Author: Jason M Kendall / Editor: Jason M Kendall / Codes: CMP1, CAP28, PMP1, PAP18, HMP1, HAP28 / Published: 01/06/2011 / Review Date: 01/06/2014
The sudden nature and type of symptoms experienced in hypersensitivity reactions mean they are a common reason for attending the Emergency Department. Urticaria (hives) and angioedema are part of a spectrum of allergic symptoms and occasionally have a non-allergic aetiology. They can be present in isolation or as part of a wider anaphylactic reaction. Basic knowledge of the pathophysiology of these conditions will help you recognise the type of reaction and treat patients effectively from the outset.Clinical assessment
Urticaria (hives) is histamine mediated localised oedema of the dermis. It is at one end of the allergic reaction spectrum with anaphylactic shock at the other end. Exposure to an allergenic protein produces IgE mediated mast cell degranulation and histamine release. This produces vascular dilation and transudation of fluid from the affected vessels. Unlike in allergic angioedema and anaphylaxis, this vascular dilatation is limited to the dermis.
Angioedema (AE) is pathogenetically similar to urticaria but involves the deeper dermal and subcutaneous tissue. The aetiology of angioedema can be either allergic (IgE and histamine mediated as in urticaria) or non-allergic. 90% of attacks of angioedema are of the allergic type. Non-allergic AE can be further subdivided (1) into drug induced (e.g. ACE-inhibitors), Hereditary (C1-esterase-inhibitor deficiency), Acquired, Idiopathic and Pseudoallergenic (see Diagram). Unlike the allergic form, the non-allergic drug induced, hereditary and acquired forms are mediated by bradykinin.
Drug reactions can cause angioedema through several of the above mechanisms. Those eliciting a Type 1 hypersensitivity reaction will produce angioedema within minutes whereas those causing angioedema by inhibiting bradykinin may not be seen for months (2). The commonest drug classes associated with angioedema are listed in the table below.
|Top 10 drugs / drug classes associated with angioedema (2)|
|Selective Serotonin Reuptake Inhibitors (SSRIs)|
|Angiotensin 2 antagonists|
|Non-steroidal anti-inflammatory drugs (NSAIDS)|
|Proton Pump Inhibitors|
HAE is an autosomal dominant condition caused by C1 esterase inhibitor deficiency or functional deficiency. This can be confirmed clinically by low levels of C4 and C1 esterase inhibitor function. The exact prevalence of hereditary angioedema (HAE) is unknown with approximately 1 in 10,000 to 1 in 50,000 people affected (3).
Signs & Symptoms
Urticaria produces wheals and papules of non-pitting, oedematous, erythematous and intensely pruritic skin (see Figure 1). These can appear as crops mainly on the limbs and trunk and can spontaneously resolve quickly.
Figure 1. Urticaria (Hives) (4)
Angioedema involves the deeper dermal structures with little pruritis. It commonly involves swelling of the face, lips (see Figure 2), mouth, tongue, extremities (see Figure 3) and the genitalia in men. Laryngeal involvement can produce stridor and lead to complete airway obstruction. Angioedema is also associated with abdominal symptoms caused by bowel wall oedema, such as colic-like pain, nausea, vomiting and diarrhoea. However cutaneous attacks are the most common form.
Figure 2 Angioedema of the lips (5)
Figure 3 Angioedema of the hand (6)
Symptoms can occur singly or in combination; acute urticaria presents with angioedema in about 50% of cases and alone in 40% of cases (7). Angioedema presents alone in approximately 10% of cases which should prompt consideration of a non-allergic form.
|Allergic Angioedema||Non-Allergic Angioedema||Anaphylaxis|
|Anatomically localised attack||Anatomically localised attack||Systemic symptoms|
|Urticaria||Gradual onset||Rapid onset and progression|
|Pruritis||No Pruritis||Respiratory failure (wheeze, fatigue, cyanosis, hypoxia, tachypnoea)|
|Normotension||Previous identical episodes||Cardiovascular Collapse (Diaphoretic, hypotensive, tachycardia, drowsiness)|
- Evolving Anaphylaxis
- Contact Dermatitis
Assessment of potentially life-threatening conditions should follow a structured ABC pattern. The initial management goals in acute urticaria and angioedema are to ensure adequate airway protection and cardiovascular stability. If an evolving anaphylactic reaction is suspected then treatment should follow that of anaphylactic shock. The Resuscitation Council has an excellent algorithm http://www.resus.org.uk/pages/anaalgo.pdf (8).
Urticaria & Allergic Angioedema
Urticaria as a sole symptom is unlikely to be life-threatening. In the absence of airway compromise, treatment with H1-receptor blockers (e.g. chlorpheniramine) is indicated. As 85% of histamine receptors in the skin are of the H1 type with the remainder being H2, there is a theoretical benefit to treatment with H2-receptor blockade (e.g. cimetidine, ranitidine) in a histamine mediated reaction (9).
One randomised controlled trial has shown faster initial symptom resolution using a combination of both H1 and H2 antagonists (level of evidence 2) (10).
Anti-histamines (as above) are also the first-line treatment for mild allergic angioedema.
