Acute angioedema can cause significant morbidity and mortality 1. Several different subtypes of angioedema have been described, and their prevalences range between 1 : 4000 and 1 : 50 000 2,3 2,3. However, epidemiological data are lacking for some subtypes; thus, the actual prevalence of this condition may be higher. Misdiagnosis of angioedema may lead to inappropriate management, and delayed diagnosis and treatment can be fatal in patients with swelling of the upper respiratory tract. There is therefore a need for greater awareness among emergency healthcare professionals of the symptoms and causes of acute angioedema, as well as clear guidance on its optimal management.
To address this need, a panel of independent emergency physicians and immunologists was convened by Shire Human Genetic Therapies. Our group developed an algorithm providing guidance on distinguishing between the different forms of angioedema in the emergency department (ED). The algorithm is presented here, together with comprehensive information about the underlying pathological mechanisms of angioedema and recommendations for the prompt and effective treatment of this condition in the ED.
Information sources and selection criteria
Our recommendations have been developed on the basis of expert opinion and the findings of literature searches. Literature searches were conducted in PubMed on 16 May 2011 using Medical Subject Heading terms and keywords relevant to the diagnosis and management of acute angioedema, for example angioedema, emergency, critical care (see Table, Supplemental digital content 1, http://links.lww.com/EJEM/A29 for details of literature searches). To ensure relevance to the modern-day clinical setting, literature searches were limited to articles published since 1 January 1995. To ensure as complete a listing as possible of important literature, further articles identified by the authors were also included. Only articles from peer-reviewed literature were included in this review.
What is angioedema?
Angioedema is defined as localized and transient swelling of the skin and/or the mucous membranes of the upper respiratory or gastrointestinal tract 4. It occurs when increased vasodilation and capillary permeability lead to extravasation of fluid into the interstitial spaces 4. A variety of inflammatory mediators can trigger this process, including histamine, prostaglandins, leukotrienes, and bradykinin.
Unlike other forms of edema, angioedema is nonpitting, not affected by gravity (i.e. is not dependent), and frequently asymmetrical. Swellings have ill-defined margins and the skin is often not discolored or may be slightly erythematous. In contrast to urticaria, which is characterized by itchy, raised, erythematous papules, angioedematous swellings are not itchy and often painless, although they may sometimes cause a burning sensation. It should be noted, however, that some forms of angioedema (particularly mast-cell-mediated angioedema) may be accompanied by urticaria 5. Typical examples of angioedema affecting the lips are shown in Fig. 1.
Angioedema mediated by mast cell degranulation (antihistamine-sensitive)
The degranulation of mast cells results in the release of histamine and other proinflammatory mediators. These act to increase vascular permeability, leading to angioedema and/or urticaria 4. There are a variety of causes of mast cell degranulation and a thorough assessment of clinical history is therefore required to identify potential triggers.
In allergic angioedema, degranulation is caused by interaction between a specific allergen and immunoglobulin (Ig)E antibodies on the surface of mast cells and basophils. This occurs in individuals already sensitized to the allergen. A precipitant (e.g. food, drug, insect sting) should be sought from the clinical history, keeping in mind that reactions usually occur within minutes of exposure. In autoimmune angioedema, circulating IgG autoantibodies interact with IgE receptors on the surface of mast cells to stimulate their degranulation in the absence of allergens.
Mast cell degranulation can also be triggered without the involvement of IgE antibodies or their receptors. It may occur in direct response to some drugs, such as opiates and radiocontrast dye, or following physical stimuli (e.g. pressure, heat, cold).
Patients with angioedema mediated by mast cell degranulation (whether IgE-mediated or non-IgE-mediated) present with a rapid onset of swelling, frequently with associated urticaria (Fig. 1a) 4. Mast-cell-mediated angioedema often responds to treatment with antihistamines.
