Dermatology JC085: Urticaria, Angioedema And Anaphylaxis

Question 1

Not everything is allergy!!!

Answer 1

Allergy:
- ***Inappropriate immunological response against usually harmless substance

Manifestations of allergy —> BUT can be NOT due to allergy!!!

1. Wheals (Hives)
   3 features:
   - **Central swelling (i.e. raised palpable lesion)
   - **Pruritus
   - ***Fleeting nature (<24 hours i.e. come and go —> skin go back to normal)
   - vs Urticarial vasculitis: painful, >24 hours, constitutional symptoms, post-inflammatory hyperpigmentation
2. Angioedema (血管水腫)
   - Swelling of **deep dermis / **SC tissue (NOT skin!)
   - **Painful (rather than pruritic)
   - **Slower resolution (~72 hours)
   —> IMPORTANT to differentiate: With / Without wheals!
3. Anaphylaxis
   - a syndrome of different manifestations
   - always **Histaminergic
   - **Acute, **Serious, Life-threatening systemic hypersensitivity reaction
   —> various definitions
   —> usually involvement of **>=2 organ systems
   —> esp. with cardiac / respiratory involvement

Question 2

Allergy vs Tolerance vs Atopy (JC + SpC Medicine)

Answer 2

Allergy = specifically implies an immunological based reaction
- In most instances (for food), implies a type I (IgE) mediated response
- Risk of severe + life-threatening anaphylaxis on re-exposure
- Other non-immediate-types also exist (and more common for some drugs)

Intolerance = usually implies a non-immunological based reaction
- e.g. enzyme deficiencies like lactose intolerance etc.
- Usually more benign

Atopy = Tendency to produce an exaggerated IgE immune response to otherwise harmless environmental substances (c.f. allergy = clinical manifestation of inappropriate immune response)
- Atopic dermatitis, allergic rhinitis, asthma, (food allergy)
- Allergic march during childhood

Question 3

Anaphylaxis

Answer 3

EAACI definition:
1. Multisystem involvement (>=2 systems)
- **Skin, Mucosal tissue
AND
- **Respiratory (e.g dyspnea, bronchospasm) / ***Cardiovascular (hypotension) / GI tract (incontinence) / MSS (hypotonia)

2. S/S usually occur within ***2 hours of exposure
   - within 30 mins for food allergy / even faster with parenteral medication / insect stings

Question 4

Urticaria

Answer 4

Umbrella term

Definition:
- Wheals and/or Angioedema

Pattern is important to distinguish ***different pathomechanisms —> different clinical course + management
—> Angioedema with Wheals
—> Angioedema without Wheals

Question 5

***Classifying Angioedema by mechanism: 2 different pathomechanisms (endotypes) causing Angioedema

Answer 5

1. Histaminergic
   - **Mast cell-meditated
   - Angioedema with / without Wheals
   - **Rapid onset / offset
   - **Respond to Antihistamines / Steroid
   - +/- Systemic symptoms (—> Anaphylaxis)
   - Temporal relationship if allergy (<1 hour)
   - Can be:
   —> **Allergic: Type 1 hypersensitivity —> Activated via FcεRIα (receptors of Fc portion of IgE) —> IgE-sensitised Mast cell —> Degranulation —> Inflammatory markers (esp. Histamine)
   —> ***Non-allergic (mast cell stimulated without allergens —> histamine released without allergens)
2. Bradykinergic
   - Kinin-related
   - Mast cell **independent
   - **CANNOT lead to Wheals (Hives) —> Angioedema **without Wheals
   - **Slower onset / offset
   - NOT respond to Antihistamine / Steroid
   - May respond to Bradykinin antagonists (Icatibant)
   - Bradykinin generated through activation of plasma contact system (Kallikrein-Bradykinin pathway)
   —> HMWK —> Bradykinin (Vasoactive molecules, broken down by ACE, C1-esterase inhibitor) —> Vasodilation + Swelling + Pain
   - Regulated by ***C1-esterase inhibitor (also break down Bradykinin)