In moderate to severe attacks of allergic angioedema intramuscular epinephrine should be considered. Its adrenergic actions address both peripheral vasodilatation and oedema formation (alpha adrenoceptors) and inhibit further mediator release (beta adrenoceptors) (level of evidence 4). Emergency airway protection by a cuffed endo-tracheal tube may be required if laryngeal or oropharyngeal swelling threatens airway occlusion.
Further modulation of the immune response may be achieved with systemic corticosteroids (e.g. hydrocortisone, prednisolone). These drugs take 6-8 hours to have their effect and may reduce the length of an attack. Topical steroids are of no value (7) (level of evidence 4).
As angioedema associated with C1 esterase inhibitor deficiency is modulated by bradykinin it requires an alternative management strategy. It often does not respond to treatment with epinephrine, anti-histamines and corticosteroids.
Attacks of HAE should be treated with Icatibant (a bradykinin B2 receptor antagonist) or C1 esterase inhibitor concentrate (if available). C1 esterase inhibitor is also found in fresh frozen plasma and two units are effective in abolishing an attack (7). Icatibant is administered as a single subcutaneous injection and has been shown to start producing symptomatic improvement in under an hour (11). C1 esterase inhibitor concentrate and FFP are derived from donated blood and require intravenous administration.
Prognosis & Followup strategies
Patients who have experienced urticaria alone do not need formal follow up and can be discharged from the emergency department. They should be advised to avoid the precipitating cause (if known) and to take oral anti-histamines for further attacks. Similar advice can be given to those presenting with mild to moderate angioedema who have only required treatment with anti-histamines.
Drug precipitants for the attack should be sought and discontinued if implicated. Patients experiencing ACE inhibitor related angioedema will need their ACE inhibitor discontinuing and replacing with another anti-hypertensive agent. Angioedema has also been associated with angiotensin II receptor antagonists (12) and therefore may not entirely prevent recurrence.
Those patients who have had a severe attack requiring epinephrine or those who are suspected of having a diagnosis of HAE will need follow-up in an allergy clinic for formal diagnosis. Comparison of mast cell tryptase levels taken during an attack with those during convalescence can aid diagnosis of an allergic attack. These patients should also be considered for an epipen prescription.
Key Learning Points
- Urticaria and Angioedema can be presenting signs of both allergic and non-allergic disease
- Antihistamines +/- Epinephrine are the first line treatment in both conditions. (Level of evidence 4)
- Addition of an H2 receptor blocker may speed initial symptoms resolution. (Level of evidence 2)
- Angioedema due to hereditary C1 esterase inhibitor deficiency will not respond to normal management and should be treated with a bradykinin receptor antagonist (Icatibant), C1 esterase inhibitor concentrate or fresh frozen plasma. (Level of evidence 3)
Safety pearls and Pitfalls
The correct identification of the likely type of angioedema the patient is experiencing is critical for allowing correct treatment to be started. Rapid onset with urticaria should suggest an allergic pattern while recent (within months) commencement of a new medication should prompt thought of a drug induced angioedema. Previously undiagnosed HAE sufferers may describe several prior occurrences of non-pruritic attacks without explanation or have attacks that do not respond to anti-histamine therapy.
- Non-allergic angioedema: role of bradykinin. Bas, M. 2007, Allergy, Vol. 62, pp. 842-856.
- West Midlands Centre for Adverse Drug Reaction Reporting. Drug Induced Angioedema. [Online] [Cited: 22 May 2010.] www.adr.org.uk/factsheets/angioedema.pdf.
- Hereditary and acquired angioedema:. Agostini A, et al. 2004, J Allergy Clin Immunol, Vol. 114, pp. S51-131.
- Hives (urticaria) on the Chest. [Online] 28 April 2008. [Cited: 12 April 2010.]http://www.clarian.org/ADAM/doc/PediatricCenter/2/2481.htm.
- Angioedema. Pharmacy and Drugs.com. [Online] [Cited: 12 April 2010.] http://www.pharmacy-and-drugs.com/Skin_diseases/Angioedema.html.
- FAQ. US Hereditary Angioedema Association. [Online] [Cited: 12 April 2010.]http://www.hereditaryangioedema.com/pamphlet.php.
- Marx, John A, [ed.]. Rosens Emergency Medicine. 6th. s.l. : Mosby Elselvier, 2006. p. 1835. Vol. 2.
- Anaphylaxis. Resuscitation Council (UK). [Online] [Cited: 15 May 2010.]http://www.resus.org.uk/pages/anaalgo.pdf.
- Chronic Urticaria and Angioedema. Kaplan, AP. 2002, N Eng J Med, Vol. 346, p. 175.
- Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Lin RY, Curry A,Pesola GR,Knight RJ,Lee HS,Bakalchuk L,Tenenbaum C,Westfal RE. 5, 2000, Annals of Emergency Medicine, Vol. 36, pp. 462-468.
- Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant).Bork, K, et al. 6, June 2007, The Journal of Allergy and Clinical Immunology, Vol. 119, pp. 1497-1503.
- Are Angiotensin II Receptor Antagonists Safe in Patients With Previous Angiotensin-Converting Enzyme InhibitorInduced Angioedema? Fuchs, SA, Koopmans, RP and H, Guchelaar. 1, 2001, Hypertension, Vol. 37, p. e1.