Bernstein and Moellman International Journal of Emergency Medicine 2012, 5:39

http://www.intjem.com/content/5/1/39

REVIEW Open Access

Emerging concepts in the diagnosis and

treatment of patients with undifferentiated
angioedema
Jonathan A Bernstein1* and Joseph Moellman2

Abstract
Angioedema is a sudden, transient swelling of well-demarcated areas of the dermis, subcutaneous tissue, mucosa,
and submucosal tissues that can occur with or without urticaria. Up to 25% of people in the US will experience an
episode of urticaria or angioedema during their lifetime, and many will present to the emergency department with
an acute attack. Most cases of angioedema are attributable to the vasoactive mediators histamine and bradykinin.
Histamine-mediated (allergic) angioedema occurs through a type I hypersensitivity reaction, whereas
bradykinin-mediated (non-allergic) angioedema is iatrogenic or hereditary in origin.
Although their clinical presentations bear similarities, the treatment algorithm for histamine-mediated angioedema
differs significantly from that for bradykinin-mediated angioedema. Corticosteroids, and epinephrine are effective in
the management of histamine-mediated angioedema but are ineffective in the management of
bradykinin-mediated angioedema. Recent advancements in the understanding of angioedema have yielded
pharmacologic treatment options for hereditary angioedema, a rare hereditary form of bradykinin-mediated
angioedema. These novel therapies include a kallikrein inhibitor (ecallantide) and a bradykinin β2 receptor
antagonist (icatibant). The physician’s ability to distinguish between these types of angioedema is critical in
optimizing outcomes in the acute care setting with appropriate treatment. This article reviews the pathophysiologic
mechanisms, clinical presentations, and diagnostic laboratory evaluation of angioedema, along with acute
management strategies for attacks.

Review wheals involve both the mid- and papillary dermis,

Up to 25% of people in the US will experience an episode whereas angioedema involves the reticular (deep) dermis
of urticaria, angioedema, or both at some point during and subcutaneous and submucosal tissues. Isolated
their lifetime. It is estimated that each year more than 1 angioedema can sometimes manifest with symptoms of
million patients present to a physician with signs or pain and tenderness, whereas itching can be present with
symptoms of urticaria or angioedema, many of whom or without urticaria in patients with angioedema [3,5].
present to the emergency department with an acute at- Angioedema is a presenting sign that results from an
tack [1-3]. Symptoms of urticaria are similar to those of underlying pathophysiologic process involving the loca-
allergic angioedema and may be a component of ana- lized or systemic release of one of several vasoactive
phylaxis [1,4]. mediators, most frequently histamine or bradykinin.
Although both urticaria and allergic angioedema are Angioedema resulting from the biochemical cascade
mediated by the activation of mast cells, there are many initiated by the release of bradykinin is distinct from that
differences between the two conditions. Unlike angioe- caused by histamine release; however, the resulting
dema, urticaria rarely affects mucosal tissue. Urticarial clinical signs and symptoms may be quite similar. Both
mediators induce vascular leakage and consequent non-
* Correspondence: Jonathan.Bernstein@uc.edu pitting interstitial edema, which results in transient swel-
1
Department of Internal Medicine, Division of Immunology/Allergy, University ling of well-demarcated areas. Although angioedema may
of Cincinnati Medical Center, 231 Albert Sabin Way, PO Box 670563,
Cincinnati, OH 45267-0550, USA occur at any site of the body, it most commonly involves
Full list of author information is available at the end of the article

