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URTICARIA
1. DEFINITION
This is a condition characterized by transient itchy pale dermal swellings secondary to the release of histamine and other vasoactive agents.
2. AETIOLOGY
An urticarial wheal results from release of histamine, and possibly other vasoactive mediators from mast cells leading to a sudden increase in vascular capillary permeability allowing the escape of fluid from the circulation into the tissues. Mast cells may degranulate as a result of physical, chemical, pharmacological and immunological stimuli.
Immunological mechanism is probably not important in the pathogenesis of chronic urticaria. The type I hypersensitivity is mediated through the IgE attached to the mast cell which will degranulate on exposure to the specific antigen. This type of allergic urticaria is associated with a personal or family history of atopy. Mast cell can degranulate by other non-immunological stimuli. Certain drugs for example morphine, codeine, ethanol, polymyxin B, and bacterial, plant or invertebrate toxins stimulate mast cells to degranulate directly. Other drugs like salicylates and NSAIDs act through a pharmacological effect in relation to the cyclo-oxygenase pathway. It has been postulated that food additives such as tartrazine, azo dyes, benzoates and sulphites provoke urticaria through a similar mechanism.
In the biopsy of a typical urticarial lesion there is vasodilatation, dermal oedema and a mild perivascular infiltration of lymphocytes and eosinophils. However, in a small number of urticaria patients, repeated lesional skin biopsies may show a predominance of neutrophils and eosinophils without endothelial damage, which is the picture seen in late phase reaction. It also suggests that other cellular element and mediators are involved in the pathogenesis of urticaria.
3. CLASSIFICATION OF URTICARIA
Various types of classifications exist, the following classification adopts a more practical approach.
3.1 Acute Urticaria and Urticaria with an Identifiable Cause
In acute urticaria, a self evident precipitating factors is usually present. Some patients with chronic urticaria may also have a well defined cause although this is uncommon.
3.2 Chronic Idiopathic Urticaria
Defined arbitrarily as urticaria that persisted for six weeks or more without any identifiable cause.
3.3 Physical Urticaria
cholinergic urticaria
symptomatic dermographism
delayed pressure urticaria
solar urticaria
cold urticaria
aquagenic urticaria
vibratory urticaria
3.4 Angio-Oedema
May accompany any types of urticaria. Hereditary angioedema is due to C1 esterase inhibitor deficiency. An acquired form of this enzyme deficiency is also known. ACE inhibitor can provoke angio-oedema through inhibition of the kinin system.
3.5 Others : hereditary urticaria, contact urticaria, papular urticaria, urticarial vasculitis, and urticaria pigmentosa.
Table 1 : Common Causes of Urticaria
Drugs salicylates, penicillin, ACE inhibitors, NSAID, allopurinol and many others.
Foods fish, nuts, egg, strawberries, milk, cheese, wine and many others.
Food additives azo dyes, benzoates sulphites and yeast.
Infections hepatitis B, infectious mononucleosis, candidosis and focal sepsis.
Inhalants grass pollens, moulds, house dust mites, etc.
Infestation enterobius, filariasis, ascariasis.
Immune complex transfusion reaction, drugs
4. CLINICAL FEATURES
The lesions of urticaria is usually not difficult to recognize. They are intensely itchy and have a white palpable centre of oedema with a variable halo of erythema .The size and shape can be highly variable and individual lesions usually last for several hours, except in urticarial vasculitis and angio-oedema where the lesions may persist longer. Frequently patients do not have any lesion during the visit to the clinic and one has to rely on the description from the patient to diagnose a prior attack of urticaria.
The history is very important for the diagnosis of different types of urticaria especially for physical urticarias. The frequency, the duration, the severity, and the timing of the attacks may give clues to the diagnosis and are essential for subsequent management. A thorough food and drug history should be elicited. The characteristic rash of physical urticaria, if present on examination, together with the typical history would usually allow the diagnosis be made easily. In case of doubt, simple tests can be done to confirm it.
