Urticaria, angioedema and hypersensitivity reactions

• Urticaria is a condition in which wheals (hives), angioedema, or both appear and disappear again; about one in five people have it at some point, and most episodes are self-limiting. ^[1]
• Chronic urticaria means symptoms on most days for more than 6 weeks; it is defined by time, not by a single cause, and it is usually not an allergy. ^[1]
• The Gell and Coombs system groups hypersensitivity reactions into four types (I to IV) by mechanism: immediate IgE (I), antibody against cells (II), immune-complex (III) and T-cell (IV). ^[3]
• Histaminergic angioedema (with urticaria) is itchy or burning, rapid, and responds to H1 antihistamines; bradykinin angioedema (ACE inhibitor, hereditary) is painless, without hives, slower, and does not respond to antihistamines or adrenaline. ^[1]
• Management is stepwise: standard-dose second-generation H1 antihistamine, then up to four times the standard dose, then omalizumab, then (specialist) ciclosporin. ^{[2] [1]}

By the end of this page you should be able to:

1. Classify hypersensitivity reactions into Gell and Coombs types I to IV and match each to mechanism, timing and clinical examples.
2. Define urticaria, acute versus chronic urticaria, CSU and CIndU, and angioedema.
3. Explain histamine-driven wheals and the difference between histaminergic and bradykinin-mediated angioedema.
4. Describe how to distinguish urticaria from anaphylaxis and from urticarial vasculitis.
5. Outline the step-up drug treatment of urticaria with doses, and when to refer.
6. Discuss prognosis, triggers, prevention and the approach in pregnancy and children.

Wheals are superficial skin swellings of variable size, usually surrounded by reflex erythema, with an itching or sometimes burning sensation. They are short-lived and the skin returns to normal, usually within 30 minutes to 24 hours. ^[1] Angioedema is sudden, pronounced swelling of the lower dermis and subcutis or mucous membranes; it may be painful rather than itchy and can persist for up to 72 hours. ^[1]

Chronic urticaria is subdivided by cause:

• Chronic spontaneous urticaria (CSU): symptoms occur without a consistent identifiable trigger and often persist for months to years. ^[2]
• Chronic inducible urticaria (CIndU): wheals appear in response to a defined stimulus such as cold, heat, pressure, vibration, water, sunlight or exercise. ^[1]

Angioedema is localised swelling of the deeper tissues. In urticaria it is mast cell mediated; histaminergic angioedema is rapid and tends not to be fatal. Bradykinin-mediated angioedema (hereditary angioedema, ACE inhibitor angioedema) evolves more slowly and can be life-threatening when the airway is involved. ^[1]

Urticaria has a lifetime prevalence of approximately 20%. ^[1] Chronic spontaneous urticaria has a reported prevalence between 0.5 and 1.4%, and occurs about twice as often in women as in men. ^[2] Geographic estimates vary (0.6% in Spain, 1.8% lifetime and 0.8% point prevalence in Germany), so figures are best read as estimates rather than as universal constants. ^[1] Cholinergic urticaria peaks between ages 15 and 30, while CSU more commonly presents around age 40. ^[1]

Risk factors and associated triggers for acute urticaria include:

• Recent viral upper respiratory infection.
• Intake of non-steroidal anti-inflammatory drugs (NSAIDs) or other medicines.
• Insect bites or stings (previously called papular urticaria).
• Stress, fatigue and, rarely, identifiable food triggers. ^[1]

Identification of a trigger can help patient education, but most acute episodes never have a proven, reproducible cause. ^[1]

A wheal is produced when mast cells in the superficial dermis degranulate. The released mediators (histamine, leukotrienes, prostaglandins, cytokines) increase vascular permeability. Plasma leaks into the superficial dermis, producing a raised, itchy plaque; reflex erythema produces the surrounding flare. ^[1]

Angioedema is the same process in the deeper dermis and subcutaneous tissue, so swelling is larger, softer and slower to resolve. ^[1]