Mast-cell-mediated angioedema may be localized or it may be associated with life-threatening systemic symptoms (e.g. hypotension or respiratory compromise). A reaction should only be described as anaphylaxis if such systemic features are also present 7,8 7,8.
Histamine-mediated angioedema may occur independent of mast cell involvement, for example in scombroid fish poisoning. This is caused by the ingestion of contaminated fish containing large quantities of histamine, resulting in histaminergic symptoms including urticaria and angioedema 9.
Angioedema mediated by bradykinin (antihistamine-insensitive)
Several forms of angioedema are mediated by proinflammatory molecules other than histamine, in particular, bradykinin. The interaction of bradykinin with its B2 receptors on the surface of vascular endothelia stimulates vasodilation and increases vascular permeability, resulting in the swelling experienced during acute angioedema 4. Bradykinin-mediated angioedema is not believed to involve mast cell degranulation. It is not accompanied by urticaria and does not respond well to treatment with antihistamines.
Angiotensin-converting enzyme inhibitor-associated angioedema
Approximately 1 in 200 patients treated with angiotensin-converting enzyme (ACE) inhibitors experience angioedema 2,10 2,10. ACE inhibitors are believed to cause local elevations in plasma bradykinin because of inhibition of its normal breakdown 11. In susceptible individuals, this results in angioedema that typically affects the lips, face, and tongue. It can cause airway swelling, and deaths have been reported 12. Gastrointestinal involvement is rare 13. The diagnosis of ACE inhibitor-induced angioedema is complicated by the fact that it may not occur until months or even years after the initiation of therapy 13.
Hereditary angioedema (HAE) is associated with transient increases in bradykinin in individuals with reduced C1 esterase inhibitor (C1-INH) activity 14. C1-INH is an important regulator of the complement pathway and also controls the production of bradykinin through the kallikrein–kinin system. Patients may either have reduced circulating levels of C1-INH (HAE type I) or dysfunctional C1-INH (HAE type II) 15. Most patients with HAE first experience swelling episodes during childhood or early adolescence and have a family history of similar attacks.
A variety of stimuli are known to precipitate acute attacks in patients with HAE, including trauma, dental surgery, oral contraceptives, and infection 14,16,17 14,16,17 14,16,17. However, many attacks occur with no obvious trigger 16. A prodromal reticulate rash is experienced by some patients with HAE 18, but urticaria is not a feature of this condition 14,16 14,16. Swelling associated with this form of angioedema is typically slow in onset, taking several hours to reach the maximum intensity, and can last for up to 5 days 14. Importantly, laryngeal oedema may lead to life-threatening upper airway obstruction.
Acquired angioedema (AAE), also known as acquired C1-INH deficiency, is associated with lymphoproliferative diseases and autoimmune disorders. AAE develops in these conditions as a result of the production of neutralizing autoantibodies against C1-INH 19 or increased C1-INH consumption.
The clinical manifestations of AAE are similar to those of HAE (i.e. slow-onset angioedema without urticaria) because both forms result from C1-INH deficiency and are mediated by bradykinin 19. The distinguishing feature of AAE is its later age of onset compared with individuals with HAE (typically after 40 years of age) in patients without a family history of angioedema 19.
Angioedema mediated by other mechanisms
The action of NSAIDs on arachidonic acid metabolism can lead to the accumulation of proinflammatory leukotrienes, which may result in angioedema/urticaria 20. Angioedema with urticaria may also occur in association with other rare disorders, such as hypereosinophilia, in which the release of proinflammatory mediators from eosinophils and basophils leads to vasodilation, contributing to angioedema 21.
Angioedema is termed idiopathic or spontaneous if, even after a thorough assessment, a trigger or a cause cannot be identified. It may occur with or without accompanying urticaria 4, and it may involve histamine or other mediators, such as bradykinin 22.
