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Contents A. Case study B. More information C. Editors' comments D. References E. CEU questions

Index

A. Case study
A 16-year-old girl had been experiencing occasional urticaria, mainly on her arms and legs, for 2 months. As it was summer, her arms and legs were exposed most of the time, so that she was self-conscious, especially as she would be going back to school soon. She did not experience any other symptoms that would indicate a risk of anaphylaxis. She had not experienced urticaria before, but had had milk allergy as a young child.

THOUGHT PROCESS:
What could the possible causes be?
a. Idiopathic urticaria (since in about 80% of people with chronic urticaria, no cause is found)
b. Viral, bacterial or parasitic infection
c. Food allergy (possibly recurring milk allergy) or another type of allergy
d. Contact allergy
e. Autoimmune disorder
f. Physical urticaria
g. Any of the above, aggravated by stress or exercise

DISCUSSION:
a and d. The patient was screened for underlying conditions, but nothing could be identified.
b. The patient could not identify an association with a specific food. She had been drinking milk on the days that she had not experienced any symptoms, so milk allergy was unlikely. She had no prior allergy to any food additive or drug.
c. No connection could be made to contact with a new type of food or chemical on the sites where she had experienced symptoms.
e. This was ruled out.
f. As physical urticaria can often present for the first time in young adults, this needed to be explored further.
g. As it was the summer holiday, she had little stress, but she had been doing various strenuous activities such as swimming and hiking. The urticaria was not coincident with swimming but was always experienced after hiking, so exercise-induced urticaria was ruled out (as it did not follow exercise every time).

Therefore, a food allergy, a physical urticaria, and idiopathic reasons were possibilities.

THOUGHT PROCESS:
As mentioned previously, most cases of chronic urticaria are idiopathic. This needed to be shared with the patient at the start so that she would have realistic expectations for the investigation. Although food allergy is rarely the cause of urticaria, this possibility needed to be explored. What can be done to determine whether food allergy is a cause?
a. Serum-specific IgE testing (which takes preference over skin prick testing, as physical urticaria may be a cause of symptoms and could lead to a false positive result)
b. Food-symptom diary
c. Elimination diet and oral challenges

DISCUSSION:
As there was no indication of a specific food or foods responsible, it would have been difficult to decide which foods to test for or to eliminate from the diet. A food-symptom diary was therefore a better option at first. However, physical urticaria also needed to be explored.

The various forms of physical urticaria were discussed with the patient. The apparent possibilities were dermatographism, heat-induced urticaria, and solar urticaria. She had spent a lot of time outdoors during the past 2 months, swimming, hiking and doing other activities with friends.

Tests were performed: stroking of the forearm for dermatographism, application of warm water for heat-induced urticaria, and exposure to UV light for solar urticaria. Dermatographism was positive and the others negative. By going through the history of the patient’s reactions again, an association between the urticaria episodes and a type of scratching of the affected area was found. This made food allergy appear even more unlikely.

Please see Prof Janice Joneja’s Editorial Comment below.

TIP for Allergy Advisor users: In Allergy Advisor assessment guides for urticaria can be found under the Assessment tab - Assessment Guides/Checklists - Assessment Guides - Urticaria. The following sheets are listed: Classification of Urticaria; Diagnostic Evaluation of Urticaria; and Aid to Diagnostic Evaluation of Urticaria – Mechanisms.

B. More information:
Urticaria is a complex disease caused and influenced by a number of factors. This review aims to remind the reader of this condition and to highlight a few of the factors involved. However, the condition is too complex for this review to cover in full.

1. What is urticaria?
Urticaria (also called hives, wheals and welts) is characterised by the rapid appearance of wheals and/or angioedema (swelling). A wheal has 3 typical features: 1) a central swelling of variable size, almost always surrounded by a reflex erythema, 2) an itching or burning sensation, and 3) a fleeting nature, with the skin usually returning to its normal appearance within 1 to 24 hours.