© 2012 Bernstein and Moellman; licensee Springer. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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the head, neck, lips, mouth, tongue, larynx, and pharynx, PAE is a form of drug-induced, non-allergic angioe-
along with the subglottal, abdominal, and genital areas dema, and its pathogenesis is related to the mechanism
[1,3,6,7]. of action of the inciting medication. One example of PAE
Angioedema can progress rapidly, and cases that in- is the allergic reaction to aspirin and nonsteroidal anti-
volve the mouth, tongue, larynx, lips, or face constitute a inflammatory drugs (NSAIDs), where severe broncho-
medical emergency. Swelling of these tissues can occur constriction, severe laryngeal angioedema, urticaria, or
in a matter of minutes in the case of histamine-mediated shock occurs within 3 to 4 h of ingestion of the drug.
angioedema compared with a typical slower onset with PAE in response to aspirin is thought to occur through
bradykinin-mediated angioedema. However, both forms the inhibition of cyclooxygenase and consequent gener-
of angioedema can lead to imminent airway obstruction ation of cysteinyl leukotrienes, which serve as mediators
and a life-threatening emergency. Thus, emergency phy- for the resultant angioedematous reaction [1,9].
sicians must have a basic understanding of the pathophy- IAE, which is not well understood, is a diagnosis of ex-
siologic processes involved in acute angioedema. This clusion assigned to cases of recurrent angioedema for
review focuses on angioedema induced by histamine or which no exogenous agent or underlying genetic abnor-
bradykinin release, and not pseudoallergic and idiopathic mality can be identified. Some authors have included
angioedema, which are discussed only briefly [1]. urticaria-associated angioedema in this category, while
others have restricted the diagnosis of IAE to patients
with recurrent angioedema without urticaria [10].
Forms of angioedema
Histamine-mediated angioedema occurs through an Pathophysiology of angioedema
allergic mechanism, specifically a type I hypersensitivity In general, the pathophysiology of angioedema involves
reaction, which occurs after a patient has had prior a sudden increase in the permeability of vessel walls in
“sensitization” to a particular antigen. Upon re-exposure the skin and submucosa. This increased permeability
to that antigen, mast cells are activated and release pre- permits local extravasation of plasma and consequent
formed mediators such as histamine and newly formed tissue swelling [5].
mediators such as leukotrienes. Increased concentrations
of histamine and these other bioactive mediators are re- Histamine-mediated angioedema
sponsible for the characteristic edema and swelling that Histamine-mediated or allergic angioedema occurs
occur during an acute attack. through a type I IgE-mediated hypersensitivity immune
In general, non–histamine-mediated angioedema occurs response, which is largely mast cell-dependent. Genetic-
through the increased production of bradykinin due to a ally susceptible individuals with prior exposure to an
lack of regulation of the contact pathway, ultimately leading offending allergen become “sensitized.” Sensitization
to edema. Bradykinin-mediated angioedema is divided into occurs when the allergen is taken up by antigen-
three distinct types: hereditary angioedema (HAE), presenting cells (i.e., dendritic cells, macrophages, or B
angiotensin-converting enzyme inhibitor (ACEI)-induced cells) and is broken down into small peptides (9–11
angioedema, and acquired angioedema (AAE) [1]. amino acids in length). The relevant peptides are then
Similarities between the clinical presentations of differ- presented to the cell surface in conjunction with major
ent types of angioedema complicate their management. histocompatibility class 2 (MHC2) antigens. This
Although diagnostic blood tests can be very helpful in MCH2 peptide complex is recognized by T-helper
differentiating between the different types of angioe- lymphocyte receptors and a number of other co-
dema instigating an acute attack, performing these tests stimulatory molecules, resulting in T-cell activation and
takes time and results usually cannot be obtained im- the release of Th2 cytokines, including interleukin (IL)-
mediately during the acute emergency treatment of an 4, IL-5, and IL-13, that promote increased production
attack. In such cases, achieving a positive clinical out- of IgE and the differentiation and migration of eosino-
come depends heavily on the clinician’s ability to dis- phils, in addition to many other functions leading to al-
tinguish among the different types of angioedema at lergic inflammation. These cytokines also cause B
the bedside through a comprehensive history and phys- lymphocytes to differentiate into plasma cells that pro-
ical examination [8]. duce specific IgE antibodies that specially recognize the
Importantly, other forms of angioedema exist that are original sensitizing antigenic peptide. These specific
relatively rare, do not occur through an allergic mechan- antibodies bind to high-affinity IgE receptors (FcεR-1)
ism, and are provoked by the release of a vasoactive me- and can persist on these receptors for months or years.
diator other than histamine or bradykinin. These other Upon re-exposure to the inciting agent, the allergenic
forms include pseudoallergic angioedema (PAE) and peptide is recognized by the antigen-binding sites of
idiopathic angioedema (IAE) [1]. the specific IgE antibodies bound to the high-affinity
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IgE receptors, leading to a series of chemical reactions factor XII [10,13,14]. Because C1-INH is a key inhibitor of
that result in activation of the mast cell and the release three enzymes in the kallikrein-kinin cascade—factor XIIa,
of preformed and newly formed bioactive mediators factor XIIf, and plasma kallikrein—deficiency of functional
(Figure 1) [4]. These mediators, such as histamine, can C1-INH in patients with HAE results in the uncontrolled
then bind to selective receptors (i.e., H1 receptors) on activation of the entire cascade [13].
the vascular endothelium, leading to vasodilation and In an acute attack of HAE, relative overactivation of
increased permeability [4,11]. the kallikrein-kinin cascade generates excessive bradyki-
nin. Consequently, the vasodilator properties of bra-
Bradykinin-mediated angioedema dykinin augment vascular permeability, eliciting the
Kinins are a group of pharmacologically active peptides characteristic HAE symptoms of localized swelling, in-
that are released into body fluids and tissues following flammation, and pain (Figure 3) [12].
the enzymatic action of kallikreins on kininogens, which
occurs through a complex proteolytic cascade of events ACE inhibitor-induced angioedema
called the kallikrein-kinin cascade (Figure 2). The Angiotensin-converting enzyme plays a major role in the
kallikrein-kinin cascade, also referred to as the “contact renin-angiotensin-aldosterone system, through two pro-
activation pathway” or intrinsic pathway, is initiated teolytic mechanisms: conversion of angiotensin I to
when factor XII (Hageman factor) binds to damaged tis- angiotensin II and degradation of bradykinin. These two
sue, becoming activated through conversion to factor actions make ACE inhibition a chief target in the treat-
XIIa. Factor XIIa converts prekallikrein to plasma kallik- ment of hypertension, myocardial infarction (MI), heart
rein, and these two proteins autoactivate each other failure, and type I diabetic nephropathy. Treatment with
through a positive feedback loop. Plasma kallikrein then an ACEI following MI improves survival, rate of
cleaves high-molecular-weight kininogen (HMWK), hospitalization, symptoms, and cardiac performance; in
thereby liberating bradykinin [12]. The binding of brady- addition to the low cost of these agents, these factors ac-
kinin to bradykinin β2 receptors induces vasodilation count for the widespread use of ACEIs [15,16].
and increased endothelial permeability, yielding the ACEI-induced angioedema is associated with the re-
characteristic signs and symptoms of an acute attack of duction in bradykinin degradation that is caused by
angioedema [1,13]. ACEIs. As in HAE, increased levels of bradykinin lead to
the symptoms of swelling, pain, and inflammation that
Hereditary angioedema HAE is a rare (1:10,000- are seen in patients who present with an acute attack.
1:50,000 prevalence), autosomal dominant disorder char- ACEI-induced angioedema most often involves the head,
acterized by a quantitative (type I) or qualitative (type II) neck, face, lips, tongue, and larynx. Rarely, it involves
deficiency of C1 esterase inhibitor (C1-INH) due to a mu- visceral organs. Life-threatening edema of the upper air-
tation of the C1-INH SERPING1 gene, located on chromo- way presents in 25-39% of cases of ACEI-induced
some 11q. HAE with normal C1-INH (type III) occurs angioedema. Although studies have noted that ACEI-
because of one of two known mutations in the gene for induced angioedema most commonly occurs shortly
after treatment is initiated, it can develop long after
treatment has started [17]. Interestingly, angiotensin re-
—IgE
ceptor blockers (ARBs), also referred to as AT1-receptor
—FcεRI antagonists or blockers, appear to induce angioedema at
Mast a lower frequency than do ACEIs [1]. When ACE activ-
cell ity is inhibited, the enzyme aminopeptidase P (APP)
Soluble
antigen metabolizes bradykinin. Bradykinin amasses during ACE
inhibition in individuals who have subnormal activity of
Histamine APP due to a genetic mutation in a gene-encoding
Proteolytic enzymes membrane–bound APP [12].
Cyotkines (IL-4, IL-5, TNF-α)
Leukotrienes
Chemokines Acquired angioedema The prevalence of AAE is
believed to be 1:100,000 to 1:500,000, and it primarily
affects adults and the elderly. AAE results from a non-
Tissue damage genetic C1-INH deficiency. Ten to fifteen percent of
Figure 1 Type I hypersensitivity is mediated by IgE and induces patients have an underlying lymphoproliferative dis-
mast cell degranulation. FcεRI, high-affinity IgE receptor; IgE, order; therefore, screening these patients with blood
immunoglobulin E; IL-4, interleukin 4; IL-5, interleukin 5; TNF-α,
tests and possibly bone marrow biopsy to exclude malig-
tumor necrosis factor-alpha [4].
nancy is recommended. Many of these patients may also
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Negative surface exposed by

