does present in childhood as well. Like chronic spontaneous
tive substances (e.g., histamine, prostaglandin D2, leuko- urticaria, chronic angioedema (with or without urticaria) is of-
triene C4, D4, and platelet-activating factor) and activation ten idiopathic. Some patients with chronic urticaria/angioedema
of the kinin pathway. This can occur through IgE-mediat- (up to 40% in some cohorts) will have detectable IgG antibod-
ed, type I hypersensitivity reactions (triggered by foods, ies directed against the α subunit of the IgE receptor (and a few
medications, insect stings, etc.) or through direct mast cell with antibodies against the α subunit of IgE) and thus can be
degranulation (triggered by radiocontrast media, opiates, classified as autoimmune urticaria/angioedema [11••].
etc.). The second pathway involves unregulated activation
of the kinin pathway resulting in excess bradykinin. NSAID-Induced Angioedema
Bradykinin binds to the bradykinin B2 receptor on vascular
endothelial cells and causes phosphorylation of vascular Non-steroidal anti-inflammatory drugs can lead to angioedema
endothelial cell cadherin (VE-cadherin) leading to destruction through COX-1 inhibition and the generation of various effector
of VE cadherin. VE-cadherin is the key protein involved in the mediators such as cysteinyl leukotrienes or by IgE-mediated
formation of endothelial tight junctions and loss of it leads to reactions [12]. Various NSAIDs are associated with angioedema
water movement from vascular space to extracellular space (with aspirin possibly being the most common, but this may be
causing angioedema [6]. This latter pathway is the pathway simply dependent on the commonness of use). In one large
involved in HAE and ACE inhibitor-induced angioedema retrospective review of pediatric patients, 4.1% of atopic patients
discussed below. 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
Etiology and Classification of Angioedema under 5 years old) [13]. In another recent study of pediatric
patients presenting with angioedema without urticaria, 6% were
Based on the above pathophysiologic pathways, angioedema reported to have NSAID-induced angioedema and all of these
can be classified into one of the following categories, which patients were reported to have NSAID-induced cross reactivity
may aid the clinician in diagnosis and development of a treat- [8]. Finally, angioedema can be the most frequent presenting
ment plan. As for timing, classically, angioedema is separated symptom and sign in children with NSAID hypersensitivity
into chronic if it has occurred for 6 weeks or longer. [14]. Thus, clinicians should be aware of this and asking about
NSAID use should be done in all patients (pediatric and adult)
Allergic (Histaminergic) Angioedema presenting with angioedema or urticaria/angioedema.

Angioedema is more likely to be allergic when it is associated Hereditary Angioedema

with urticaria and/or pruritus; however, it can present without
these even when caused by an allergic trigger. For example, in HAE is a rare autosomal dominant disease caused by muta-
reports examining successive patients presenting with angio- tions in the C1-inhibitor (C1-INH) gene (SERPING1), which
edema without urticaria, approximately 10–15% of patients leads to decreased C1-INH protein levels (Type 1 HAE) or
Curr Allergy Asthma Rep (2017) 17:60 Page 3 of 8 60

