|CONTINUING MEDICAL EDUCATION
|Year : 2001 | Volume
| Issue : 1 | Page : 11-20
PV S Prasad
Department of Dermatology, Raiah Muthiah Medical College & Hospital, Annamalai University, Annamalai Nagar-608 002, India
Department of Dermatology, Raiah Muthiah Medical College & Hospital, Annamalai University, Annamalai Nagar-6008 002, India
|How to cite this article:|
Prasad PS. Urticaria. Indian J Dermatol Venereol Leprol 2001;67:11-20
| Definition|| |
The term urticaria is defined as a transient eruption of circumscribed edematous and usually itchy swellings of the dermis. The other names given are nettle rash, hives or weals. These lesions last for a few hours but not exceeding 48 hours. The term angioneurotic oedema denotes similar but larger swellings of the deep dermal, sub-cutaneous and sub mucosal tissues. The other names are angioedema, giant urticaria and Quinke's oedema. Urticaria and angio-oedema are important components of systemic anaphylaxis which is an acute life threatening condition. Several well illustrated monographs are available on urticaria which may be referred for details.,,
| Classification|| |
Urticaria may be broadly classified on the basis of duration and trigger factors. It is classified into 'acute' and 'chronic' on the basis of duration. This is an arbitrary division and is between 6 weeks to 8 weeks. Acute urticaria is diagnosed retrospectively with a history of less than 6-8 weeks duration. The causative factor is easily identified in acute urticaria whereas it is difficult in chronic urticaria. When there is no detectable cause in chronic urticaria it is also known as chronic idiopathic urticaria. Recently studies after thorough examination of patients with chronic idiopathic urticaria revealed that 30% had Ig G autoantibodies against the Ig E receptor.
Immune complex urticaria comprises of serum sickness and urticarial vasculitis, both of which are classical examples of Type III immunological reaction. Papular urticaria is the result of hypersensitivity to bites from certain insects like mosquitoes, gnats, fleas, mites and beg bugs. Physical urticarias are triggered by various physical agents like heat, cold, pressure, sunlight and water. In all these, the physical stimulus induces reproducible wealing.,
| Pathogenesis|| |
Activation of cutaneous mast cells liberates various mediators predominantly histamine which induces increased permeability of capillaries and venules which in turn produces uriticaria. The clinical response of urticaria to antihistamines proves this hypothesis., Mast cells may be activated by allergic or non-allergic mechanisms. Allergic mast cell activation occurs as a result of linkage of two adjacent a sub - units of high affinity eg. penicillin. As a result of this, preformed histamines, proteases, prostaglandin D2, LT4 and interleukin 4 (IL-4), IL - 8 and tumour necrosis factor (TNF - a) are released. Non allergic mast cell activation occurs with a variety of substances like neuropeptides (substance P), drugs like morphine, codeine, vancomycin, radio contrast media and some foods such as strawberries.,
Chronic idiopathic urticaria patients can develop Ig G antibodies directed against the sub unit of the FCE RI or against the receptor bound Ig E.,, Immune modulating therapy like plasmapheresis and intravenous immunoglobulin were associated with remission in some patients. Thus, in 30% of patients with chronic idioapathic urticaria, an autoimmune mechanism could play a role.
Histamine can stimulate sensory afferent nerves to release substance P as these are situated close to the mast cells. This stimulates further release of mast cell histamine and also expression of various adhesion molecules like P selectin and E selectin which amplifies wealing reaction.
Interleukins like IL-4 regulates vascular endothelial adhesion molecules whereas, IL - 8 causes neutrophil leukocyte accumulation. IL-4 also stimulates T - lymphocyte differentiation and immunoglobulin production. However a direct role of these interleukins has not been found.,,
Plasma derived mediators such as bradykinin and complement have no role in chronic urticaria. However, bradykinin plays a role in production of angio-oedema. Complement activation occurs in urticarial vasculitis and immune complex urticaria. Lymphocytes, neutrophils and eosinophils also may release a variety of cytokines which may enhance or perpetuate the weal response. This mechanism is demonstrated by their presence in the venous effluent from physical urticarias like cold, cholinergic and solar urticarias. Increased substance P and vasoactive intestinal peptide (VIP) have been demonstrated in cold and cholinergic urticarial lesions. Urticarial vasculitis, also called hypocom- plementaemic vasculitis, resembles systemic lupus erythematosus in its pathogenesis. However it may also involve abnormal genetic immunoregulation in some.