Urticaria can vary from small to large bumps, of which the shape can vary. It may be localised to one part of the body, or widespread. It may start off localised, only to spread to other areas with time. Although it more commonly appears on the arms, legs and trunk, it can occur anywhere.

Urticaria usually includes redness of the skin, itchiness, and mild to moderate swelling because of leakage of fluid into the tissues. Hives are generally not an emergency, but when they appear suddenly, spread rapidly and are accompanied by a swollen throat, tightness of the chest, wheezing or difficulty breathing, this indicates a severe allergic reaction that requires immediate medical attention.

An urticarial wheal is typically present on the skin for less than 24 hours; if it persists longer, urticarial vasculitis, which rarely has an allergic aetiology, must be suspected. Diseases such as mastocytosis and urticaria pigmentosa are not associated with allergy, and will not be discussed in this article.

2. What is angiodema?
Angioedema is a variant of urticaria in which there is swelling but no redness. There may be pain rather than itchiness, and mainly the subcutaneous tissues, rather than the dermis, are involved. The tissue swells asymmetrically, and the resolution is slower than for urticaria, taking up to 72 hours. Angioedema is frequently associated with urticaria (in about 1 in 3 patients), but either may occur independently.

3. How common is urticaria?
Acute urticaria is said to affect 10%-20% of the population at some time during life. It is not uncommon in childhood, but the greatest incidence appears to be in young adults (15%). Chronic urticaria occurs more frequently in mid-life, especially in women.

4. Types of urticaria
Urticaria and angioedema constitute a heterogeneous group of disorders that may be classified by duration and trigger factors. In a single patient, different subtypes of urticaria can coexist.

4.1 Acute urticaria:
The duration of acute urticaria is normally limited to less than 6 weeks. The lifetime prevalence for acute urticaria may be 15-20% and is higher in persons with atopic diseases. Although food and drugs can cause it, the most frequent cause of acute urticaria appears to be viral infection, which is usually present a few days before the onset of wheal formation.

4.2 Chronic urticaria:

This classification is suitable from a clinical point of view because the physical urticarias are rarely associated with any other disease (including food allergy); therefore, extensive investigations are rarely needed. It is, however, important to emphasise the frequent combination of physical urticaria and chronic idiopathic urticaria in the majority of patients.

5. What causes urticaria?
In the literature there are many approaches to classifying urticaria. Here are a few:

Onset:
• Acute
• Chronic
• Physical

Internal and external triggers of acute urticaria:
• Infections
• Food
• Food Additives
• Aeroallergens
• Drugs

Causes of chronic urticaria:
• Idiopathic and/or autoimmune type associated with anti-IgE-receptor auto-antibody
• Urticarial vasculitis (relatively rare)
• Physical urticaria

The involvement of the immune system:
• Immunologic
• Non-immunologic

There are many causes of urticaria, allergic and non-allergic. In about 80% of adults with chronic urticaria, no cause is found even after exhaustive investigations, while in children the cause is more likely to be found. In acute urticaria the chances of determining the cause are higher. For example, many cases of acute urticaria in children are associated with a viral, bacterial or parasitic infection. Stress can certainly make established symptoms worse, but it is very rarely the direct cause of urticaria.

Allergic urticaria is usually due to an allergy to foods, spices, food additives, insect stings or drugs. The most common foods that cause urticaria are seafood, berries, nuts, eggs and chocolate (but almost every food has been implicated), and the most commonly implicated additives are preservatives, nitrates, and colourants such as tartrazine. Naturally occurring substances in foods such as vasoactive amines (e.g., histamine and tyramine) also needs to be considered. Drugs commonly implicated are over-the-counter medications, antibiotics, aspirin, medicines containing tartrazine, birth control pills and medication for colds. Insect bites, worm infestations and other infections, contact with dogs, cats, pollens and plants, as well as blood transfusions, may also cause urticaria. Autoimmune mechanisms may also be involved.

