Urticaria (hives) and angioedema

Meet the patient

A 28-year-old woman arrives with itchy, raised, red wheals with pale centres scattered across her trunk and arms, and a swollen lower lip she says feels tight rather than itchy. The wheals appeared this morning; by the time you examine her, the first ones have already faded and new ones have cropped up elsewhere. She has had something like this on and off for eight weeks, worst at night.[1][2]

Three questions now frame the whole topic: is each wheal truly gone within 24 hours? (it is — so this is urticaria, not vasculitis), is the angioedema histamine- or bradykinin-driven? (it itches and she has wheals — so histamine), and is this acute or chronic? (eight weeks — so chronic spontaneous urticaria, and the next step is a second-generation antihistamine). Hold those three and the page slots into place.[2][3]

The wheal and the 24-hour rule

The single most reproduced fact in a urticaria stem is the 24-hour rule: each individual wheal appears, migrates, and is gone within 24 hours, leaving no bruise, no scale, no mark. That one sentence separates urticaria from almost everything in its differential.[1]

A wheal is a raised, erythematous plaque with a pale centre — central pallor from vasoconstriction rimmed by erythema from vasodilation, the visible signature of mast-cell histamine opening dermal vessels. They range from pinpoint (cholinergic) to large coalescent plaques over 10 cm, and they are intensely pruritic.[1]

The classic trap: wheals that persist beyond 24 hours, that are painful or burning rather than itchy, or that leave bruising or hyperpigmentation are not urticaria — that is urticarial vasculitis, and the next step is a biopsy, not an antihistamine. Memorise the 24-hour rule as the fence between two diseases with radically different management.[7]

The 6-week fork — acute or chronic?

Urticaria splits on a single clock: under 6 weeks is acute, over 6 weeks is chronic. The fork matters because the two have different causes, different work-ups, and different stakes.[1][3]

Acute urticaria — under 6 weeks — is common, usually post-viral in children, and driven by an identifiable trigger: infection, a drug, a food, or a sting. It resolves within days to weeks and needs no work-up beyond a careful history. Lifetime prevalence is around 20 percent, so you will meet it constantly.[1]

Chronic urticaria — over 6 weeks — divides again into chronic spontaneous (CSU), where wheals appear without an obvious external trigger and roughly half are autoimmune, and chronic inducible, where a specific physical stimulus fires each wheal. CSU affects 0.5 to 1 percent of the population, runs a mean course of one to five years, and is the form that climbs the treatment ladder to omalizumab.[2][3]

Etymology for viva gold: urticaria comes from the Latin urtica, the stinging nettle — because the wheal looks and feels exactly like a nettle sting. Angioedema joins the Greek angeion (vessel) with oidēma (swelling). Both names outlived their metaphors because the bedside sign never changed.[1]

The trigger hunt — six categories, one history

Triggers shape the history, guide provocation testing, and tell the patient what to avoid. Cluster them as six — food, drug, physical, contact, infection, autoimmune — and the history writes itself.[1][3]

The six-cluster trigger hunt:[1]

• Food — true IgE allergy (milk, egg, peanut, tree nut, fish, shellfish) is rare in chronic disease; pseudoallergens (salicylates, amines, additives in strawberries, cheese, red wine) matter more in CSU, and a three-week low-pseudoallergen diet helps selected patients.
• Drugs — NSAIDs and aspirin trigger up to 30 percent of CSU via COX-1 inhibition and a leukotriene shift; opiates, vancomycin and quinolones degranulate mast cells directly; ACE inhibitors cause angioedema without urticaria by blocking bradykinin breakdown, sometimes weeks to years after starting.
• Physical stimuli — cold, pressure, heat, vibration, water and stroking each have a standardised provocation test.
• Contact — latex, cosmetics, plant saps and animal saliva produce localised wheals within an hour of skin contact.
• Infection — viral upper respiratory infection is the commonest cause of acute urticaria in children; Helicobacter pylori, hepatitis and parasitic infection drive chronic disease.
• Autoimmune — anti-FcεRIα or anti-IgE autoantibodies fire roughly half of CSU, and thyroid autoimmunity (anti-TPO) travels with it in 20 to 30 percent.[1][3][6]