Papular urticaria is due to type I and type IV hypersensitivity reaction but the antigen remains undetermined.
| Prevalence|| |
The exact figures are lacking from many countries but it is not an uncommon condition. Sheldon reported an incidence of 15% and the prevalence is reported as 0.1% by Hellgren. More than one fifth of the population suffer at one time. 60% of patients are in the age group of 20-40 years. Incidence is higher in older age group.
| Clinical features|| |
Each episode starts with itching. Following this, erythematous macules and weals appear which are transient and disappear within a few hours to a maximum of 24 hours. The weals may vary in size ranging from a few millimeters to many centimeters. The weals appear on any part of the body and may be associated with angio-oedema. The skin lesions resolve without any trace. Eventhough many patients claim worsening of the lesions during full moon and new moon days there is no convincing evidence for this. Inspite of severe pruritus there are no scratch marks in urticaria as the patients tend to rub the skin. Urticaria occasionally may be associated with a few systemic symptoms such as vomiting, giddiness, malaise, headache, abdominal pain, diarrhoea, dizziness and rarely anaphylaxis. Premenstrual exacerbation may be noticed in some.
| Causes of urticaria|| |
Many drugs cause urticaria through allergic or non allergic mechanisms., Drugs produce acute urticarial reactions usually within 36 hours of administration. Penicillins, cephalosporins, sulfonamides and tetracyclines are some examples of drug - induced urticaria. Acetyl salicylic acid and non steroidal anti inflammatory drugs are responsible to produce urticaria through allergic mechanism. Drug which is taken for a long time is unlikely to cause urticaria. On the contrary even a small quantity of penicillin present in the dairy products may produce severe urticaria in a sensitive person.
Infections may produce either acute or chronic urticaria.,, Non specific infections may be responsible for acute urticaria. Hepatitis B viral infection, streptococcal throat infection, and Campylobacter jejuni are a few examples which can produce acute urticaria. Bacterial infections of the dental, throat, respiratory, urinary tracts and gall bladder rarely may be responsible for chronic urticaria. The urticarial lesions do not alter with treatment of underlying chronic infection.' Tebbi et al stressed the role of Helicobacter pylori in chronic urticaria.
Gastro-intestinal parasites were thought to be commonly responsible to cause urticaria. Ankylostoma, strongyloides, echinococcus and Toxacara canis are few examples. However this has become a rare cause as shown in recent Indian studies. Ascariasis produces urticaria through allergic mechanism while the other intestinal parasites produce the lesions through non allergic mechanism.
Various substances like grass, pollens, mould, spores, animal danders, and house dust may cause acute or chronic urticaria.
Food and food additives can cause both acute and chronic urticaria. Fish, milk, peanut, beans, potato, rice, carrot and drumstick are responsible for acute urticaria mediated through IgE dependant mechanism. The reaction can occur in a few minutes to many hours. Though a variety of foods are attributed to produce urticaria a double blind challenge reproduced the lesions only in some. Among the alcoholic beverages red wine may cause urticaria in some.
6. Insect bites
Papular urticaria occurs through the bite of insects most commonly mosquitoes and bed bugs. These are chronic and recurrent. On the contrary bee or wasp stings (hymenoptera) may produce severe acute urticaria or anaphylaxis through allergic mechanism which may be life threatening.
Parenteral injection of therapeutic sera produces serum sickness through complement mediated Type III reactions.
Dental prosthesis and metal pins used in orthopaedics practice may rarely cause urticaria.
