OS 216: Immunology and Allergology
12
Lec 10:
09: Urticaria and Angioedema
November
2013
Nov 28, 28,
2013
Jovilia M. Abong
Abong, MD
TOPIC OUTLINE
I.
II.
III.
IV.
V.
VI.
VII.
Urticaria and Angioedema
Differentiating Acute from Chronic Urticaria
Classification of Chronic Urticaria
Chronic Urticaria Diagnostic Evaluation
Management of Ordinary Chronic Urticaria
Recommendation for Chronic Urticaria/Angioedema
Conclusions
Objectives:
1. To recognize the causes of acute urticaria and angioedema
2. To recognize the causes of chronic urticaria and angioedema
3. To recognize the provocative challenges for physical urticaria
4. To discuss the treatment of urticaria and angioedema
Legends:
From the Powerpoint presentation
From the lecturer
From other sources (textbook, Internet, etc.)
T/N: Good news! We removed some parts of 2016’s trans which were not discussed
AND added notes mentioned by the lecturer but are NOT on 2016’s trans. Sweet!
I. URTICARIA AND ANGIOEDEMA
 A wheal and flare reaction initiated at the level of the small venules of
the skin in response to substances that cause:
 Vasodilatation
 Increased vascular permeability
 Axon reflex
 Histamine stimulates type C unmyelinated afferent cutaneous
neurons to release neuropeptides
Figure 2. Urticaria/Hives. Skin reaction pattern characterized by
transient, pruritic, edematous, lightly erythematous papules or wheals,
frequently with central clearing.
PATHOPHYSIOLOGY
 Most types of urticaria are due to promiscuous activation of dermal
mast cells, although basophils may also be involved.
 Release of histamine and other mediators (including eicosanoids,
proteases, cytokines) causes local vasodilation, vasopermeability, fibrin
deposition, perivascular infiltration by lymphocytes, neutrophils, and
eosinophils, and pruritus
 There is minimal endothelial swelling and no leukocytoclasis
 No destruction of neutrophils
Substances that cause hive formation when injected into the skin
include:
 Histamine
 Leukotrienes C and D
 Platelet activating factor (PAF)
 Bradykinin and Substance P (neuropeptide)
GROUPINGS OF URTICARIA
On the latest EAACI classification of urticaria there are 3 major groups:
spontaneous, physical, and other urticarial disorders.
Table 1. Groups of urticaria
GROUP
SUBGROUP
Spontaneous
Acute urticaria (< 6 weeks duration)
urticaria
Most common
Physical
Urticaria
Figure 1.Factors that affect the occurrence of urticaria. Not all
urticaria are immune-mediated; not all immune-mediated urticaria are
IgE-mediated.
Mast cell degranulation releases mediators that cause vasodilation and
increase in permeability leading to urticaria and angioedema
Involves:
 Genetic Factors (Hereditary Angioedema)
 Chemical Histamine Liberators (e.g. strawberry)
Prevalence:
 25% of the population affected at some time in their lives
 25% of urticaria cases chronic (> 6 weeks duration)
 Over 75% of chronic cases idiopathic
(Affects 0.1% to 3% of
population)
A. URTICARIA
 Common problem
 Affects up to 20% of the population
CHARACTERISTICS
 Pruritic
 Blanching
 Evanescent
 “Leaves no trace” / no scarring
 < 24 h
 Skin is hot to touch
 Distribution: Any part of the body
GoGoGo
Other urticarial
disorders
Chronic urticaria (> 6 weeks duration)
Cold contact urticaria
Delayed pressure urticaria
Heat contact urticaria
Solar urticaria
Dermographic/Urticariafacticia
Vibratory urticaria
Aquagenicurticaria
Cholinergic urticaria
Contact urticarial
Exercise-induced anaphylaxis/urticaria
 Urticaria affects 15-20% of the population.
 More than 80% of new onset urticaria resolves in 2 weeks and more
than 95% resolves in 3 months
B. ANGIOEDEMA
 Edema of the deep layers of the dermis and subcutaneous tissue.
CHARACTERISTICS
 Non-pitting edema
 Skin is not hot
 Non-dependent areas
 Not pruritic
 ± Pain
 Distribution
 Involves the face, tongue, extremities, or genitalia
 Do not characteristically occur in dependent areas
 Asymmetrically distributed
 Transient
Page 1 / 5
Lecture 09: Urticaria and Angioedema
OS 216
B. PHYSICAL URTICARIA
 Reproducible by environmental factors
 Physical stimuli
 Most frequently in young adults
 Episodic and often limited to areas of inciting stimulus
 Overall, treatment with non-sedating antihistamines
 Usually
unresponsive to corticosteroids except for delayed
pressure urticaria
 Example: See Table 1 for more subgroups.