Some people experience urticaria following exposure to contact with materials such as metals, especially nickel and latex. This is contact urticaria.

In acute urticaria, an identifiable allergenic trigger is more commonly found and is often a food or drug. The incidence of acute food-dependent urticaria is about 1-10%, depending on which study is quoted. In food allergy, acute urticaria is normally present together with symptoms and signs from other or¬gan systems, such as the respiratory or gastrointestinal systems. However, the most common cause of acute urticaria is still infection, especially in infants and children.

Chronic urticaria has been associated with food; food additives; infections; noninfectious chronic inflammatory processes, e.g., gastritis and reflux esophagitis; and also, rarely, autoimmune disorders such as systemic lupus erythematosus (SLE). Allergy is only rarely proven as a cause.

No consensus could be reached on the incidence of food and food additives as causes of chronic urticaria; the discrepancies among the reported inci¬dences are too large. Therefore, a diet omit¬ting additives may be worth trying only in severe cases of chronic urticaria unresponsive to conventional antihistamine therapy.

The types of physical urticaria:
Dermographic urticaria / Dermatographism:
This literally means “writing on the skin”. If the skin is stroked firmly with a solid object, a characteristic wheal and flare reaction occurs. An observer would be able to read what has been “written” on the skin for a prolonged period of time. Skin prick testing will therefore not produce a reliable result in these patients, and is contra-indicated as a diagnostic tool. Most wheals appear rapidly and itch intensely. This sensitivity mainly affects young adults and has a mean duration of 6.5 years.

Delayed-pressure urticaria:
The typical lesions are deep, painful swellings, developing 4-8 hours after exposure to a vertical static pressure and persisting for 8-48 hours. Typical areas involved are palms and soles, as well as buttocks and the back when exposed to pressure, e.g., from a hard chair. Males are twice as frequently affected as females; the average age of onset is 30 years, and the mean duration 6-9 years.

Cold-induced urticaria:
Urticaria can occur after exposure to the cold, cold objects, cold water or even cold air. This urticaria is usually localised to exposed areas, but sudden total body exposure, as in swimming, may cause a drop in blood pressure and can, in rare cases, be fatal. It is more frequently found in women than in men, affecting mainly young adults, with a mean duration of 4.2 years.

Heat-induced urticaria:
This is a rare form of urticaria, induced by direct contact of the skin with warm objects or warm air. The eliciting temperature ranges from 38 to more than 50 degrees Celsius, and affected areas can remain refractory for 24 hours or more.

Solar urticaria:
Wheals are elicited by light in wavelengths ranging between 280-760 nm. The eliciting wavelength varies among individuals, but it is mainly UV-light that is responsible. Women are more frequently affected, and the disease usually starts in young adulthood. Areas affected are those constantly exposed to sunlight, such as the face and hands.

Vibratory urticaria/angioedema:
This is a rare condition in which strong vibrating mechanical forces, e.g., from a pneumatic hammer or clapping, induce angioedema. Bumps can be seen within minutes after the stimulus and disappear within an hour.

Other urticaria types:
Cholinergic urticaria:
Urticaria occurs due to a brief increase of the body core temperature. The most frequent reasons are physical exercise; passive warmth, e.g., a hot bath; and emotional stress; but, rarely, warm or spicy food or alcoholic beverages can also induce a brief rise in body core temperature. The typical clinical picture is pin-point-sized wheals, surrounded by an erythema, but larger wheals can also occur. It is frequent in young adults, with a prevalence of 11.2% in the age group 16-35 years.

Adrenergic urticaria:
It is extremely rare, and characterised by pin-point-sized red wheals with white halos, in contrast to the erythemas of cholinergic urticaria. Wheals are elicited by stress and not by exercise or an increase in body core temperature.