A step-by-step approach to the diagnosis and management of acute angioedema in the emergency department
When a patient with acute angioedema presents to the ED, it is essential that he or she receives the most effective treatment as quickly as possible. For this to be achieved, the physician must establish the likely working diagnosis, evaluate the severity of angioedema, and decide on the appropriate treatment priorities. The algorithm shown in Fig. 2 summarizes the step-by-step approach described in the following paragraphs.
Management of threatened airway and shock
If there is evidence of upper airway involvement (e.g. swelling of the pharynx or the larynx) or if anaphylactic shock is suspected, a senior clinician with experience in airway management should be involved immediately, and anaphylaxis protocols should be followed 23–25 23–25 23–25.
In life-threatening situations of impending airway obstruction, emergency endotracheal intubation and/or the establishment of a surgical airway may be necessary 3. If airway patency is not under immediate threat, the diagnostic algorithm should be followed to ascertain the most appropriate treatment (Fig. 2).
Is urticaria present?
An important discriminating feature in individuals with acute angioedema is the presence or absence of urticaria. Urticaria is commonly observed in patients with angioedema mediated by mast cell degranulation 5. In contrast, HAE, AAE, and ACE-inhibitor-associated angioedema are not accompanied by urticaria 16,19,26 16,19,26 16,19,26.
In cases of suspected allergic angioedema, referral to an immunologist or an allergist may be useful. In the acute setting, an elevated mast cell tryptase level is suggestive of mast cell degranulation 27. Investigations in the immunology/allergy clinic to identify potential allergic triggers may involve skin prick testing or blood tests for specific IgE.
Is the patient known to have hereditary angioedema or acquired angioedema?
It should be determined whether the patient has an established diagnosis, such as HAE or AAE. It may be necessary to contact the patient’s primary care physician or immunologist for relevant details of their normal treatment regimen. Many patients who have been diagnosed with HAE or AAE carry a letter from their immunologist describing how their attacks should be managed. A patient alert card for patients with HAE, providing information about their diagnosis and the appropriate treatment for acute attacks, has been produced recently by the Primary Immunodeficiency Association 28. A significant proportion of patients also carry a supply of the drug required for their emergency treatment.
Does the patient have no established diagnosis?
In patients with no established diagnosis, a comprehensive medical history should be taken. Important information to be gathered includes details of any known allergies, history of previous attacks (including age at first onset), drug history, family history of similar episodes, and details of any concomitant diseases. In particular, confirmation of the speed of onset of angioedema may help to identify the cause of swelling: in allergic reactions, angioedema typically develops within minutes, whereas HAE, AAE, idiopathic, and ACE-inhibitor-associated angioedema may take several hours to reach maximum severity 4.
Is hereditary angioedema or acquired angioedema possible?
A family history of angioedema in a patient with angioedema but no urticaria and/or a history of recurrent abdominal pain should alert the clinician to the possibility of HAE, especially if the age at onset was in the first or the second decade of life. The presence of known triggers for an acute HAE attack should be considered (e.g. trauma, infection, dental surgery) 10.
Patients in whom HAE is clinically suspected should be referred to an immunologist for further investigation. This will include measurements of C3, C4, and C1-INH levels and function. Reductions in C4 levels and reduced C1-INH levels and/or function are typically found in patients with HAE.
In patients with swelling without urticaria, no family history of angioedema, and whose symptoms first occurred at a later age (typically over 40 years), the possibility of AAE associated with lymphoproliferative or autoimmune disorders should be considered 19. Patients suspected to have AAE should also be referred to an immunologist for further investigation.
Is the patient taking an angiotensin-converting enzyme inhibitor?
If a patient presents with acute angioedema without associated urticaria, their medical history should be examined to determine whether they are or have been using ACE inhibitors. The first episode of ACE-inhibitor-associated angioedema can occur months or years after the initiation of treatment 13.
Is there a history of precipitant or possible exposure to allergen?
Potential precipitants of angioedema should be sought from the medical history. Specific questions related to triggers such as foods consumed immediately before the onset of swelling, drugs (e.g. penicillin), and insect bites or stings should be asked.