[1] [6]

The angioedema firewall — mast cell vs bradykinin

This is the firewall that saves airways, and examiners test it relentlessly. Angioedema is deep dermal or submucosal swelling — non-pitting, non-dependent, affecting lips, tongue, eyelids, genitals and larynx — but it is driven by one of two mediators, and the mediator decides the drug.[1][11]

Histamine-driven angioedema comes with urticaria and itch, has a normal C4, and responds to antihistamines — it is mast-cell degranulation, and the same ladder that treats the wheals treats the swell. Bradykinin-driven angioedema comes without urticaria or itch, has a low C4 in hereditary disease, and does not respond to antihistamines, corticosteroids or adrenaline — it needs C1-INH concentrate or icatibant.[9][11]

[1] [9] [11]

The discriminator line: if the angioedema itches or sits with wheals, it is histamine — antihistamines work; if it is isolated swelling without itch, suspect bradykinin — and reaching for adrenaline wastes the window.[9]

Why it happens — mast cells, histamine, and the bradykinin detour

Mast cells degranulate when FcεRI — the high-affinity IgE receptor — is cross-linked by allergen-IgE complexes. The same receptor is fired directly in CSU by functional anti-FcεRIα and anti-IgE autoantibodies, which is why half of chronic disease needs no external allergen at all.[1][6]

Degranulation releases histamine (H1 receptor drives vasodilation, permeability and itch; H2 adds to the vasodilation), prostaglandin D2, the leukotrienes LTC4, LTD4 and LTE4, tryptase, and the cytokines TNF-alpha, IL-4 and IL-13. The net effect is dermal vasodilation and leak, and the wheal is the visible result.[1][4]

The bradykinin detour is the other engine, and it explains the angioedema firewall. Bradykinin raises permeability in the deep dermis and submucosa — producing angioedema without wheals — and is normally broken down by angiotensin-converting enzyme and kept in check by C1-inhibitor. ACE inhibitors block the enzyme; C1-INH deficiency (hereditary angioedema) removes the brake. Either way bradykinin climbs, and because histamine is not involved, antihistamines and adrenaline do nothing.[9][11]

CSU — the autoimmune engine

Chronic spontaneous urticaria is not an allergy you can avoid; for roughly half of patients it is an autoimmune disease of the mast cell itself. Functional autoantibodies against FcεRIα or IgE cross-link the receptor without any external allergen, firing degranulation on a loop.[2][6]

The autoimmune link shows in the company CSU keeps: thyroid autoimmunity (anti-TPO positive in 20 to 30 percent), Helicobacter pylori, coeliac disease and other autoimmune conditions. The practical consequence is that the CSU work-up is limited and targeted — the EAACI/GA²LEN guideline explicitly recommends against routine allergy testing, because food allergy is rarely the driver of chronic disease.[3][6]

The CSU work-up — limited and targeted:[3]

• FBC and CRP or ESR — to exclude systemic inflammation or infection.
• TSH and anti-TPO — thyroid autoimmunity is the commonest autoimmune comorbidity.
• Helicobacter pylori stool antigen or breath test — treat if positive (the link is controversial but treatable).
• Autologous serum skin test (ASST) — intradermal autologous serum; a wheal suggests autoimmune urticaria.
• Basophil activation test or anti-FcεRIα assay — specialist or research use.

[3] [6]

The seven inducible urticarias — scratch, cold, press, heat, sun, water, vibrate

Chronic inducible urticaria fires on a specific physical stimulus, and each subtype has a named provocation test. Cluster them as seven and the viva answer is half-written.[1][3]

[1] [3]

Treat to target — UAS7 and UCT

Chronic urticaria is now a treat-to-target disease: aim for complete control — UAS7 of zero and UCT of 12 or more — and hold it for one to three months before tapering. The two scores are the dashboard that drives every step-up decision.[3][12]

UAS7 is the prospective daily diary: each day the patient scores wheal number (0 none, 1 under 20, 2 twenty to fifty, 3 over 50) and itch intensity (0 none, 1 mild, 2 moderate, 3 intense), summed over seven days to a maximum of 42. The bands that matter: zero is the goal, 1 to 6 well-controlled, 7 to 15 mild, 16 to 27 moderate, and 28 to 42 severe — the threshold that points to omalizumab.[1][12]