If see Wheals —> Histaminergic
If see Angioedema —> Histaminergic / Bradykinergic

Question 6

Histaminergic “Allergic” reaction

Answer 6

• IgE mediated
• Type 1 hypersensitivity
• Presence of allergens
  —> B cells recognise allergens
  —> IgE production
  —> Attach to FcεRIα on Mast cells
  —> Re-exposure
  —> Cross links IgE on Mast cells
  —> FcεRIα stimulation
  —> Mast cells degranulation
  —> Inflammatory markers (esp. Histamine, Cytokines)
  1. Induce sensory nerve stimulation —> **Pruritus
  2. Increased vascular permeability —> **Angioedema
  3. Vasodilation —> **Distributive shock
  4. Contraction of bronchial + intestinal SM —> **Bronchospasm + Diarrhoea + Vomiting

Examples:
1. Food allergy
2. Drug allergy
3. Allergic rhinitis (hay fever)
4. ***Asthma
5. Anaphylaxis

Question 7

Bradykinergic Angioedema

Answer 7

• Characterised by swelling attacks (Angioedema)
• Absence of wheals, pruritis
  —> Angioedema ***without Wheals

Site:
- **Face
- Atypical regions also involved: **Extremities, **Abdomen, **Upper airway (most dangerous) (vs Face, Periorbital region, Tongue in Histaminergic angioedema)
- Can be asymmetrical

Causes:
1. **Drug-related (ACEI) (commonest)
2. **Hereditary (born with defective / deficiency of C1 esterase inhibitor) —> recurrent bout of Bradykinergic Angioedema
3. Acquired

Question 8

***DDx of Histaminergic angioedema / urticaria

Answer 8

1. True allergy: Allergic type 1 hypersensitivity reaction (e.g. foods, drugs, venom)
   - mostly IgE-mediated reactions
   —> if severe + multiple systems involved
   —> ***Anaphylaxis (IgE-mediated, Non-IgE mediated, Idiopathic (20%))
2. Spontaneous / Autoimmune urticaria + angioedema (Chronic Spontaneous Urticaria) (most common)
   - **Non-allergic type of Histaminergic urticaria
   - **Autoimmune condition
   - ***Anti-FcεRIα Ab (mast cells) (自動trigger mast cell degranulation)
3. Inducible urticaria + angioedema
   - ***Non-immune mediated
4. Urticarial vasculitis
5. Auto-inflammatory syndromes

Question 9

Idiopathic anaphylaxis

Answer 9

• Keep on looking for trigger / explanation
• A diagnosis of exclusion
• with complete workup —> actually 90% can identify specific causes (e.g. wheat)

Hidden allergens vs ***Anaphylaxis mimics

Anaphylaxis mimics:
- **Acute urticaria / angioedema
- **Asthmatic attack
- ***Vasovagal syncope
- Panic attacks
- Shock + other causes of sudden collapse / respiratory distress

Question 10

Management of Anaphylaxis

Answer 10

Diagnosis of possible Anaphylaxis
—> Acute management with **IM Adrenaline
—> Collect blood for Acute serum **tryptase
—> History taking to identify possible allergens / triggers
—> Observation for **biphasic reaction (respiratory symptoms: observe for >=6-8 hours, hypotension / collapse: observe for 12-24 hours) (late phase: other immune-mediated cytokines / chemokines takes time to recruit —> also vasodilation, skin rash, further mast cell degranulation)
—> Consider need for **AAI prescription + patient education
—> Collect blood for Baseline serum **tryptase (> 24 hours)
—> Referral to **Allergist