The Gell and Coombs classification describes hypersensitivity by mechanism, and the four types are the backbone of clinical immunology. The type names and mechanisms below follow StatPearls. ^[3]

• Type I (immediate, IgE-mediated): allergen-specific IgE binds mast cells and basophils; re-exposure releases vasoactive mediators. This produces urticarial rash, pruritus, flushing, angioedema and, in severe cases, hypotension and anaphylaxis. ^[3]
• Type II (cytotoxic): IgG or IgM binds cellular or matrix antigens, leading to cell destruction. Onset is delayed, typically 5 to 8 days. Examples include drug-induced haemolytic anaemia and thrombocytopenia. ^[3]
• Type III (immune-complex): antigen-antibody complexes deposit in tissues, activate complement, and produce inflammation in joints, kidney and vessels. Onset takes weeks. Examples include serum sickness and drug-induced vasculitis. ^[3]
• Type IV (delayed, T-cell mediated): T lymphocytes drive the reaction, with subtypes IVa (macrophages), IVb (eosinophils), IVc (T cells) and IVd (neutrophils). Onset takes days. Examples include contact dermatitis, acute generalised exanthematous pustulosis, Stevens-Johnson syndrome and DRESS. ^[3]

Urticaria and anaphylaxis are classic type I reactions, while a drug rash that appears days after therapy can be type IV. ^[3] Pseudoallergic (non-immunologic) reactions look like allergy but bypass IgE. ^[3]

Both look alike but the mechanisms and treatments differ:

• Histaminergic (mast cell mediated): usually with wheals, itch or burn, rapid onset, and responds to adrenaline and H1 antihistamines. ^[1]
• Bradykinin (ACE inhibitor, hereditary or acquired C1 inhibitor deficiency): recurrent painless swelling without wheals or itch, slower evolution, and generally does not respond to antihistamines, corticosteroids or adrenaline. ^[1]

Bradykinin accumulation occurs when C1 inhibitor is deficient or dysfunctional, or when ACE (the main bradykinin-degrading enzyme) is inhibited by an ACE inhibitor. ^[1]

Wheals in urticaria appear suddenly. They are usually pruritic or burning, last less than 24 hours at a given site, and fade completely without residual change; angioedema may last up to 72 hours. ^[1] Ask about:

• Timing and duration; whether individual lesions last more than 24 hours (think urticarial vasculitis).
• Systemic symptoms: vomiting, diarrhoea, breathlessness, fainting, which suggest anaphylaxis rather than urticaria.
• Triggers: infection, drugs (NSAIDs, ACE inhibitors), physical triggers, insect stings, foods.
• Mood, sleep and quality of life.
• Pregnancy, contraception and menstrual pattern where relevant.

An Irish series reported that 71% of patients referred to an allergy clinic had suspected food allergy as the main concern; in 61% wheals and/or angioedema was the presenting symptom and 56% received the final diagnosis of chronic spontaneous urticaria; only 9% had IgE-mediated food allergy. ^[1] This is a reminder that urticaria is usually not a food allergy.

Examine the whole skin and photograph lesions for the record. Look for erythema, warmth, pain, or purpura that suggests urticarial vasculitis rather than urticaria. Check the thyroid (goitre can accompany CSU). ^[1]

Two questions matter: first, what else produces wheals or swelling; second, what else produces similar rashes.

Anaphylaxis is a cross-check topic for Emergency Medicine: see the MedGrasp topic "Anaphylaxis and angioedema in adults" for adrenaline doses, biphasic reactions and ACE-inhibitor and hereditary angioedema care.