 Dermatographism – a physical urticaria
Figure 3: Angioedema of the face
II. DIFFERNTIATING ACUTE AND CHRONIC URTICARIA




A. ACUTE URTICARIA
Duration of few days to few weeks (< 6 weeks)
Incidence of 15-20% of population
Etiology usually detected
Most cases are mild and never seen by physician (because it quickly
disappears; seek consult when prolonged)
CAUSES
 Viral infections
 particularly in children
 In adults: prodrome of HBV, infectious mononucleosis (EBV)
 Drugs
 NSAIDS, penicillins and derivatives, radiocontrast media
 Foods
 Non–allergic (e.g., scombroid fish poisoning)
 Allergic/IgE–mediated (e.g., nuts, shellfish)
 Immunization
 vaccines (e.g., MMR, tetanus toxoid)
INVESTIGATION OF ACUTE URTICARIA
 Many cases require no investigation
 The cause is evident to patient and doctor alike
 Skin prick tests may support the diagnosis
 Avoid SPT in severely affected patients and in patients with current
angioedema or a history of angioedema
 Serum IgE testing may also help confirm the culprit
B. CHRONIC URTICARIA AND ANGIOEDEMA
 > 6 weeks
 Probability of having urticarial and/or angioedema:
 Hives and angioedema (40%)
 Hives alone (40%)
 Angioedema alone (20%)
ETIOLOGY
 Difficult to determine; cause is rarely found
 Common in 3rd and 4th decade of life
 Usually not foods, drugs, pollens, infections, “dyes”
 Bad News: May last for years
MOST COMMON CAUSES OF CHRONIC URTICARIA
 66-93% chronic spontaneous
 4-33% physical
 1-7% cholinergic
DURATION OF SYMPTOM RESOLUTION
 50% of patients become symptom-free after 3 months and 80% after 12
months
 11% suffer for 5 years
 Peak between 20-40 years of age (during working age)
 Women twice more affected than men
III. CLASSIFICATION OF CHRONIC URTICARIA





A. CHRONIC SPONTANEOUS URTICARIA (IN CHILDREN)
Success rate of locating etiology: 21-55%
Infections appear to have a more significant role (recurrent URTI,
pharyngitis, tonsillitis, sinusitis, otitis, UTI)
 Streptococci, H. pylori, Staphylococci, Chlamydia
 Chronic infection is a more common trigger in children
Food allergy (egg, milk, soy, peanut, seafood, wheat)
 More common cause of acute urticaria
Food intolerances (additives) and drug allergy may be present
Comorbid diseases: thyroid autoimmunity, coeliac disease
GoGoGo
Figure 4. Dermatographism. Scratching skin results in hives lasting 30
mins to 2 hours.
CASE
 If shoulder swells (angioedema) 4-6 hours after carrying a heavy
shoulder bag?
 Answer: Delayed pressure-induced urticaria and angioedema
 Note: may require corticosteroids
 If patient develops hives only while mowing the lawn?
 Answer: Vibratory-induced urticaria
DIAGNOSTIC PROCEDURES
Table 2. Diagnostic procedures to elicit physical urticaria
Types
Procedure
Aquagenic urticaria
Apply water compresses
Cholinergic
Have the patient run up and down stairs to
urticaria
induce sweating (appears when core body
tempearature is increased by 1ºC)
Cold urticaria (ice
cube test)
Delayed pressure
urticarial
Dermatographism
Solar urticaria
Vibratory
angioedema
Can be induced by stress, warm bath and
exercise
Holding an ice cube to the forearm removing,
then re-warming will quickly elicit a hive
Weight the skin with a sandbag for a short
period, then observe skin after three hours
[observe for angioedema]
Stroking the back will produce a hive in a few
minutes
Phototest patient (special lamp needed)
Apply a vibratory lab mixer to the forearm
[observe for urtication]
 Interestingly, a negative ice cube test does not negate the possibility of
cold urticaria. If you suspect cold urticaria, and have a negative ice
cube test, then place the whole arm in cold water, or if the outside
temperature is cold enough, ask the patient to stand outside for a few
minutes.
 Cholinergic – small hives with widespread erythema
 Dermographism can be induced with a calibrated, spring loaded
dermographometer
C. ASSOCIATION OF CHRONIC URTICARIA AND ANGIOEDEMA TO
AUTOIMMUNE DISEASE
Table 3. Diseases associated with chronic urticaria
Associated
Diseases
Autoimmune
 Person develops autoantibodies to the high
affinity IgE receptor (FcεR) (40%)
 Hives: 4-36 h
Thyroid Disease
 Thyroid function tests
Association
 Thyroid autoantibodies (i.e. Hashimoto’s)
 Hives: 4-36 h?