UCT is the retrospective four-question test over the previous four weeks, scored 0 to 16. Twelve or more means well-controlled; eleven or less means step up. A change of three points is the minimal clinically important difference.[1]

The five-step ladder — antihistamine to omalizumab

[1]

The EAACI/GA²LEN ladder is the single most examined algorithm in urticaria, and it runs to five steps. Each step is added only when the previous fails to reach the UAS7 target.[3][12]

Step 1 — second-generation H1 antihistamine, standard dose, for all urticaria. Choose cetirizine 10 mg, levocetirizine 5 mg, fexofenadine 180 mg, loratadine 10 mg, desloratadine 5 mg or bilastine 20 mg once daily. Second-generation agents are non-sedating and have minimal anticholinergic effect — they displaced the first-generation sedating drugs for good reason.[3][12]

Step 2 — up-dose the same H1 antihistamine to two, three, or up to four times standard dose. Cetirizine 40 mg daily is the worked example. This is off-label but evidence-based and safe, and the guideline explicitly supports pushing to fourfold before adding anything else.[3][12]

Step 3 — add-on therapies. An H2 blocker (famotidine 20 mg twice daily), a leukotriene receptor antagonist (montelukast 10 mg at night, especially for NSAID-exacerbated CSU), or a sedating first-generation H1 at night (hydroxyzine 25 to 50 mg) for nocturnal pruritus.[1]

Step 4 — omalizumab, the anti-IgE monoclonal antibody. Dosed 150 to 300 mg subcutaneously every four weeks, it is licensed for refractory CSU and works in roughly 65 percent of patients, often within one to two weeks. It reduces free IgE, downregulates FcεRI on mast cells and basophils, and is approved by NICE, the FDA and the EMA.[2][12]

Step 5 — immunosuppression for severe refractory disease. Ciclosporin 3 to 4 mg/kg/day for three to six months inhibits T-cell activation but is nephrotoxic, so monitor blood pressure and renal function. Dupilumab, ligelizumab and the oral BTK inhibitor remibrutinib are the emerging additions.[12]

The doses — the numbers examiners quote:[3][12]

[3] [12]

Anaphylaxis — the one that cannot wait

Urticaria with throat tightness, dyspnoea, wheeze or hypotension is anaphylaxis until proven otherwise, and the first drug is intramuscular adrenaline. Everything else is adjunctive.[1]

Give adrenaline 0.5 mg — 0.5 mL of 1 in 1000 — into the anterolateral thigh, and repeat after five minutes if there is no response. Add high-flow oxygen, IV crystalloid, chlorphenamine 10 mg IV and hydrocortisone 200 mg IV (both slow-onset adjuncts), place the patient in the recovery position, and call for help with early ICU involvement if the airway is threatened.[1]

[1] [9]

Hereditary angioedema — C1-INH, never adrenaline

Hereditary angioedema is autosomal dominant, bradykinin-driven, and the textbook example of angioedema without urticaria that does not respond to antihistamines. Missing it round after round — treating it as anaphylaxis — is the classic and dangerous trainee error.[9][10]

Deficiency of C1-inhibitor (the SERPING1 gene) removes the brake on kallikrein, excess bradykinin follows, and the patient gets episodic swelling of the face, airway and gut — the last causing severe abdominal pain from bowel-wall oedema — without wheals and without itch. Attacks last 24 to 72 hours and are triggered by trauma, dental work, surgery, stress, infection, menstruation, ACE inhibitors and oestrogen.[9][10]

The three types:[9]

• Type I (85 percent) — low C1-INH antigen and function.
• Type II (15 percent) — normal or high antigen but a dysfunctional protein (low function).
• Type III — normal C1-INH, F12 mutation, oestrogen-sensitive, females only, rare.