In the history and examination, one should always try to look out for underlying infections and other systemic diseases. Focal sepsis, such as dental abscess and urinary tract infection have been reported to cause chronic urticaria. Urticaria can also be symptomatic of connective tissue diseases but usually other features of the disease would be evident on presentation.
Other associated involvements should always be looked out for. Acute urticaria can be just part of the manifestation of serum sickness with systemic symptoms like fever, arthritis and nephritis. Similarly systemic symptoms are also seen in patients with urticarial vasculitis.
Table 2 : Tests for Physical Urticaria
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Cholinergic Urticaria exercise test, whole body warming -
Dermographism light stroke on the skin, dermographometer -
Cold urticaria ice cube test -
Solar urticaria phototesting -
Aquagenic water at 25 ºC compresses
5. INVESTIGATION
For many patients with urticaria, the diagnosis can be reached after history taking and physical examination. A complete blood count with ESR is adequate for the majority who has no other abnormal physical finding. Other investigations can be performed when necessary.
(i) Complete blood count and ESR- look for eosinophilia
(ii) Complement C3 and C4
(iii) C1 esterase inhibitor level
(iv) Investigating underlying infections - x ray chest, urine for culture, stool for ova, throat swab, HBsAg, viral study etc.
(v) ANF, RF etc. in suspected connective tissue disease
(vi) Skin biopsy - urticarial vasculitis, urticaria pigmentosa
(vii) RAST - controversial as to its usefulness
(viii) Skin prick test - useful for contact urticaria. Difficult to interpret for chronic idiopathic urticaria
6. ACUTE URTICARIA
The cause of acute urticaria is often evident and history of similar attack is often positive. A differential white cell count and ESR measurement help to identify systemic disease. The presence of eosinophilia points to parasitic infestation. Other possible causative factors are listed above.
The attacks are usually being first seen by general practitioners or in the A & E department. Since the causal factor can usually be withdrawn, subsequent attack is avoided and long-termed treatment is not required. Challenge test is not advisable since acute urticaria is frequently IgE mediated and there is a definite risk of anaphylaxis during the test. Although the prognosis for acute urticaria is good, it must be remembered that chronic urticaria commonly has a acute onset. Thus it is not unusual for some patient with acute urticaria to have persistent symptoms and finally merge into the picture of chronic idiopathic urticaria.
Treatment of acute attack usually required antihistamine for a few days. In acute urticaria of serum sickness type hypersensitivity, short course of systemic steroid may be necessary. Parenteral adrenaline is life saving in case there is anaphylaxis or bronchial constriction. Resuscitation procedures should be carried out as indicated.
7. CHRONIC IDIOPATHIC URTICARIA
Chronic idiopathic urticaria is defined as urticaria which lasts longer than 6 weeks, for which no obvious cause can be found. This is the commonest type of urticaria in a dermatology clinic and a study by Champion reported that 80% of cases of urticaria were chronic idiopathic urticaria. Although most patients' symptoms can be controlled with drug therapy, many of them suffer from continuous symptoms for years without true remission.
Numerous factors have been suggested for causing this disease, for example, sea food, azo dyes, food preservatives, candida in the gut and trace of penicillin in dairy products. Occasional patient may benefit with elimination of one of these factors, but for most others the cause of the disease remains obscure.
By definition , no obvious aetiological factor is apparent and special investigations are nearly always unhelpful. For most patients with chronic idiopathic urticaria, a complete blood count, ESR for screening may be adequate. Stool for ova is indicated if there is eosinophilia. Other tests detailed above should be performed for individual patient as directed by the history and examination. Prick test and intradermal skin test are often positive but are difficult to interpret. Challenge tests with food coloring agents and preservatives if available, is helpful in the management.
