Acute and Chronic Urticaria

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Spontaneous urticaria is defined as spontaneous episodes of hives and/or angioedema. In acute urticaria hives are present for less than 6 weeks of duration. Chronic Spontaneous Urticaria (CSU) is defined as hives that are present for at least or greater than 6 weeks and for the most days of the week. Physical urticaria is present only when certain physical stimuli are applied. These hives are intermittent and technically are not chronic.

Spontaneous Urticaria is primarily a clinical diagnosis, based on a thorough history and physical examination. History should include all possible eliciting factors and significant aspects of the nature of the urticaria. Questions should be asked regarding the following items:

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  • Time of onset of disease, including timing of symptoms in relation to changes in medications or other exposures.

  • Frequency and duration of wheals.

  • Shape, size, and distribution of wheals.

  • Associated subjective symptoms of lesions, e.g., itch and its intensity, pain, burning.

  • Diurnal variation, and occurrence in relation to weekends and holidays.

  • Association with the season, menstrual period, or other pattern.

  • Relation of urticaria to occupation and leisure activities.

  • Associated angioedema or systemic manifestations (e.g., headache, joint pain/swelling, GI symptoms).

  • Known precipitating factors of urticaria (e.g., food, medication, physical stimuli, exercise, stress).

  • Family and personal history regarding urticaria and atopy.

  • Previous or current allergies, infections, internal diseases, travel history, or other possible causes.

  • Psychosomatic and psychiatric diseases.

  • All current medications, prescription and over-the-counter, in particular, NSAIDs.

  • Surgeries and surgical implantations.

  • Type of work and hobbies.

  • Stress (eustress and distress).

  • Quality of life related to urticaria and emotional impact.

  • Previous therapy and response to therapy.

  • Characteristic findings on physical examination

Urticaria is characterized by the sudden appearance of wheals (see Figure 1). Typical features of wheals:

Figure 1.

Chronic urticaria.

  • Raised central swelling of variable size, almost invariably surrounded by an erythema.

  • Associated significant pruritus.

  • A fleeting nature: individual lesions typically last for 1-24 hours, at most up to 36 hours. They do not leave skin discoloration (hypo- or hyperpigmentation) or scaring. While some lesions are fading, new lesions appear. Tip: If you are unsure whether the lesions are truly wheals, circle single lesions with a pen and ask patient to come back the next day to ensure their fleeting nature.

  • Involves superficial dermis.

  • Usually generalized.

Angioedema is characterised by:

  • Pronounced swelling involving deeper dermis, non-pitting.

  • Burning or painful sensation rather than itching.

  • Frequent involvement of mucous membranes.

  • Resolution that is slower than for wheals and can take up to 72 hours.

  • Usually localized.

  • Occurs in 40-50% of patients with urticaria, occurring simultaneously with wheals or separately.

  • Expected results of diagnostic studies

A routine patient evaluation, which should reveal classical wheals and/or angioedema in the history and physical examination, should be used to verify the disease. Hives should be present without any other abnormalities on physical exam. See Table I for the algorithm of wheals or angiodema.

Table I

Diagnostic algorithm of wheals or angioedema

Intensive and costly general screening programs for causes of urticaria are strongly advised against.

For Acute Urticaria, allergy skin testing (or serum IgE test) may be performed.

Different forms of Physical Urticaria may be confirmed by specific challenge tests.

For Chronic Spontaneous Urticaria, current recommendations are to perform a limited number of laboratory tests to confirm or exclude an underlying condition, such as infection, autoimmune disease, or an endocrine disorder.

Routine tests include:

  • CBC with differential

  • ESR, CRP, or both

  • Liver function tests

  • TSH

Other tests are optional, depending on patient’s history, risk factors, and clinical suspicion. They may include (but not limited to): thyroid auto-antibodies, serum protein electrophoresis, immunofixation, complements (C3, C4, CH50), ANA, rheumatoid factor, hepatitis B and C serologies, cryoglobulins, urinalysis, stool for ova and parasites (if eosinophilia present).

Increased levels of anti-thyroglobulin or anti-thyroid peroxidase antibodies in euthyroid (i.e., normal thyroid-stimulating hormone levels) subjects are commonly detected, although the clinical implications of this finding are unclear.

Routine performance of Autologous Serum Skin Test (ASST) and screening for autoantibodies against either IgE or the high affinity IgE receptor is currently not recommended.

A newer laboratory test evaluates the in vitro histamine release from basophils – Chronic Urticaria Index, identifying a subset of patients with autoimmune urticaria.

