Kanani et al. Allergy Asthma Clin Immunol 2018, 14(Suppl 2):59 Allergy, Asthma & Clinical Immunology https://doi.org/10.1186/s13223-018-0288-z REVIEW Open Access Urticaria and angioedema Amin Kanani1*, Stephen D. Betschel2 and Richard Warrington3 Abstract Urticaria (hives) is a common disorder that often presents with angioedema (swelling that occurs beneath the skin). It is generally classifed as acute or chronic. Second-generation, non-sedating, non-impairing histamine type 1 (H1)-receptor antihistamines represent the mainstay of therapy for both acute and chronic urticaria. Angioedema can occur in the absence of urticaria and can be broadly divided into histamine-mediated and non-histamine- mediated angioedema. Histamine-mediated angioedema can be allergic, pseudoallergic or idiopathic. Non-histamine mediated angioedema is largely driven by bradykinin and can be hereditary, acquired or drug-induced, such as with angiotensin-converting enzyme inhibitors. Although bradykinin-mediated angioedema is often self-limited, laryngeal involvement can lead to fatal asphyxiation. The mainstay of management for angioedema is to avoid specifc triggers, if possible. For hereditary angioedema, there are specifcally licensed treatments that can be used for the management of acute attacks, or for prophylaxis in order to prevent attacks. In this article, the authors will review the causes, diagnosis and management of urticaria (with or without angioedema) and isolated angioedema. The diagnostic and therapeutic approaches to these two conditions are considerably diferent, and this review is designed to highlight these diferences to the reader. Keywords: Urticaria, Angioedema, Acute urticaria, Chronic urticaria, Chronic spontaneous urticaria, Inducible urticaria, Hereditary angioedema, Acquired angioedema Background histamine, leukotrienes and prostaglandins, which, in Urticaria is a common disorder, occurring in 15–25% of turn, cause vasodilation and leakage of plasma in and individuals at some point in life [1, 2]. It is characterized below the skin. Tere is also a more delayed (4–8 h) by recurrent, pruritic, wheals with pale, central swelling secretion of infammatory cytokines (e.g., tumor necrosis and surrounding epidermal erythema which can appear factor, interleukin 4 and 5) that potentially leads to over any part of the body (see Fig. 1). Te lesions can further infammatory responses and longer-lasting range in size from a few millimeters to several centimeters lesions [1]. in diameter, and are often transient, resolving within Urticaria is generally classifed as acute or chronic, about 24 h without scarring; however, some lesions may depending on the duration of symptoms and the presence last up to 48 h [1–4]. Approximately 40% of patients or absence of inducing stimuli (see Fig. 2) [5–7]. Acute with urticaria also experience angioedema (swelling that urticaria refers to urticaria with or without angioedema occurs beneath the skin) [3]. which lasts less than 6 weeks. Chronic urticaria is Mast cells are the primary efector cells in urticaria defned as urticaria with or without angioedema that and in many cases of angioedema. Tese cells are widely has been continuous or intermittent for at least 6 weeks. distributed in the skin, mucosa, and other areas of the Chronic urticaria can be further classifed as chronic body, and have high-afnity immunoglobulin E (IgE) spontaneous urticaria (CSU) and inducible urticaria. Te receptors. Mast cell degranulation leads to the rapid latter represents a distinct subgroup of chronic urticaria release of various infammatory mediators, such as that is induced by physical stimuli, such as scratching (dermatographism, a common form of physical urticaria), *Correspondence: [email protected] cold, heat, sunlight, vibration and pressure. 