Although no definite cause of the disease can be found for most patients, they can be reassured that their symptoms can be controlled with modern therapy without much disturbance to their daily life. Depending on the patient's tolerance, a sedating or non sedating antihistamine can be prescribed during daytime. Because most patients have more severe attack at night time, an additional nocte dose of more sedating drug like promethazine can help to give the patient a good sleep. The patient should be encouraged to keep a food diary. Food containing tartrazine dye and preservatives should be avoided as well as drugs that known to aggravate urticaria. In suitable cases, elimination diet can be carried out with the help of a dietitian.
Tolerance to antihistamine therapy may develop in a patient whose symptoms are previously under control. This tolerance cannot be overcome by increasing the dosage or by changing the antihistamine. The cause of tolerance is thought to be due to the down regulation of the H1 receptors. Ketotifen and sodium cromoglycate Terbutaline has been tried with some success in this situation and the responsiveness to antihistamines may return afterwards. In some difficult urticaria the patient may need to be admitted to hospital for further management and alternative therapy should be considered.
8. CHOLINERGIC URTICARIA
This is a common condition in young adults. The intensely itchy and short-lived eruption develops in response to sweating, exercise, emotion and hot foods. It is postulated that an increase in blood temperature triggers a neural reflex which releases acetylcholine from sympathetic nerve endings, in turn activate the mast cell to degranulate. The lesions are characteristic small wheals of less than 2 mm in diameter with surrounding red halo. Thus the condition is also called micropapular urticaria. They are more profuse on the upper trunk and proximal parts of the upper limbs. Associated systemic symptoms include faintness, headache, wheezing and palpitation.
Diagnosis is established from the history and by finding the characteristic rash during an attack. The rash can also be brought up on exercise or whole body warming. These lesions can often be reproduced by intradermal injection of cholinergic drugs, e.g., metholyl or acetylcholine.
Treatment is unsatisfactory. Patients, especially those with associated systemic symptoms, should be told to avoid situations that can precipitate an attack. Some patients improve with antihistamine therapy. It can be taken regularly or at times when they forecast attacks. Fortunately for most patients the condition tends to improve spontaneously.
9. DELAYED PRESSURE URTICARIA (DPU)
This rather rare condition is not true urticaria. Delayed cutaneous erythema and oedema and subcutaneous oedema occur in response to the sustained application of pressure to the skin. The lesions itch and burn. They appear between 30 min and 9 hours after the stimulus. A large proportion of these patients have associated chronic idiopathic urticaria.
The lesions occur after certain activities : sitting on hard chairs, carrying bags, leaning against furniture, wearing seat belts and lying on hard mattresses. Swelling of the feet and hands, often indistinguishable from angio-oedema, occurs after walking, jogging, running, climbing ladder and using a screwdriver. During severe attacks, arthralgia and a flu-like illness may accompany the rash.
The pathogenesis of DPU is not known. Histamine is probably not an important mediator of this disease and treatment with antihistamine (except Cetirizine which can suppress eosinophil infiltration) is disappointing. Other forms of treatment including use of NSAIDs and colchicine have been tried with varying results. Systemic steroid is an effective agent but is limited by its side effects.
10. SYMPTOMATIC DERMOGRAPHISM
Dermographism means whealing after direct pressure on the skin. The patient notes that the skin irritates and linear wheals appear as a result of scratching. The itching and whealing reach their maximum in 5-10 minutes after the stimulus and disappear 30-60 minutes later. It is an exaggerated response of the skin to trauma.
Lesions frequently appear in areas where clothing is tight and at sites of scratching. The patients are often young adults although patients of all age group can be affected. No associated systemic disease has been recognized and no increased incidence in patients with chronic idiopathic urticaria is noted. The diagnosis can be confirmed by using the more sophisticated dermographometer. Any patient who itches and wheals at or below a stroking pressure of 3.5 x 105 Pa has symptomatic dermographism. The tendency to dermographism ultimately disappears but it may last for years.
11. SOLAR URTICARIA
Solar urticaria is a rare photodermatosis of unknown aetiology. It is occasionally associated with polymorphic light eruption, other urticarias, lymphocytoma cutis or lupus erythematosus. It may also be symptomatic of porphyria cutanea tarda.