secretion of dysfunctional protein (Type 2 HAE). Both forms Miscellaneous Causes

lead to elevated levels of bradykinin which is thought to be the
major mediator of the angioedema [6]. HAE is rare and is Among children, infections, particularly viral infections, seem
actually an uncommon cause of angioedema in the pediatric to be a leading trigger for other causes of angioedema. Viruses,
population. Few reports have examined how often HAE is the e.g., herpes simplex, coxsackie A and B, hepatitis B, Epstein–
cause of all comers with angioedema in the pediatric popula- Barr, and other viral illnesses such as upper respiratory tract
tion specifically. One report out of a tertiary care center in infections, may produce circulating immune complex resulting
Turkey showed that out of nearly 100 successive pediatric in anaphylatoxins. Bacterial infections, e.g., otitis media, sinus-
patients presenting with angioedema, none were eventually itis, tonsillitis, upper respiratory tract infections, and urinary
diagnosed with HAE [8]. Nevertheless, HAE clearly occurs tract infections, are also associated with angioedema in chil-
in children. In fact, the majority of all HAE patients have the dren. Other etiologies may include hypereosinophilic syn-
initial swelling episode during the first or second decade of drome, urticarial vasculitis, autoimmune disease, and autoim-
life, with almost all patients manifesting symptoms by age 18, mune thyroiditis; although these are not commonly associated
and many patients experiencing a worsening of symptoms with angioedema alone and are rare in children [7, 8, 28].
around puberty [15, 16]. In one large US cohort, the median Finally, clinicians must be aware that factitious angioedema
age of first swelling was 11 years [16]. Cohorts reporting these can occur in the pediatric patient population (as well as the
data typically rely on recall through questionnaires of adult adult) and should consider this when evaluating patients, espe-
patients. Pediatric-specific cohorts are rare, although a few cially in patients with normal lab findings [29].
groups have recently reported on their experiences with pedi-
atric HAE, mainly through retrospective studies [17–19].
These are summarized in Table 1. Diagnosis
In pediatric-specific cohorts, the extremities and abdomen
appear to be the two most common sites of attacks [17–19]. As with most other diseases, the history and physical exami-
Subjects can have prodromal symptoms, most commonly fa- nation remain fundamental to making a diagnosis and deter-
tigue, nausea, and flu-like symptoms [20]. They can also have mining the etiology of the angioedema. Perhaps the single
a rash (typically prodromal) that is described as a non-urticar- most important aspect of the history is whether or not the
ial, erythematous rash with a reticulate and serpentine appear- angioedema is associated with urticaria or pruritus (or any
ance similar to that of erythema marginatum, which can be other sign/symptom of mast cell-mediated disease), as the
seen in up to 50% of patients [21]. In fact, some newborns answer to this question should steer the clinician down two
with HAE may present with erythema marginatum within the very different diagnostic paths. Other aspects of importance
first few days of life, which can be a sign of bradykinin activ- include the duration of symptoms, the location of swelling,
ity and prompt work up for HAE if appropriate [22]. and any family history of angioedema. Specific inquiry should
Type III HAE is mainly seen in women, and these patients also be made about the triggering factors, e.g., foods, medica-
have normal levels and functional C1-INH. Some patients tions including OTCs, insect bites/stings, exposure or contact
demonstrate activating mutations in the coagulation factor with inhalant allergens, exposure to physical agents (pressure,
XII (Hageman factor; HAE-FXII) [23]. Type III is essentially heat), exercise, emotional stress, and alcohol ingestion. Patients
irrelevant in children and adolescents [24]. should be asked about recent viral and bacterial illness or fevers
as infection may trigger angioedema as discussed above. In
Acquired Angioedema addition to asking about medication triggers, the clinician
should ask about the response to medications, specifically
In acquired angioedema, there is thought to be an acquired antihistamines and steroids as this can be extremely helpful
deficiency of C1 INH secondary increased consumption in (allergic/histaminergic angioedema may respond to these ther-
conditions such as lymphoproliferative disorders like lympho- apies, while non-allergic/bradykininergic angioedema would
ma, leukemia, multiple myeloma, solid cancers, infections, not be expected to respond).
and autoimmune diseases, e.g., SLE or possibly due to auto- Recurrent angioedema without urticaria suggest the possi-
antibodies against C1INH [25]. This type of angioedema is bility of hereditary angioedema (HAE) and work up for this
quite rare in the pediatric population. (discussed below) will be quite different than the work up for
angioedema associated with urticaria/pruritus.
ACE Inhibitor (ACEI)-Induced Angioedema
Diagnostic Testing
ACEI-induced angioedema is less common in children than
adults, and only case reports are available [26, 27] and thus Diagnostic testing should be selective and based on the history
will not be discussed in detail in this review. and physical as above. If the angioedema is associated with
60 Page 4 of 8 Curr Allergy Asthma Rep (2017) 17:60

Table 1 Findings from pediatric only cohorts with hereditary angioedema

Nanda et al. [18] Bennet et al. [19] Farkas et al. [17]

Number of patients 21 25 50
Gender (% male) 71% 48% 46%
Ethnicity (% White) 95 Not reported Not reported
Family History of HAE 86% 84% 84%
Median age at symptom onset 5.7 years 7.7 years 5 years
Median age at diagnosis:
With family history 5.0 years 7.2 years 8 years
Without family history 10.0 years 9.5 years (Data not broken down by family history)
Type of HAE Not reported 100% Type I 90% Type I
Most common site of attack Abdominal Upper extremity Upper extremity

