Urticaria & Angioedema Management Sanjay Ghosh, Saurav Kundu
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UrticariaChapter 1

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Definition
  • Urticaria is characterized by the rapid appearance of wheals with or without angioedema.
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Figure 1.1: Typical wheals
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Figure 1.2: A typical wheal on elbow
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Figure 1.3: A typical angioedema on face
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Figure 1.4: A typical angioedema on back
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Figure 1.5: Urticaria and angioedema in a child
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Figure 1.6: Angioedema on left side of face
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Figure 1.7: Angioedema on side of chest
Comparison between wheals and angioedema
Wheals
Angioedema
Superficial dermis
Deep dermis/subcutis/mucosa
Last for several hours
Last for several days
Hand and feet
Head region, hand and feet
 
History
  • Clinical descriptions of urticaria have been found in the writings of Hippocrates in the 4th century BC to Heberden and Willan at the end of the 18th century AD.
  • The pathophysiological era is dawned by the discovery of mast cell (mastzellen) by Paul Erlich in 1877.6
  • Mast cell as a source of histamine was identified by Riley and West.
  • Histamine was discovered by Dale in 1906 from extracts of ergot and described all important actions of histamine.
  • Lewis first outlined the potency of histamine as a mediator of wealing in human skin.
  • The characterization of reaginic immunoglobulin E (IgE) by Ishizaka enabled the understanding of autoallergic urticaria but the pathogenesis of chronic idiopathic urticaria remained obscure.
  • The autologus serum skin test by Grattan in 1986 first demonstrated that the cause of chronic urticaria was endogenous. However, the factors such as dysregulation of intracellular signal transducer in mast cell and basophils is also important.
 
Epidemiology
  • Around 15–20% of people have urticaria at least once during their lifetime.
  • There is no age bar for urticaria or angioedema although urticaria is mostly seen after adolescence.
  • The highest incidence of urticaria is seen in young adults.
  • Exact epidemiology of chronic urticaria in India is not known. World wide it occurs in 0.1–3% of the population.
  • Women are twice commonly affected compared to men.
 
Etiopathogenesis
  • Urticaria is a disease with varied clinical presentations and etiologies.
  • The clinical patterns and the triggers guide the physician to investigate and manage the individual appropriately.7
  • Most types of urticaria are due to promiscuous activation of mast cells, although basophils are also involved.
  • Histologically, wheals are characterized by edema of upper and mid-dermis with diltation of post-capillary venules whereas in angioedema mainly lower dermis and subcutis is affected. There is a mixed cellular infiltrate of both acute and chronic inflammatory cells. Different cells and the mediator pathways, which play a pivotal role in urticaria have been discussed below.
 
Histaminergic
  • Mast cell is the key effector cells of acute and chronic urticaria. Studies using conventional histochemical stains show mast cell predominance in urticarial leisons.
  • Among the mediators released during mast cells degranulation histamine and leukotrienes, LTC4, D4, E4 appear to be most important.
  • Roles of heparin and tryptase remain unclear.
  • Histamine is mainly responsible for the wheals and itch whereas flare is mediated by substance P.
  • LTC4, D4, E4 plays an important role in non-selective NSAIDs induced urticaria which result in diversion of arachidonic acid metabolism from PGE2 to leukotrienes. The reduced PGE2 level has a permissive effect on immunological mast cell degranulation. That is not seen with selective COX2 inhibitors (Fig. 1.8).
  • Other cells which play an important role in the late phase of urticaria has been shown in Table 1.1.
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Figure 1.8: Inhibition of cyclo-oxygenase (COX) pathway. NSAIDs blocks COX pathway leading to diversion of arachidonic acid metabolism from prostaglandins to leukotrienes. PGE2 normally inhibits immunological mast cell degranulation and leukrotriene production. Low PGE2 formation by NSAIDs encourages immunological mast cell degranulations. Selective COX-2 inhibitor does not block this pathway
Table 1.1   Role of other cells in the late phase of urticaria
Cells
Released mediators
1. Eosinophils
Major basic protein, eosinophil cationic protein
2. Basophil
Histamine and leukotrienes
3. PMNs
No specific role although found in increased number in the lesions
4. T helper lymphocyte
IL3,TNF-α
9
 
Non-Histaminergic
  • Stimulation of Hageman factor XII activates the intrinsic coagulation system, generation of plasmin and production of bradykinin.
  • There is a complex interconnecting system of feedback loops involving the C1 esterase inhibitor which has a inhibitory influence on the complement, kallikrein, coagulation and fibrinolytic system.
  • The bradykinin which is generated by the action of kallikrein on kininogen appear to be the primary mediators of hereditary angioedema. Whereas the angiotensin-converting enzymes inhibitors (ACEIs) result in accumulation of kinin and lead to angioedema without wheals.
 