For acute urticaria no investigations are needed; routine testing is more likely to confuse than to help. ^[1]

If the episode continues and becomes chronic spontaneous urticaria, basic tests are worthwhile before referral: a full blood count with differential, C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and a focused history. ^[1]

Consider selected tests only when the history points to a specific condition (for example thyroid disease, when a goitre is found or CSU is refractory). ^[1]

There is no single diagnostic test for urticaria; it is a clinical diagnosis. ^[1] Resolution of a wheal within 24 hours and migration of new lesions are characteristic. ^[1]

Because an IgE-mediated allergy is rarely the cause of chronic urticaria, routine allergy testing is discouraged unless the history is clearly suggestive. ^[1]

In the context of wheals and/or angioedema, one of the two following pictures defines anaphylaxis, and separates it from urticaria. ^[1]

• Acute onset of wheals with or without angioedema, plus acute respiratory compromise and shock (hypotension, collapse, syncope), or
• Any two of: rapid onset wheals with or without angioedema; respiratory compromise; reduced blood pressure with associated symptoms; acute vomiting or severe crampy abdominal pain with or without diarrhoea; reduced blood pressure after exposure to a known allergen. ^[1]

About two-thirds (67.1%) of anaphylaxis patients present with wheals or urticaria, and 41.3% with angioedema. ^[1] Whichever presentation, treat and follow Emergency Medicine guidance.

A written stepwise summary:

1. Reassure and explain: acute urticaria is distressing but not dangerous; it rarely needs investigation; most cases resolve within 2 to 3 days. ^[1]
2. Acute urticaria: treat with a standard dose of a second-generation (non-sedating) H1 antihistamine. ^[1] First-generation antihistamines are discouraged because of their side-effect profile. ^{[1] [2]}
3. If symptoms are very distressing: a short course (3 to 5 days) of oral corticosteroid at no more than 1 mg per kg body weight per day may be used, with clear safety counselling. ^[1]
4. If symptoms reach 6 weeks: chronic urticaria. Continue a second-generation H1 antihistamine and increase the dose up to four times the standard dose in patients with an insufficient response. ^[1][2]
5. If still symptomatic at the higher dose: refer to a specialist and consider adjunctive omalizumab. ^[2]
6. Inadequate response to high-dose antihistamine plus omalizumab: ciclosporin may be used by specialists as an add-on. ^[2]
7. Short course (rescue) systemic glucocorticoids may be used for an acute exacerbation, but are not a maintenance treatment. ^[2]
8. Try withdrawal every 3 to 6 months once remission is achieved, to see whether natural remission has occurred. ^[1]

Shared decision-making, reassurance, and editing avoidable triggers (NSAIDs, ACE inhibitors where relevant, temperature extremes in CIndU, scratching) are the foundation. Avoid unnecessary restrictive diets; do not over-investigate. ^[1]

• Histaminergic angioedema with urticaria: treat as urticaria (antihistamines; adrenaline and airway care if systemic). ^[1]
• Angioedema without wheals: refer for investigation of bradykinin-mediated angioedema; stop ACE inhibitors permanently in all patients with ACE-inhibitor angioedema. ^[1]
• Hereditary or acquired bradykinin angioedema is managed with C1 inhibitor concentrate, icatibant or ecallantide for attacks; international care is described in the Emergency Medicine topic "Anaphylaxis and angioedema in adults".

The stepwise ladder is endorsed by the international urticaria guideline (EAACI/GA²LEN/EuroGuiDerm/APAAACI, 2022). ^[4] The international guideline's pharmacological ladder is reproduced in primary-care reviews as follows: standard-dose second-generation H1 antihistamine, then up-dosing to four times the licensed dose, then omalizumab, then ciclosporin. ^[2]

• Second-generation H1 antihistamine: standard adult oral dose initially; up to four times the standard dose when response is incomplete. ^[1][2]
• Oral corticosteroid rescue: up to 1 mg per kg body weight daily for 3 to 5 days in distress, with counselling on risks. ^[1]
• Omalizumab: anti-IgE biologic used for CSU refractory to high-dose antihistamines. ^[2] Dosing follows the product licence and local protocol, following specialist assessment.
• Ciclosporin: specialist add-on only, with monitoring (renal function, blood pressure). ^[1][2]

(Exact omalizumab dosing regimens per product label and local protocol; check your local formulary before prescribing.)

