Are You Confident of the Diagnosis?
What you should be alert for in the history
When evaluating patients with urticaria, of all the diagnostic procedures, the most important is to obtain a thorough history including all possible eliciting factors and significant aspects of the nature of the urticaria. Questions should be asked regarding the following items.
While all of the features are important in the history, when evaluating the physical urticarias, induction by physical agents or exercise is of paramount importance.
Time of onset of disease
Frequency and duration of wheals
Occurrence in relation to weekends, holidays, and foreign travel
Shape, size, and distribution of wheals
Associated subjective symptoms of lesion, e.g. itch, pain
Family and personal history regarding urticaria, atopy
Previous or current allergies, infections, internal diseases, or other possible causes
Psychosomatic and psychiatric diseases
Surgical implantations and events during surgery
Gastric/intestinal problems (stool, flatulence)
Induction by physical agents or exercise
Use of drugs (NSAIDs, injections, immunizations, hormones, laxatives, suppositories, ear and eye drops, and alternative remedies)
Observed correlation to food
Relationship to the menstrual cycle
Type of work
Stress (eustress and distress)
Quality of life related to urticaria and emotional impact
Previous therapy and response to therapy
Step two is the physical examination of the patient. This should include a test for dermographism where indicated by history (please note: antihistamine therapy should be discontinued for 2-3 days).
Characteristic findings on physical examination
Dermographic urticaria: Dermographic urticaria (synonym: factitial urticaria) is defined by wheal formation induced by shearing forces on the skin. The wheals generally appear rapidly and itch (Figure 1).
Delayed-pressure urticaria: Characterized by deep, painful swellings developing 4–8 hours after exposure to a vertical static pressure and persisting for 8–48 hours. Palms, soles, buttocks and the back are commonly afflicted areas e.g. due to sitting on a hard chair (Figure 2).
Cholinergic urticaria: Lesions in cholinergic urticaria are due to a brief increase of the body core temperature = 0.5°C. Common elicitors are physical exercise, passive warmth, and emotional stress; less commonly, spicy food or alcoholic beverages can also induce a brief rise in body core temperature (Figure 3). The typical clinical picture involves pin-sized wheals surrounded by an erythema. The wheals can also be larger.
Aquagenic urticaria is another form of special urticaria that can form wheals, at times follicular based. This typically happens 1-15 minutes after exposure to water. Drinking water, tears, sweat and rain may be triggers. Symptoms can include pain and pruritus.
Expected results of diagnostic studies
Intense and costly general screening programmes for urticaria are not suggested. Standardized diagnostic tests for a number of urticaria subtypes are summarized in the table (Figure 4). Further tests may be required but should be reserved for selected patients.
Routine diagnostic tests
This table (Figure 4) gives a selection of procedures in frequent physical urticaria subtypes to be considered in diagnosis or differential diagnosis. Additional measures may have to be considered depending on patient history (ESR (erythrocyte sedimentation rate), ANA, antinuclear antibodies).
For the diagnosis of urticaria it must always be remembered that in one patient different subtypes of urticaria can coexist, e.g. chronic urticaria and dermographic urticaria. It may thus happen that diagnosis reveals an eliciting cause for one of the subtypes, which then goes into remission after the appropriate treatment, while the other subtype remains unchanged.
There are no other tests available to confirm the diagnosis, nor are they required.
Differential diagnosis – Adrenergic urticaria. Adrenergic urticaria is an extremely rare condition, characterized by pin-point sized red wheals with a white halo, in contrast to cholinergic urticaria. Wheals are elicited by emotional stress and can be inhibited by beta-blockers.
Who is at Risk for Developing this Disease?
There are no identified risk factors for physical urticaria. The prevalence of physical urticaria varies in the literature. This is due to the variance in the strength of the physical stimulus required. Thus, it has been shown that in normal subjects 44.6% can react with an urticarial dermographism if a considerably increased pressure is used for testing. However, these subjects do not normally show signs of urticaria.
Dermographic urticaria is the most frequent form of physical urticaria, affecting mainly young adults. The mean duration is 6.5 years.
With pressure urticaria, males are twice as frequently affected as females, the average age of onset is 30 years, and the mean duration is 6–9 years. Pressure urticaria can be disabling for patients whose jobs involve physical work.
Cholinergic urticaria is frequent in young adults. The prevalence is 11.2% in the age group of 16–35 years. In the majority of cases symptoms are mild, and 80% of those affected by cholinergic urticaria do not seek medical advice for the condition. However, some patients are severely affected with symptoms that occur very easily, for instance after a light walk, and systemic symptoms, like dizziness, nausea and headache, are observed in up to 11% of the patients. The main differential diagnosis is exercise-induced anaphylaxis.