Classification
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Figure 1.9: Dermographism on the back
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Quality of Life
  • Urticaria is a disease which has severe social, physical and emotional impact on individual.
  • It has a detrimental effect on both objective functioning and subjective wellbeing.
  • The tool most widely used to assess the QoL is chronic urticaria quality of life questionnaire (CU-Q2oL).
  • Questionnaire is also developed for angioedema patients.
  • Impairment of QoL due to chronic urticaria has been shown to be equal in magnitude to that experienced by patients with triple coronary artery disease awaiting bypass surgery.
  • Chronic urticaria is a source of significant economic cost due to absenteeism and cost of medications.
  • The impact of chronic urticaria on patient's quality of life (QoL) is similar or greater than that of other chronic skin conditions that cause severe impairment, such as psoriasis and atopic dermatitis.
 
Clinical Features
 
Acute Urticaria (Figs 1.10 to 1.12)
  • Spontaneous appearance of wheal and angioedema which last less than 6 week.
  • Life time prevalence estimated to be around 15–20%.
  • The prevalence of acute urticaria is higher in people with atopic disease, such as hay fever, allergic asthma and atopic dermatitis.
  • It is characterized by discrete scattered wheals size usually larger than 1 cm.
  • Angioedema associated in 5% of patients.
  • Depending on the body area affected severity of the disease can be categorized as shown in Table 1.2.
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Figure 1.10: Acute urticaria on the back
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Figure 1.11: Acute urticaria in a child (Post-viral)
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Figure 1.12: Acute urticaria in an adult male (drug-induced)
Table 1.2   Types of acute urticaria
Severity of urticaria
% area affected
Mild
<10%
Moderate
10–50%
Severe
>50% of systemic affection
 
Systemic Symptoms Associated with Acute Urticaria
  • Shortness of breath
  • Dizziness
  • Headache
  • Nausea
  • Diarrhea.
 
Triggering Factors of Acute Urticaria
  • Acute viral upper respiratory tract infection (most common in children).
  • Foods and food additives (most common in children), most frequent offender being cows milk.14
  • Drugs-mainly penicillin and NSAIDs (IgE mediated). Among the NSAIDs aspirin has the highest propensity to trigger acute urticaria.
 
Diagnosis
  • Identification of any trigger such as prior infection or drug intake.
  • Prick test.
  • Oral provocation tests.
    (In case of NSAIDs these tests are not helpful owing to the pseudoallergenic nature of these drug reactions).
 
Prognosis
  • Acute urticaria is mostly self-limited in more than 99% patients.
  • Progression to chronic urticaria is rare.
 
Chronic Urticaria (Fig. 1.13)
  • Chronic urticaria is characterized by rapid and non-induced appearance of wheal with or without angioedema, which are usually short-lived.
  • Wheals usually last for several hours but angioedema last for several days.
  • Disease is episodic in nature, with disease period varying from few days to months.
  • Peak age is 20–60 years, female commonly affected than male.
  • Associated itching or burning.
  • Mast cells activation is the primary event triggering the disease process.
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Figure 1.13: Chronic spontaneous urticaria in a lady
 
Clinical Features
  • About 50% of CU patients have wheals and angioedema together.
  • About 40% patients shows only wheal and 10% shows only angioedema.
  • Wheals most commonly develop in the evening hours.
  • Symptoms usually episodic with symptoms-free period ranging from several days to several months.
  • Mean duration of disease is 4 years.
  • In 50% cases, there is spontaneous remission within 10 years.
16
 
Triggering Factors of Chronic Spontaneous Urticaria
  • Autoreactivity
    • About 40% of chronic urticaria patients have mast cell activating factors
    • In only about 20% cases, these factors are anti-IgE or anti-IgE receptor antibody (Fc€RI)
    • CU due to autoreactivity is readily detected by auto-logous serum skin test.
  • Infection
    • Bacterial infection
      • Helicobacter pylori gastritis
      • Upper respiratory tract infection by Group A Streptococci
    • Viral infections
      • Hepatitis A and B
    • Parasitic infection
      • Toxocara canis
      • Giardia lamblia
      • Blastocystis hominis
    • Fungal
      • Intestinal candidiasis
        (Toll like receptors present on mast cells functioning as sensors for bacteria, virus and parasites are likely to play an important role in mediating urticarial lesions.)
  • Food intolerance
    • Non-allergic dose dependant delayed hypersensitivity to food pseudoallergens, such as
      • Food colorants
      • Taste intensifiers
      • Preservatives
      • Naturally occurring substances (fruits, vegetables, and spices)17
        • Aromatic compounds
        • Biogenic amines
        • Salicylic acids
          (Diagnosed by oral challenge tests with pseudoallergens)
    • Chronic inflammatory process
      • Gastritis
      • Reflux esophagitis
      • Chronic cholecystitis
      • Autoimmune disease, such as systemic lupus erythematosus.
    • Non-specific triggers
      • Physical exertion
      • Stress.
 