Disease activity and control are tracked with UAS7 and UCT; review every 3 to 6 months after control is achieved, withdrawing treatment to test for natural remission. ^[1]

• Anaphylaxis (rare in urticaria alone, more often in allergic reactions with wheals) — see Emergency Medicine. ^[1]
• Quality-of-life impairment, anxiety, sleep disturbance and impaired sexual function. ^[1]
• Unnecessary investigation and misdiagnosis as food allergy, delaying correct treatment. ^[1]
• ACE-inhibitor and hereditary angioedema causing life-threatening airway obstruction. ^[1]
• Undertreatment with first-generation antihistamines, which have poorer efficacy and more sedation. ^[1]

Natural history is generally favourable. Most cases of acute urticaria resolve within 2 to 3 days. ^[1] For CSU, roughly half resolve by 6 months, 30% by 3 years, 10% by 10 years and a small minority persist beyond 25 years. ^[1] The average duration of CSU is roughly 1 to 4 years. ^[2]

Treatment outcomes: about 40% of CSU patients achieve control with up to four times standard dose second-generation antihistamine; response can rise to about 70% when omalizumab is added. ^[1] CIndU is generally slower to remit than CSU. ^{[1] [2]}

There is no population screening test for urticaria. Prevention is trigger avoidance and patient education: avoid NSAIDs where possible, review ACE inhibitors in anyone with unexplained angioedema, and counsel swimmers with cold urticaria about cold water exposure. ^[1]

Acute urticaria is common in children after infections and is usually self-limiting. ^[1] Antihistamines should be dosed by age and weight and are often unlicensed at higher multiples; doses should follow local paediatric formularies. ^[1] Cold-induced urticaria is potentially dangerous for children swimming in cold water, so warn before specialist review. ^[1]

Data are limited. Use the lowest effective dose of a safe second-generation antihistamine when symptoms are troublesome, reassure about the generally benign course, and avoid unnecessary medication. ^[1] There is no specific urticaria guideline adjustment for pregnancy in the sources used; treat individual patients on their merits.

Polypharmacy is the key issue: many older patients take ACE inhibitors or NSAIDs, either of which can provoke angioedema or urticaria. Use non-sedating H1 antihistamines and review for drug-induced causes before labelling CSU. ^[1][3]

The table in Differential diagnosis above covers how urticaria and angioedema differ from anaphylaxis, vasculitis, dermatitis and the bradykinin-mediated swellings.

• Urticaria is wheals, angioedema, or both, classed as acute (under 6 weeks) or chronic (over 6 weeks). ^[1]
• Lifetime prevalence is about 20%; CSU affects roughly 0.5 to 1.4% of people and is about twice as common in women. ^[1][2]
• A wheal comes from mast-cell degranulation and increased vascular permeability; each wheal fades within 24 hours. ^[1]
• Histaminergic angioedema is itchy, rapid, comes with wheals and responds to antihistamines; bradykinin angioedema is painless, without wheals, and antihistamines do not help. ^[1]
• The four hypersensitivity types (I IgE immediate, II cytotoxic, III immune-complex, IV T-cell delayed) frame the causes of urticaria and drug reactions. ^[3]
• Do not over-investigate acute urticaria; tests are the exception, reserved for selected chronic cases. ^[1]
• Step up treatment: second-generation H1 antihistamine at standard dose, then up to four times the standard dose, then omalizumab, then ciclosporin under specialist care. ^[1][2]
• Use UCT and UAS7 to measure control and review every 3 to 6 months, withdrawing therapy to test for remission. ^[1][2]
• Acute anaphylaxis with wheals is not urticaria and needs Emergency Medicine care. ^[1]
• The EAACI/GA²LEN/EuroGuiDerm/APAAACI international urticaria guideline (2022) underpins this approach. ^[4]