1. Acute serum tryptase
   - check within **6 hours of onset, **24 hours after onset for baseline level
   - substance stored within mast cells —> high level indicate mast cell degranulation
   - positive: ***(Baseline + 20%)+2 or >11.4 ng/ml
   - level not necessarily correlate anaphylaxis severity
   - specific but not sensitive (anaphylaxis但無升)
2. Ascertain any potential allergens
   - within 1 hour of onset
   - foods, drugs, venoms
   - co-factors: **exercise, **NSAID, ***alcohol, menstruation, illness, stress
3. **Adrenaline
   - IM adrenaline (0.01 ml/kg or **1:1000 solution) (1:1000 for IM, 1:10000 for IV)
   - ***AAI (adrenaline autoinjector, no calculation needed)
4. **Antihistamine, **Steroid, **Bronchodilator
   - **Adjuncts only
   - Antihistamine useful for skin, GI symptoms, but little use for CVS / resp symptoms (SpC Paed)
   - Steroid not too helpful for initial phase (∵ take several hours to work) (SpC Paed)

Question 11

3 key points for Anaphylaxis survivors

Answer 11

1. ***Strict allergen avoidance
2. Antihistamine + Close observation for mild reactions (i.e. skin ONLY, no respiratory / CVS / other systems involved)
3. ***AAI + Emergency medical attention

Question 12

Histaminergic urticaria (i.e. Non-allergic)

Answer 12

Urticaria are classified by:
1. Duration
- Acute (<6 weeks)
- Chronic (>=6 weeks)

2. Clinical presentation
   - **Spontaneous (no specific trigger / eliciting factors) (most common)
   - **Inducible (identifiable trigger but are NOT allergens triggering IgE reaction i.e. **Non-immune mediated)
   —> **Physical (e.g. dermographism, sunlight, heat / cold contact)
   —> Other forms (e.g. exercise-induced, cholinergic, aquagenic)

Question 13

Chronic Spontaneous Urticaria (CSU)

Answer 13

• ***Autoimmune disease
• Mechanisms not completely identified
• Spontaneous: ***No exogenous stimulus / cause (i.e. not allergy)
• Chronic auto-inflammatory skin disease (***>=6 weeks)
• Concomitant autoimmune ***thyroid disease in 10%
• Prevalence: 1%, F>M (10:1)

Pathogenesis:
AutoAb against IgE / FcεRI
—> activate basophils + mast cells
—> Degranulation spontaneously
—> Histamine + other mast cell mediators
—> Histamine binds to H-receptors located on endothelial cells + sensory nerves

Diagnosis: Clinical

Treatment:
1. Identify + Eliminate eliciting factors (if any) (A diagnosis of exclusion by history taking)
2. Pharmacological treatment

Question 14

CSU treatment: Antihistamines (1st line therapy)

Answer 14

**2nd gen Antihistamine only
- not cross BBB
- taken regularly
- avoid different antihistamine at the same time
- up-dosing up to **4x fold in unresponsive patients
—> referral to specialist
—> consider **Omalizumab (Anti-IgE) / **Cyclosporin if still refractory
- safety data available for use of several years continuously

Question 15

Urticaria activity score 7 (UAS7)

Answer 15

• ***Only for CSU
• Measures disease activity
• Combines **No. of wheals (0-3) + **Intensity of pruritus (0-3) over 7 days
  —> max 6 score each day
  —> total 42 score over 7 days

Question 16

Bradykinergic angioedema

Answer 16

• Angioedema without Wheals
• Slower onset / offset
• ***NOT respond to Antihistamine / Steroid
• May respond to Bradykinin antagonists (***Icatibant)

Causes:
1. ACEI-induced angioedema (**most common)
- 0.1% of ACEI patients
- **not time-dependent (can have angioedema after years of taking, can occur at any time)
- switch to ARB if a patients on ACEI presents with angioedema

2. Hereditary angioedema (HAE) (Type 1, 2, 3 etc.)
   - 1:10,000 population
   - rare in HK (41 patients)
   - **↓ level (Type 1) / function (Type 2) of C1-esterase inhibitor
   - **Absent C4 (screening test, ∵ C1-esterase inhibitor prevent degradation of C4)
3. Acquired C1-esterase inhibitor deficiency
   - 1:100,000 population
   - **autoimmune problem —> ↓ level / function of C1-esterase inhibitor
   - onset >40 yo, associated with **malignancy (paraneoplastic phenomenon), ↓ C1q level