urticaria, this should drive one line of testing. In these in- Type 3 HAE patients have normal laboratory testing but are
stances, if the history suggests it, appropriate skin prick testing exclusively female and have strong family history. Low C1 q
or serum-specific IgE to foods, drugs, or venoms may be levels point to a diagnosis of acquired angioedema, although
helpful to determine the etiology in acute cases. However, in this diagnosis is rare in the pediatric population. These labo-
cases of chronic urticaria/angioedema, allergy testing is rarely ratory parameters are normal in idiopathic angioedema, drug-
warranted. There are recent guidelines published from both induced angioedema including ACEI- and NSAID-induced
US and European organizations to help guide testing for urti- angioedema, and allergic angioedema.
caria/angioedema, and the authors refer to these guidelines for For drug-induced angioedema, the clinician has to make a
a more in-depth discussion for this work up [11••, 30]. Briefly, decision whether a drug challenge is warranted to make the
typically no testing is warranted in these patients; however, diagnosis (i.e., if the benefits of the challenge outweigh the
tests such as a CBC with differential, sedimentation rate (or C- risks) and this is likely to be case-dependent.
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 Treatment
limited number of cases. Many times, in the authors’ experi-
ences, these labs can serve to help soothe and address the fears In cases of acute angioedema, identification of the trigger and
of the patient/parent as much as they can add to the decision avoidance of the trigger is the mainstay of therapy. As
making process. discussed however, it is more common than not that a trigger
If the angioedema is not associated with urticaria, then this will not be identified. There are up to date guidelines to aid
should lead the clinician down a separate diagnostic pathway. clinicians in the treatment of chronic urticaria/angioedema
In patients suspected of having HAE, measuring complement [11••, 30]. Briefly, non-sedating H1 antihistamines remain
C4 levels is the best initial screening test to exclude a diagno- the primary treatment option. Studies have used standard
sis of HAE. The vast majority of patients will have low C4 at dosing to up to four times standard dosing with success and
baseline, and essentially all patients will have a low C4 level minimal side effects [34•]. However, those caring for pe-
during an attack [31•]. The next step should be to obtain diatric patients should be aware that the majority of these
C1INH antigenic level and C1INH function. The C1INH studies were in adults with some enrolling pediatric pa-
functional level should be less than 50–60% to be compatible tients down to 12 years of age. To the authors’ knowledge,
with diagnosis of HAE. Laboratory testing is similar in ac- there are no trials of four times standard dosing in the
quired angioedema. Of special note in the pediatric popula- pediatric population specifically. The addition of H2 anti-
tion, complement and C1INH levels can be low physiologi- histamines, leukotriene receptor antagonists, and sedating
cally in neonates, and thus, experts recommend delaying 1st generation antihistamines are typically the next step in
checking these until 1 year old age if possible (with genetic management if the patient does not respond to non-sedating
testing available if absolutely needed prior to that time) [32•]. H1 antihistamines.
One recent report suggests that while this is true for C4, the The addition of immunomodulators is typically withheld
C1INH level and functional assessments may be accurate in until the patient fails the above measures. In the authors’ prac-
patients under 1 year of age however [33] Thus, it may be tice, typically pediatric patients are considered failures
reasonable to send these labs even in infants <1 year of age. 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– the pediatric population [42]. We outline all of the therapies in
7 years and 10 mg twice daily in children >7 years) plus an as Table 2 and briefly discuss them below.
needed sedating antihistamine (1 mg/kg hydroxyzine). Of
available immunomodulators, omalizumab and cyclosporine
probably have the most data in the pediatric population C1 Inhibitor Replacements
(omalizumab studied down to 12 and cyclosporine down
to 9 years of age for this condition) [35, 36•, 37, 38]. Berinert (CSL Behring, Marlberg, Germany) is a plasma-de-
Other immunomodulators (dapsone, hydroxychloroquine, rived, human C1INH that currently has an FDA-approved
sulfasalazine, colchicine, and methotrexate) have been report- indication for treatment of acute attacks of HAE in the pedi-
ed more often in adults. Oral or systemic corticosteroids are atric population. Berinert has been studied in both retrospec-
not recommended, especially for long-term management. tive studies and prospective studies (most often for acute at-
HAE patients do not respond to the above therapies (anti- tacks, but has been reported for prophylaxis) [17, 43–47]. In
histamines, corticosteroids, and immunomodulators) as bra- Europe, where it has been available for a longer period of
dykinin is the primary mediator of the angioedema. The cur- time, it has been reported on in children down to 2.5 years
rent treatment strategies involve either replacement of CINH, of age (fixed dose) [43]. In the US studies, it has been reported
inhibiting the generation of bradykinin, or blocking the action down to 6 years of age (weight-based) [44, 45]. It has been
of bradykinin. There are various medications approved for shown to be safe and effective when administered at home in
treating acute attacks and/or for prophylaxis, and there are the pediatric population [46].
now multiple national and international guidelines on the Cinryze (Shire/Viropharma, Lexington, MA) is also a plas-
treatment of HAE [31•, 39–41]. In addition, a recent US med- ma-derived, human C1INH. While it has been studied for
ical advisory board of experts as well as a European consensus acute attacks in the pediatric population and appears safe
of experts have published recommendations on treatment of and effective down to 6 years of age [48, 49], currently
HAE specifically in the pediatric population [24, 32•] While Cinryze only has an FDA indication for prophylaxis in ado-
an in-depth discussion of each of these therapies and their use lescents and adults.
in the pediatric population is beyond the scope of this review, Haegarda (CSL Behring, Marlberg, Germany) is a plasma-
there is a recent review specifically examining C1INH use in derived C1INH that was just recently approved by the FDA