Contact urticaria:
It is defined by the appearance of wheals at sites where chemical substances have come into contact with the skin. The disease can be strictly confined to the areas of contact, but generalised systemic symptoms can occur. Common eliciting factors include food, plants, drugs, cosmetics, industrial chemicals, animal products and textiles.

The substances involved are numerous and may be chemically defined molecules such as cinnamic acid, benzoic acid, and parabens, or chemically undefined, such as are found in arthropods, plants, spices, fruits, and fish.

Aquagenic urticaria:
This is a distinct form that needs to be differentiated from contact urticaria because of the fact that water is not itself the causative agent but instead liberates a water-soluble substance from the stratum corneum, a substance which then acts as an allergen after diffusion into the dermis.

6. Treatment of urticaria
IgE-mediated food allergy is rare in urticaria. If identified, the specific food allergens need to be omitted as thoroughly as possible, and symptoms should clear within 24 to 48 hours. However, in a subgroup of chronic urticaria patients where pseudoallergic reactions are caused by additives, an avoidance diet may supply results only in 2-3 weeks’ time.

Therefore, as a first line of defense, triggering factors should be avoided as far as possible and any associated disease should be treated. Elimination diets and avoidance of physical triggers are the most desirable approaches, but they are unfortunately not applicable for the majority of patients, as the exact eliciting stimulus is frequently unknown. In the majority of patients, symptomatic pharmacological treatment is possible with new-generation antihistamines, with a very low adverse effect profile and good patient compliance.

7. Papular urticaria
Papular urticaria is a term used to describe crops of grouped, itchy, reddened papules or small blisters. Each bump lasts for 2 - 10 days and may leave behind pigmentation. The cause in the case of cats and dogs is usually bites of fleas or mites. In humans, the flea, bedbug, mosquito and dog louse can cause urticaria, with the worldwide flea and bedbug being the most common causes. The symptoms occur mainly on the "bathing-costume area" – the thighs, buttocks and lower torso. However, the distribution depends largely on the insect responsible; in some cases the forearms, arms and face are affected. Fleas may cause papular urticaria with 2 to 3 lesions showing in a row.

Papular urticaria is rare in the first year of life. It is most common in children between the ages of 2 and 7 but may occur in adults. The incidence decreases with age, presumably because of desensitisation with successive bites. Papular urticaria is frequently seasonal, especially in temperate climates where the triggers are worst in the summer. However, it can occur throughout the year.

C. Comments by our editors

Prof Janice M. Joneja Ph. D., RDN A cause for the patient’s symptoms in this case study may be histamine intolerance, a condition that is being increasingly recognized as a disease entity separate and distinct from allergy. Urticaria (hives) and angioedema (swelling) are symptoms that occur in response to excessively high levels of histamine in the body. Histamine has also been implicated as an important mediator in some types of headaches which are thought to differ from migraine; digestive tract symptoms, especially diarrhea; and chronic rhinitis (nasal congestion). Because of the multifaceted nature of the symptoms, and their similarity to food allergy, the existence of histamine intolerance is greatly underestimated. However, in cases of histamine intolerance, tests for antigen-specific IgE to food allergens are usually negative, which differentiates the condition from food allergy. Histamine intolerance results from a disequilibrium between accumulated histamine and the body’s capacity for histamine degradation . Whereas high doses of histamine are toxic for all humans, individual tolerance is the important characteristic that determines reactivity to small quantities. Symptoms occur when the speed of release and rising histamine levels exceed the capacity of the enzyme systems (principally diamine oxidase), that break down histamines to keep the amine at a "normal" level. It is likely that differences in levels of tolerance are of genetic origin, but tolerance can be reduced by disease, fluctuating hormone levels (especially at puberty and menopause), and some medications. Reduction in “total body histamine” will often reduce the incidence and severity of the histamine-associated symptoms. Histamine occurs to various degrees in a variety of different foods. In many instances a decrease in total body histamine to a level that does not provoke symptoms can be achieved by reducing or eliminating extrinsic sources of histamine in the form of the histamine-containing and histamine-releasing foods . In the case study presented here, the patient would benefit from a four-week trial on a histamine-restricted diet to determine whether histamine intolerance is the cause of her symptoms2. References: 1. Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007 May;85(5):1185-1196 2. Joneja, J.M.Vickerstaff Dealing with Food Allergies: A Practical Guide to Detecting Culprit Foods and Eating a Healthy, Enjoyable Diet Bull Publishing Company, Boulder, Colorado 2003 pp 233-254