Patients notice erythema, burning, and urticarial wheals within minutes following exposure to sunlight or visible light. Wheals can develop anywhere on the body, mostly in the sun exposed skin. If the whole body is irradiated, severe generalized solar urticaria can occurred with haemodynamic disturbance. The action spectrum of solar urticaria is broad, ranging from UVC, UVB, UVA to visible spectrum. Phototesting can be performed with monochromator on areas that are normal covered e.g. the buttock. If monochromator is not available, lesions of solar urticaria can be reproduced outdoor by direct exposure to sunlight or visible light.
Avoidance of sunlight is very important. The body should be covered with clothing and the patient should be advised to use an appropriate sunscreen. Antihistamines can give symptomatic relief. Other treatment modalities that have been used include hardening with UVB, UVA, or visible light, PUVA, and plasmapheresis.
12. COLD URTICARIA
Patients with cold urticaria develop whealing on exposure to cold. Characteristic urticaria appears on exposed areas on a cold day. Handling of cold objects causes immediate local reaction. Swelling of the mouth and oesophagus may occur on drinking cold water. Extensive cold urticaria may be associated with systemic symptoms like faintness, wheezing and palpitations. Syncope can occur when the patient immerses in cold water. Diagnosis is established by placing an ice cube (wrapped in plastic bag) on the skin for 30 seconds to 10 minutes. Wheals form on rewarming. In some cases, water at 7C is more effective in bringing out the wheal.
It is important to warn patients against swimming in cold water. Antihistamine treatment is partially effective in suppressing symptoms, Cyproheptadine is said to be the drug of choice. Salbutamol and aminophylline can relieve the pruritus of cold urticaria. Unlike antihistamines these drug suppress histamine release from skin mast cell. Doxepin and ketotifen may also be useful.
Desensitization to cold has a place in the management of this condition. This should be carried out in the hospital under antihistamine cover. The procedure begins with putting one limb in water at 15°C for 5 min, hourly at first and then at longer intervals up to 24 hours. Other limbs and the face can then be treated. The exposure needs to be repeated indefinitely at 24 hours intervals to maintain the effect.
It should be remembered that occasionally cold urticaria is secondary to the presence of cryoglobulin, cold haemolysin and cryofibrinogen in the circulation. These condition should be ruled out accordingly.
13. AQUAGENIC URTICARIA
This is a rare type of physical urticaria in which brief contact of the skin with water of any temperature causes an immediate urticarial eruption on the site of contact, the morphology of which closely resembles cholinergic urticaria. This condition may persist for many years.
Aquagenic pruritus is a related but distinct condition in which brief contact of skin with water evokes intense local pruritus without any skin lesion. Patients with this disorder, which is probably quite common in the elderly, are often wrongly labelled as psychoneurosis or senile pruritus. Complete blood count should be checked as this condition may be symptomatic of polycythaemia rubra vera. Both disorder involve histamine release from skin mast cells and respond well to antihistamine. UVB therapy is also helpful.
14. VIBRATORY ANGIOEDEMA
Vibratory angioedema is an acute short-lived itchy swelling of the skin that occurs within minutes of application of a vibratory stimulus to the skin. The condition is rare and may be genetically transmitted and there are sporadic reports of acquired disease. The disease is benign and the familial form is not associated with any other physical urticaria. Affected patients generally limited their activities, to avoid symptoms. The lesions can be reproduced by massage, scratching, shivering and running. Clapping, using a vibratory machine such as massage chair, and riding a motor bike may also produce lesions. The severity of symptoms is proportional to the intensity of the provoking stimulus. If the stimulus is sufficiently strong, facial and/or generalized erythema may occur. Headache and faintness are also reported. The urticarial response occurs within minutes of the stimulus, maximal at 5 minutes and disappears within an hour. Treatment with antihistamine is usually effective.