Skin biopsy should be performed when vasculitis is suspected or when other non-urticarial immunologic skin diseases are a consideration.

  • Diagnosis confirmation

Diagnosis confirmation is clinical since the clinical findings of the fleeting wheals and/or angioedema, as pointed out above, are diagnostic.

If the history and physical examination are consistent with CSU, the yield of identifying an underlying condition as the cause is poor.

Who is at Risk for Developing this Disease?

Both acute and chronic urticaria have a high prevalence in the general population and currently there are no known risk factors to predict who’s likely to develop urticaria. Chronic urticaria is more frequent in women, up to 70%.

What is the Cause of the Disease?


Acute Urticaria:

– Typically, due to allergy to food, medication, hymenoptera sting, or other external exposure (e.g., contact allergy to pets or chemicals).

– Can be related to a transient viral or other infectious illness, mostly in children.

Physical Urticaria:

– Dermatographism. The most common form of physical urticaria, affecting 2-5% of population but only small proportion is symptomatic to the extent of medical attention.

– Cholinergic, cold urticaria, exercise-induced, solar, aquagenic, vibratory, and delayed-pressure urticaria/angioedema.

Physical urticaria syndromes may present in combination with each other or concomitant with CSU.

Causes of Chronic Spontaneous Urticaria include:

– Chronic infections (e.g., hepatitis B and C, EBV, herpes simplex, Helicobacter pylori, or parasites)

– Autoimmune and connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis)

– Endocrine disorders (e.g., Hashimoto thyroiditis, Graves disease) and hormonal therapies (e.g., oral contraceptives)

– Malignancies, in particular lymphoproliferative disorders, multiple myeloma, and other gammopathies (e.g., MGUS, Schnitzler syndrome)


Pathogenically, there is mast cell activation, degranulation, release of histamine and other mast cell mediators, leading to increased vascular permeability and extravasation of fluid into adjacent tissue.

On histology, the classical fleeting wheal demonstrates edema of the upper and mid dermis, with dilatation of the postcapillary venules and lymphatic vessels of the upper dermis. Lymphocytes are predominant cells in the lesions of both acute and chronic urticaria. However, mixed inflammatory cellular infiltrates are frequently present, consisting of lymphocytes, neutrophils and/or eosinophils, macrophages, and T-cells. Skin affected by wheals exhibits upregulation of endothelial adhesion molecules. In some subtypes of urticaria, upregulation of adhesion molecules and altered cytokine expression are also seen in uninvolved skin. Activation of complement and coagulation cascades has been demonstrated.

These findings highlight the complex nature of the pathogenesis of urticaria and show a systemic underlying inflammation. However, these changes are also seen in a wide variety of inflammatory reactions and are thus not specific or of diagnostic value. Currently, the clinical picture is more important than the histology and allows diagnosis and classification without doubt.

Systemic Implications and Complications

In both acute and chronic spontaneous urticaria, angioedema can co-occur. Angioedema, associated with CSU, typically does not involve larynx and fatal cases have not been observed.

Acute urticaria and/or angioedema could be manifestations of anaphylaxis. In anaphylaxis, laryngeal edema may lead to asphyxiation and could be fatal. Other symptoms of anaphylaxis may develop, such as respiratory (including severe bronchospasm), gastrointestinal, cardiovascular (including hypotension and shock), and neurological (including unconsciousness). The latter two are not described in association with CSU. Severe anaphylaxis requires immediate medical attention, treatment with epinephrine, and sometimes hospitalization for further management and observation.

Treatment Options

The recommended treatment options are based on an algorithm using first-, second-, third-, and fourth-level options in consecutive order. The therapies listed in the algorithm (see Table II) are evidence-based and have been widely used in daily practice.

Table II.

Treatment algorithm – Urticaria

Step 1: First line therapy – monotherapy with second or third generation H1-antihistamines (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine).

Step 2: Second line therapy – dose advancement of antihistamine used in step 1, up to fourfold increase in the FDA-approved dose.

  • First generation antihistamines may be added at bed-time when pruritus interferes with sleep.

  • Leukotriene receptor antagonists may be added to second line therapy but the literature does not support strongly their use.

  • H2 receptor antagonists have been eliminated from the most recent European guidelines but the American guidelines have still retained them. Their effect in CSU is weak.

Step 3: Third line therapy – Omalizumab or Cyclosporine. Both are highly effective in treatment of CSU, with efficacy rate 65-75% and 60-80%, respectively.

