Urticaria and angioedema, also known as urticaria and neurogenic edema, can occur separately or simultaneously. They manifest as non-pitting edema of the skin and sometimes involve the upper respiratory tract or gastrointestinal mucosa. Urticaria only affects the superficial layer of the skin, presenting as red, migratory-edged wheals with pale centers, which may sometimes merge into large wheals. Angioedema involves the deeper layers of the skin (including subcutaneous tissue), appearing as easily recognizable localized edema. These symptoms can appear and disappear rapidly and transiently. Episodes recurring for no more than six weeks are considered acute, while persistent reactions are classified as chronic.

bubble_chart Pathogenesis

According to different {|###|}mechanisms of disease{|###|}, urticaria-angioedema can be classified into four major categories: IgE-mediated, complement-mediated, non-immune, and idiopathic (Table 21-1); the related {|###|}causes of disease{|###|} are also listed in the table.

Table 21-1 Classification of urticaria-angioedema

In summary:

1. Only IgE-dependent and IgA deficiency with IgG-mediated conditions fall under immediate hypersensitivity reactions.
2. Most chronic urticaria is idiopathic.
3. Angioedema without urticaria, due to C1 esterase inhibitor (C1INH) deficiency, may be congenital autosomal dominant or acquired; both are classified into Type 1 (C1INH deficiency) and Type 2 (non-functional C1INH). In these patients, uncontrolled C1 esterase activity leads to excessive consumption of C4 and C2, increased breakdown products, and activation of vasoactive peptides like bradykinin, resulting in angioedema. Urticaria and angioedema associated with serum sickness or idiopathic cutaneous necrotizing vasculitis are related to immune complex activation of the complement system.
4. The non-immune {|###|}mechanism of disease{|###|} primarily involves substances listed in the non-immune category of Table 21-1, which enter the body and stimulate mast cells to release histamine, or factors like emotional stress, exercise, and heat that promote acetylcholine and histamine release.

bubble_chart Pathological Changes

The pathological features of urticaria are characterized by dermal edema, whereas angioedema involves both the dermis and subcutaneous tissue. In the affected areas, collagen bundles are widely separated, capillaries are dilated, and perivascular infiltration may include lymphocytes, eosinophils, and neutrophils, forming a polymorphous infiltrate.

bubble_chart Clinical Manifestations

It can occur at any age, but is more common in young and middle-aged adults. Urticaria manifests as sudden wheals on the skin, which usually subside within minutes or hours and generally do not last more than 24 hours. They occur in batches and may reappear multiple times a day, presenting as bright red or pale yellow. The red ones indicate milder vascular exudation, while the white ones result from anemia caused by extensive exudation compressing capillaries. The wheals vary in size, with larger ones reaching up to 10 cm in diameter or more. Sometimes, blisters may appear on the surface, arranged sparsely, and adjacent lesions may merge to form distinctive circular, annular, or map-like patterns. They can spread all over the body and leave no traces after subsiding, accompanied by intense itching, burning, or stinging pain. Generally, the acute type resolves within a few days to 1–2 weeks, but some cases may recur persistently, lasting for more than 1–2 months or even years, turning chronic. Angioedema occurs in loose subcutaneous tissues or mucous membranes, presenting as localized, transient, large swellings with indistinct edges and no itching. It commonly affects the eyelids, lips, tongue, external genitalia, hands, and feet, often occurring alongside urticaria. If the upper respiratory tract is involved, it may obstruct the throat and become life-threatening; if the gastrointestinal tract is affected, it may cause abdominal pain, sometimes accompanied by nausea and vomiting, leading to unnecessary surgical exploration. It usually disappears within 2–3 days.

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1. Cold urticaria is divided into hereditary and acquired types. The former begins in infancy, with symptoms diminishing with age but often persisting for life. Wheals appear hours after whole-body exposure to cold, presenting as erythematous papules no larger than 2 cm in diameter, possibly accompanied by fever, chills, arthralgia, myalgia, and headache, lasting up to 48 hours. The latter typically starts in childhood, with symptoms appearing immediately after skin exposure to cold. Inhaling cold air or consuming cold food or drinks may occasionally cause mucous membrane swelling. Besides wheals on exposed areas, systemic symptoms may occur, such as loss of consciousness or even drowning after immersion in cold water. Symptoms usually resolve within months but may persist in some cases.

2. Cholinergic urticaria occurs after emotional stress, exercise, or heat exposure, presenting as 1–2 cm wheals surrounded by larger red halos. Sometimes, only cutaneous pruritus without wheals is observed, possibly accompanied by salivation, sweating, abdominal pain, and diarrhea, lasting from months to years.

