ASHRAF OKBAPROF. OF INTERNAL MEDICINE

AIN SHAMS UNIVERSITYCAIRO - EGYPT

DEFINITIONUrticaria is defined as a skin lesion consisting

of a wheal-and-flare reaction in which Iocalized intracutaneous edema (wheal) is surrounded by an area of redness (erythema) that is typically pruritic.

Individual hives can last from as briefly as 30 minutes to as long as 36 hours.

They can be as small as a millimeter or 6 to 8 inches in diameter (giant urticaria).

They blanch with pressure as the dilated blood vessels are compressed, which also accounts for the central pallor of the wheal.

Photo Images of Hives

Angioedemas (quinkes edema) affect deeper dermal ,subcutaneus and sub mucosal tissues.

They are usually painfull rather than itchy ,poorly defined and pale or normal in color

AngioedemaSwelling of lips, face, hands, feet, penis or scrotum

Facial swelling most prominent in periorbital area

May be accompanied by swelling of the tongue or pharynx

Larynx virtually never involved

Urticaria is classified to acute and chronic with a time devision between 6w and 3m.

When urticaria is present daily or almost daily for less than 6w it is acute.

CLINICAL CLASSIFICATION OF URTICARIA:1)ORDINARY URTICARIA (acute or chronic)2)physical and cholinergic3)Urticarial vasculitis4)Contact Urticaria5)angioedema

Up to 50%of patients previously diagnosed as chronic idopathic urticaria have an autoimune bases.

Acute ordinary urticaria may be due to allergy especially in atopics but not in chronic.

ASSOCIATIONS1)an association between chronic ordinary u and

autoimune thyroid disease2)there is a higher frequency of autoimune

diseases in patients with autoimune uThe older litrature suggest that chronic idiopathic

u may be associated with chhronic infection especially dental and candida of the bowel but now it occures rarely if at all

4)it has been proposed that H.PYLORI infection may play an indirect role in autoimune chronic u by molecular mimicry in genetically predisposed individuals

5)no association with malignancies was found in a large study

PREVALANCE:POINT PREVALANCE=0.1%Cumulative life time prevalance:0.05-23.6%

in general population but a range of 1-5% is more realistic

72% ordinary urticaria,20%physical and choloinergic,3.4%allergic(exept stings and injected drug),2.1% u.vasculitis,0.5% hereditary angioedema

GENETICSHereditary C1 Estrase defficiency

angioedemaMuckle Well SynFamilial cold urticaria

Highly significant linkage of HLA DR4 and HLA DQ8 in chronic ordinary urticaria.

Phathophysiology:

Urticaria is due to a local increase in permeability of capillaries of venules.

It is due to activation of cutaneus mast cells that contain many mediators predominantly histamin.

Pathophysiology of UrticariaNon-immunologic factors Immunologic factorsChemical histamine liberatorseg. Opiates, polymyxin antibiotics,thiamine

Physical agents, e.g.cold, heat, sunlight

genetic factors

modulating factors

Alternativecomplement

pathway action

Types II and IIIcomplement

activation

Type I IgEmediated

Anaphylatoxins (C3a, C5a)

URTICARIA

Cholinergicendogenoushormone

vasodilatingfactors

released mediators(particularly histamine)

Small bloodvessel

vasodilation

Clinical features of acute or chronic urticaria:Ithcing erythematous macules develop into

weals consisting of pale to pink edematous raised areas of skin often with a surrounding flare

It occurs any where (scalp and palms),in any number and size, any shape even bulla.

Wheals are often very itchy especially at night and resolve in a few hour without any residue.

Patient always rub not scratch so excoriation is absent.

Sometimes they bruise like in thigh. Wheals are more prominent at evening and

premens

In 50% of of urticaria: there may be angioedema.

Angioedema color is like skin ,most frequently on the face but any other area such as ear ,genitalia,hand and feet

It may last for several days,It is not always itchy and and may be painful

Urticaria may be proceeded with vomiting. It may be associated with: malaise loss of concentration feeling hot or cold headache vomiting abdominal pain diarrhoea arthralgia dizziness scyncope And even anaphylaxies

Urticaria in infancy:Cows milk allergy is the commonest etiology

of urticaria in infants under 6mIn infants there may be less itching and more

tendency to purpuric wheals,Bizzarly shaped wheals are more common

ACUTE URTICARIA:1) Idiopathic:

Most common type: >50% of cases

Sometimes is observed following URTI

2)ALLERGIC:Is due to interaction of allergen with IgE

bound to mast cellsmore common in atopics,Although it is unusual to find an allergic

cause, any drug ,food, inhalatant and foreign substance( implants, contactants and injection should be considered).

In an IgE mediated reaction there have been a previous exposure and the reaction will occur in minutes (less than 60 min)

Acute urticaria from drug is common and usually occur within 36h (it is unusual for a drug that is contiuously taken for months

Antibiotics especially penicilin and cephalosporin are common causes.