Question 17

Summary

Answer 17

Urticaria = Angioedema and/or Wheals
Allergy = Always Histaminergic (cannot be Bradykinergic) (by definition)
Anaphylaxis = Always Histaminergic “allergic” (cannot be Histaminergic “non-allergic”, Bradykinergic) (by definition)

Histaminergic reactions
- Angioedema **with / without Wheals
- **Mast cell mediated
- presentation from mild (wheals only) to severe (anaphylaxis)
- Rapid onset / offset
- ***Respond to Antihistamines / Steroid
- 2 types:
1. Allergic (severe form: Anaphylaxis: multiple systems involved)
2. Non-allergic (Histaminergic urticaria)
- Chronic spontaneous urticaria (CSU) (most common)
- Inducible urticaria (physical triggers)

Bradykinergic angioedema
- Angioedema **without Wheals
- **Exclude ACEI exposure first (other causes: HAE)
- Slower onset / offset
- ***NOT respond to Antihistamine / Steroid

Question 18

History taking in Allergy (JC + SpC Medicine)

Answer 18

記: **Context, **Timing, **Manifestation, **Severity

Allergy:
1. Is it really allergy (i.e. Immune-mediated reaction)?
- ABCDE
- Allergen: Likely cause? Clinically plausible?
- Better explanation: Non-immune mediated reaction? Urticaria?
- Clinical features: Typical presentation? Immune-mediated symptoms?
- Duration since index reaction: Childhood history (potentially improve after growing up) vs Recent history
- Extra information: Tryptase level, Test results (beware validity)
- Onset of symptoms: Ask ***last exposure (NOT first exposure) to possible agents

2. How severe is it? Is it worth re-testing?
   - Immediate: Airway / Cardiopulmonary compromise / Anaphylaxis
   - Delayed: SCAR
3. Immediate / Delayed? —> Determine which test to do
   - Personalised risk stratification —> **In-vitro tests if In-vivo tests deemed unsuitable / **CI (e.g. SCAR)
   - Whether drug is a commonly used drug
   - Degree of severity of symptoms

Question 19

Immediate (Type 1) vs Delayed (Type 4) hypersensitivity

Answer 19

Immediate (classically IgE):
- Generation of allergen-specific IgE
- Develops early (<1 hour) if there has been previous exposure to the causal allergen (7-14 days if first treatment course (time for sensitisation))
- Clinical features:
1. **Urticaria, Angioedema
2. **Rhinitis, Bronchospasm, Asthma
3. **Abdominal pain, Vomiting, Diarrhoea
4. **Anaphylaxis

Non-immediate / Delayed (non-IgE):
- Activation & expansion of allergen-specific **T cells —> **Inflammatory response (e.g. Dermatitis)
- Lesions last days and develop >1 hour (usually **2-4 days) after exposure to allergen
- Clinical features:
1. **Maculopapular rashes
2. **Contact dermatitis
3. **Fixed drug eruption
4. **Erythema multiforme
5. **Severe cutaneous adverse reactions (SCAR)
- SJS-TEN (30% mortality)
- DRESS (10% mortality)
- AGEP (1% mortality)

Question 20

Epidemiology of allergy

Answer 20

Penicillin allergy: 2% (as labeled in HK) (Carbapenem only 1% cross-reactivity: Safe in penicillin allergy) (but only 10% of these 2% are truly allergic to Penicillin)
Food allergy: 10% (most common in HK)
Co-factor induced anaphylaxis: 67%
Unidentified cause of anaphylaxis: 13%

Question 21

Allergy tests

Answer 21

In-vivo:
1. Skin prick test (SPT) (Immediate type)
- Droplet + Lancet (Epicutaneous)
- Histamine positive control
- Saline negative control
- Forearm (up to 40)
- Read in **15mins
- **Wheal expansion (>=3mm) & flare: Positive
(- Not do right after anaphylaxis episode ∵ already exhausted all mast cells granules (SpC Paed))