Is another medical condition present?
A thorough clinical assessment may identify an underlying disease process, such as infection or inflammation, that may be the cause of angioedema with or without urticaria. When appropriate, further investigations should be conducted and treatment of the underlying condition should be instituted.
Idiopathic or spontaneous angioedema may be diagnosed in patients showing typical angioedema symptoms with no history of exposure to precipitants, and where HAE, AAE, or angioedema associated with ACE inhibitors have been excluded. Idiopathic angioedema is frequently associated with urticaria, but may occur in isolation 29.
Unless HAE is suspected, routine laboratory studies are not necessary in the evaluation of acute angioedema 30. A thorough clinical history and examination are useful to exclude any underlying pathology and to direct further investigations.
What are the treatment options for alleviating acute angioedema?
Recommendations for the treatment of acute angioedema in the ED are shown in the algorithm (Fig. 2). It should be kept in mind that because of variations in regional policies, not all treatments are available at every hospital. Even when pharmacological treatment is available, patients should be observed closely, with measures taken to protect the airway if necessary, until the attack has fully resolved.
Angioedema mediated by mast cell degranulation
The emergency management of angioedema mediated by mast cell degranulation is the same for both IgE-mediated and non-IgE-mediated cases. For patients with allergic angioedema, removal of the suspected allergen is essential, and treatment should be initiated with antihistamines for example cetirizine hydrochloride (10 mg orally once daily or up to four times daily) 5,31,32 5,31,32 5,31,32 and corticosteroids for severe attacks (e.g. a single dose of prednisolone up to 40 mg orally) 31.
If there is evidence of associated cardiorespiratory compromise, bronchoconstriction, or wheeze, intramuscular adrenaline should be administered (0.01 mg/kg body weight, up to a maximum of 0.5 mg intramuscularly, every 5–20 min as necessary) 33 and anaphylaxis protocols should be followed. In addition to the administration of adrenaline, the use of oxygen therapy, intravenous fluid replacement, and vasopressors should be considered for patients with symptoms of anaphylaxis 7. It should be noted that there is no evidence that either antihistamines or corticosteroids are effective in the acute treatment of anaphylaxis 7. Provision of self-injectable adrenaline should be considered for patients who experience allergic angioedema affecting the upper airway, particularly when there is a risk of further unpredictable exposure to the allergen (e.g. foods, insect stings) 34.
Angioedema associated with angiotensin-converting enzyme inhibitors
Patients experiencing angioedema associated with ACE inhibitors should stop taking them immediately. Discontinuation of ACE inhibitors leads to the resolution of symptoms in most patients 35. Owing to the apparent role of bradykinin in ACE-inhibitor-associated angioedema, the injection of a bradykinin B2 receptor antagonist (e.g. icatibant) may provide rapid relief of symptoms and may be considered in patients with airway involvement. Although icatibant is not licensed for the treatment of ACE-inhibitor-associated angioedema, a small case series showed that icatibant injection was followed by a rapid and sustained relief of symptoms in patients with this condition (the mean time to complete resolution of symptoms in eight patients with ACE-inhibitor related angioedema who received an icatibant injection was 4.4 h, compared with 33 h in 47 similar patients who received antihistamine and steroid treatment) 36. The efficacy of icatibant in the treatment of ACE-inhibitor-associated angioedema is being investigated in a randomized-controlled clinical trial 37.
Although antihistamines and corticosteroids are unlikely to be effective in resolving angioedema caused by ACE inhibitors, it should be kept in mind that not all episodes of angioedema experienced by patients taking an ACE inhibitor result from the action of the drug on bradykinin levels. The possibility of other forms of angioedema, unrelated to ACE inhibitor use, should also be considered in these patients. If it is possible that the swelling could be histamine-mediated, nonsedating antihistamines or corticosteroids should be administered. Control of angioedema may require doses of antihistamine beyond the license recommendation 5.