Risk factors: previous exposure reaction to a drug or chemically related

drug intermittant and multiple drug therapy , familial predisposition

Food: common within minutes but occasionally many hours after due to slow absorption or metabolism

Common food: Shrimp, Crab, Fish, Milk, Nuts, Beans, potatoes, Carrots, Spices, Rice, Banana, Apples, Oranges,

Bee sting allergy usually require multiple exposure but wasp sting allergy is unpredictable

Bee sting allergy usually require multiple exposure.

3- None-allergic causes: ASA, NSAIDS, Codein, Morphine, Radiocontast media, Vancomycin,Ciprofloxacin,Polymyxin, Anesthetics can cause histamine release.

Urticaria may follow: EBV,HBV,STREPTOCOCAL THROAT infection in child,Campylobacter

CHRONIC URTICARIA:1)Most cases are idiopathic2)drugs:mostly attributable to acute type: Aspirin can aggravate 20-30% of CH.U The relationship with penicilin is complex

and non-confirmed. ACEIs can cause angioedema or aggravate

urticaria

3)reaction to additives in less than10%(tartrazin)

4)Infection:CH.U is frequently flared by viral infections.

Incidence of bacterial infections such as sinusitis, UTI ,and others are variable,

But if present the treatment of the infection,does not improve urticaria.

H.Pylori, candida and intestinal parasites and toxocara are suggested but not confirmed.

5)Inhalants:Grass,pollens,mould spores,animal danders,house dust and even tobacco smoke are trigger of A or CH U.

If pollen allergy is proven desensitization may be succesfull.

6)Systemic dis:CVD(SLE and Sjogren),IgM macroglu.

Neither hypo nor hyperthyroidism is commonly associated with CHU,but increased incidence of thyroid autoAb and disturbance of throid function have been reported.

There is no evidence of association with malignancy.7)U may worsen premense but if it occures

predominantly ,it has been attributed to progestrone sensitivity.

8)Flare up of U do occur at times of psychological stress.Depression and anxiety were found more frequently in CHU.

DIAGNOSIS1)HX taking(onset,duration,and course)Weals lasting more than 24-48hr particularly

if painful or tender suggest the possibility of U.vasculitis or delayed pressure U.

Location, number and shapes of wheals are usually not helpful in most urticarias except for small uniform short lasting weals of cholinergic urticaria or linear lesions of dermatographism .

A family history of atopy ,autoimmunity or angioedema may be useful.

Physical factors should be evaluated.The presence of angioedema should be noted

especially in pharynx or larynx.Enquire about infection, drug, medication,

and food.

INVESTIGATION1)Acute U: In patients with life threatening

reactions to an allergen ,confirmation is possible with RAST (radioallergosorbent test).

For moderately severe acute reaction, skin prick test may be helpful but is potentially dangerous in a background of anaphylaxis .

2)Chronic U: history ,specially medications like NSAIDS.

If weals are painful and persist,with present of systemic symptoms ,U vasculitis should be considered.

Allergy to foods is rare,but a food diary may be helpful (time may vary from few second to 24 hr).

Only a CBCdiff ,ESR (SLE,UV,MG), screening test for thyroid autoAB(%14)may be worthwhile.

If angioedema is a major component, screening test for C1 sterase inhibitor deficiency ,should be performed by C4.It is reduced between attacks of angioedema.

If the weals persist for more than 48hr,and not respond to antihistamines a skin biopsy may be helpful.

NATURAL HISTORY There is no way of predicting the duration of

an attack but the severity is often greatest at the onset.

In general spontaneous improvement can occur in%50 within 6months.But %50 of those associated with angioedema can still be expected to have their condition 10 yrs later.

Physical UrticariasMay occur so intermittently as to appear

acute but typically are chronic entities – most idiopathic

Physical UrticariasSymptomatic DermatographismCholinergicCold Induced (Familial or Acquired)Vibratory (angioedema)Pressure – induced, Solar, Aquagenic

Physical urticaria

Symptomatic Dermatographism

Simply scratching the skin promotes linear hives within minutes

Delayed form describedTypically is short-lived in

duration (1/2 to 3 hours) and responds readily to antihistamines

Symptomatic Dermatographism

Cholinergic Urticaria

Cholinergic UrticariaGoal of raising body temperature (oral) by 0.7oC

Hot bath to 420C or having patient exerciseSmall pruritic papules result surrounded by

erythema (but without hypotension) resultPassive heat challenge may separate exercise-

induced anaphylaxis from cholinergic urticariaMethacholine skin test insensitive (positive result

in only 33% of patients with cholinergic urticaria)

Cholinergic urticaria

Cold-Induced Urticaria

Familial (autosomal dominant) vs acquired (usually infection associated)

Acquired form -positive ice-cube challenge

Usually responds to cyproheptadine

Cold-induced urticaria

Cold Stimulation Time Test (CSTT)Positive in acquired cold-induced urticariaIce cubes and water in a plastic bag applied

to patient’s forearm up to 10 minutesUrticaria results after warming of areaTiming of cold stimulus indirectly

proportional to severity (less time needed, worse symptoms upon exposure to cold)

Many patients with good history for cold-induced urticaria may have negative CSTT

Diagnosis of cold-induced urticaria

Delayed Pressure Urticaria

Delayed Pressure Angioedema~ 37% incidence of delayed pressure

urticaria in chronic urticaria

15 pound weight suspended by thick strap over the shoulder and worn for 15 minutesTypically, erythema with induration and

tenderness occurs at least 2 hours after the test

Vibratory angioedema

Lawlor F et al Br J Dermatol 1989; 120: 93-99

Vortex to induce angioedema in a patient with swelling of hands while driving car

MANAGEMENTExplanation and nonspecific measures like

minimizing overheating, stress and alcohol may be helpful.