Adrenergic urticaria is extremely rare and only isolated cases have been reported.
What is the Cause of the Disease?
All forms of physical urticaria have in common the urticarial reaction to external and specific physical stimuli (pressure, cold, heat, light). The underlying pathomechanism is unclear, although it is known that mast cell degranulation is involved. In some forms, eg, solar urticaria, IgE-sensitization has been demonstrated to endogeneous proteins undergoing changes under UV light.
Systemic Implications and Complications
In general, the physical urticaria subtypes are not associated with systemic disease. One exception is cold urticaria, where rare familial forms exist, often associated with fever and arthritis. Cold urticaria can also be part of a syndrome e.g. Muckle-Wells syndrome. These diseases are summarized under Caps (cryoprene-associated periodic syndrome) and based on a genetic overproduction of interleukin-1 beta.
Complications can occur in rare cases, principally in all subtypes of physical urticaria, if a massive stimulus is applied to the whole or to large areas of the skin. In this case histamine-mediated forms of anaphylactic reactions similar to IgE-mediated anaphylaxis can be observed, although unconsciousness is extremely rare. The most dangerous form of physical urticaria in this aspect is cold urticaria, where patients underestimate the disease and e.g. jump into cold water, where unconsciousness could lead to drowning.
An important aspect to be excluded is co-existing mastocytosis. In those patients having mastocytosis and physical urticaria, reactions will be much more severe than in general. These patients need to be carefully advised and given emergency treatment consisting of corticosteroids, antihistamines and possibly adrenaline autoinjector to carry. In general in physical urticaria, it is most important to explain the triggers to the patients and explain the possibly more harmful conditions.
In general the systematic treatment with drugs is similar to chronic urticaria (Figure 5).
The recommended treatment options are based on an algorithm using first, second, third and fourth-level options in consecutive order for non-remittant patients. These therapies mentioned in the algorithm are evidence-based and have been widely used in daily practice.
However, there are a large number of additional possible treatments which have been described in small case series or case reports, or which have not been added to the algorithm due to the fact that they have either very high costs (eg immunoglobulin treatment) or are associated with a higher incidence of adverse events.
Optimal Therapeutic Approach for this Disease
Although the subtypes of urticaria are elicited by a great variety of factors, its treatment mainly follows some basic principles.
Avoidance or elimination of the eliciting stimulus
Inhibition of mast cell mediator release
Therapy of target tissues of mast cell mediators
Avoidance of existing stimuli
With this therapeutic approach, an exact diagnosis is a basic prerequisite.
Suspected triggers should be omitted entirely or another class of drugs should be substituted. Drugs causing pseudoallergic reactions, such as aspirin, can elicit urticaria and simultaneously aggravate pre-existing chronic urticaria.
Controlling exposure to the relevant stimulus in daily life helps; thus it is important to have very detailed information about the physical stimuli. In both dermographic urticaria and delayed-pressure urticaria, it should be noted that pressure is defined as force per area; it may be sufficient to e.g. carry heavy bags with a broader-than-normal handle in order to avoid symptoms
Removal of infectious agents and treatment of inflammatory processes
Infections have been found to be a cause in very few cases of physical urticaria. Unlike in chronic urticaria which is more often associated with inflammatory infectious processes, the causal relationship to infection has mainly been described in single cases of cold urticaria.
The incriminated infections include syphilis, borreliosis, HIV, viral infections, and Epstein-Barr virus, but since a causal relationship could never be clearly established, the guidelines do not encourage an extensive search for infections except in those cases where there is a clinical history. However, cold urticaria is the only physical urticaria which in treatment sometimes responds to a 3 week course of antibiotics (penicillin, doxycycline).
However, the trials are not double-blind placebo controlled and although it is widely used, it must be assumed that the positive effect is not necessarily due to treating an unknown infection, but could as well be related to the anti-inflammatory properties of antibiotics which is especially pronounced in doxycycline.
Patient quality of life in urticaria is severely affected. The disease should thus be promptly managed, with close collaboration between patient and physician. Triggering factors should be avoided. Doctors should tell the patient that urticaria is a benign and easily treated disease, even if the underlying cause cannot always be found. Most patients respond well to symptomatic pharmacologic treatment with new-generation antihistamines, with a very low adverse effect profile and good patient compliance. In nonresponding patients, higher dosages (up to fourfold) and alternative medication should be tried.
Unusual Clinical Scenarios to Consider in Patient Management
Unusual clinical scenarios which must be remembered in physical urticaria include cases where underlying autoimmunity, especially systemic lupus erythematosus, are present. However, the most frequent unusual clinical scenario involves the abortive forms of physical urticaria, where histamine is released from mast cells but not enough to form wheals.