Specific approaches to the treatment of patients with HAE depend on the severity of the attack, and physicians should follow their local treatment protocol and individual patient management plans where available. Airway involvement always requires prompt treatment, and intubation and tracheotomy may be necessary 3.
Acute laryngeal, abdominal, and cutaneous attacks in patients with type I and II HAE may be treated using first-line drugs such as an intravenous infusion of C1-INH [plasma-derived C1-INH, 20 U/kg of body weight (Berinert; CSL Behring, King of Prussia, Pennsylvania, USA) or 1000 U (Cinryze; ViroPharma Inc., Exton, Pennsylvania, USA) or recombinant C1-INH, 50–100 U/kg body weight] 38–40 38–40 38–40 or by a subcutaneous injection of the bradykinin inhibitor icatibant (30 mg) 41,42 41,42. Solvent detergent-treated fresh-frozen plasma (2 U) may be used as a second-line agent only in the absence of first-line agents 14. The selection of the therapeutic agent in individual patient management plans for acute attacks and the threshold for initiating treatment will be influenced by individual patient preferences and local policy.
Randomized-controlled trials have shown that both C1-INH concentrate and icatibant are effective in resolving swelling in patients with HAE types I and II. In a study of 125 patients with HAE, the median time to the onset of symptom relief was significantly shorter in patients who received the plasma-derived C1-INH concentrate Berinert than in those who received placebo (0.5 and 1.5 h, respectively, P=0.0025) 38. Another study showed that the median time to unequivocal relief from an angioedema attack was 2 h in 35 patients with HAE who were treated with the nanofiltered C1-INH concentrate Cinryze, compared with 4 h in 33 similar patients who received placebo (P=0.02) 39. The administration of recombinant human C1-INH significantly reduced the time to the beginning of symptom relief in 29 patients with HAE compared with 29 similar patients who received saline (66 and 495 min, respectively, P<0.001) 40.
In the most recent clinical trial of icatibant, the median time to almost complete symptom relief was significantly reduced in 43 patients with HAE experiencing cutaneous or abdominal angioedema who received icatibant injections, compared with 45 patients experiencing similar attacks who received placebo (8.0 and 36.0 h, respectively, P=0.012) 43. This finding is consistent with the results of previous studies on icatibant 42.
Analgesics, such as NSAIDS and opioids, and antiemetics may contribute toward symptom control for patients with abdominal edema 3,14 3,14. Mild peripheral swellings may not require active treatment; however, therapy may be required in severe cases where cutaneous swelling is disfiguring or disabling. Patients should be re-evaluated frequently until symptoms start to improve. Jaiganesh and colleagues have proposed guidelines on the management of HAE in the ED 28.
Acute attacks in patients with AAE should be treated in a manner similar to those in patients with HAE, because both conditions are bradykinin-mediated forms of angioedema associated with C1-INH deficiency. Although no acute treatments are licensed for AAE, an intravenous infusion of C1-INH concentrate may be effective in resolving swelling in some patients with AAE (nine of 12 patients with AAE who received an infusion of C1-INH concentrate showed a rapid positive response) 2,19,44 2,19,44 2,19,44. In addition, icatibant was effective in rapidly resolving four attacks in a patient with this form of angioedema who was not responsive to plasma-derived C1-INH 19. However, the efficacy of icatibant in the treatment of AAE is yet to be investigated in randomized-controlled clinical trials.
Episodes of idiopathic angioedema should initially be treated with nonsedating antihistamines (e.g. cetirizine hydrochloride, 10 mg orally once daily or up to four times daily) 29,31,32 29,31,32 29,31,32. Extended courses of corticosteroids should be avoided. Patients who do not respond to high-dose antihistamines should be reviewed in an allergy or an immunology clinic. If laryngeal swelling threatens airway patency, intramuscular adrenaline should be administered (0.01 mg/kg body weight, up to a maximum of 0.5 mg intramuscularly, every 5–20 min as necessary) 33.