ASA, NSAIDS,and opiates should be avoided (paracetamol is safe).

If allergy to food additives is present ,a modified diet may be helpful.

MANAGEMENTFirst line therapy:1)H1 ANTIHISTAMIN:H1 is the main

mediator of urticaria which cause weal, itch and flare.H1 antihist are rapidly absorbed reach to peak serum level in 2h

Traditional antihistamine have side effects like sedation and anticholinergic and paradoxical excitation in children.

HYDROXYZINE is the most potent of the classic antihist.

DOXEPIN is both TCA and ANTIHIST so can be used in anxious patients at night but not with MAO INH

Now the low sedative antihist are the treatment of choice.

They are as effective as hydroxyzine and no tolerance after continued use

Terfenadin,astemizole and mizolastin is better not be used because of Q-T prolangation

Loratadin and cetirizin are used with the dosage of 10 mg/d but cetirizin is sedative and should be used at night

NOTE THAT ANTIHIST CROSS THE PLACENTA BUT THERE IS NO EVIDENCE OF TERATOGENICITY BUT THEY SHOULD BE AVOIDED IN PREGNANCY ESPECIALLY IN THE FIRST TRIMEST .IF WE HAVE AN OBLIGATION THEN CHLORPHENIRAMIN IS THE LEAST RISKY.

WE CAN USE LOW SEDATIVE ANTIHIST AT DAY AND HIGH SEDATIVES AT NIGHT.

A COMBINATION OF HI AND H2 BLOCKERS ARE MORE EFFECTIVE THAN H1 ALONE.HERE RANITIDIN IS A BETTER CHOICE THAN CIMETIDIN

SECOND LINE THERAPIES:1)ORAL CS: in sever urticaria they are effective

in higher doses like 0.5-1mg/kg/d short courses are usefull but they shouldn’t be used in long term (they are especially effective in delayed pressure u and u.vasculitis

In non hereditary anioedema with respiratory distress the emergency treatment is epinephrin as an inhalor or IM or SC injection that can be repeated each 10-15 min

2)The choice of other second line therapies depend on the clinical presentation .these include leukoterian receptor antagonist that can be used in ASA sensitivity

3)mast cell stabilizers such as the Beta agonist TERBUTALIN and and Ca chanel antagonist NIFEDIPINE has been combined with H1 blockers in some patients

4)narrow band phototherapy may help some

THIRD LINE THERAPY:

In patients with sever ,nonremitting urticaria ,not responding to conventional therapy immunomodulatory strategies can be used.

Plasmaphoresis improved some patients for 3-8w only

IVIG 0.4g/kg/d for 5 dayCyclosporin 2.5-3.5mg/kg/d for 1-3m

Physical and cholinergic uIn physical urticaria a specific physical

stimulus is presentCholinergic urticaria occurs in response to

sweating and is usually associated with physical urticaria

Wealing usually occurs in minutes at the site of contact and lasts for 2h

Delayed pressure urticaria occurs in 30% of patients with CH.U.

Wealing occurs at the site of sustained pressure to the skin after a delay of 30min to 9h(4-8h)and lasts for 12-72h.

lesions may be itchy but are often tender .they often occur under tight clothing ,hands, buttock ,lower back and feet.

It may have systemic symptoms like arthralgy ,malaise and flu like.

Delayed P.U respond poorly to antihist.Cetirizin in high doses (10mg tds), NSAIDS,

MONTELUKAST, Colchicine ,DAPSON may be effective.

SYS CS can be used for short courses.The prognosis is variable and may improve

spontaneously

DERMOGRAPHISM(the response that result from firm stroke of the skin )responds well to low sedative antihist but in refractory cases there is no benefit from the addition of H2 blockers.

UVB or PUVA may be effective

In CHOLINERGIC urticaria partial relief may acheived from antihist but most have to modify their life style by reducing exercise.

KETOTIFEN is more effective than usual antihist and DANAZOL may also be effective.

After each attack there may be a rafractory period for 24h

In COLD urticaria, low sedative antihist, induction of tolerance by exposure to cold and warning against cold bathing are useful.

IN HEREDITARY ANGIOEDEMA RESPONSE TO ORDINARY TRAETMENTS ARE POOR.

LONG TERM PROPHYLAXIES IS WITH DANAZOL OR STANOZOL AND SHORT TERM WITH EPSILON AMINOKAPROIC ACID OR TRANERXAMIC ACID.

A PARTIALLY PURIFIED C1 EST INH MAY BE USED DURING ATTACKS.

Photo Images of Hives

Photo Images of Hives

Photo Images of Hives

Photo Images of Hives

Photo Image of Angioedema of Face