1. Urticaria and Angioedema
Dr Amir Hossein Siadat

2. DEFINITION
Urticaria 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.

3. 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.

4. Photo Images of Hives

5. 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

6. Angioedema Swelling 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

8. 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.

9. CLINICAL CLASSIFICATION OF URTICARIA:
1)ORDINARY URTICARIA (acute or chronic)
2)physical and cholinergic
3)Urticarial vasculitis
4)Contact Urticaria
5)angioedema

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

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

12. ASSOCIATIONS
1)an association between chronic ordinary u and autoimune thyroid disease
2)there is a higher frequency of autoimune diseases in patients with autoimune u
The 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

13. PREVALANCE: POINT PREVALANCE=0.1%
Cumulative life time prevalance: % 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

14. GENETICS Hereditary C1 Estrase defficiency angioedema Muckle Well Syn
Familial cold urticaria
Highly significant linkage of HLA DR4 and HLA DQ8 in chronic ordinary urticaria.

15. 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.

16. Non-immunologic factors Anaphylatoxins (C3a, C5a)
Pathophysiology of Urticaria
Non-immunologic factors
Immunologic factors
Chemical histamine liberators
eg. Opiates, polymyxin antibiotics,
thiamine
Types II and III
complement
activation
Alternative
complement
pathway action
Anaphylatoxins (C3a, C5a)
Type I IgE
mediated
Physical agents, e.g.
cold, heat, sunlight
genetic factors
Cholinergic
released mediators
(particularly histamine)
modulating factors
endogenous
hormone
Small blood
vessel
vasodilation
vasodilating
factors
URTICARIA

17. 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.

18. 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

19. 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

20. 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

21. Urticaria in infancy:
Cows milk allergy is the commonest etiology of urticaria in infants under 6m
In infants there may be less itching and more tendency to purpuric wheals,
Bizzarly shaped wheals are more common

22. ACUTE URTICARIA: 1) Idiopathic: Most common type: >50% of cases
Sometimes is observed following URTI

23. 2)ALLERGIC:
Is due to interaction of allergen with IgE bound to mast cells
more 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).

24. 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

25. 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

26. 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

27. Bee sting allergy usually require multiple exposure.

28. 3- None-allergic causes: ASA, NSAIDS, Codein, Morphine, Radiocontast media, Vancomycin,Ciprofloxacin,Polymyxin, Anesthetics can cause histamine release.

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

30. CHRONIC URTICARIA:
1)Most cases are idiopathic
2)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

31. 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.

32. 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.

33. 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.

34. DIAGNOSIS 1)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.

35. Physical factors should be evaluated.
The presence of angioedema should be noted especially in pharynx or larynx.
Enquire about infection, drug, medication, and food.

36. INVESTIGATION
1)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.

37. 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.

38. 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.

39. This is a patient with typical urticarial plaques covering the majority of her back – they are pruritic and responded well with antihistamine therapy. 39

40. Physical Urticarias Physical urticaria
May occur so intermittently as to appear acute but typically are chronic entities – most idiopathic
Physical Urticarias
Symptomatic Dermatographism
Cholinergic
Cold Induced (Familial or Acquired)
Vibratory (angioedema)
Pressure – induced, Solar, Aquagenic

41. Symptomatic Dermatographism
Simply scratching the skin promotes linear hives within minutes
Delayed form described
Typically is short-lived in duration (1/2 to 3 hours) and responds readily to antihistamines
Perhaps the most common of all chronic urticarias is dermatographism. In some instances, the dermatographism may be occult and only after firmly scratching the surface of the skin will it be defined. Most patients with dermatographism have a baseline pruritis. 41

42. Cholinergic Urticaria

43. Cholinergic Urticaria
Goal of raising body temperature (oral) by 0.7oC
Hot bath to 420C or having patient exercise
Small pruritic papules result surrounded by erythema (but without hypotension) result
Passive heat challenge may separate exercise-induced anaphylaxis from cholinergic urticaria
Methacholine skin test insensitive (positive result in only 33% of patients with cholinergic urticaria)

44. Cold-Induced Urticaria
Familial (autosomal dominant) vs acquired (usually infection associated)
Acquired form -positive ice-cube challenge
Usually responds to cyproheptadine

45. Diagnosis of cold-induced urticaria
Cold Stimulation Time Test (CSTT)
Positive in acquired cold-induced urticaria
Ice cubes and water in a plastic bag applied to patient’s forearm up to 10 minutes
Urticaria results after warming of area
Timing 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
A seperate entitiy, know as familial cold-induced anti-inflammatory syndrome was previously considered in the differential of cold-induced urticaria and angioedema . Hoffman, H, Wanderer A, Broide D. J Allergy Clin Immunol 2001; 108:
However, this particular entity is not only autosomal dominant, but also is characterized by fever and flu-like arthrlagias when the patient is chilled. Patients with urticaria and angioedema do not typically manifest other symptoms except the pruritis or discomfort (respectively) that accompanies their symptoms. 45

46. Delayed Pressure Urticaria

47. 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 minutes
Typically, erythema with induration and tenderness occurs at least 2 hours after the test
This is often considered but rarely demonstrated because of the predilection for involvement of pressure-dependent areas. Also consider delayed dermatographism in the differential. In some instances, it may be associated with a food allergy Davis KC, Mekori YA, Kohler PF, Schocket Possible role of diet in delayed pressure urticaria--preliminary report. J Allergy Clin Immunol Apr;77(4): This is one of the most difficult articarias to treat and often requires oral steroids for resolution. 47

48. Vibratory angioedema Vortex to induce angioedema in a patient
In some instances, patients may present with angioedema affecting one area of the body. Vibration, as in the case of a car whose wheels were out of balance, often induces the reaction. Antihistamines often will result in relief.
Vortex to induce angioedema in a patient
with swelling of hands while driving car
Lawlor F et al Br J Dermatol 1989; 120: 93-99 48

51. MANAGEMENT
Explanation 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.

52. MANAGEMENT First 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.

53. 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

54. 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.

55. 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

59. 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 min

60. 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

61. 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 day
Cyclosporin mg/kg/d for 1-3m

62. Physical and cholinergic u
In physical urticaria a specific physical stimulus is present
Cholinergic 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

63. 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.

64. 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

65. 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

66. 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.

67. 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.

68. Photo Images of Hives

69. Photo Images of Hives

70. Photo Images of Hives

71. Photo Images of Hives

72. Photo Image of Angioedema of Face