trauma or unknown precipitants
CLASSICAL LECTIN ALTERNATIVE
Prekallikrein Kallikrein Antigen: antibody MBP Polysaccharides
stimulates complex MASPs 1-3 endotoxin
C5a release
C1q/C1r/C1s C3
Kallikrein C4
C4
B
HMWK
C4b+C2 C4b+C2
D,P
Bradykinin

C3 C3
C4b2a C3bBbP
Edema Classical C5 Alternative
Fluid extravasation C3 convertase C3 convertase
Pain

C4b2a3b C3bBbC3b
C5 convertase C5 convertase

Primary effect C5a

Secondary effect C5b
Inhibited by C1-INH C6-9

C5b-9
Membrane attack complex
Cytokine release:
IL-1 , TNF- , IL-6, IL-8
Neutrophil recruitment

Figure 2 Kallikrein-kinin cascade. During an acute HAE attack, reduced activity of C1 esterase inhibitor (C1-INH) results in overactivation of the
kallikrein-kinin cascade and subsequent production of bradykinin. Bradykinin is the likely mediator of the vasodilation, edema, and pain that
characterize acute HAE attacks. HMWK, high-molecular-weight kininogen; IL, interleukin; MASP, MBP-associated serine protease; MBP, mannose-
binding protein; TNF-α, tumor necrosis factor-alpha.

Contact system

Endothelial cell surface +

factor XII
or
prolylcarboxypeptidase Factor XIIa

C1-INH
Complement system
Prekallikrein
HK C1
H
IN

Kallikrein
1-
C

C1rs C4
IN
H

1-
IN

C
1-
C

Plasminogen C2
C
1-
IN
H

Bradykinin

MBL + Masp2
Plasmin

Bradykinin 2 receptor Fibrinolytic system

Figure 3 The contact, complement, and fibrinolytic systems. C1-INH, C1 esterase inhibitor. Republished with permission from [37].
[PERMISSION PENDING].
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have an autoantibody to C1-INH. Treatment of the these reactions can be recurring, and when they persist
underlying lymphoproliferative disorder and/or the C1- for more than 6 weeks are considered chronic [5].
INH autoantibody can be curative [18]. Although histamine-mediated attacks of angioedema
most commonly occur in hyperallergic or atopic indivi-
duals (i.e., patients with allergic rhinitis, extrinsic asthma,
Clinical manifestation of angioedema
or atopic dermatitis/eczema), attacks induced by a food
Patients with angioedema may present with or without
or medication may be seen in the absence of atopy. In
urticaria [8]. Angioedematous lesions tend to be non-
addition to acute swelling and edema, allergic angioe-
pitting and non-pruritic. Despite their non-pruritic na-
dema always involves a recognizable trigger, most com-
ture, these lesions can invoke significant sensations of
monly insect stings, food, or medications [10].
pain and burning [7]. Although they do not in them-
Angioedema that is mediated by histamine typically
selves appear desquamated or discolored, the pruritic
responds to antihistamines (Table 1). Swelling can occur
component of angioedematous lesions may cause
at any site of the body, but histamine-mediated angioe-
scratching or rubbing, with resultant discoloration [6].
dema has a predilection for the facial area, particularly
the lips and periorbital area and, less commonly, the
Histamine-mediated angioedema genitalia. Isolated allergic angioedema may involve the
Some of the classic signs associated with histamine- throat or larynx, resulting in dyspnea or stridor caused
mediated angioedema are the “wheal and flare” reaction by laryngeal edema. In some instances, patients can pro-
of the superficial layers of the skin and interstitial edema gress to anaphylaxis, a potentially fatal systemic allergic
of underlying subcutaneous, mucosal, and submucosal reaction [4]. Anaphylaxic manifestations can include dif-
layers of the skin [4]. These reactions therefore fre- fuse hives, angioedema, gastrointestinal symptoms, and
quently manifest as pruritic hives with or without hypotension. In its most severe form, loss of conscious-
angioedema. Also of importance is the evanescent nature ness due to vascular collapse may occur [4]. Pulmonary
of these attacks in contrast to non-histamine-mediated symptoms, including hyperinflation, peribronchial con-
angioedema. Acute attacks of urticaria and/or angioe- gestion, submucosal edema, edema-filled alveoli, and eo-
dema are typically self-limited; swelling typically lessens sinophilic infiltration are often noted during anaphylaxis
or resolves over the course of 24 h. Not infrequently, [4]. Although these cases are responsive to antihistamine

