Urticaria: Brief Review

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

Acute urticaria

Urticaria (hives) is a common skin condition caused by a type 1 hypersensitivity reaction most commonly to foods and drugs. Acute urticaria affects 15-25% of the population at some point in their lives. In 50% of patients, no cause is identified. Hypersensitivity to a specific food can be confirmed by skin prick testing or ImmunoCAP. Skin biopsy (rarely done) shows mast cell infiltration. The flare is mediated by neuropeptides and axon reflex.

Urticaria is either acute (present for less than 6 weeks) or chronic (longer than 6 weeks).

Angioedema involves swelling of the deep dermal and subcutaneous/submucosal tissues. Approximately 50% of patients have both urticaria and angioedema. Angioedema is non-pitting and non-hot.

When you see a patient with angioedema, the first question is: "are you on ACE inhibitor?" ARBs are well tolerated as an alternative therapy.

Figure 1. Urticaria appearing on right arm. Image source: Wikipedia, public domain.

ACE-inhibitor-induced angioedema affecting the upper lip

Which substance has both diagnostic and therapeutic use in acute urticaria?

Epinephrine administration invariably leads to resolution of acute urticaria -- an effect which can be used for both diagnosis and therapy.

Acute urticaria is treated with avoidance of allergens, antihistamines, and steroids in patients with insufficient response to steroids. The mnemonic for treatment is ALAS:

Local (topical) treatments

Figure 2. Diagram (mind map) of acute urticaria.

Causes of acute urticaria: IF DVR Stings

Food: fruits, seafood, nuts, dairy, spices, tea, chocolate
Drugs: antibiotics (PCN) and sulphonamides; ASA, NSAIDs
Viral infections
Radio contrast media
Stings - wasp or bee

Hives that are due to foods, for example, do not last two weeks. They usually last a matter of hours (AAAAI).

A more complete mnemonic for the major causes of urticaria and angioedema: FIT MID CHIMP

Foods or food additives
Inhalation, ingestion of, or contact with antigens
Transfusion reactions

Infections: bacterial, fungal, viral, and helminthic; Insects (papular urticaria)
Drug reactions

Collagen vascular diseases
Hereditary diseases
Idiopathic: chronic idiopathic urticaria and chronic angioedema
Mastocytosis, systemic: urticaria pigmentosa
Physical urticarias

Based on: Middleton's Allergy: Principles and Practice, 6th ed., from MerckMedicus.com (requires registration).

Infections are a very rare cause of urticaria, antibiotics used to treat them are a much more common cause.

Insect-related urticaria in children is found on the dependent area of the body - lower legs and arms.

Urticaria pigmentosa is characterized by Darier's sign - a scratch causes urticaria. Urticaria pigmentosa/systemic mastocytosis can become malignant.


Systemic mastocytosis is characterized by clonal expansion of mast cells, and most patients present with a genetic mutation in the stem cell factor receptor (KIT) gene. KIT or C-kit receptor is also called CD117. KIT is a cytokine receptor expressed on the cell surface. KIT receptors binds to stem cell factors which causes certain types of cells to grow. Some patients present with eosinophilia and symptoms may overlap with the hypereosinophilic syndromes.

Chronic urticaria

Chronic spontaneous urticaria (CSU) is defined as the presence of urticaria with daily or almost daily symptoms for 6 weeks or more. CSU affects 0.1%-0.8% of the population. http://buff.ly/1rDwQ4P

Chronic urticaria is defined as widespread itchy weals (hives) for at least 6 weeks. Skin lesion can be present either continuously or intermittently. When no cause is found, chronic urticaria is labeled as chronic idiopathic urticaria (CIU). Most cases of chronic urticaria are not due to allergy. Most cases of acute urticaria are due to allergy (type I hypersensitivity to food and drugs).

Acute urticaria

Chronic urticaria
Cause unknown, 75%

Incidence of atopy is not increased in chronic urticaria. It is much more common in women than in men ("women pay more attention to their skin") -- 3:1 ratio of female : male in chronic urticaria.

Chronic urticaria is "bad news" for the patient:

- it is difficult to find a cause
- 10-20% persist beyond 10 years
- no treatment is consistently effective

Skin biopsy (rarely done) shows up to 10-fold increase of mast cells. In cold urticaria, a cube is placed on the arm and blood drawn above the cube shows a massive increase in plasma histamine.