Angioedema associated with other medical conditions, for example infection or inflammation, should be treated in the same way; in addition, the underlying pathology should be investigated and, if identified, treated.
Patients treated for anaphylaxis should be observed for at least 6 h in a clinical area capable of treating life-threatening airway, breathing, and circulation problems 24, and it seems sensible to extend this approach to other forms of angioedema associated with urticaria. Inpatient management in a critical care setting is required whenever senior clinicians remain concerned about potential threats to airway patency.
Not all patients with acute attacks of HAE, AAE, or ACE-inhibitor-associated angioedema require hospital admission following ED assessment. Decisions should be guided by existing individual patient management plans, the presence or absence of symptom progression, and response to treatment.
Acute angioedema is an often distressing and potentially life-threatening condition. A stepwise approach in which early attention to airway management is followed by the rapid establishment of a working diagnosis on the basis of key historical features can help guide optimal treatment by targeting the underlying pathophysiology. It is hoped that greater knowledge of this complex condition among emergency physicians will help to improve the standard of care given to patients who experience acute angioedema.
The authors are grateful to Dr David Webster of the Primary Immunodeficiency Association for his assistance in developing the algorithm. Shire Human Genetic Therapies, a division of Shire Pharmaceuticals, produces the bradykinin B2 receptor antagonist icatibant (Firazyr) for the treatment of acute attacks of type I and type II HAE in adults. CSL Behring produces human plasma-derived C1-INH concentrate (Berinert) for the treatment of acute episodes of type I and type II HAE. Shire Human Genetic Therapies paid for the editorial assistance provided by Dr Ruth Gandolfo and Dr Jonathan Morton (Oxford PharmaGenesis, Oxford, UK), and reviewed the manuscript to ensure the accuracy of all statements regarding the treatment of acute angioedema with icatibant.
The authors developed the initial concept for the article and diagnostic algorithm. The article was drafted by R.G. and J.M. (Oxford PharmaGenesis) on the basis of an outline provided by the authors. All authors critically appraised and revised the article at key points in its development, and all approved the final version. The algorithm was developed by the authors and was professionally redrawn by Oxford PharmaGenesis Ltd. T.J. accepts full responsibility for the manuscript and controlled the decision to publish.
Conflicts of interest
Dr Thiagarajan Jaiganesh received travel expenses and an honorarium for participation in an advisory board sponsored by Shire Pharmaceuticals.
Dr Martin Wiese received travel expenses and an honorarium for participation in an advisory board sponsored by Shire Pharmaceuticals.
Dr John Hollingsworth received travel expenses and an honorarium for participation in an advisory board sponsored by Shire Pharmaceuticals. He has also received honoraria and travel expenses from Shire Pharmaceuticals for lectures and presentations.
Chris Hughan acted on behalf of the Primary Immunodeficiency Association (PiA). Travel expenses and honoraria from Shire Pharmaceuticals and CSL Behring were received by the PiA for lectures and presentations. The PiA has also received unrestricted educational grants from Baxter, Octapharma, CSL Behring, Shire Pharmaceuticals, Bio Products Laboratory, Biotest, AMT/Convatec, Grifols, Viropharma, and The Binding Site to support its annual meeting and other activities.
Dr Mohamed Kamara received travel expenses and an honorarium for participation in an advisory board sponsored by Shire Pharmaceuticals.
Dr Philip Wood has received travel expenses and honoraria for participation in advisory boards sponsored by Shire Pharmaceuticals and CSL Behring.
Dr Claire Bethune received travel expenses and honoraria for participation in advisory boards sponsored by Shire Pharmaceuticals and Swedish Orphan Biovitrum. She has also received support from Shire Pharmaceuticals and CSL Behring to attend meetings and for nursing sessions in her department.
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