15. ANGIOEDEMA
This is a variant of urticaria where massive oedema involves subcutaneous tissues rather than the dermis. It may involve any part of the body surface like the lips, eyelids, the tongue and larynx. This can be associated with urticaria of any cause. The hereditary form is caused by a quantitative or functional deficiency of C1 esterase inhibitor and is inherited as an autosomal dominant trait. An acquired form of C1 esterase inhibitor may develop in patients with lymphoproliferative disorders and systemic lupus erythematosus.
Hereditary Angioedema
In hereditary angioedema attacks are infrequent in childhood, common in adolescence and early adult life and may subside later. It is precipitated by trauma and the lesions may affect the skin, mucosal surface and intestine. Subcutaneous swelling is not itchy and typically persisted for a few days. Intestinal oedema may causes symptoms simulating acute abdomen. Laryngeal oedema may lead to upper airway obstruction and death.
The C2 and C4 level are low in between attacks and C3 is normal. There is a low C1 esterase inhibitor level.
In acute airway obstruction, subcutaneous adrenaline may be life saving. Fresh frozen plasma should be administered by intravenous infusion or, alternatively a purified C1 esterase inhibitor concentrate can be given. For long term management attenuated androgens stanozolol or danazol can be used for prophylaxis. They act by stimulating hepatic synthesis of C1 inhibitor. Antifibrinolytic agents like tranexamic acid and epsilon aminocaproic acid are less effective as prophylaxis but can be tried in patient who cannot tolerate androgenic steroids.
16. CONTACT URTICARIAS
Contact urticaria is a local immediate or delayed erythema or urticarial reaction at the site of epidermal or mucosal contact with a causative agent. It may be associated with generalized cutaneous reactions, rhinitis , asthma, or anaphylaxis. It is commonly an IgE mediated immediate reaction and non immunological mechanism is also possible.
Probably the most important cause of contact urticaria is natural rubber latex present in gloves and other rubber products. Latex contact urticaria symptoms vary from mild itching to bronchial asthma, anaphylaxis, and death. Up to ten allergenic proteins have been isolated from latex.
Small molecular weight chemicals may cause contact urticaria. Chemicals, acting as haptens, for example ethylene oxide, isocyanates, chloramine-T, epoxy resins and nickel sulphate have caused IgE-mediated allergies. This can be confirmed by using skin prick testing.
17. URTICARIAL PIGMENTOSA
This condition is in fact not urticaria but is a disorder of mast cell proliferation. Clinically there is multiple guttate or larger pigmented macules on the trunk and limbs of the baby and urticated lesion may appear on rubbing the pigmented lesions. The biopsy of the skin shows increase in number of mast cells.
18. URTICARIAL VASCULITIS (cf Vasculitis)
19. THERAPEUTIC MODALITIES FOR URTICARIA
19.1 Antihistamines
This group of drugs has H1 receptor blockers action and is the mainstay of therapy for chronic idiopathic urticaria. There are many antihistamines available. While the classical ones have been used for many years and are effective and cheap, they have more anticholinergic action and can cause more sedation. The newer antihistamines are more expensive and less sedating. In general there is little difference in the efficacy between the two groups of antihistamines and there is a lot of individual variations in response to treatment.
As a guideline one should prescribe an antihistamine that one is familiar with and gradually increase the dosage according to response. It is worthwhile to switch to an antihistamine of another class if the response is not good while the maximum dosage has been given. Alternatively, in order to select out the most suited agent for the patient, an antihistamines self-assessment questionnaire can be used.
The classical antihistamines (see table 3) are to be group into 6 classes according to their chemical structures, but the introduction of the newer drugs has greatly complicated this.