Recognized Association of Chronic Urticaria
  • Angioedema: Occurs in 40–80% of patients, mainly affecting eyelids, lips and tongue.
  • Physical urticaria: Usually symptomatic dermographism or delayed-pressure urticarial occurs in about 50%.
  • Functional thyroid disease: Can be associated with both hyper- and hypothyroidism in about 20%. Hashimoto's disease is found in 15% patients.18
 
Autoimmune Urticaria
An autoimmune process is causative in some patients with chronic urticaria referred to as autoimmune urticaria.
  • About 25% to 50% of patients of chronic urticaria have complement activating IgG1 and IgG3 autoantibodies against high affinity IgE receptor (Fc€R1) or less commonly against IgE receptor.
  • These autoantibodies dimerize IgE receptors expressed on dermal mast cells leading to complement activation (C5a) and dermal mast cell activation. No hypocomplimentemia associated.
  • These autoantibodies have an association with HLA DRB1*04 and HLA DQB1*0302 (also associated with autoimmune disease).
  • Presence of autoantibodies commonly associated with antithyroid antibodies.
  • Basophils of patients with chronic urticaria are hyporesponsive to circulating anti-IgE antibody.
  • Cases of autoimmune urticaria are clinically and histologically indistinguishable from ordinary urticaria.19
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    Figure 1.14: Autoimmune urticaria in a lady
  • These cases tend to run a more aggressive and treatment resistant course.
  • Histologically, increased number of neutrophils and eosinophils, if any, is suggestive, but not confirmatory.
 
Symptomatic Dermographism
  • Most common form of dermographism where patients complains bouts of itching triggered by a frictional stimuli.20
  • Can be seen alone or in combination with chronic spontaneous urticaria.
  • Commonly encountered physical urticarial, which is frequently overlooked.
 
Triggering Factor
  • Movement of clothing or jewellery on the skin, straps of watches, belts or elastic tops of socks.
  • Even touching or rubbing eyes can elicit a response.
  • Even a power shower or towelling dry may cause whealing.
 
Clinical Features
  • Onset within minutes and patient complains of generalized itching and red wheals.
  • Wheals are polymorphic varying from linear or oblong shape to patchy papular erythema, which can all occur simultaneously.
  • Usually take the shape of stimulus applied.
  • Mucous membrane is not affected and angioedema is rare.
  • The duration is maximum up to 1 hour and disease intensifies in the evening.
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Figure 1.15: Symptomatic dermographism in a young adult
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Figure 1.16: Dermographism in an adult
22
 
Delayed Pressure Urticaria
  • There is a delayed response to persistent pressure on skin.
  • Suspected in patients who are unresponsive to antihistamines.
  • Concurrent with chronic spontaneous urticarial in 40% of cases.
  • A sustained pressure stimulus when applied to the skin produces a whealing response, which appears between 30 minute and 6 hour.
 
Clinical Features
  • Painful or itchy erythematous plaques and nodules appear mainly distributed in shoulder, waist, thigh.
  • Swelling of hands and feet can occur.
  • Lesions comprises of edematous erythematous plaques and nodules and are painful rather than itchy.
  • Lesions are deeper than lesions of ordinary urticaria and may persist for a period of 48 hours.
  • Associated rarely with arthralgia, malaise and rigors.23
  • DPU is a disease of varying severity combined with episodes of remissions and exacerbations over weeks and months.
  • May be concurrent with chronic spontaneous urticarial and dermographism.
  • Lifestyle modification such as wearing loose clothing, soft slightly loose shoes is equally important to pharmacological management (Figs 1.17 and 1.18).
 
Heat and Cold Urticaria
  • Cold urticaria is a commonly encountered subtype of physical urticaria with prevalence of 0.5% in general population with highest prevalence in young adults.
  • Disease is of variable severity and stimulation temperatures vary widely among individuals.
  • Sometimes generalized urticaria can be elicited even at room temperature.24
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    Figure 1.17: Delayed pressure urticaria in a lady at her waist line by petticoat's pressure
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    Figure 1.18: Delayed pressure urticaria along waist line in a male
  • Severe forms can sometimes be accompanied by hypotension and fainting.
  • Heat urticaria resembles cold urticaria but the eliciting stimulus is contact with objects having temperatures above normal skin temperature.25
 
Types of Cold Urticaria (based on cold stimulation test)
  • Positive cold stimulation test
  • Negative cold stimulation test.
 
Pathogenesis
  • Most important cell in pathogenesis of cold urticaria is mast cell which get activated on cooling below threshold liberating vasoactive mediators.
  • Neutrophils, eosinophils and platelets also suggested to play a role.
  • About 30–40% patients of cold urticarial have autoantibodies against IgE or against high affinity receptor for IgE.
  • Mediators are mainly histamine, prostaglandin D2 and platelet activating factor.
  • But the mechanism of heat urticaria is unclear.26
 
Clinical Features (Fig. 1.19)
  • Heat and Cold urticaria can be triggered by
    • Exposure to cold or warm environments
    • Ingestion of cold or warm food and beverages
    • Handling of cold or warm objects
    • Aquatic activities.
  • Major symptoms are immediate development of pruritic wheals and or angioedema which are typically non pseudopodic.
  • Wheals or angioedema may be localized or generalized.
  • Exposure of cold to upper aerodigestive tract may lead to swelling of lips, tongue, pharynx or larynx and even lead to syncope.
  • Severity depends on two factors:
    1. Area of skin involved
    2. Difference between temperature of stimulus and patients threshold.
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Figure 1.19: Cold urticaria in a child of 10 years
27
  • It may be dangerous when attacks occur during aquatic activities as it may lead to drowning.
 