9. Systemic disease
Systemic lupus erythematous produces urticarial vasculitis more commonly than chronic urticaria. Increased incidence of patients with thyroid auto antibodies have been reported and treatment with thyroxine can result in clinical remission in some.,
Psychological stress may favour urticaria whereas depression decreases the threshold for pruritus. In young children, cows milk can produce allergy.
| Differential diagnoses|| |
More often persistent erythemas and purpuras have to be differentiated from urticaria. These lesions last longer than 24 hours whereas urticarial weals resolve by that time. Erythema multiforme and early vesico bullous eruptions have also to be distinguished from urticaria.
| Prognosis|| |
In a follow up study by Champion at London in 554 patients 50% still had active disease after 6 months. Of these patients 40% continued to have intermittent symptoms 10 years later. The prognosis worsened in patients with angio-oedema.
| Investigations|| |
Routine hematological investigations are to be carried out in all patients. Erythrocyte sedimentation rate (ESR) if high may reflect on occult infection. Repeated microscopic examination of the stools may reveal an unusual intestinal parasite. Other investigations are done according to symptomatology. If history does not reveal a cause investigations rarely provide an answer either in acute or chronic urticaria. If weals persist and are painful, with the presence of systemic symptoms, a skin biopsy may be done to rule out urticarial vasculitis. Screening tests for thyroid functions may reveal an abnormality in 7% of patients with chronic urticaria. Extensive biochemical tests, total IgE levels and RAST are not indicated routinely. Intracutaneous or epicutaneous tests are less helpful.
| Urticarial vasculitis|| |
In urticarial vasculitis the clinical lesions resemble urticaira and the histological features resemble vasculitis. The histopathology reveals a typical necrotizing vasculitis of the small venules with deposition of immunoglobulin and complement. In patients with low serum complement (hypo complementemic vasculitis) neutrophils predominate whereas in the other group lymphocytic infiltrate is more typical. The lesion demonstrates histological changes ranging from a sparse inflammatory infiltrate to dense infiltrate and finally vasculitis.
The cutaneous lesions of urticarial vasculitis resemble chronic idiopathic urticaria but feels firmer and lasts for more than 24 hours. These lesions leave an ecchymotic area due to extravasation of red blood cells on clearing. Systemic symptoms are common. More than 50% of cases have arthralgia. In another 20% gastro intestinal symptoms like nausea and vomiting may be associated. Angio-oedema may be present in 40% of cases. Urticarial vasculitis is a Type III hypersensitive reaction suggested by the presence of circulatory immune complexes and deposition of immunoglobulin and complement in the vessel walls. Viral infections like hepatitis B and C, Epstein-Barr virus and Borrelis burgodoeferi, serum sickness, collagen vascular disease, hypergamma globulinemia, drugs like cimetidine, diltiazem and hematological diseases are the causes of urticarial vasculitis. However no definite etiology can be found in majority of the cases. Laboratory abnormalities include raised ESR and reduced complement levels. Auto antiboides may be present and there may be evidence of renal damage. The disease has a benign course lasting for 3 years.
| Papular urticaria|| |
This results from hypersensitivity to bites from certain insects such as mosquitoes, gnats, fleas, mites and beg bugs. It is common in childhood. It is characterized by symmetrically distributed pruritic papules and papulovesicles. Pruritus may give rise to secondary pyoderma. Skin lesions occur in crops. Histopathology shows perivascular and periadnexal eosinophilic infiltrate. Type I hypersensitivity plays a role in the pathogenesis but the antigen remains undetermined.
| Physical urticarias|| |
In this type of urticaria the physical stimulus induces a reproducible wealing. Physical urticarias amount to 19% of patients with urticarias. Dermographism and cholinergic urticarias are the common types of physical urticarias. Physical urticarias can give rise to angio-oedema if the stiumulus is sufficiently great or if the patient is sensitive.
| Dermographism|| |
This is also called as factitious urticaria which involves the weal flare phenomenon of triple response of Lewis. This is elicited by firm stroking of the skin at a pressure of less than 36 g/mm2 which induces erythema due to capillary vasodilatation followed by oedema and a surrounding flare. If this physiological response is exaggerated, persists and the patient has itching then it is called as 'symptomatic dermographism'. In some patients stroking the skin is followed by only itching and not wealing. The symptoms are milder. This is called as 'simple dermographism'. Dermographism is idiopathic in nature. There is no correlation between food allergy and dermographism. Rarely penicillin reaction may cause this. The incidence of dermographism is not increased in patients with chronic idiopathic urticaria. Cholinergic urticaria may be associated with 'cholinergic dermographism'. In 'red dermographism' repeated rubbing is necessary to produce weals. In 'delayed dermographism' the immediate response will fade away which may be followed by a late response which persists for more than 48 hours. 'White dermographism' is due to capillary vasoconstriction which occurs in atopics. Pressure from a metallic object on the skin may give rise to discoloration which is termed as 'black dermographism'.