Differential diagnosis of chronic urticaria: VIP

Vasculitis, confirmed by biopsy
Idiopathic, 75% of patients
Physical, benign

Figure 3. Diagram (mind map) of chronic urticaria.

Physical urticaria

Physical urticaria is defined as hives provoked by physical stimulus such as:


Cold urticaria due to cooling the skin
Dermographism due to stroking the skin
Cholinergic urticaria due to exercise, emotion, or heat
Solar urticaria due to sun exposure

Physical urticaria can be confirmed by challenge testing, and is best treated symptomatically by avoidance of provocative stimuli and antihistamines.

Testing procedures for diagnosis of physical urticarias depend on the cause (stimulus):

- Dermographism: Stroking with narrow object, e.g. a tongue depressor
- Cold urticaria: ice cube test
- Heat urticaria: test tube water at 44°C (111°F)
- Pressure urticaria: Sandbag test or a bag with heavy books (Middleton's Allergy textbook, 2 volumes)
- Vibratory urticaria: vibration with laboratory vortex for four minutes
- Cholinergic urticaria: exercise for 15-20 minutes or leg immersion in 44°C (111°F) bath
- Aquagenic urticaria: challenge with tap water at various temperatures

Figure 4. Dermatographic urticaria is sometimes called "skin writing". Image source: Wikipedia, public domain.

Dermatographism can be reproduced by using a standardized tool which applies pressure of 3600 gm/cm2.

Physical urticaria does not respond to steroids since they do not inhibit mast cell degranulation. That is why steroid use is not a contraindication to skin prick testing. Epinephrine, which is used for both diagnostic and therapeutic purposes, inhibits mast cell degranulation.

There are several types of cold urticarias. Acquired (essential) cold urticaria can be deadly. For example, a swimmer with history of cold urticaria jumped into a cold water lake, developed urticaria and hypotension which led to brain ischemia.

Familial cold autoinflammatory syndrome (FCAS) is characterized by neutrophil infiltration of skin which differentiates it from "typical" urticaria characterized by mast cell infiltration.

Delayed pressure urticaria/angiodema develops after clapping at a concert or carrying a heavy bag/backpack. The diagnostic test involves appearance of dermatographism after wearing 15-pound weights for 20 minutes, for example a bag with 4 volumes of Middleton's Allergy textbook in a bag over the shoulder.

Vibratory angioedema can develop after cutting the lawn.

Urticarial vasculitis

In urticarial vasculitis, hives invariably persist for more than 24 hours which differentiates from urticaria. Diagnosis is confirmed by skin biopsy which shows vasculitis. Patients with urticarial vasculitis need a complete work-up for SLE and other CTD.

Hypocomplementic Urticarial Vasculitic Syndrome (HUVS) is seen on the dependent body areas - lower legs, arms, back (not on the abdomen),

Chronic idiopathic urticaria (CIU)

When no cause is found, chronic urticaria is labeled as chronic idiopathic urticaria (CIU). CIU affects up to 0.1-3% of the population at some point in their lives (acute urticaria affects 15-25%). Acute urticaria occurs more often in atopy but there is no such correlation in CIU. 20% of patients with CIU have symptoms for longer than 10 years.

CIU is divided in 2 groups:
- autoimmune CIU, 50% of patients with CIU
- "truly idiopathic" CIU, 50%

About 90% of patients with CIU also have angioedema.

Autoimmune chronic urticaria (AICU)

Autoimmune chronic urticaria occurs in 50% of patients with CIU. These patients have autoantibodies against either the high-affinity IgE receptor FcR1 or, less commonly, IgE.

"Truly idiopathic" CIU

In the remaining 40-60% of cases of CIU, no cause can be identified and they are truly "idiopathic." It is likely that those cases also have an autoimmune basis but autoantibodies have not been yet detected.

Laboratory tests in chronic urticaria

Diagnostic tests
Skin prick testing or ImmunoCAP

Diagnosis of Chronic Urticaria (click to enlarge the image).

Autologous serum/plasma skin test

A patient is injected with:
1. Control (saline) - no reaction.
2. Their own serum - no reaction.
3. Their own plasma - reaction, proves autoantibody presence.