Diagnosis
  • Cold stimulation test done by placing melting ice cube in thin polythene on volar aspect of forearm for 5 minutes and observing the wheal appearing after minutes of removal of stimulus (The ice should be melting to avoid skin damage at temperature <0°C and should be placed in a plastic bag to avoid confusion with aquagenic urticaria).
  • Temperature test is a new method to determine the patient's threshold temperature by exposure of the skin to the thermal elements with defined temperatures to assess the stimulation temperature and time.
    Temperature test using testing kits can be used to determine the critical temperature thresholds for cold contact urticaria and the more rare heat contact urticaria.
  • Differential leukocyte count
  • ESR and CRP
  • Autologous serum skin test to evaluate the autoimmunity
  • Antinuclear antibody
  • Infectious mononucleosis and syphilis serology
  • Total complement level
  • Cryoglobulin levels.
 
Prognosis
  • Prolonged course with mean disease duration exceeding 10 years.28
  • Apart from the pharmacological treatment tolerance induction plays an important role in desensitization.
 
Solar Urticaria
  • It is characterized by whealing response of skin which develop between 5–10 minute of exposure to visible light or UV light.
  • Itching or burning sensation commonly associated with wheals.
  • Lesions usually last for few hours and affect mainly covered body areas than the face and hands.
  • Usually occur in between 2nd and 4th decade and more prevalent in females.
  • It may be associated with systemic symptoms such as headache, nausea, wheezing, dyspnea, etc.
  • It occurs usually between spring and autumn.
 
Pathogenesis
  • Degranulation of mast cells releasing histamine among other mediators plays an important role in whealing response
  • Eosinophils and neutrophils also participate in pathogenesis
  • Wheals are caused by exposure to specific wavelength of light, called action spectra which include visible light, UVA and UVB.
  • Autologous photoallergens play an important role in the pathogenesis.29
  • Patients with action spectrum 400–500 nm have a photoallergen of molecular weight 25–45 Kd, while those with action spectrum 330–520 nm have photoallergen of molecular weight 300–1000 Kd.
  • Two types of photoallergens identified:
    • Patient specific photoallergen.
    • Nonspecific photoallergens, i.e. found universally in all persons.
  • Suspected photoallergens include:
    • Porphyrin-responsible for solar urticaria in patients of erythropoietic porphyria and porphyria cutanea tarda.
    • Drugs such as tetracycline, chlorpromazine, progesterone.
    • Chemicals such as coal tar, pitch.
 
Diagnosis
  • Provocation test using a solar simulator to apply UVA (up to 6 J/cm2) and UVB (up to 0.06 J/cm2) or a projector to apply visible light (to exclude other causes) to patches of skin on the buttocks. An urticarial response is usually visible within 10 minutes.
 
Cholinergic Urticaria (Fig. 1.20)
  • Cholinergic urticaria is characterized by small short lived wheals occurring after a rise in the core temperature.
  • Most frequently occurs in young adults with no sex predilection.
  • Peak prevalence seen in between 10 and 30 years of age.
 
Pathogenesis
  • Mast cell degranulation and histamine release has been implicated.30
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    Figure 1.20: Cholinergic urticaria
  • Role of acetylcholine released from local sympathetic nerve ending has been speculated.
  • Type 1 hypersensitivity reaction to sweat have been suggested but not substantiated.
 
Clinical Features
  • Triggers of cholinergic urticaria
    1. Activities which increase core body temperature such as:
      • Exercise to the point of sweating
      • Emotion
      • Eating hot and spicy food
      • Exposure to high ambient temperature
      • Hot shower
    2. Patients undergoing hemodialysis
  • Extremely itchy wheals which are characteristically small (2–3 mm) having a large surrounding flare.31
  • Multiple wheals may coalesce to form plaques.
  • Commonly found on upper trunk and proximal limbs.
 
Disease Associations of Cholinergic Urticaria
  • Chronic spontaneous urticaria.
  • Cold urticaria.
  • Dermographism.
 
Diagnosis
  • Lesions elicited by exercising the patient to the point of sweating
  • Passive warming by hot bath test can be done to reproduce the lesions where patient is almost immersed in a bath at 42°C for 15 minute
    • False negative results may be found in:
      • If the patient is in refractory period after an attack
      • Already on treatment, hence treatment should be withdrawn before testing.
    • Patients should be carefully monitored during testing as anaphylaxis can occur during testing.
  • Provocative test includes ergometric testing (use of an exercise machine or physical activity of any description to the point of sweating). If this test is positive it should be followed by bathing at 42°C for 15 minutes to increase body temperature by ≥1°C. A positive exercise test but negative hot bath test indicates exercise-induced urticaria.32
 