Table 2 Products available for

the treatment of hereditary Products Route of administration FDA-approved age Indication
angioedema with pediatric focus
C1 inhibitor concentrate
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 Curr Allergy Asthma Rep (2017) 17:60

for prophylaxis and can be administered subcutaneously twice Most experts do agree that no matter the selected treatment,
weekly. It was studied down to 12 years of age [50•]. HAE patients should have a treatment plan in place, attacks
Ruconest (Pharming Technologies BV, Leiden, the should be treated early, and patients should avoid triggers such
Netherlands) is a recombinant C1INH that currently has as estrogens and ACE inhibitors. For children, this may mean
FDA-approved indication for treatment of acute attacks in discussing with school how attacks need to be managed, wear-
adults and adolescents (phase III trial enrolled down to ing medical alert jewelry, having an understanding of where
13 years of age), with a very recent open-label extension study treatment for an acute attack should be given (local emergency
specifically evaluating its safety and efficacy in adolescents departments may need to be aware of their treatment and may
[51, 52]. 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
Other Therapies to surgeries or dental procedures.

Icatibant (Firazyr; Shire, Lexington, Mass) is a bradykinin B2

receptor antagonist that currently has FDA approval for the Conclusions
treatment of acute attacks in adults only. It has recently been
studied in pediatric patients down to 2 years of age however Angioedema is a common symptom in the pediatric popula-
with results similar to the adult trials [53]. tion. Most commonly, this seems to be associated with infec-
Ecallantide (Kalbitor Shire, Lexington, MA) is a human tion or allergy (mast cell-mediated) when acute. When chron-
plasma kallikrein inhibitor that has FDA approval for the treat- ic, the most common type is idiopathic. When not associated
ment of acute attacks in patients 12 years of age or older. The with pruritus or urticaria, the clinician must consider HAE and
initial efficacy study enrolled subjects 10 years of age and send off diagnostic studies accordingly.
olderm and there has since been a follow-up study pooling There are now national and international guidelines to aid
all pediatric subjects in four efficacy trials, suggesting that the clinician in diagnosing and treating all causes of angioede-
ecallantide is as effective and safe in adolescents as it is in ma with some specific guidelines geared toward the pediatric
adults [54, 55]. patient. In the realm of HAE, there are new therapies available
Avoralstat, an oral inhibitor of the conversion of that have now been studied in both adolescents and pediatric
prekallikrein to plasma kallikrein, has been studied in adults patients.
[56]. However, it does not appear that this molecule (in
its current form) will proceed through further testing. Compliance with Ethical Standards
Lanadelumab is a fully human monoclonal antibody that in-
hibits kallikrein. Results from the initial study on its use in Conflict of Interest The authors declare no conflicts of interest relevant
adults have now been published [57]. Further studies down to to this manuscript.
12 years of age have been conducted with no results published
Human and Animal Rights and Informed Consent This article does
to date. not contain any studies with human or animal subjects performed by any
Other therapies include Danazol, fresh frozen plasma, and of the authors.
tranexamic acid. These therapies were used more often prior
to the advent of the more recent therapies discussed above. Funding Source None.
Danazol, in particular, is not recommended for children any
longer given its side effect profile and the efficacy of the
newer products. References
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