[9] [10]

The screening test is a C4 level — low at baseline and during attacks. Confirm with C1-INH antigen and function (the functional assay is more sensitive), and check C1q to separate hereditary disease (normal C1q) from acquired C1-INH deficiency (low C1q, linked to lymphoproliferative disease). Genetic testing confirms SERPING1 or F12 mutations.[9][10]

[9] [10]

The mantra: histamine angioedema itches and responds to antihistamines; bradykinin angioedema does neither — and the drug is C1-INH or icatibant, never adrenaline.[9]

[1]

Urticarial vasculitis — when the wheal overstays

The wheal that will not leave within 24 hours is not urticaria; it is urticarial vasculitis, and the next step is a biopsy. Three features ring the alarm: lesions persisting beyond 24 hours, pain or burning rather than itch, and residual bruising or hyperpigmentation.[7]

Systemic features may follow — fever, arthralgia, abdominal pain, renal disease with proteinuria or haematuria, and pulmonary involvement. Hypocomplementaemic urticarial vasculitis (low C3, C4, C1q) travels with SLE, and Schnitzler syndrome is the named cluster to know: chronic urticaria plus a monoclonal IgM gammopathy, fever and bone pain, driven by interleukin-1 and treated with anakinra or canakinumab.[7][8]

A punch biopsy of a lesion over 24 hours old shows leukocytoclastic vasculitis — neutrophilic infiltrate, nuclear dust and fibrinoid necrosis of the post-capillary venules. Treatment escalates from antihistamines (often insufficient) through NSAIDs, colchicine and dapsone for mild disease, to systemic corticosteroids, hydroxychloroquine, mycophenolate or rituximab for refractory or hypocomplementaemic disease.[7][8]

The differential — five mimics with one discriminator each

Five eruptions wear urticaria's clothing, and each has a one-line giveaway. The history and the 24-hour clock prise them apart.[1][7]

[1] [7]

Special populations

Children mostly have acute, post-viral urticaria that needs reassurance and weight-adjusted antihistamine dosing; omalizumab is licensed for CSU in children aged 12 and over. In pregnancy, cetirizine and loratadine are the safe choices, aspirin and NSAIDs are best avoided, and omalizumab is held where possible for lack of data.[5]

Hereditary angioedema families need screening — a C4 level plus genetic testing for first-degree relatives — a medic-alert bracelet, emergency C1-INH or icatibant to carry, and strict avoidance of ACE inhibitors and oestrogen.[10]

Traps, confessions and preventable harm

Everyone reaches for steroids in chronic urticaria. That is how you delay the omalizumab that actually works. Systemic corticosteroids dampen a flare but do not alter the disease, and prolonged courses carry real harm; the guideline ladder exists precisely to move patients to up-dosed antihistamines and then omalizumab rather than parking them on steroids.[2][12]

Everyone forgets the ACE inhibitor. Angioedema without urticaria, sometimes months or years after the drug was started, in a patient who looks well between attacks — that is ACE-inhibitor angioedema until proven otherwise, and the fix is to stop the drug, not to escalate antihistamines. It is commoner in Black patients.[11]

Consultant confession: the single most useful question in chronic urticaria is not "what are you allergic to?" but "do the individual wheals come and go within a day, or do some stay for days and leave a mark?". That one question separates urticaria from urticarial vasculitis more reliably than any blood test — and it picks out the patient who needs a biopsy before anything else.[1][7]

The preventable-harm list:[1]

• Giving adrenaline or antihistamines for hereditary angioedema — ineffective; the drug is C1-INH or icatibant.
• Parking CSU on repeated oral steroid courses instead of climbing the ladder to omalizumab.
• Missing urticarial vasculitis because no one timed the wheals — biopsied only after organs are involved.
• Forgetting to stop the ACE inhibitor in isolated angioedema.
• Advising a patient with cold urticaria that swimming is fine — cold-water immersion can cause anaphylaxis and drowning.