Differential Diagnosis
To be differentiated from other cutaneous disorder precipitated by rise in the core temperature:
  • Cholinergic pruritus
    • Short-lived itching occurs.
  • Exercise-induced anaphylaxis
    • Anaphylaxis is precipitated by exercise only, not by other causes of increase core temperature.
  • Persisting cholinergic erythema
    • Multiple monomorphic red itchy macules in a widespread distribution confirmed by observing the persistence of lesions upto 1–2 hours.
  • Cold induced cholinergic urticaria and Cholinergic dermographisim
    • Lesions can be reproduced by reduction of core temperature or by stroking the skin respectively.
  • Localized heat urticaria
    • Confirmed by the development of lesions at the site of contact of warm objects against the skin, without any need for rise in core body temperature.
  • Aquagenic urticaria
    • Triggered by exposure to water of any temperature for, e.g. taking a tepid bath with water at 37°C will trigger aquagenic urticaria but not cholinergic urticaria.
  • Dermographism after bath
    • Rubbing of skin during bath may trigger dermographism.
    • Can be confirmed by gentle scratching the skin (pressure less than 36 g/mm3).
    • To rule out atopic dermatitis as these patients complains of itching after bath.
33
 
Exercise induced Anaphylaxis (EIA)
  • It is a rare entity where only physical exertion can lead to anaphylaxis.
  • EIA is not induced by other passive causes of an increased core temperature not even by sweating. This distinguishes it from cholinergic urticaria.
  • In some cases ingestion of foods such as wheat, shell fish, apples, peaches or drugs, such as aspirin play a permissive role in the attack.
  • More common in atopics.
  • Sex ratio varies among different studies.
  • Mast cell degranulation play an important role during attack.
  • Cutaneous symptoms include:
    • Pruritus
    • Wheals (sometimes of cholinergic type)
    • Flushing
    • Angioedema.
  • Associated systemic features are:
    • Cough, dyspnea and wheezing
    • Intestinal colic, nausea, diarrhea
    • Headache, vertigo, tinnitus
      • Systemic symptoms may last from 30 minures to 4 hours, but headache can last up to 72 hours.
 
Diagnosis
  • History is sufficient most of the times.34
  • Lesions can be reproduced by exercising the patient but with proper monitoring with treatment of anaphylaxis available.
  • Prick tests or specific IgE measurement to individual food stuff when there is positive challenge.
 
Vibratory Urticaria
  • Subjects with vibratory angioedema experience pruritus and swelling with exposure of the skin to a vibratory stimulus.
  • This condition can be familial.
  • Vibratory angioedema can be confirmed by demonstrating an exaggerated response after exposure of the skin to a vortex mixer (1000 rpm) for 10 minutes on the forearm.
 
Contact Urticaria
  • It is defined as the wheals that appear following contact of exogenous substances with the skin (Figs 1.21 and 1.22).
  • This is of two types
    • Immunologic contact urticaria/allergic contact urticaria
    • Non-immunologic contact urticaria.
 
Immunologic Contact Urticaria
 
Immunological Contact Urticaria: Common Inducers
  • Animal products like hair, blood, gelatin etc. Amniotic fluid is a major problem in veterinarians.35
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    Figure 1.21: Contact urticaria in a lady from hair dye
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    Figure 1.22: Contact urticaria in a lady from fragrance
  • Plant products mainly latex can trigger allergic reaction in those using latex gloves. Those with latex allergy are also at an increased risk of developing allergic reactions to foods such as bananas and tomatoes
    • Use of low powder, low latex containing gloves has greatly reduced sensitization rates.
  • Food such as banana, tomatoes, onion, garlic, dairy product, fish etc.36
    • Protein contact dermatitis is a type of contact urticaria seen in food handlers who develop itching, erythema, wheals and dyshidrosiform changes.
    • Intake of offending foods may lead to perioral erythema, tingling, burning and swelling of lips, tongue, oral mucosa.
    • Diagnosed by positive skin prick tests and positive RAST.
  • Contact with medication like phenothiazine, pyrazolone, benzocaine.
  • Miscellaneous: Ammoniumpersulfate (used as bleaching agents by beauticians), epoxies and acrylic.
 
Non-Immunologic Contact Urticaria
Non-immunological Contact Urticaria: Common triggering factors:
  • Plants—Stinging nettle (contain toxin in their leaves)
  • Animal—caterpillers, jellyfish, mosquito, ants and fleas
    • Papularurticaria like lesions commonly seen.
    • Sometimes, lesions can be found at distant sites mimicking immunologic urticaria.
    • Scabies can present with urticaria due to sensitization to mite.
  • Direct histamine liberators
    • Spices for example, mustard, cinnamon
    • Fragnance for example, cinnamon aldehyde, balsam of Peru
    • Medications for example, menthol, camphor, benzocaine, alchohol, bacitracin, polymyxin
    • Preservatives for example, benzoic acid, sorbic acid, formaldehyde.37
 
Diagnosis
  • Repeat open application test (ROAT).
  • Open patch test (open patch test to be done instead of closed method by Fin chamber as closed one may induce more absorption of allergens that may lead to anaphylaxis).
  • Desensitization following controlled exposure, such as repeated wearing of latex gloves.
  • Prick test (should be done with prior withdrawal of antihistamines for 72 hours. The test should not be performed during acute disesase activity)
  • In-use challenge prick testing with potential triggers (e.g. fruits, latex gloves etc.) applied directly to the skin (any provocation test should be conducted with caution and facilities for emergency treatment during provocation should be available).
  • Radioallergosorbent test (RAST).
 