Idiopathic
 Hives: 4-36 h
Urticarial
 Rare
Vasculitis
 Systemic or isolated
 Hives: > 24 hours
 Leaves a faint hyperpigmentation after they
disappear
AUTOIMMUNE ASSOCIATION
 35% to 40% of patients have IgG antibody to ɑ subunit of IgE
Page 2 / 5
Lecture 09: Urticaria and Angioedema
OS 216
 Hashimoto’s disease is the only systemic disorder with common
association (possibly reflects underlying autoimmune process for both)
 Occasionally manifestation of a connective tissue disease such as SLE
(cutaneous vasculitis accounts for < 1%)
URTICARIAL VASCULITIS
 Inflammatory injury of capillaries and postcapillary venules in the skin
(as well as increased vascular permeability)
 Etiology: Manifestation of systemic disease (usually); some are
isolated in the skin
 Clinically:
 Hives persisting > 24 h
 Pruritic
 Painful, stinging, burning sensation
 “Leaves a trace”
 Faint residual hyperpigmentation, indicating RBC extravasation
(usually colored light brown)
Figure 6. Autoantibodies involved in chronic immune urticaria. IgG
anti-FcεRI is more common than IgG anti-IgE.
B. DIAGNOSTIC ALGORITHM
 See Appendix 1.
Figure 5. Urticarial vasculitis
CAUSES OF URTICARIAL VASCULITIS
 Autoimmune connective tissue disease: (Sjogren’s syndrome, SLE,
RA)
 Viral hepatitis B and C
 Paraproteinaemia: (Schnitzler’s syndrome occasionally has a vasculitic
histology)
 Inflammatory bowel disease
IV. CHRONIC URTICARIA: DIAGNOSTIC EVALUATION
 There is no single test for urticaria!
1. History & Physical Exam
 Diary (food intake, medications, environment, activities)
 Relationship of hives with menstrual cycle?
C. ASST
 Detects autoantibodies to the IgE receptor
 Positive test (auto-reactivity) seen in 1/3 of patients with CSU
 ASST – positive patients have more severe symptoms, longer duration
of disease, require higher doses to control symptoms
 Significance of a negative ASST: essentially rules out autoimmune
urticaria
 Significance of a positive ASST: indicates the presence of
autoreactivity in the serum, but in- vitro confirmation is required before
this can be identified as due to functional autoantibodies
V. MANAGEMENT OF CHRONIC ORDINARY URTICARIA
A. MANAGEMENT GOAL 1: GENERAL TREATMENT
 Avoidance of:
 NSAIDS, alcohol, spicy food
 Overtiredness and stress
 Wearing of tightly fitting garments, footwear
 Strenuous physical exercise
 Overheated ambient temperature
B. MANAGEMENT GOAL 2: SYMPTOMATIC THERAPY
2. Provocative tests for physical causes (if physical urticaria is
suspected)
3. Laboratory tests:
 CBC with differential, ESR, CRP, UA, LFTs
 Thyroid function, anti-thyroid antibodies
 Skin tests
 Autologus serum skin test (ASST) – autoantibody against IgE
receptor for chronic autoimmune urticaria
 Complements
4. Skin biopsy
 Generally, not helpful except in urticarial vasculitis
 Indications:
 Lesions lasting > 24-48 h
 Atypical?
 Scarring
 RBC extravasation
 Cutaneous vasculitis
 Urticaria pigmentosa
− lesions where there are many mast cells in the area
5. Refractoriness to therapy
Figure 7. Anti-histamines. 1st generation anti-histamines are nonselective (i.e., they have anti-cholinergic and anti-muscarinic effects) and
sedating.
A. DIAGNOSIS OF CHRONIC IMMUNE URTICARIA
 Autoantibodies (Fig. 6)
 Functional IgG anti-FcεRI (30%) – more common
 Functional IgG anti-IgE (5-10%)
 Antihistamines must be considered as first-line symptomatic
treatment for urticaria because all symptoms of urticaria are mediated
by H1 receptors on nerves and endothelial cells.
 Immunoblotting has been unsuccessful
 ASST
 Intradermal injection of subject’s serum
 Wheal and flare reaction after 30 min
 Basophil CD203c Expression
 To confirm previous procedure, but not available in the Philippines
GoGoGo
THERAPEUTIC OPTIONS
 Main therapy: H1 ANTI-HISTAMINES
 Why? Non-sedating, long-acting
 2nd and 3rd generation antihistamines are more specific for H1
receptor, are less likely to cross the blood-brain barrier (hence
non-sedating), and can be effective from 12-24 h.