3. Solar urticaria appears within minutes of sun exposure, limited to exposed areas, and lasts 1–2 hours.

4. Peptone urticaria: In cases of overeating, emotional agitation, or concurrent alcohol consumption, peptones from food protein decomposition are absorbed through the intestinal mucosa, causing the disease. Symptoms include skin redness, congestion, and wheals, accompanied by headache and fatigue, resolving within 1–4 hours but sometimes lasting 1–2 days.

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Elevated blood eosinophils, IgE may be elevated. Cold globulin or cold fibrinogen can be detected in the serum of patients with cold urticaria. Patients with serum sickness urticaria have elevated circulating immune complexes, decreased complement C2 levels and total complement activity. Patients with C₁ esterase inhibitor-deficient angioedema lack C₁INH or only have inactive C₁INH in their serum, and may also have abnormal levels of early complement components (C₁, C₄, C₂).

bubble_chart Diagnosis

Based on the skin lesions being wheals, which appear quickly and subside rapidly, and considering the characteristics of each type, the diagnosis is not difficult to establish. Once diagnosed, the relevant causative factors should be identified. This condition needs to be differentiated from papular urticaria and erythema multiforme.

bubble_chart Treatment Measures

First, the disease cause should be identified and eliminated. Symptomatic treatment often involves the use of antihistamine H₁ receptor antagonists, such as hydroxyzine 25–50 mg three times daily, which is particularly effective for chronic urticaria, especially physical urticaria. Cyproheptadine 4 mg three times daily or azatadine 1 mg four times daily works well for cold urticaria, while hydroxyzine is highly effective for psychogenic and cholinergic urticaria. These medications may cause drowsiness. In recent years, a new generation of antihistamines has emerged. These drugs exhibit only grade I or no anticholinergic effects and have limited ability to cross the blood-brain barrier, thus avoiding dry mouth and drowsiness. Examples include acrivastine (Semprex) 8 mg once daily, terfenadine 10 mg once daily, and cetirizine (Zyrtec) 10 mg once daily. Cetirizine not only inhibits histamine-mediated early-phase reactions but also suppresses the migration of inflammatory cells, particularly neutrophils and eosinophils, to allergic sites, as well as abdominal mass, thereby inhibiting late-phase [third-phase] allergic reactions. Juhlin reported its inhibitory effects on histamine, bradykinin, platelet-activating factor, and others. Mequitazine (Primalan) 10 mg twice daily blocks mast cell degranulation and the effects of inflammatory mediators such as histamine, peanut arachidonic acid, and platelet-activating factor on H₁ receptors. It also regulates vagal nerve tension, thereby preventing the progression of chronic symptoms.

For refractory cases unresponsive to antihistamine receptor antagonists, a combination with H₁ receptor antagonists such as cimetidine or ranitidine may yield satisfactory results. Ketotifen can also be used in combination.

Sympathomimetic drugs are primarily used for acute urticaria and/or angioedema, especially in cases of laryngeal edema. A subcutaneous injection of 0.1% adrenaline (0.5–1 mL) is recommended. For severe acute allergic reactions, 0.5 mL may be administered every 20–30 minutes. In cases of frequent episodes, long-acting formulations such as adrenaline oil may be tried.

Corticosteroids are indicated for acute, severe cases such as anaphylactic shock, serum nature of disease urticaria, or urticaria associated with necrotizing cutaneous vasculitis, but they are less effective for chronic sexually transmitted disease cases.

Intravenous aprotinin has shown some efficacy in treating chronic urticaria, with 10 sessions constituting one course of treatment. Patients may undergo 2–3 courses. Other options for chronic urticaria include intravenous procaine, intramuscular histamine-protein, and oral hydroxychloroquine, reserpine, or vitamin K. Aminophylline and β-adrenergic agents can increase intracellular cyclic AMP levels, reducing histamine release. Calcium preparations improve capillary permeability. For cases triggered by psychological factors, sedatives like diazepam may be used.

Antibiotics and sulfonamides are suitable for urticaria patients with overt or latent gastrointestinal or respiratory infections.

Attenuated androgens such as danazol, stanozolol (Stanozolol), and oxymetholone (Oxymetholone) can treat congenital C₁ INH deficiency by correcting generation and transformation defects and preventing attacks. However, they are contraindicated in children and pregnant women. The latter may only use antifibrinolytic agents like 6-aminocaproic acid (6–8 g daily), which can sometimes control spontaneous episodes and prevent attacks in some cases.

For respiratory tract, especially laryngeal edema, tracheotomy or intubation should be performed when necessary to maintain airway patency. For external use, antipruritic lotions such as 1% camphor or 1% Mentha calamine lotion can be applied multiple times a day.