  • Omalizumab is preferred due to the excellent side-effect profile. It is well-tolerated and does not require monitoring. Proportion of patients completely free of both hives and itching is approximately 40%. There is 69-78% improvement in QOL after 12 weeks of treatment. Treatment with 300 mg of omalizumab results in earlier response (before week 4).

  • Cyclosporine is contraindicated in patients with hypertension and compromised renal function. A blood urea nitrogen, creatinine, urinalysis, and blood pressure should be checked at the onset, and then repeated at 4-6–week intervals while on cyclosporine.

Step 4: Options to consider if steps 1-3 fail – dapsone, methotrexate, sulfasalazine, colchicine, hydroxychloroquine, IV gamma globulin, and plasmapheresis. However, there are no double-blind, placebo-controlled studies of any of these agents with a success rate significantly higher than 30% (the rate of success with placebo).

While corticosteroids are appropriate for acute urticaria, they should be avoided for the treatment of chronic urticaria because the dosages necessary to suppress symptoms are usually high with significant adverse effects. In some patients, short-term use, 1-3 weeks’ duration, may be required to control the disease until other treatments become effective. Mostly, corticosteroids are reserved for treatment of severe exacerbations.

Optimal Therapeutic Approach for this Disease

The first and most desirable strategy for patients with urticaria, is avoidance or elimination of the eliciting stimulus. These may include foods, medications, contact allergens. However, avoidance/elimination is unfortunately not applicable in the majority of patients with CSU, as the exact eliciting stimulus is frequently unknown. Some medications, such as NSAIDs and opiates, may not only elicit symptoms themselves, but also aggravate pre-existing urticaria and/or angioedema, and therefore should be avoided anyway.

The next strategy should be directed at symptoms control, using treatment algorithm as described above.

The optimal treatment approach should aim:

  • at complete symptom control

  • to be early as possible

  • to be safe as possible

  • to improve patients’ quality of life

  • to reduce the duration of the disease.

Only with complete symptom control can the vicious circle of underlying inflammation and constant reactivation of mast cells be broken. Modern antihistamines, especially when up-dosed, exert action not only on H1 receptors but inhibit a variety of proinflammatory cytokines involved in urticaria and are therefore first choice to be used.

Patient Management

Patient quality of life in urticaria is severely affected. There is frequent embarrassment, anxiety/depression, social isolation, sleep disturbance, particularly due to the itch. It affects daily living, both work and school. In fact, quality of life impairment in patients with chronic spontaneous urticaria is comparable to that experienced by older patients who have ischemic heart disease. Management of the disease should therefore be prompt and include close cooperation between patient and physician. As a first line, triggering factors should be avoided as much as possible. It is important to tell the patient that urticaria is a benign and treatable disease – even if the underlying cause cannot be found in all cases.

See Figure 2 and Figure 3 for management of patients with acute and chronic urticaria and/or angioedema, respectively.

Figure 2.

Management of patients with acute and chronic urticaria and/or angioedema (Urticaria)

Figure 3.

Management of patients with acute and chronic urticaria and/or angioedema (Angiodema)

Unusual Clinical Scenarios to Consider in Patient Management

The important issue is to be sure that the clinical diagnosis of spontaneous urticaria is correct. In case of doubt, the wheals should be evaluated once more.

There are several other conditions that can produce urticarial lesions but have a different pathophysiology:

  • Urticarial vasculitis: individual wheals last > 24 hours, painful, leave residual hyperpigmentation or purpura

  • Cutaneous mastocytosis: orange – brown hyperpigmentation of the lesions, lesions persist; Darier sign positive: urtication upon scratching over lesion

  • Arthropod bites: lesions last several days, frequently insect exposure history

  • Erythema multiforme: lesions last several days, “target” appearance, may have fever

  • Viral exanthema: not pruritic, individual lesions last for days, mostly maculopapular lesions, may have prodrome and fever.

These conditions are diagnosed primarily by history and physical examination and should thus not have been overlooked if the questionnaire for urticaria, as outlined above, has been gone through with the patient.

Sometimes angioedema is the sole form of disease manifestation. If this is the case, histaminergic angioedema should be differentiated from bradykinin-mediated. The latter one is non-pruritic, not associated with urticaria, develops slower – within 24 hours, and does not respond to antihistamines, corticosteroid or epinephrine. The following conditions should be ruled out: hereditary or acquired angioedema with C1 esterase inhibitor deficiency (see chapter on Hereditary and Acquired Angioedema), ACE-inhibitor – induced angioedema, and other rare conditions (e.g., Melkersson-Rosenthal syndrome, characterized by recurrent swelling of the face and lips).