The autologous serum/plasma skin test is not commonly used. The positive and negative predictive values of the autologous serum skin test (ASST) in CIU patients are 53 and 70%, respectively.

27-50% of patients with CIU have autoantibodies against the α-chain of the high-affinity IgE receptor (FceRI) or less commonly against IgG. A positive autologous serum skin test (ASST) is an in-vivo test which reflects the presence of anti-FceRI and/or anti-IgE autoantibodies capable of activating mast cell degranulation.

Screening laboratory tests are usually not helpful.

Screening tests

- UA
- Thyroid function tests (TFTs), for example, TSH, T4, and thyroid autoantibodies (antimicrosomal and antithyroglobulin antibodies)
- Anti-FceR1 Autoantibodies
- Chronic urticaria index (positive if greater than 10) is a proprietary index, a positive result that makes autoimmune urticaria more likely

In patients with angioedema and when lesions last longer than 24 hours:
C1q, C4, C2 levels

C1-esterase inhibitor - qualitative and quantitative
CH50, total hemolytic complement

Other tests if indicated by history

Stool analysis for ova and parasites (O&P)
H. pylori workup, for example, H. pylori IgG (blood test)
Hepatitis B and C workup
ANA, RF, cryoglobulin

Testing procedures for diagnosis of physical urticarias depend on the cause (stimulus)

- Dermographism: Stroking with narrow object, e.g. a tongue depressor
- Cold urticaria: ice cube test
- Heat urticaria: test tube water at 44°C (111°F)
- Pressure urticaria: Sandbag test or a bag with heavy books (Middleton's Allergy textbook, 2 volumes)
- Vibratory urticaria: vibration with laboratory vortex for four minutes
- Cholinergic urticaria: exercise for 15-20 minutes or leg immersion in 44°C (111°F) bath
- Aquagenic urticaria: challenge with tap water at various temperatures

Treatment of chronic idiopathic urticaria: ALAS

Avoidance of precipitating factors
Local (topical) treatment are not generally helpful, one recommendation is 1% menthol in aqueous cream.
Antihistamines: H1- and H2-blockers

Other treatments: Cyclosporin A, intravenous immunoglobulins, plasmapheresis, and omalizumab.

Omalizumab (Xolair) (single dose, 300 mg) is effective against chronic idiopathic urticaria but reimbursement for therapy may be a challenge in the U.S.

Cyclosporin is one of the most commonly used steroid-sparing drugs for treatment of CIU.

How does cyclosporine work?

Cyclosporin binds to the cytosolic protein cyclophilin (immunophilin) of T-lymphocytes. This complex of cyclosporin and cyclophylin inhibits calcineurin, which is responsible for the transcription of interleukin-2. Cyclosporin inhibits lymphokine production and interleukin release and leads to a reduced function of effector T-cells.

This mode of action is similar to pimecrolimus (Elidel), an ascomycin macrolactam derivative, which binds to macrophilin-12 and inhibits calcineurin. Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells.

Cyclosporin is an immunosuppressant drug used in post-allogeneic organ transplant. Initially isolated from a Norwegian soil sample, Cyclosporin A is a cyclic peptide of 11 amino acids produced by the fungus Tolypocladium inflatum Gams, and contains D-amino acids, which are rarely encountered in nature.

Therapy for chronic spontaneous urticaria


1 Nonsedating, second- or third-generation antihistamines taken 4 times a day. Decrease the dose as tolerated once control of symptoms is attained. Dose of cetirizine, loratadine, desloratadine, or levocetirizine corresponding to hydroxyzine or diphenhydramine at 50 mg 4 times daily is 6 tablets per day. If response inadequate, proceed to step 2.

2 Omalizumab, 300 mg monthly. If no response after 2 injections, proceed to step 3.

3 Cyclosporine, 200-300 mg/d

4 Options to consider if steps 1-3 fail: dapsone, methotrexate, sulfasalazine, hydroxychloroquine, intravenous γ-globulin, and plasmapheresis.