Urticarial Vasculitis (Figs 1.23 to 1.25)
  • Clinicopathological entity characterized by:
    • Urticarial papules and plaques usually lasting longer than 24 hours duration
    • Resolving with faint purpura or residual hyperpigmentation
    • Histologically characterized by presence of leukocytoclastic vasculitis in capillaries and postcapillary venules, with or without fibrinoid deposits.
  • Prevalence is 5% in general population with female predominance.
  • Peak incidence in 4th decade of life.
  • Deposition of immune complexes appears to trigger the inflammatory cascade.38
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    Figure 1.23: Urticarial vasculitis in a man: lesion persisting more the 24 hours
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    Figure 1.24: Urticarial vasculitis in a man: post-urticarial pigmentation
  • Triggers of urticarial vasculitis include:
    • Autoimmune connective tissue disease
      • Sjogrens’ syndrome
      • Systemic lupus
      • Rheumatoid arthritis.39
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        Figure 1.25: Urticarial vasculitis in another man with post-urticarial pigmentation
    • Infections
      • Hepatitis B and C
    • Paraproteinemias
    • Inflammatory bowel disease
    • Serum sickness like drug reaction
    • Idiopathic.
 
Types
  • Normocomplimentemic urticarial vasculitis
  • Hypocomplimentemic urticarial vasculitis
  • Hypocomplimentemic urticarial vasculitic syndrome (HUVS) when associated with constellation of systemic features
(IgG autoantibodies to the collagen like region of C1q found commonly in patients of HUVS are also detectable in fair number of patients of SLE and even more in SLE with glomerulonephritis.40
Hence these patients are to be properly followed up).
 
Clinical Features
  • Urticarial papules and plaque which are burning and tender rather than pruritic.
  • Angioedema seen in 42% cases
  • Giant lesions less common
  • Lesions common in areas subject to pressure
  • Lesions resolve with residual purpura or hyperpigmentation
  • Rarely, associated with livedo reticularis, erythema multiforme or bullae.
 
Systemic features
  • Musculoskeletal involvement
    • Transient and migratory peripheral arthralgia
    • Jacoud's arthropathy (patients at increased risk of valvular heart disease).
  • Renal involvement
    • Proteinuria and microscopic hematuria
    • Mesangial proliferative glomerulonephritis
    • Interstitial nephritis.
  • Pulmonary involvement
    • Dyspnea and cough
    • Hemoptysis
    • Pleuritis
    • Emphysema and COPD.
  • Gastrointestinal involvement
    • Abdominal pain
    • Nausea and vomiting
    • Diarrhea.
  • Ophthalmological involvement
    • Conjunctivitis41
    • Episcleritis
    • Uveitis and iritis.
  • Miscellaneous
    • Pericarditis and pericardial effusion
    • Valvular heart disease
    • Pseudo tumor cerebri
    • Peripheral neuropathy
    • Raynauds phenomenon.
 
Investigations
  • Skin biopsy
    • Shows leukocytoclastic vasculitis with fibrinoid necrosis of post-capillary venules
  • Direct immunofluorescence
    • Shows presence of immunoglobulins, compliments and fibrin within vessel walls
  • Complete hemogram
  • Shows elevation of ESR and C reactive protein
  • Viral screen
    • For hepatitis A and B
  • Plasma protein electrophoresis
  • ANF, anti-Ro, Rheumatoid factor
  • Chest X-ray, ECG and echocardiogram
  • Compliment screen
  • Measurement of serum C1q, C3, C4 and CH50.42
 
Differential Diagnosis
  • Papular urticaria: Commonly seen in children on exposed area as tiny urticarial lesions with central puncta induced by insect bites. Atopics are more prone (Fig. 1.26).
  • Erythema multiforme: May resemble urticaria usually showing targetoid lesions usually on acral areas (Fig. 1.27).
  • Polymorphous light eruption: Differs from solar urticaria in that the onset usually occurs minutes to hours after sunlight exposure and the eruption, which occurs in different forms, including papules, papulovesicles, and plaques, lasts for days compared with solar urticaria, which is short-lived between exposures.
  • Polymorphic eruption of pregnancy (Pruritic urticarial papules and plaques of pregnancy or PUPPP): Urticaria-like dermatoses can occur at various stages of pregnancy.
  • Autoimmune progesterone-induced dermatitis: Women presenting with cyclical urticaria related to menstruation.
  • Recall urticaria: Urticaria is observed at the site of a previous sting or injection after re-exposure to the same inciting factor.
  • Hypereosinophilic syndrome: Peripheral total eosinophil count exceeds 1500/mL in the absence of other causes for peripheral eosinophilia.
  • Cutaneous mast cell disorders: Present with urticaria-like lesions include urticaria pigmentosa, mastocytomas, and telangiectasia macularis eruptiva perstans. Apart from urticaria and angioedema patients usually have additional systemic symptoms.
  • Bullous pemphigoid: This can present initially with urticaria-like papules or small plaques that might be excoriated by the patient before noticeable blistering occurs.43
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    Figure 1.26: Papular urticaria in a child
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    Figure 1.27: Erythema multiforme on back
  • Cheilitis granulomatosa (Melkerrson-Rosenthal syndrome): Persistent swelling of the lips without evidence of eczematous dermatitis.44
  • Thyroid opthalmopathy: Swelling of the medial portion of the upper eyes, a sign of thyroid ophthalmopathy, may be misinterpreted as angioedema.
  • Gleich syndrome: Episodic attacks of angioedema and weight gain alongwith eosinophilia.
  • Schnitzler syndrome: Caused by an IgM or more rarely IgG monoclonal gammopathy present with nonpruritic urticaria (that spares the face), bone pain, and intermittent fever.
 