Table 1 Clinical and diagnostic features of various types of angioedema

Angioedema type Clinical and diagnostic features
Histamine-mediated
Allergic angioedema Angioedema usually accompanied by urticaria and sometimes anaphylaxis; may be pruritic; associated with exposure
to allergens; attacks last for 24–48 h; responsive to antihistamines or corticosteroids
Angioedema with urticarial Angioedema accompanied by urticaria; there may be petechiae or purpura after swelling resolves; symptoms of
vasculitis underlying vasculitis
Bradykinin-mediated
Hereditary angioedema Recurrent attacks without urticaria; erythema marginatum is a cardinal finding; onset in childhood or young
types I and II adulthood, worsening at puberty; family history in 75% of patients; attacks unresponsive to antihistamines or
corticosteroids
Hereditary angioedema Associated with mutations in factor XII; more common in women; may be estrogen dependent; typical onset after
type III childhood; face, tongue, extremity involvement is more frequent than abdominal; recurrent tongue swelling is
cardinal symptom; more disease-free intervals than in HAE types I and II; family history of angioedema; attacks
unresponsive to antihistamines or corticosteroids
Acquired angioedema Attacks similar to HAE; onset in middle age or later; no family history; attacks unresponsive to antihistamines or
corticosteroids
ACE inhibitor-induced History of ACE inhibitor use; no urticaria; face and tongue most frequent sites; more common in blacks and smokers;
angioedema patients usually can tolerate ARBs
Not mediated by histamine or bradykinin
Idiopathic angioedema Angioedema sometimes accompanied by urticaria; swelling may persist for up to 48 h; attacks may occur daily;
responsive to antihistamines or corticosteroids
Pseudoallergic angioedema Urticaria typically present; usually class-specific reaction; thought to be mediated by cysteinyl-leukotrienes; includes
NSAID-induced angioedema, which occurs because of cyclooxygenase inhibition and subsequent release of cysteinyl-
leukotrienes
ACE angiotensin-converting enzyme, ARB angiotensin receptor blocker, NSAID nonsteroidal anti-inflammatory drug.
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therapy, identifying a specific cause can be elusive. Often can manifest before the onset of an attack in patients
patients and/or physicians implicate a food or drug as with either type I or type II HAE; however, urticaria and
the trigger without adequately proving cause and effect, pruritus are not typically associated with these two types
which can lead to erroneous elimination of important of HAE (Table 1) [7,10].
medications or unnecessarily restrictive diets. Therefore, A recent analysis of 195 patients with HAE found
once stabilized, these patients should be evaluated by a that 54% experienced an average of more than 12
physician experienced in the management of urticaria/ attacks per year; symptom-free years were rare, repre-
angioedema to establish whether these reactions are sec- senting only 370 (6.5%) of the 5,736 patient-years
ondary to a specific cause or are idiopathic, as the latter included in the analysis [19]. Although clinical presen-
is often the case. tation varies, HAE types I and II often present during
childhood (Table 1). Most patients experience progres-
HAE type III HAE type III was first used to describe a sive worsening of symptoms over several hours; these
group of women who presented with angioedema similar episodes can be quite protracted, lasting from 2 to 5
to that seen with HAE types I and II but without any days without treatment [20].
complement abnormalities. Patients with HAE type III
more commonly experience angioedema in the facial re- ACE inhibitor-induced angioedema
gion involving the tongue, and lips; in severe cases, they ACEI-induced angioedema occurs in 0.1-0.7% of
may develop laryngeal edema. Prodromes such as ery- patients treated with these agents. The incidence of
thema marginatum have not been commonly observed ACEI-induced angioedema appears to be highest (25%)
in HAE type III patients [7]. during the first month of treatment [21] but can occur
Patients diagnosed with HAE type III usually manifest from months to years after the initiation of treatment.
symptoms later in life and have a well-defined gener- Less commonly, ACEI-induced angioedema has been
ational history of angioedema (Table 1). A recent study associated with medications such as NSAIDs—via in-
found the mean age of symptom onset for HAE type III hibition of the COX enzyme pathway leading to
to be 26.8 years (SD ± 14.9 years, range = 1–68 years). changes in prostaglandin synthesis [5,11]—and alteplase
Another characteristic of this form of angioedema is that [22]. Although rare, angioedema can also be induced
it is frequently exacerbated by estrogen surges during by ARBs; for the most part, ARBs are considered safe
pregnancy or by treatment with oral contraceptives and for use by patients who have a history of ACEI-
hormonal replacement therapy [19]. The original de- induced angioedema [21].
scription of this variant form of HAE was in a family ACEI-induced angioedema is not associated with urti-
where a gain-of-function mutation in factor XII was caria [8,23] and most commonly involves the tongue,
observed [20]. However, subsequent investigations of this lips, and face [21]. ACEI-induced angioedema appears to
mutation in other cases of HAE type III have not yielded be four to five times more common in African-
similar findings, and as of yet the underlying genetic and American than in Caucasian individuals [21] owing to
mechanistic cause of this condition is unknown. genetic polymorphisms in APP, a critical enzyme for me-
The clinical course of patients with HAE type III typ- tabolizing ACEIs.
ically differs from HAE types I and II in that they have
more disease-free intervals during the course of disease. Acquired angioedema
There is still a great deal of uncertainty regarding how The presentation of AAE is, broadly speaking, similar to
to definitively diagnose and treat this condition. that of HAE types I and II, with recurrent attacks of sub-
cutaneous and/or submucosal swelling without urticaria.
Bradykinin-mediated angioedema, HAE types I and II As mentioned, AAE is much less common than HAE,
The most frequently encountered symptoms in HAE affecting approximately one-tenth as many patients. Clinical
types I and II (HAE due to C1-INH deficiency) are skin characteristics that differentiate this form of angioedema
edema, abdominal pain, and life-threatening laryngeal from HAE are older age (the typical patient is elderly) and
edema. Skin swelling occurs most commonly in the ex- the absence of a family history of angioedema [23].
tremities and less frequently involves the face and other
body sites. Abdominal attacks, which are also very Differential diagnosis of angioedema
prevalent in these patients, are caused by transient Angioedema is a clinical sign that may be associated with
edema of the bowel wall and manifest with significant one of several different clinical conditions. In addition to al-
pain, vomiting, and diarrhea due to partial or complete lergic and non-allergic angioedema, in the differential diag-
intestinal obstruction, ascites, and hemoconcentration. nosis for angioedema the following should be ruled out:
In up to one-third of patients, erythema marginatum, facial cellulitis, acute contact dermatitis, photodermatitis,
which is a serpiginous erythematous non-pruritic rash, Crohn’s disease (particularly if the lips and mouth are
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involved), dermatomyositis, facial lymphedema, cellulitis, Histamine-mediated angioedema