1 Division of Allergy and Immunology, Department of Medicine, Although acute urticaria can generally be easily University of British Columbia, Vancouver, BC, Canada managed and is associated with a good prognosis, Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kanani et al. Allergy Asthma Clin Immunol 2018, 14(Suppl 2):59 Page 116 of 127 chronic urticaria. Investigations for these conditions are not warranted unless there are clear features of their presence on clinical evaluation. A variety of chronic infections have also been reported to be associated with chronic urticaria, including viral hepatitis B and C, Epstein-Barr virus, herpes simplex virus, Helicobacter pylori infections, and helminth parasitic infections. With the exception of parasitic infections, these are not believed to play a signifcant role in most cases of chronic urticaria. Acute urticaria Te most common causes of acute urticaria (with or without angioedema) are medications, foods, viral Fig. 1 Urticaria (hives) infections, stress, parasitic infections, insect venom, and contact allergens (e.g., latex) [9]. Medications known to commonly cause urticaria with or without angioedema include antibiotics (particularly beta lactams chronic, severe urticaria is often associated with and sulfonamides), non-steroidal anti-infammatory signifcant morbidity and diminished quality of life (QOL) drugs (NSAIDs), acetylsalicylic acid (ASA), opiates and [8]. Inducible urticaria also tends to be more severe and narcotics. Te predominant foods that cause urticaria long-lasting, and can sometimes be challenging to treat are milk, eggs, peanuts, tree nuts, fsh, and shellfsh. [1, 3]. Acute urticaria should be diferentiated from anaphylaxis Te frst section of this article will focus on the causes, which has similar triggers including food, medication, diagnosis and management of the most common types and insect stings; however, treatment approaches will of urticaria (with or without angioedema). Te second be diferent. In approximately 50% of patients with acute section will review the work-up and management of urticaria, the cause is unknown and the condition is angioedema without urticaria. Tis type of angioedema referred to as acute spontaneous urticaria (ASU) [1–3, can be broadly divided into histamine-mediated and 10]. Up to 36% of patients with ASU can progress to CSU non-histamine-mediated angioedema. Distinguishing [11]. between these two types of angioedema is important as investigations and management difer considerably. Inducible urticaria Urticaria Inducible urticaria is triggered by a physical stimulus. Te most common physical urticaria is dermatographism Classifcation and etiology (also known as “skin writing”), in which lesions are Chronic urticaria created or “written” on the skin by stroking or scratching Te prevalence of chronic urticaria has been estimated to the skin. Pressure areas from clothing such as the be 0.5–5%. Chronic urticaria is more common in adults, waistline (i.e., after wearing tight-ftting pants) and the with a peak age of onset between 20 and 40 years, and area of the ankles or calves that makes contact with the it afects women more frequently than men [3, 5–7]. In elastic band of socks are commonly afected [1–3, 10, CSU, an external trigger cannot usually be identifed (see 12]. Cholinergic urticaria is also common and results Fig. 2). In approximately 45% of these patients, circulating from a rise in basal body temperature that occurs immunoglobulin G (IgG) autoantibodies recognize IgE following physical exertion or exposure to heat. Other antibodies or the alpha subunit of the high-afnity IgE physical stimuli which can trigger urticaria include receptor on dermal mast cells and basophils, leading exposure to cold (cold-induced urticaria), ultraviolet light to chronic stimulation of these cells and the release of (solar urticaria), water (aquagenic urticaria), vibration histamine and other infammatory mediators that cause and exercise. Te lesions produced by these physical urticaria and angioedema. CSU is also associated with stimuli are typically localized to the stimulated area antithyroid antibodies in approximately 27% of cases and often resolve within 2 h. However, some patients [5–7]. Numerous other autoimmune disorders, including may experience delayed-pressure urticaria which, as the rheumatoid arthritis, systemic lupus erythematosus name implies, comes on slowly (i.e., 30 min to 12 h) after (SLE), dermatomyositis, polymyositis, Sjogren’s pressure has been applied, and can last several hours or syndrome, and Still’s disease, have been associated with even days. Typical areas afected include the hands and Kanani et al. Allergy Asthma Clin Immunol 2018, 14(Suppl 2):59 Page 117 of 127 Urticaria > 48 hours* < 48 hours* Urticarial vasculitis > 6 weeks* <6 weeks* Chronic urticaria Acute urticaria Spontaneous Other Inducible Chronic spontaneous Infection urticaria (CSU) Food Dermatographism Medication Venom Cholinergic Latex Contact Cold induced Solar Aquagenic Exercise Delayed-pressure Fig. 2 Classifcation of urticaria: overview. *The 48-h cut-of refers to individual