Diagnosis of Acute Urticaria
  • Acute urticaria and angioedema more frequently associated with identifiable conditions.
  • Acute urticaria and angioedema will usually resolve spontaneously, laboratory evaluation for chronic illness not required unless supported by the clinical history or physical examination.
  • Empiric elimination diets (not guided by history and testing) are not recommended.
  • Some cases of acute urticaria are caused by viral or other infectious illnesses. However, extensive evaluation for specific viral pathogens or antiviral therapy is not indicated unless suggested by the clinical history.
  • Skin testing or immunoassays to identify specific triggers for acute urticaria and angioedema can be helpful if an allergic cause is suggested by history.
    (Skin testing is to be done after the resolution of acute urticaria and after withdrawal of antihistamines or by serologic testing in the presence of significant dermatographism).45
 
Diagnosis of Chronic Urticaria
  • Because of the heterogeneity of the disease initial evaluation should start with history and routine physical examination.
  • Specific laboratory test and provocation test should be performed if there are suggestive features in history.
  • Invasive and costly investigations are to be strongly discouraged.
  • Infectious cause should be considered in urticaria associated with ear, nose and throat infections, dental infections and H. pylori infections.
  • Anisakis simplex, a sea fish nematode is frequently associated with urticarial in population who consume uncooked sea fish.
  • Other infections associated with urticaria are H. pylori, Streptococcus spp, Staphylococcus spp, Giardia, hepatitis, etc.
  • Ruling out malignancies is warranted only if patient's history is suggestive.
 
 
 
Routine questionnaire for evaluating a case of urticaria include:
  1. Time of onset of disease.
  2. Frequency/duration of and provoking factors for wheals.
  3. Diurnal variation.
  4. Occurrence in relation to weekends, holidays, and foreign travel.
  5. Shape, size, and distribution of wheals.
  6. Associated angioedema.
  7. Associated subjective symptoms of lesions, for example, itch, pain, etc.46
  8. Family and personal history regarding urticaria, atopy.
  9. Previous or current allergies, infections, internal diseases or other possible causes.
  10. Psychosomatic and psychiatric diseases.
  11. Surgical implantations and events during surgery, for example after local anesthesia.
  12. Gastric/intestinal problems.
  13. Induction by physical agents or exercise.
  14. Use of drugs (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), injections, immunizations, hormones, laxatives, suppositories, ear and eye drops, and alternative remedies).
  15. Observed correlation to food.
  16. Relationship to the menstrual cycle.
  17. Smoking habits (especially use of perfumed tobacco products or cannabis).
  18. Type of work.
  19. Hobbies.
  20. Stress.
  21. Quality of life related to urticaria and emotional impact.
  22. Previous therapy and response to therapy.
  23. Previous diagnostic procedures/results.
 
Recommended Tests
Types
Subtypes
Routine diagnostic tests
Extended diagnostic tests(if history suggests)
Spontaneous urticaria
a. Acute spontaneous urticaria
None
None
b. Chronic spontaneous urticaria
Differential blood count, ESR, CRP, omission of suspected drugs
Tests for infectious disease, type 1 allergy, functional autoantibodies, thyroid hormones and autoantibodies, skin tests including physical tests, pseudoallergen free diet for 3 weeks, tryptase assay, ASST, lesional skin biopsy
Inducible urticaria
a. Cold urticaria
Cold provocation test
Differential blood count, ESR, CRP, cryoproteins and infectious disease detection
b. Delayed pressure urticaria
Pressure test (Fig. 1.28)
None
c. Heat urticaria
Heat provocation test
None
d. Solar urticaria
UV and visible light threshold test
Rule out other photodermatosis
e. Symptomatic dermographism
Test for dermographism
Differential count, ESR, CRP
f. Vibratory angioedema
Test with vortex
None
g. Aquagenic urticaria
Wet clothes at body temperature for 20 minutes
None
h. Cholinergic urticaria
Exercise and hot bath provocation
None
i. Contact urticaria
Prick test
None
Abbreviations: ESR, erythrocyte sedimentation rate; CRP, creactive protein
48
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Figure 1.28: Delayed pressure urticaria detecting Instrument
 
Clinical Approach in a Case of Lesions with Hives (Fig. 1.29)
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Figure 1.29: Algorithm in clinical approach in urticaria
49
 