tumid discoid lupus erythematosus, Ascher syndrome, A definitive diagnosis of histamine-mediated angioedema
Melkersson-Rosenthal syndrome, and superior vena cava can be achieved through laboratory evaluation for mar-
syndrome [5]. kers of mast cell degranulation (elevated urine histamine
and serum tryptase levels) (Table 2). Prick skin testing or
serum-specific IgE assays may be appropriate if the his-
Laboratory evaluation of angioedema tory is suggestive of sensitization to a suspected allergen
A possible algorithm is presented for the diagnostic such as a food. If laboratory test results for urine hista-
workup patients with suspected non-allergic angioedema mine and serum tryptase levels are unavailable, the diag-
(Figure 4) [8] or HAE (Figure 5) [24]. nosis relies on history and clinical presentation [21].

Angioedema
(without urticaria)

Review all medications

Stop all medications known to cause angioedema,

such as ACE inhibitors, NSAIDs, estrogens

Measure the C4 complement level in serum to

screen for C1-INH deficiency

C4 level WNL C4 level decreased

HAE unlikely: consider other HAE likely: confirm the diagnosis by

causes such as type 3 HAE measuring the C1-INH in serum by
and idiopathic quantitative and functional assay and
the C1q

C1-INH level and C1-INH level within C1-INH level and function
function below normal range, but below normal range
normal range functionally below C1q level below normal range
C1q WNL range
C1q WNL

HAE type 1 HAE type 2 Acquired C1-INH deficiency

Rule out
underlying malignancy and
autoimmune disorders with
anti-C1-INH auto-antibodies

Figure 4 Diagnostic considerations in patients who present with nonallergic angioedema. ACE, angiotensin-converting enzyme; NSAIDs,
nonsteroidal anti-inflammatory drugs; C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema; WNL, within normal limits. Modified from [8];
with permission. [PERMISSION PENDING].
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Consider hereditary angioedema:

- Recurrent angioedema (without urticaria)
- Recurrent episodes of abdominal pain and vomiting
- Laryngeal edema
- Positive family history of angioedema

Measure: serum C4,

C1-INH antigenic protein,
C1-INH functional level if available

C4 and C1-INH protein C4 quantity low but C4, C1-INH protein

quantities decreased C1-INH protein normal normal
or elevated

Confirm decreased Determine C1-INH Confirm C4, C1-INH

C4 and C1-INH protein function and repeat C4 normal during attack
by second measurement and C1-INH protein levels

Family history No family C1-INH C1-INH Consider angioedema

of angioedema history of function normal function types other than HAE
angioedema decreased C1-INH types I and II

Angioedema from medications

(eg, ACE inhibitors)
HAE Measure C1q and Consider other HAE
C1-INH consider age of non-HAE C1-INH HAE type III
type I onset of symptoms causes of C4 Type II - HAE-FXII
consumption - HAE-unknown

Earlier age of Later age of

onset and onset and/or
C1q normal low C1q

Consider
acquired
angioedema

Figure 5 International consensus algorithm for the diagnosis of hereditary angioedema. ACE, angiotensin-converting enzyme; C4,
complement factor 4; C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema. Modified from [24]; with permission. [PERMISSION PENDING].

HAE type III requires laboratory evaluation. In HAE type I, the serum
In patients with HAE Type III, the level and function of C4 level is decreased during and between attacks, and
C1-INH are normal. The serum C4 level is also normal the serum C1-INH level is decreased and sometimes un-
(Table 2) [8]. detectable. In HAE type II, the serum C4 level is
decreased during and between attacks, while the serum
Bradykinin-mediated angioedema: HAE types I and II C1-INH level is within normal limits or even increased,
Because the clinical signs and symptoms of HAE types I but C1-INH is functionally deficient (Table 2, Figures 4
and II are very similar, distinguishing between the two and 5) [8]. Typically, in type II, the serum C2 level is
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Table 2 Complement profiles involved in each type of angioedema

Angioedema type Urine Serum C4 C1-INH Level C1-INHLevel C1q C3
histamine tryptase level (antigenic) (functional) level level
Histamine-mediated angioedema ↑ ↑ NL NL NL NL NL
Hereditary angioedema types I NL NL ↓ ↓ (type I) ↓ NL NL
and II
NL (type II)
Hereditary angioedema type III NL NL NL NL NL NL NL
Acquired angioedema NL NL ↓ ↓ or NL ↓ ↓ ↓ or
NL
ACE inhibitor-induced NL NL NL NL NL NL NL
angioedema
Idiopathic angioedema NL NL NL NL NL NL NL
Pseudoallergic angioedema NL NL NL NL NL NL NL
ACE angiotensin-converting enzyme, C3 complement factor 3, C4 complement factor 4, C1-INH C1 esterase inhibitor, NL normal.