| Delayed pressure urticaria|| |
In this type, sustained pressure applied to the skin produces wealing within half-an-hour to 10 hours. The lesion may last from few hours to few days. This is usually associated with chronic ordinary urticaria. The mechanism of this condition is not known and no allergen has been identified. The cellular changes point to an up-regulation of vascular adhesion molecules like E-selectin. The process may be amplified by IL-6 and fibrin present in lesions. Weals occur under areas of pressure. Lesions are itchy or tender and painful when it may mimic urticarial vasculitis. The lesions may be reproduced by applying 7kg weights for 15 minutes over the shoulder. Delayed pressure urticaria may spontaneously resolve after many years.
| Cholinergic urticaria|| |
This is a distinctive type of urticaria where small weals appear associated with itching in response to exercise and sweating. Acetylcholine can release histamine which is responsible for sweating. The release of acetylcholine could be due to the stimulation of cholinergic post- ganglionic sympathetic nerve fibers to the sweat glands. Adachi postulated an allergy to sweat recently. The skin lesions arise within minutes after exercise, emotions or taking hot spicy foods. The lesions last for 1-2 hours. The urticaria may be associated with systemic symptoms like flushing and fainting. The weals may be reproduced after excercise in a hot environment Intradermal injection of methacholine produces sweating and weal formation but is not a reliable test.
| Cold urticaria|| |
In this type, cold in any form like cold winds, cold temperature, cold liquids etc., precipitate urticaria. Idiopathic cold urticaria is the most common type. On exposure to cold itching and wealing of the skin occur within minutes and lasts upto 1 hour. The diagnosis may be confirmed by keeping an ice cube on the forearm for 10 minutes and reproducing the weal response. Familial cold urticaria is inherited as an autosomal dominant trait. Cold urticaria occurs in 3% of people with cryoglobulenemia. Dermographism and cholinergic urticaria may be associated with idiopathic cold urticaria. The average duration of this condition was 6 years in one series. The antigen responsible to produce cold urticaria may be a protein produced normally by cold exposure. Histamine is an important mediator although PGD2 may also be responsible.
| Solar urticaria|| |
This is a rare disorder in which the weals are produced by various spectrum of sunlight. It may occur as a primary or sometimes secondary to topical tar preparations or oral agents like chlorpromazine. The skin lesions are confined to the exposed areas. There is a sharp demarcation at the margins of clothing. Lesions slowly disappear within a few hours. The skin lesions may be reproduced by exposure to artificial light sources. Solar urticaria occurs as an allergic Type I hypersensitivity response to cutaneous or circulating photo-induced antigen. Protective clothing and avoidance of sunlight seem to be beneficial to these patients. Secondary solar urticaria improves if triggering factors are avoided.
| Aquagenic urticaria|| |
This is caused by contact with water which carries an epidermal antigen to the senstitized mast cells. Contact urticaria occurs due to direct contact allergens like foods, food additives, drugs, animal dander, caterpillar, grass pollen, algae etc. Hair dressers may develop contact urticaria to ammonium persulfate.
| Angio-oedema|| |
This is a variant of urticaria where there is involvement of the subcutaneous tissue. The skin lesions may appear on the eyelids, lips, genitalia, tongue and pharynx. Sudden onset appears to be characteristic. The skin lesions last for few hours to few days. Angio-oedema may present as an emergency in dermatology and needs to be treated aggressively. Heriditary angio-oedema is a rare disorder transmitted as an autosomal dominant trait on chromosome. It starts in childhood as recurrent swellings on the skin and mucus membrane and persists throughout life. The skin lesions are non itchy. The lesions may precede a trauma or appear spontaneously. The condition occurs due to deficiency of C1 esterase inhibitor. The cause of death has been attributed to respiratory obstruction. Angiotensin converting enzyme inhibitors (ACEI) can also produce angio-oedema. Acquired C1 esterase inhibitor deficiency may occur rarely in B-cell lymphoma or systemic lupus erythematosus. Muckle and Wells, in 1961 described the combination of urticaria, deafness and amyloidosis which is named after them. This syndrome is inherited as autosomal dominant.