 Improve pruritus and decrease formation of hives in mild chronic
urticaria
Page 3 / 5
Lecture 09: Urticaria and Angioedema


Moderate/severe forms may benefit from higher doses (up to 4x the
normal dose)
Desloratidine, Loratidine, Fexofenadine Ebastine, Levocetirizine,
Cetirizine
 SEDATION WITH ANTIHISTAMINES
 Clearly more evident with first generation antihistamines and
more likely to adversely affect performance
st
 If the patient sleeps poorly due to nocturnal sx, 1 generation may
be helpful.
 CORTICOSTEROIDS
 Indicated when unresponsive to H1/H2 receptor blockers and LTRA
 Effective but with substantial side effects
 So alternate day therapy if must be used
 One approach – start 15-20 mg qod and taper to 2.5-5mg q three
weeks, d/c after 4-5 months
OS 216
NIKA: Fight! 
ADA:
Roads go ever, ever on,
Under cloud and under star.
Yet feet that wandering have gone
Turn at last to home afar.
Eyes that fire and sword have seen,
And horror in the halls of stone
Look at last on meadows green,
And trees and hills they long have known.
- JRR Tolkien
FRANCIS: 
 COMBINED H1-H2 RECEPTOR ANTAGONISTS
 85/15 ratio of skin H1/H2 receptors
 More H1 than H2 receptors; that’s why you have to give them
as a combination
 Combination of anti H1 and H2 blockers provides additional
treatment benefit
 Doxepin blocks (tricyclic anti-H1 blocker) both receptors and is a
more potent anti-H1 blocker than diphenhydramine or hydroxizine
 Sedation may limit usefulness of doxepin
 SYMPATHOMIMETIC AGENTS
 Oral
sympathomimetics (e.g. terbutaline) studied to reduce
erythema/swelling
 Substantial side effects (insomnia, tachycardia)
 Low efficacy
 LTRA (leukotriene receptor antagonists)
 Zafirlukast and montelukast superior to placebo in treatment of
chronic urticaria
 Have not been compared to therapy with antihistamines
 No additional effect once maximal antihistamine effect is achieved
 EXPERIMENTAL THERAPIES
 Cyclosporine at low doses (2.5-3 mg/kg) is effective and steroid
sparing
 High dose (6 mg/kg) is very effective but with severe side
effects
 Other
less
studied
agents
include
sulfasalazine,
hydroxychloroquine and dapsone, IV IgG
 Plasmapheresis is effective for patients with autoimmune urticaria
(anti-IgE Ab) but it is impractical for long-term treatment
RECOMMENDATIONS FOR CHRONIC URTICARIA AND
ANGIOEDEMA
 Combination of therapies
 Triple drug therapy: H1 & H2 antagonists + LTRA
 Tricyclic antidepressants (doxepin)
 Immunomodulators (e.g. steroids, cyclosporine)
 Hydroxychloroquine, dapsone,
 CCBs, methotrexate, colchicine, pentoxyfilline, cyclophosphamide
 Antihistamines: mainstay of therapy (H1 and H2)
 Nonsedating at low/high doses effective for mild/moderate disease
 Older, sedating antihistamines more effective for severe urticaria
and/or angioedema
 LTRAs are worth trying
 Minimize systemic corticosteroids (alternate day)
VI. SUMMARY
 Hives are very common
 Acute urticaria
 < 6 weeks
 History is key to diagnosis
 Non-sedating anti-histamines as drug of choice
 Physical urticaria
 History is key to diagnosis
 Provocative tests as diagnostic tool
 Non-sedating anti-histamines
 Chronic urticaria
 > 6 weeks
 Etiology is rarely determined
 Therapy is difficult
IT’S PAST YOUR BEDTIME. GO TO SLEEP.
GoGoGo
Page 4 / 5
Lecture 09: Urticaria and Angioedema
OS 216
APPENDIX 1: DIAGNOSTIC ALGORITHM
 If chronic urticaria, do the following tests:
 Autoimmunity screening;
 Infectious disease screening; and
 Malignancy screening.
 HAE (hereditary angioedema):
 Recurrent angioedema alone
 C1 inhibitor (C1-inh) deficient
 Request for C1-inh screening
 If all (-): idiopathic urticaria
 Because we’re too idiot to know and the patient’s pathetic
APPENDIX 2: CLASSIFICATION OF CHRONIC URTICARIA
GoGoGo
Page 5 / 5