also reduced during attacks, which may be helpful in [1]. If attempts at nasotracheal intubation are unsuccess-
making the diagnosis [8]. ful, cricothyrotomy or tracheotomy is indicated [6,14].
In the following sections, acute management approaches
ACE inhibitor-induced, idiopathic, and acquired for attacks of histamine-mediated angioedema, ACEI-
angioedema induced angioedema, and HAE, along with drug therapies
Patients who present with attacks of angioedema due to for HAE, will be addressed. Although a discussion of
ACEIs will have normal levels of C4 and C1-INH prophylactic approaches to reduce the risk of subsequent
(Table 2, Figure 5) [10]. Similarly, in IAE, C4 levels along attacks is beyond the scope of this article, such approaches
with all other laboratory results are normal. IAE is pri- should be considered for all patients following the reso-
marily a diagnosis of exclusion (Table 2, Figures 4 and 5), lution of an acute attack.
In AAE, C4 levels and complement protein C1q are
reduced; C3 levels may be low or normal (Table 2) [1]. Severe histamine-mediated angioedema, or anaphylaxis
The priority of the acute management of angioedema is
Management of acute attacks of angioedema airway maintenance. Intramuscular (IM) epinephrine
The international consensus from the third international may be used to control symptoms and sustain blood
conference on HAE is that for all forms of angioedema, pressure during an anaphylactic reaction; it may be life-
airway patency is the first priority in an acute attack. saving for patients with acute laryngeal edema or ana-
[24]. An algorithm for the management of acute angioe- phylaxis [8]. Epinephrine 1:1,000 is administered IM 0.2-
dema (duration < 6 weeks) is presented in Figure 6. 0.5 mg thigh (adults); 0.01 mg/kg (up to 0.03 mg) thigh
A low threshold for intubation is recommended. In- (children). This dose can be repeated every 5–15 min-
tubation must be performed at the first sign of airway utes, with close monitoring for signs and symptoms of
compromise, and all cases involving laryngeal edema are toxicity [25].
considered a medical emergency [8,14,21]. The α-adrenergic, vasoconstrictive effect of epineph-
In cases of angioedema involving the tongue, oral in- rine reverses peripheral vasodilation, which reduces
tubation is difficult at best and often impossible. Direct angioedema and urticaria. The β-adrenergic properties
fiberoptic nasotracheal intubation is the preferred of epinephrine cause bronchodilation, increase myocar-
method to achieve airway patency in patients with sig- dial output and contractility, and suppress further me-
nificant laryngeal edema. Blind nasotracheal intubation diator release from mast cells and basophils. It is
should be avoided because of the increased potential for important to note that epinephrine, administered in low
localized trauma and consequent worsening of the concentrations (e.g., 0.1 mg/kg) is paradoxically asso-
edema. ciated with vasodilation, hypotension, and the increased
During an episode of acute angioedema, it may be release of inflammatory mediators. Because of the risk
technically difficult to insert an endotracheal tube. If for potentially lethal arrhythmias, intravenous (IV) epi-
time permits, consultation with an otolaryngologist nephrine 1:10,000 or 1:100,000 dilutions should be
should be obtained for provision of a surgical airway. In administered only during cardiac arrest or to patients
the event that all other airway methods have failed and who are profoundly hypotensive or have failed to re-
ENT consultation is unavailable, the emergency phys- spond to both IV volume replacement and multiple
ician should be prepared to perform a surgical airway injections of epinephrine [25].
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Physician diagnoses angioedema

HAE less likely: Acute angioedema Chronic angioedema

Urticaria present
treat as indicated (duration <6 weeks) (duration >6 weeks)

Angioedema of the skin, gastrointestinal tract, or both Angioedema associated with

life-threatening symptoms:
syncope, hypotension/shock
(anaphylaxis), bronchospasm,
vomiting, diarrhea, abdominal pain
Unknown cause Known deficiency of C1-INH

Emergency care as required

Draw blood for serum tryptase,
quantitative and functional
If throat involvement or Hereditary type: Acquired type: measurements of C4 and C1q
intestinal wall edema: Check C4, consider Check C4 and C1q components of complement
Check C4, C1q treatment with plasma- complement, consider
complement derived C1-INH treatment with plasma-
concentrate derived C1-INH Stabilize patient and hospitalize to
Rule out VCD by ENT
concentrate regular floor or ICU
specialist and CT of the Stabilize patient
Upon discharge refer patient to
throat Refer to allergist Stabilize patient
allergist
Empiric treatment with (if throat involvement) Refer to allergist
antihistamines, Hospitalize to regular (if throat involvement)
epinephrine, and floor or ICU Hospitalize to regular
corticosteroids floor or ICU
Hospitalize or refer
patient to allergist

Figure 6 Algorithm for the management of patients who present with acute angioedema. C1-INH, C1 esterase inhibitor; CT, computed
tomography; ENT, ear, nose, and throat; ICU, intensive care unit; VCD, vocal cord dysfunction. Modified from [8]; with permission [PERMISSION
PENDING].