Test for Autoantibodies
  • Currently, the only generally available test to screen for autoantibodies against either IgE or FcεR1 (the high affinity receptor) is the autologous serum skin test (ASST), a nonspecific screening test that evaluates the presence of serum histamine-releasing factors of any type, not just histamine-releasing autoantibodies.
  • In some countries, a basophil release test is available and may be used, which is a more refined laboratory test that evaluates the in-vitro histamine release from basophils.
(Autologous plasma skin test (APST): Higher positive response than ASST. This could be due to coagulation factors enhance vascular permeability or induce mast cell granulation).
ASST: Limitations
There are no definitive studies demonstrating that patients with refractory CU and a positive ASST result respond differently to certain medication regimens compared with those patients with CU with a negative ASST result.50
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Figure 1.30: Autologous serum skin test (immediately after)
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Figure 1.31: Autologous serum skin test (significantly positive after 30 minutes)
51
Current evidence does not support routine performance of ASSTs or autologous plasma skin tests (APST) in patients with CU.
 
Additional Blood Tests
  • Antinuclear antibody test can also be considered if the patient history suggests.
  • An elevated D-dimer level seen in some CSU patients, who responded to anticoagulation therapy.
  • Several groups have noted blood basopenia and that blood basophils exhibit suppressed IgE-receptor-mediated histamine release to anti-IgE. Blood basophils are detected in skin lesions and in nonlesional skin of CSU patients. CSU remission is associated with increases in blood basophil numbers and IgE receptor triggered histamine response.
 
Tests for Physical Urticaria
  • In physical urticaria, the routine diagnosis attempts to identify the subtype by the appropriate physical stimulation tests and to determine trigger thresholds. The latter is important as it allows for assessing disease severity and response to treatment.52
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    Figure 1.32: Delayed pressure urticaria: Detection by instrument with different weights (Modified-illing method)
  • For most types of physical urticaria, no validated tools for provocation testing exist.
 
Tests for Contact Urticaria
Contact urticaria should be demonstrated with cutaneous provocation tests, for example prick tests or open patch test (Fig. 1.33).
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Figure 1.33: Open patch test in a suspected case of contact urticaria
 
Diagnosis in Children
  • Urticaria can occur in all age groups.
  • Acute spontaneous urticaria is common in infants and young children, particularly in atopics.
  • Triggers include acute viral infection or (more frequently than in older children and adults) ingestion of food such as milk, egg, or peanut, to which the infant/child is sensitized.
  • In young patients, food-induced generalized acute urticaria often triggers anaphylaxis. They should be investigated for54 sensitization to foods suggested by the history, in order to confirm their specific food trigger and, through avoidance of this trigger, prevent subsequent episodes.
  • The underlying causes of CSU appear not to be different between children and adults. Thus diagnostic approach should be the same as in adults except possibly in infants.
55
 
Annexure
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Urticaria Diet
As it is well known that IgE dependent allergic reaction to food play a role in acute urticaria specially in children but not useful in chronic urticaria. Only conduction of pseudoallergen low diet can provide information on the presence of chronic urticaria due to food intolerance.
 
Patient should be Informed About
  • Importance of diet
  • At least 3 weeks adherence is necessary
  • Effect can be seen not until 10–14 days56
  • Intake of antihistamines and glucocorticoid must be reduced to minimum.
Foods allowed
Foods forbidden
Basic foods
Additive free bread, potatoes, rice, unprocessed cereals, flour
Cake, biscuit, potato chips
Fats
Butter, plant oils
Margarine, mayonnaise
Milk products
Fresh milk, natural yoghurt, cream without stabilisers
All others
Animal food
Fresh meat
Sea food, seasoned meat, eggs
Vegetables
Except those for bidden
Peas, mushroom, tomatoes, spinach, olives
Fruits
None
All including dried fruits
Herbs and spices
Salt and onion
All including garlic and herbs
Sweets and beverages
Sugar, honey, coffee, black tea
All sweets including chewing gum, beer, wine, spirits
 
Urticaria Activity Score (UAS)
  • An important aspect in classifying urticaria is disease activity.
  • Several scoring systems have been proposed but the most widely used scoring system is given below.
  • This has to be completed by the patients themselves.57
Score
Wheals
Pruritus
0
None
None
1
Mild (<20 wheals/24 hours)
Mild (not troublesome)
2
Moderate (21–50 wheals/24 hours)
Moderate (troublesome but not disturbing daily activities/sleep)
3
Intense (>50 wheals/24 hours or large confluent areas of wheals)
Intense (troublesome with daily activity and sleep disturbance)
[It is recommended that daily disease activity (0–6) is to be documented using the UAS over a period of 7 days, giving a total weekly Urticaria Activity Score (UAS7) of 0–42](Limitation of UAS: Not considering the size of urticaria)
 
Urticaria Control Test
The urticaria control test (UCT) is a validated instrument that can be used by the patients (with either CSU or CINDU) and physicians to assess disease control over the past 4 weeks. Four questions address the control of signs and symptoms of the disease, QoL impairment, efficacy of treatment, and overall disease control. The answer to each question is rated from 0 (very much) to 4 (not at all) and a total score is calculated, where the highest possible score of 16 indicates complete control. A score of ≤11 indicates poor disease control.