2. Intradermal test (IDT) (Immediate + Delayed type)
   - Inject 5mm intradermal wheal
   - Used for either IgE / Cell-mediated reactions
   - **Immediate readings: Read in **15mins
   - **Delayed readings: Read in **>2-3 days
   - ***Wheal expansion (>=3mm) & flare: Positive
   - Induration / vesicles: Positive
   - Beware of irritant reactions (dilutions important)
3. Skin patch test (PT) (Delayed type)
   - Patch chambers adhered for **48hrs
   - Irritant dermatitis vs Allergic dermatitis
   - Personalised, can apply >100 allergens
   - Read at Day **2 + **4
   - **Papules, Induration, vesicles: Positive
4. Challenge test

In-vitro:
1. Immediate type
- Drug-specific IgE
- Basophil activation tests
- Histamine and CysLTs release tests

2. Delayed type
   - HLA-allele determination
   - Lymphocyte transformation tests

Question 22

Food allergy

Answer 22

1. Context
   - **Food event diary
   - Actual food involved vs Colourings, MSG, Additives, Antibiotic through food (NOT allergy)
   - **Sequence of ingestion and symptom onset vs Exacerbation of existing conditions
   - Likelihood of suspected food allergens (Big 8)
   - **Co-factors involved: **Alcohol, **Exercise, **NSAID
   - Alternative diagnosis (e.g. Scombroid poisoning)
2. Timing
   - **Immediate reaction (usually <1 hour after ingestion)
   - If tolerated after re-challenge (i.e. after index reaction) —> NOT considered allergic
   - **Consistent + ***Stereotypical reaction
3. Manifestations

Question 23

Big 8 Food allergens

Answer 23

兩組兩組記
1. Peanuts
2. Tree nuts (e.g. almond, hazel nut, walnut)

3. Milk
4. Eggs (Hen’s egg (NOT called chicken egg))
5. Soy
6. Wheat
7. Fish
8. Shellfish

Question 24

Investigations for Food allergy

Answer 24

1. Skin prick test
2. Specific IgE (and components)
   - Specific IgE to entire food / component
   - Poorly standardised allergenic preparations (whole allergen source) to Clearly defined molecules (allergenic molecules)
3. Oral food challenge

Question 25

Hen’s egg allergy

Answer 25

Egg white proteins:
- Ovomucoid (Gal d 1): Heat-stable (cannot avoid)
- Ovalbumin (Gal d 2): Heat-labile (can avoid allergy by cooking egg through)
- Conalbumin (Gal d 3)
- Lysozyme (Gal d 4)
Egg yolk proteins:
- Gal d 5

Question 26

Food dependent exercise-induced allergy (FDEIA)

Answer 26

• ***MOST common culprit of adult anaphylaxis
• ***Unknown mechanism
• Combination of Food + Physical exertion (Co-factor)

Wheat Dependent Exercise-induced Anaphylaxis (WDEIA):
- **Most common type of FDEIA
- Symptoms occur after exercise / other co-factors mins-hours after eating
- Other co-factors: **Alcohol, **Exercise, **NSAID, Extreme of temp, Pollen exposure
- Diagnosis: History + Evidence of IgE-mediated reaction (SPT / sIgE)
- Omega-5 gliadin (Tri a 19) identified as important (but not only) allergen (aka Omega-5 gliadin allergy)

Treatment:
1. Strict avoidance of culprit food
- e.g. strict adherence to gluten-free diet
2. Avoid Co-factor 4-6 hours after accidental ingestion of allergens
3. Further testing to other grains to assess potential cross-reactivity
4. AAI + Individualised emergency treatment plan
5. Documentation in medical record + Medical alert bracelet

Question 27

Role of allergist

Answer 27

1. Confirm diagnosis
2. Determine cause / allergen
3. Assess presence of co-factor
4. Determine other factors that contributed to severity of anaphylaxis (e.g. comorbidities, concurrent medications)
5. Determine if amenable to Immunotherapy
6. Educate about avoidance measures + recognition + management of recurrent episodes
7. Prescribe + educate for Adrenaline autoinjector (AAI)