Dr. Harris Steinman M.B.Ch.B. Urticaria is one of the most difficult conditions to assess and manage. It requires dogged determination. If the majority of cases in adults is "idiopathic", why bother? The answer is self evident - the difference you can make in those patients where a cause can be identified. In many cases patients may need to be evaluated by a specialised allergy or immunology centre that specialises in urticaria, but many patients can be helped before this step. This review, although not extensive and focussing on every aspect or cause of urticaria, helps focus the reader firstly on urticaria as an important condition, on some aspects that need to be considered, and gives some guidance to its assessment.

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D. References
1. Carsten Bindslev-Jensen Morten Oesterballe. Food-Induced Urticaria and Angioedema, a chapter in Metcalfe, etc.
2. Zuberbier T, et al. EAACI/GA2LEN/EDF guideline: management of urticaria. Allergy 2006;61:321-331.
3. Zuberbier T, et al. EAACI/GA2LEN/EDF guideline: definition, classification and diagnosis of urticaria. Allergy 2006;61:316-320.
4. Zuberbier T. Urticaria. Allergy 2003:58:1224-1234.
5. Wai YC, Sussman GL. Evaluating chronic urticaria patients for allergies, infections, or autoimmune disorders. Clin Rev All Immunol 2002;23:185-193.
6. Kontou-Fili K, Borici-Mazi R, Kapp A, Matjevic LJ, Mitchel FB. Physical urticaria: classification and diagnostic guidelines. Allergy 1997;52:504-513.

E. CPD Questions (For South African dietitians only. Australian dietitians: where you have relevant learning goals, CEU hours related to this resource can be included in your APD log.)

PLEASE ANSWER ALL THE QUESTIONS
(There is only one correct answer per question.)

1. True or false: Urticaria has 3 typical features: 1) a central swelling, almost always surrounded by a reflex erythema, 2) associated itching, and 3) the skin usually returning to its normal appearance within 1-24 hours.
a. True
b. False

2. True or false: the greatest incidence of urticaria is in the elderly.
a. True
b. False

3. True or false: Acute urticaria is normally limited to less than 6 weeks, and chronic uriticaria lasts more than 6 weeks.
a. True
b. False

4. True or false: The most frequent cause of acute urticaria appears to be food allergy.
a. True
b. False

5. True or false: Skin prick testing is contra-indicated as a diagnostic tool in dermatographism.
a. True
b. False

6. True or false: In contact urticaria, wheals appear at sites where chemical substances, such as foods, have come into contact with the skin.
a. True
b. False

7. True or false: In about 80% of people with chronic urticaria, a cause is found.
a. True
b. False

8. True or false: An identifiable allergenic trigger is more commonly found in acute urticaria, as compared to chronic urticaria.
a. True
b. False

9. True or false: Urticaria caused by food allergy is normally present together with symptoms and signs from other or¬gan systems, such as the respiratory and gastrointestinal systems.
a. True
b. False

10. True or false: A diet omit¬ting additives may be worth trying in severe cases of chronic urticaria unresponsive to conventional antihistamine therapy.
a. True
b. False

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Urticaria
CEU Reference number: DT/A01/2007/00123

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This issue was sponsored by Abbott Laboratories S.A (PTY) LTD All Abbott products are lactose and gluten free Tel: 011-8582054