An important component of the acute management of Inhaled β2 agonists (e.g., albuterol) are helpful when
anaphylaxis presented by severe histamine-mediated bronchospasm resists epinephrine injections alone. Sys-
angioedema is volume expansion. The largest catheter temic corticosteroids are not sufficient to prevent the
possible should be inserted into the largest peripheral progression of anaphylaxis [25]. Although the use of a
vein, and the rate should be titrated to pulse and blood parenteral corticosteroid (IV methylprednisolone) pro-
pressure; infuse 1–2 l normal saline rapidly by IV in vides a benefit in histamine-mediated angioedema, its
adults (5–10 ml/kg in the first 5 min), 30 ml/kg in the therapeutic effect is not immediate.
first hour in children [25].
Antihistamines act more slowly than epinephrine,
have minimal effect on blood pressure, and should not ACE inhibitor-induced angioedema
be administered alone as treatment for anaphylaxis or For all types of angioedema, the priority of acute man-
acute allergic angioedema. Combined histamine-receptor agement is maintenance of airway patency. Because
blockade, with H1 and H2 blockers, is more effective ACEI-induced angioedema does not involve histamine,
than the use of H1 agents alone. Diphenhydramine antihistamines have not been found to be effective in ei-
should be administered 25–50 mg IV (adults), 1 mg/kg ther the acute or long-term management of these
IV up to 50 mg (children). Identical oral doses may be patients; similarly, corticosteroids are not effective for
sufficient for milder episodes. Ranitidine should be admi- these conditions. Epinephrine should be considered to
nistered 1 mg/kg (adults), 12.5-50 mg infused over 10 min temporarily constrict permeable blood vessels. For
(children) [25,26]. patients who present with an acute attack of ACEI-
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induced angioedema, an immediate first step is discon- emergency medical treatment has been IV fresh frozen
tinuation of the ACEI [6]. plasma (FFP) and epsilon-aminocaproic acid [36]. Both
The mechanism underlying ACEI-induced angioedema anecdotal and published reports suggest that FFP
(excess bradykinin) is similar to that underlying HAE. replaces plasma C1-INH, thereby aborting an ongoing
For that reason, agents shown to be effective in HAE, in- attack. There is, however, a theoretical and demon-
cluding the plasma kallikrein inhibitor ecallantide and strated increased risk of worsened swelling following ad-
the bradykinin receptor antagonist icatibant, are cur- ministration of FFP during an acute attack, which is
rently being investigated in clinical studies as treatments most likely due to the concurrent replacement of both
for acute ACEI-induced angioedema [27,28]. Several plasma proteases and substrates that are involved in the
small case studies have reported on the use of icatibant mediation of an attack. Only anecdotal reports suggest
for the treatment of ACEI-induced angioedema [29-31]. that epsilon-aminocaproic acid offers minimal relief dur-
ing an acute attack of HAE; however, there is no pub-
Hereditary angioedema lished evidence that it provides significant benefit [5,35].
In May 2010, the third international conference on HAE
was held in Toronto, Canada, where international con- C1-INH replacement therapy
sensus approaches for the diagnosis, treatment, and C1-INH replacement therapy functions to restore the
management of HAE were reviewed and updated. The missing C1-INH in patients with HAE. Berinert is a
consensus documents divide the therapy for patients human, plasma-derived, pasteurized form of C1-INH
with HAE into acute treatment, short-term prophylaxis, that was approved by the US Food and Drug Adminis-
and long-term prophylaxis. The consensus recommends tration (FDA) in 2009 for the treatment of acute abdom-
that HAE attacks be treated as early as possible [24]. inal, facial, and, more recently, laryngeal attacks of HAE
Patients with HAE are unlikely to respond to antihista- in adult and adolescent patients [32]. C1-INH concen-
mines or corticosteroids. Epinephrine has low efficacy in trate has been available in Europe for more than 20
HAE, but has been advocated for use early in the course years and is considered the standard of care for the
of attacks Therapeutic agents available for the treatment treatment of HAE in many countries. Pasteurized and
of acute attacks of HAE are summarized in Table 3 nanofiltered C1-INH is provided as a single-use vial that
[23,32-34]; see also the following discussion regarding contains 500 units of C1 esterase inhibitor as a lyophi-
differential availability of these agents. lized concentrate. Each vial must be reconstituted with
10 mL of diluent (sterile water) provided. C1-INH con-
Drug therapy for hereditary angioedema centrate must be administered using aseptic technique
Before 2008, no drug had been approved in the US that at a dose of 20 units per kilogram of body weight by IV
was predictably effective for the treatment of acute injection (Table 3) [32,37]. Recently, the FDA has
attacks of HAE [35]. Until recently, the mainstay of approved self-administration of Berinert by patients.

Table 3 Treatment summary of emergency care available in the US to patients experiencing acute attacks of
hereditary angioedema [23,32-34]
Therapy and indication Dosage Monitoring tests
C1 esterase inhibitor [human] 20 U/kg body weight IV at a rate of 4 ml/ minute • Monitor patients with known risk factors for
(Berinert; CSL Behring) thrombotic events
Indicated for the treatment of acute • Epinephrine should be immediately available to treat
abdominal or facial attacks of HAE in any acute severe hypersensitivity reactions following
adult and adolescent patients discontinuation of administration
Plasma kallikrein inhibitor (Kalbitor 30 mg (3 ml) SC in three 10-mg (1 ml) injections. If • Given the similarity in hypersensitivity symptoms
[ecallantide]; Dyax Corp) attack persists, additional dose of 30 mg (3 ml) may and acute HAE symptoms, monitor patients closely
be administered within a 24-h period for hypersensitivity reactions
Indicated for attacks at all anatomic
sites • Administer in a setting equipped to manage
anaphylaxis and HAE
Fresh-frozen plasma 2 U at 1 to 12 h before the event (only for use when • Baseline: liver function tests, hepatitis virology
C1-INH concentrate is not available)
Bradykinin β2 receptor antagonist 30 mg (3 ml) injected SC in the abdominal area. If For patients who never received Firazyr previously,
attack persists, additional injections of 30 mg (3 ml) the first treatment should be given in a medical
(Firazyr [icatibant]; Shire Orphan
may be administered at intervals of ≥6 h. No more institution or under the guidance of a physician
Therapies)
than 3 injections in 24 hours
Indicated for attacks at all anatomic
sites
C1-INH C1 esterase inhibitor, IV intravenously, SC subcutaneously.
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Plasma kallikrein inhibitor safety and efficacy of the differing treatments. Data from
In 2009, the FDA granted approval to ecallantide (Kalbi- all trials will be used to update international and na-
tor), for the treatment of acute attacks of HAE in tional HAE databases and registries [43].
patients 16 years of age and older [33]. However, the Icatibant is approved for the treatment of acute attacks
European Union (EU) recently rendered a negative opin- of HAE in the EU and the US. The recent FDA indica-
ion regarding its approval. Ecallantide is a plasma kallik- tion for icatibant allows patients with HAE aged 18 years
rein inhibitor that is effective against attacks of HAE at or older to self-administer the medication [8,43].
any anatomic location, including abdominal/gastrointes- Another difference across countries regarding the
tinal, laryngeal, and peripheral attacks (Table 3). Ecallan- treatment of HAE is the use of a recombinant C1-INH
tide binds to plasma kallikrein and blocks its binding (conestat alfa, Rhucin), which is produced in transgenic
site, inhibiting the conversion of HMWK to bradykinin. rabbit milk. Recombinant C1-INH is currently under
By directly inhibiting plasma kallikrein, ecallantide FDA review; in June 2010, the Committee for Medicinal
reduces the conversion of HMWK to bradykinin and Products for Human Use of the European Medicines
thereby treats symptoms that occur during acute epi- Agency delivered a positive opinion on the use of re-
sodic attacks of HAE. combinant C1-INH for the treatment of acute attacks in
Two randomized placebo-controlled trials demon- patients with HAE [43].
strated that a 30 mg subcutaneous dose of ecallantide Regardless of the agent selected for acute attacks of HAE,
significantly reduced the duration of symptoms in the patient and/or healthcare provider needs to be able to
patients with HAE [38,39]. The most commonly differentiate the progression of an HAE attack from that of
reported adverse events were headache (8%), nausea an allergic reaction, as there are many similar features, so
(5%), and diarrhea (4%) [38]. Because of the 2.9% inci- that erroneous treatments are not provided and erroneous
dence of anaphylaxis observed in clinical trials, the FDA diagnoses are not made. Furthermore, patients trained to
has given ecallantide a black box warning, which self-administer these agents should be advised that if they
requires the drug to be administered by a trained health- are experiencing facial, neck, and/or throat swelling, they
care professional with emergency therapy readily avail- should go to the closest emergency department for obser-
able to treat an allergic reaction should one occur [33]. vation after taking their HAE medication.