Table 3 : Commonly used 'Classical' Antihistamines
Class Generic (Proprietary) Name Usual Adult Dose
Ethanolamines Dimenhydrinate 50-100 mg qid
Diphenhydramine (Benadryl) 25-50 mg qid
Alkylamines Chlorpheniramine (Piriton)*1 4 mg tid
Dexchlorpheniramine (Polaramine)*2 2-4 mg tid
Pheniramine (Avil) 75 mg bid
Phenidenes Mebhydrolin (Incidal) 50-100 mg tid
Phenothiazines Promethazine (Phenergan)*3 10-25 mg bid
Trimeprazine (Vallergan) 10-30 mg qid
Mequitazine (Primalan) 5 mg bd
Piperazines Hydroxyzine (Atarax) 10-25 mg tid
Piperidines Cyproheptadine (Periactin)*4 4 mg tid
Azatadine (Zadine) 1-2 mg tid
*1 a short acting, good general purpose drug
*2 dextro-isomer of chlorpheniramine
*3 causes sedation, suitable for use at night time, e.g. 25 mg nocte
*4 with additional antiserotonin action, very useful for cold urticaria
Unwanted effects are common with these antihistamines, the commonest being sedation, dizziness , fatigue, insomnia and dry mouth. Paradoxical increase irritability may be seen in children. Alcohol can potentiate the sedative effect and patient should be advised to abstain from drinking while on antihistamine therapy. The anticholinergic action may cause urinary retention and precipitate glaucoma. All antihistamines are not proven safe in pregnancy and one should balance the risk and the possible benefit before prescribing antihistamines to pregnant woman. Newer antihistamines should always be avoided in pregnancy.
Table 4 : Low Sedating Antihistamines
Usual Adult Dosage Onset Duration of Action
Terfenadine 60 mg bd 1-2 hours >12 hours
Astemazole 10 mg daily days 4 weeks
Loratadine 10 mg daily 1-2 hours 24 hours
Cetirizine 10 mg daily 1-2 hours 24 hours
Acrivastine 8 mg tds 30 minutes 12 hours
Notes : 1. Fatal ventricular arrythmia has been reported with larger than normal dose, in patients with liver disease and when it is administered with erythromycin or ketoconazole.
2. Very long duration of action. Ventricular arrhythmia reported. Cautious in the elderly. Weight gain may occur during prolonged therapy.
3. Inhibitory effect on eosinophil migration, useful in DPU.
Other antihistamines and related drugs :
Ketotifen - Antihistamine-like drug with mast cell stabilising effect, worth a try in difficult urticaria and when tolerance to antihistamine therapy appears. Adult dosage : 1-2 mg bd.
Oxatamide - Properties comparable to ketotifen, dosage is 30 mg bd.
Doxepin - A tricyclic antidepressant with antihistamine activity. Suitable for administration at night. There is drug interaction with MAOIs, and can cause cardiac arrthythmia. Dosage : 10 mg nocte
19.2 H2-Receptor Blockers
The exact mode of action of H2 antagonist in urticaria is still uncertain. There is no firm ground and evidence that giving an H2 antagonist in addition to H1 antihistamine will be helpful to control urticaria more easily.
Cimetidine - 400 mg bd
Ranitidine - 150 mg bd
19.3 -Stimulants
This is considered as a second line treatment for patients with resistant chronic urticaria and antihistamine tolerance. They act directly on the mast cell and prevent degranulation. Although they are effective, their use is limited by their side effects, including tremors and tachycardia.
Salbutamol - 2-4 mg tid
Terbutaline - 0.5 mg tid
19.4 Calcium Channel Blocker
Only nifedipine is useful for stubborn urticaria. It acts by stabilising mast cell and inhibit degranulation. Side effects include hypotension and flushing attacks.
nifedipine - 5-10 mg tid
19.5 Anabolic Steroid
This has been used in patients suffering from hereditary angioedema. It is also used in cholinergic urticaria.
Danazol - 100-600 mg daily
Stanazolol - 2.5-10 mg daily
19.6 Systemic Corticosteroid Therapy
This is an effective form of therapy for urticaria but long term therapy usually outweighs its therapeutic effect because of its side effects. Systemic steroid therapy is indicated for anaphylaxis and acute urticaria of serum sickness. For chronic urticaria, this should be avoided unless it is given for a short duration to tide over an acute episode.
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