| Management|| |
Understanding the various possible causes is the first step in assessing urticaria. Allergic and druginduced urticaria respond to removal of cause. The weal is due to localized increase in capillary and venular permeability caused predominantly by histamine but other mediators are also involved. The flare is due to stimulation of axon reflex mediated by neuro peptides. Pruritus results from activation of free nerve endings in the skin by histamine and other mediators. Hence histamine is the main mediator of urticaria., Traditional classic antihistamines exhibit sedation, anti cholnergic properties and paradoxical excitation in children as side effects. An ideal antihistamine should have a quick onset of action and less side effects besides convenient dosage schedule. The new generation antihistamines fulfill these criteria and are the main stay of treatment especially in chronic idiopathic urticaria.,
Terfenadine is as effective as chlorpheniramine and hydroxyzine but less sedative. Macrolide antibiotics, antifungals and cyclosporin are avoided with terfenadine as these drugs might complete with it for metabolism. Cardiac arrhythmias may result if given in excess dosage i.e. more than 120 mg/day for an adult.
Astemizole is very useful in chronic idiopathic urticaria and also in angio-oedema; and dermographism. The dose is 10 mg/day. A dose of 20 mg/ day may cause ventricular arrhythmias.
Loratadine is intermediate between fast acting terfenadine and slower astemizole but less effective than cetirizine. The dose is 10 mg/day. Freidman reviewed 2500 patients on loratadine and found that the side effects are very minimal.
Cetirizine is compared more favourably with other non sedating anti-histamines. Dose of 10 mg/day had a more rapid and long lasting effect when compared to terfenadine or loratadine. In European studies, this drug showed only a slight increase in the incidence of sedation over a placebo. However sedation is less than that caused by classical antihistamines.
Fexofenadine has been used in the treatment of chronic idiopathic urticaria at a dose of 180 mg per day. Notably Q-T interval prolongation occasionally seen with the parent compound, terfenadine, does not occur with fexofenadine.,
Antihistamines cross the placenta but are not teratogenic. They are better avoided in pregnancy and especially in the first trimester. Terfenadine is relatively safer in pregnancy.
The ideal drug for chronic urticaria would need to have a broad spectrum of activities antagonizing not only histamine but also a range of other mediators such as neuropeptides, and possibly PAF and IL-I as well. Combination of H1 and H2 antihistamine has a limited role in refractory urticaria and may provide additional benefit in less than 50% of these patients. Cimetidine at a dose of 800 mg/ day in divided doses cleared the lesions in few patients only. Satisfactory orally effective mast cell stabilizing drugs are not available. The poorly absorbed sodium chromoglycate has been reported to be beneficial in an uncontrolled trial of food additive - aggravated urticaria. Drugs that have combined properties of H1 antihistamine and a mast cell stabilizer, such as ketotifen and oxatomide, are no more effective than antihistamines. On the contrary good therapeutic results have been obtained by Pinol. When the conventional H1 and H2 antihistamine failed, other drugs like nifidipine is used as an adjunct to antihistamines. Similarly in a limited number of patients, low-dose cyclosporin - A, treated was found to be effective. In resistant cases a brief course of systemic corticosteroid therapy may be necessary but the extended use of systemic corticosteroids should be avoided because of significant adverse effects., As urticaria patients have significant psychological problems it is suggested that adjunctive treatment of urticaria should focus primarily on stress management training aimed at relieving anxiety and group therapy which focuses on an exploration of interpersonal issues. Doxepin hydrochloride, a tricyclic antidepressant significantly suppressed histamine and codeine induced cutaneous weal response. Non specific immunotherapy such as plasmapheresis and intravenous immunoglobulin are effective in some., In an open trial topical steroids also have been found to be effective. Adrenalin is used in the emergency treatment of nonhereditary angioedema involving larynx. It can be injected intramuscularly, subcutaneously or inhaled depending upon the severity of the reaction. UVB or PUVA therapy may improve dermographism. Cold urticaria can be managed by repeated exposure to cold and inducing tolerance apart from H1 antagonists. Solar urticaria may be minimized by wearing appropriate clothing, avoidance of sunlight, or applying broad spectrum sun screens. Plasmapheresis is also useful in some.
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