Thus in most forms of physical urticaria as well as in cholinergic urticaria, forms exist where only pruritus and/or erythema are observed following a physical stimulus. This is often a question of threshold, since in everyday life conditions, patients are not exposed to a threshold high enough to provoke formation of wheals.
Unusual clinical scenarios are also sometimes seen in cold urticaria, where in some patients only a combination of stimuli can provoke symptoms, e.g. exercise in the cold (cold cholinergic cold urticaria) or symptoms can only be provoked in some body areas but e.g. not in the face or symptoms can only be provoked upon a certain type of stimulation, eg, only cold wind but not localized exposure.
Important other unusual scenarios include syndromes like Muckle Wells syndrome, associated with cold triggeral urticaria. Also in chronic urticaria unusual scenarios exist. Elaborating the patient history may help. One example is a patient always having urticaria when visiting the mother in law who always offered home-made food where aspirin was used as preservative.
What is the Evidence?
Zuberbier, T, Asero, R, Bindslev-Jensen, C, Canonica, GW, Church, MK, Giménez-Arnau, AM. “EAACI/GALEN/EDF/WAO Guideline: Definition, Classification and Diagnosis of Urticaria”. Allergy. vol. 64. 2010. pp. 1417-26. (This chapter is based predominantly on this article.)
Brzoza, Z, Kasperska-Zajac, A, Badura-Brzoza, K, Matysiakiewicz, J, Hese, RT, Rogala, B. “Decline in dehydroepiandrosterone sulfate observed in chronic urticaria is associated with psychological distress”. Psychosom Med. vol. 70. 2008. pp. 723-8. (Patients with chronic urticaria may be stressed; this may be a factor in the observed decline of DHEAS levels observed in these individuals)
Owoeye, OA, Aina, OF, Omoluabi, PF, Olumide, YM. “An assessment of emotional pain among subjects with chronic dermatological problems in Lagos, Nigeria”. Int J Psychiatry Med. vol. 37. 2007. pp. 29-38. (Emotional pain is increased in a host of dermatologic disorders when compared to healthy controls.)
Arck, P, Paus, R. “From the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch”. Neuroimmunomodulation. vol. 13. 2006. pp. 347-56. (Candidate molecules that are associated with stress such as nerve growth factor, corticotropin-releasing factor, and substance P need to be evaluated further, so that novel therapeutic interventions may be utilized for those diseases, such as urticaria, that are aggravated by stress.)
Zuberbier, T, Greaves, MW, Juhlin, L, Merk, H, Stingl, G, Henz, BM. “Management of urticaria: a consensus report”. J Investig Dermatol Symp Proc. vol. 6. 2001. pp. 128-31. (An overview with management as discussed in this chapter by the lead author.)
Zuberbier, T, Bindslev-Jensen, C, Canonica, W, Grattan, CE, Greaves, MW, Henz, BM. “EAACI/GA2LEN/EDF Guideline: management of urticaria”. Allergy. vol. 61. 2006. pp. 321-31. (An overview with management as discussed in this chapter by the lead author.)
Guyatt, GH, Oxman, AD, Kunz, R, Falck-Ytter, Y, Vist, GE, Liberati, A. “Going from evidence to recommendations”. BMJ. vol. 336. 2008. pp. 1049-51.
Guyatt, GH, Oxman, AD, Kunz, R, Vist, GE, Falck-Ytter, Y, Schunemann, HJ. “What is “quality of evidence” and why is it important to clinicians?”. BMJ. vol. 336. 2008. pp. 995-8. (This article details how the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was developed and denotes its utility.)
Guyatt, GH, Oxman, AD, Vist, GE, Kunz, R, Falck-Ytter, Y, Alonso-Coello, P. “GRADE: an emerging consensus on rating quality of evidence and strength of recommendations”. BMJ. vol. 336. 2008. pp. 924-6. (The GRADE systems measures evidence as stong or weak. This article explores those definitions.)
Brozek, JL, Baena-Cagnani, CE, Bonini, S, Canonica, GW, Rasi, G, van Wijk, RG. “Methodology for development of the Allergic Rhinitis and its Impact on Asthma guideline 2008 update”. Allergy. vol. 63. 2008. pp. 38-46. (Using the GRADE system, the guidelines for allergic rhinitis and its impact on asthma have become more evidence-based.)
Kurbacheva, O, Zuberbier, T. “A visit to the mother in law – a hidden cause for urticaria”. Allergy. vol. 62. 2007. pp. 711-712. (Acetylsalicylic acid was the culprit in this case, when used as a home preservative for canning food.)
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