[1] [9]

Prognosis and disposition

Acute urticaria is benign and self-limiting; CSU runs a mean course of one to five years and roughly half resolve within a year. The prognosis is good once the ladder is climbed correctly and omalizumab is reached when needed. Hereditary angioedema is lifelong but well-controlled with modern prophylaxis, and the danger is the laryngeal attack treated as anaphylaxis.[2][9][13]

Disposition follows the airway. Isolated urticaria or histamine angioedema without airway threat goes home on a second-generation antihistamine with safety-net advice. Anaphylaxis needs resuscitation, admission and an adrenaline auto-injector. Suspected hereditary angioedema needs C4 and C1-INH testing, an alert bracelet, and acute C1-INH or icatibant to carry. Urticarial vasculitis needs biopsy and a systemic screen.[1][9]

[1]

The ward-round test

Click to reveal the stems — answer before you open each one

Stem 1. A 30-year-old woman has itchy wheals that each come and go within a day, daily for ten weeks, worst at night. What is the diagnosis, the first-line drug, and what do you do if it fails?[3]

Answer: Chronic spontaneous urticaria. Start a second-generation H1 antihistamine (cetirizine 10 mg); if it fails, up-dose to fourfold, then add H2 and montelukast, then omalizumab — not steroids.[3]

Stem 2. A man on ramipril for two years presents with tongue and lip swelling, no urticaria, no itch. What is the diagnosis and the first action?[11]

Answer: ACE-inhibitor angioedema (bradykinin-mediated). Stop the ramipril, watch the airway; severe cases may need icatibant or C1-INH concentrate. Antihistamines and adrenaline will not work.[11]

Stem 3. A patient has wheals that persist for three days, are painful, and leave bruising. What is the diagnosis, the key investigation, and the named syndrome if there is fever, bone pain and a monoclonal IgM?[7][8]

Answer: Urticarial vasculitis — biopsy shows leukocytoclastic vasculitis; screen complement for hypocomplementaemic disease and SLE. Fever, bone pain and monoclonal IgM is Schnitzler syndrome (interleukin-1 driven; treat with anakinra).[7][8]

Stem 4. A teenager wheals within minutes of swimming in cold water and once collapsed. What is the risk, and what two pieces of advice save a life?[1]

Answer: Cold contact urticaria with risk of cold-induced anaphylaxis. Advise strictly against swimming, and prescribe an adrenaline auto-injector.[1]

References

1. [1]Kolkhir P, Giménez-Arnau AM, Kulthanan K, et al. Urticaria Nat Rev Dis Primers, 2022.PMID 36109590
2. [2]Kolkhir P, Bonnekoh H, Metz M, et al. Chronic Spontaneous Urticaria: A Review JAMA, 2024.PMID 39325444
3. [3]Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria Allergy, 2022.PMID 34536239
4. [4]Oliver ET, Saini SS Chronic Spontaneous Urticaria: Etiology and Pathogenesis Immunol Allergy Clin North Am, 2024.PMID 38937007
5. [5]Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update J Allergy Clin Immunol, 2014.PMID 24766875
6. [6]Kolkhir P, Muñoz M, Asero R, et al. Autoimmune chronic spontaneous urticaria J Allergy Clin Immunol, 2022.PMID 35667749
7. [7]Wang RX, Newman SA Urticarial Vasculitis Immunol Allergy Clin North Am, 2024.PMID 38937011
8. [8]Kolkhir P, Grakhova M, Bonnekoh H, et al. Treatment of urticarial vasculitis: A systematic review J Allergy Clin Immunol, 2019.PMID 30268388
9. [9]Betschel SD, Banerji A, Busse PJ, et al. Hereditary Angioedema: A Review of the Current and Evolving Treatment Landscape J Allergy Clin Immunol Pract, 2023.PMID 37116793
10. [10]Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update Allergy, 2022.PMID 35006617
11. [11]Smolinska S, Antolín-Amérigo D, Popescu FD Bradykinin Metabolism and Drug-Induced Angioedema Int J Mol Sci, 2023.PMID 37511409
12. [12]Kocatürk E, Chu DK, Türk M, et al. Management of Chronic Spontaneous Urticaria Made Practical: What Every Clinician Should Know J Allergy Clin Immunol Pract, 2025.PMID 40815254
13. [13]Greiner B, Nicks S, Adame M. Pathophysiology, Diagnosis, and Management of Chronic Spontaneous Urticaria: A Literature Review Clin Rev Allergy Immunol, 2022.PMID 36048326