Expected response rate based on the literature. Patient response to step 1 was 45%. Patient response to step 2 was 65% of the remainder. Calculated response rate of steps 1 plus 2 was 81%. Patient response to step 3 was 65% of the remainder. Calculated total response rate for steps 1, 2, and 3 was 92%. Source: Therapy of chronic urticaria: a simple, modern approach. Allen P. Kaplan, Annals of Allergy, Asthma & Immunology, Volume 112, Issue 5, Pages 419–425, May 2014, http://www.annallergy.org/article/S1081-1206(14)00129-X/abstract


Chronic Idiopathic Urticaria. Current Opinion in Allergy and Clinical Immunology, Medscape, 2003.
Acute and chronic urticaria. Krishnaswamy G, Youngberg G. Postgrad Med 2001;109(2):107-23.
Urticaria. eMedicine, 2004.
Allergy and the skin. Urticaria. ABC of allergies. BMJ 1998;316:1147.
Urticaria. Merck Manual.
Allergy and the skin: eczema and chronic urticaria. Constance H Katelaris and Jane E Peake. MJA 2006; 185 (9): 517-522.
Chapter 85 - Urticaria and Angioedema. Middleton's Allergy: Principles and Practice, 6th ed., from MerckMedicus.com (requires registration).
Urticaria, Angioedema, and Hereditary Angioedema. Patterson's Allergic Diseases (6th Edition), from MerckMedicus.com (requires registration).
Effect of omalizumab on patients with chronic urticaria. Spector SL, Tan RA. Ann Allergy Asthma Immunol. 2007 Aug;99(2):190-3.
Acquired cold urticaria symptoms can be safely prevented by ebastine. Magerl M, Schmolke J, Siebenhaar F, Zuberbier T, Metz M, Maurer M.Allergy. 2007 Sep 26
Omalizumab also successful in chronic urticaria. JACI, Volume 121, Issue 3, Page 784 (March 2008).
What the first 10,000 patients with chronic urticaria have taught me: A personal journey. Allen P. Kaplan, JACI, Volume 123, Issue 3, Pages 713-717 (March 2009).
Effective treatment of therapy-resistant chronic spontaneous urticaria with omalizumab, JACI, 2010 http://goo.gl/BqOb
Evaluation and management of a patient with chronic pruritus - excellent review - JACI 2012 http://buff.ly/QL3hfq
Anti-FceR1 Autoantibodies in Chronic Urticaria
Image source: Uricaria appearing on right arm, Wikipedia, public domain.

Related reading

Flickr Group: Dermatographic Urticaria (Skin Writing). A Flickr user has uploaded photos of what it looks and sounds (from the description) like cold urticaria.
Combinations of two H1 antagonists and/or an H1 plus an H2 antagonist in the treatment of chronic urticaria. Ask the Expert, AAAAI, 2011.
Urticaria and Angioedema. Allergy Capital, 2003.
Cryopyrin-associated periodic syndromes (CAPS)
Down regulation of high-affinity IgE receptor in successful treatment of chronic idiopathic urticaria with omalizumab http://goo.gl/cHKjJ
Lab Testing Not Helpful in Patients with Chronic Urticaria - according to a review from Cleveland Clinic. Journal Watch, 2011.


Blue Hives. NEJM Images in Clinical Medicine, 02/2008.
The Ice Cube Test: Cold-Induced Urticaria. NEJM Images in Clinical Medicine, 02/2008.
Artist: 'I Use My Skin as a Canvas' ABC News, 03/2008.

Published: 09/15/2007
Updated: 08/10/2012

1 comment:

Anonymous said...

From Google Buzz:

Jeffrey Benabio, MD - Thanks, Ves. Lunchtime reading for today. 11:06 am

Ves Dimov, M.D. - Don't forget to check the references at the end... :) 11:15 am

Arin Basu - Excellent set of notes! I liked the mnemonics 1:25 pm

Ves Dimov, M.D. - Thank you. You may like these too then:

Mnemonics in Allergy and Immunology


Mind Map Diagrams in Allergy and Immunology
http://allergycases.org/2006/01/mind-maps-in-allergy-and-immunology.htm l1:28 pm

Jeffrey Benabio, MD - I like zyrtec 10 mg qd titrated to bid. Successfully used CSA once. 2:45 pm

Ves Dimov, M.D. - Zyrtec can be sedating in some patients.

Loratidine bid does not have this effect in general. Allegra was not sedating at any dose in studies.

Chronic urticaria patients can take up to 4 times the daily doses of desloratidine without sedation according to recent trials.