Bradykinin receptor antagonist Conclusions

The bradykinin receptor blocker icatibant (Firazyr) (30 mg The advent of innovative pharmacologic treatment
injected subcutaneously) is a synthetic, 10 amino acid, options for acute angioedema, catalyzed by an improved
short-acting, and highly selective competitive bradykinin understanding of pathophysiologic processes, has made
β2 receptor antagonist [34,38,40]. Three trials have possible disease-specific therapies that have a positive
examined the safety and efficacy of icatibant in HAE impact on morbidity and mortality. The ability of the
[41,42]. These studies showed a decrease in median time emergency department physician to rapidly differentiate
to clinically significant symptom relief. This decrease between the various forms of angioedema is paramount
was statistically significant in the For Angioedema Sub- to the successful implementation of appropriate treat-
cutaneous Treatment (FAST)-2 and FAST-3 trials ment for these patients.
[41,42]. Adverse reactions consisted of injection site
reactions in more than 90% of subjects, pyrexia, and ele- Abbreviations
AAE: Acquired angioedema; ACEI: Angiotensin-converting enzyme inhibitor;
vated transaminase levels [41,42]. No anaphylaxis was APP: Aminopeptidase P; ARB: Angiotensin receptor blocker; C1-INH: C1
reported. Since bradykinin is thought to play a major esterase inhibitor; FFP: Fresh frozen plasma; HAE: Hereditary angioedema;
role in the antihypertensive effect of ACE inhibitors, the HMWK: High-molecular-weight kininogen; IAE: Idiopathic angioedema;
MHC2: Major histocompatibility complex 2; MI: Myocardial infarction;
icatibant package insert reports that any bradykinin β2 NSAID: Non-steroidal anti-inflammatory drug; PAE: Pseudoallergic
receptor antagonist has the potential to attenuate the angioedema.
antihypertensive effect of ACEIs [34].
Competing interests
The manuscript was financially supported by Dyax Corp. (Cambridge, MA).
Treatment variations by region and country
Because certain treatment options may be licensed in Authors’ contributions
some countries but not in others, the treatment of HAE JAB and JM meet the criteria for authorship as recommended by the
International Committee of Medical Journal Editors (ICMJE), were fully
differs across countries. Phase III clinical trials are on- responsible for all content and editorial decisions, retained full control over
going in the US for specific agents, and the standard of all content contained in this manuscript, and were involved with all stages
care for the treatment of HAE will continue to evolve as of manuscript development. They received no honorarium for their roles as
authors of this manuscript. Editorial and writing assistance in the
data from these trials become available. Rigorous phase development of this manuscript in the form of drafting and revising content
IV clinical trials will further delineate the long-term based on specific direction from the authors, collation of author comments,
Bernstein and Moellman International Journal of Emergency Medicine 2012, 5:39 Page 13 of 13
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editing, referencing, manuscript formatting, and creation of figures was 20. Zuraw BL: Clinical practice. Hereditary angioedema. N Engl J Med 2008,
provided by Publication CONNEXION (Newtown, PA). All authors read and 359(10):1027–1036.
approved the final manuscript. 21. Temiño VM, Peebles RS: The spectrum and treatment of angioedema.
The manuscript was financially supported by Dyax Corp. (Cambridge, MA). Am J Med 2008, 121:282–286.
The Medical Affairs department at Dyax Corp. was allowed several courtesy 22. Hill MD, Barber PA, Takahashi J, Demchuk AM, Feasby TE, Buchan AM:
scientific accuracy reviews by the authors and provided feedback to the Anaphylactoid reactions and angioedema during alteplase treatment of
authors for their consideration. Dyax Corp. was not involved in the writing or acute ischemic stroke. CMAJ 2000, 162(9):1281–1284.
editing of this manuscript and was not permitted to censor any content 23. Gompels MM, Lock RJ, Abinun M, et al: C1 inhibitor deficiency: consensus
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The authors wish to acknowledge the Medical Affairs department at Dyax for angioedema. Allergy Asthma Clin Immunol 2010, 6(24):1–13.
assistance in identification of the unmet medical education need addressed 25. Oswalt ML, Kemp SF: Anaphylaxis: office management and prevention.
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1
Department of Internal Medicine, Division of Immunology/Allergy, University antagonists. Ann Emerg Med 2000, 36(5):462–468.
of Cincinnati Medical Center, 231 Albert Sabin Way, PO Box 670563, 27. Bernstein JA: Evaluation of ecallantide for the acute treatment of
Cincinnati, OH 45267-0550, USA. 2Emergency Medicine, University of angiotensin converting enzyme inhibitor induced angioedema (ACE).
Cincinnati Medical Center, Cincinnati, OH, USA. ClinicalTrials.gov Website. http://clinicaltrials.gov/ct2/show/NCT01036659?
term=ecallantide+ACE+ inhibitor&rank=1. December 18, 2009. Updated
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