Dermatology JC085: Urticaria, Angioedema And Anaphylaxis Flashcards
Not everything is allergy!!!
Allergy:
- ***Inappropriate immunological response against usually harmless substance
Manifestations of allergy —> BUT can be NOT due to allergy!!!
- 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 - 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! - 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
Allergy vs Tolerance vs Atopy (JC + SpC Medicine)
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
Anaphylaxis
EAACI definition:
1. Multisystem involvement (>=2 systems)
- **Skin, Mucosal tissue
AND
- **Respiratory (e.g dyspnea, bronchospasm) / ***Cardiovascular (hypotension) / GI tract (incontinence) / MSS (hypotonia)
- S/S usually occur within ***2 hours of exposure
- within 30 mins for food allergy / even faster with parenteral medication / insect stings
Urticaria
Umbrella term
Definition:
- Wheals and/or Angioedema
Pattern is important to distinguish ***different pathomechanisms —> different clinical course + management
—> Angioedema with Wheals
—> Angioedema without Wheals
***Classifying Angioedema by mechanism: 2 different pathomechanisms (endotypes) causing Angioedema
- 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) - 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
Histaminergic “Allergic” reaction
- 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
Bradykinergic Angioedema
- 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
***DDx of Histaminergic angioedema / urticaria
- 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%)) - 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) - Inducible urticaria + angioedema
- ***Non-immune mediated - Urticarial vasculitis
- Auto-inflammatory syndromes
Idiopathic anaphylaxis
- 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
Management of Anaphylaxis
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
- 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) - Ascertain any potential allergens
- within 1 hour of onset
- foods, drugs, venoms
- co-factors: **exercise, **NSAID, ***alcohol, menstruation, illness, stress -
**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) -
**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)
3 key points for Anaphylaxis survivors
- ***Strict allergen avoidance
- Antihistamine + Close observation for mild reactions (i.e. skin ONLY, no respiratory / CVS / other systems involved)
- ***AAI + Emergency medical attention
Histaminergic urticaria (i.e. Non-allergic)
Urticaria are classified by:
1. Duration
- Acute (<6 weeks)
- Chronic (>=6 weeks)
- 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)
Chronic Spontaneous Urticaria (CSU)
- ***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
CSU treatment: Antihistamines (1st line therapy)
**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
Urticaria activity score 7 (UAS7)
- ***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
Bradykinergic angioedema
- 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
- 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) - 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
Summary
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
History taking in Allergy (JC + SpC Medicine)
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
- How severe is it? Is it worth re-testing?
- Immediate: Airway / Cardiopulmonary compromise / Anaphylaxis
- Delayed: SCAR - 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
Immediate (Type 1) vs Delayed (Type 4) hypersensitivity
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)
Epidemiology of allergy
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%
Allergy tests
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))
- 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) - 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 - Challenge test
In-vitro:
1. Immediate type
- Drug-specific IgE
- Basophil activation tests
- Histamine and CysLTs release tests
- Delayed type
- HLA-allele determination
- Lymphocyte transformation tests
Food allergy
- 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) - Timing
- **Immediate reaction (usually <1 hour after ingestion)
- If tolerated after re-challenge (i.e. after index reaction) —> NOT considered allergic
- **Consistent + ***Stereotypical reaction - Manifestations
Big 8 Food allergens
兩組兩組記
1. Peanuts
2. Tree nuts (e.g. almond, hazel nut, walnut)
- Milk
- Eggs (Hen’s egg (NOT called chicken egg))
- Soy
- Wheat
- Fish
- Shellfish
Investigations for Food allergy
- Skin prick test
- Specific IgE (and components)
- Specific IgE to entire food / component
- Poorly standardised allergenic preparations (whole allergen source) to Clearly defined molecules (allergenic molecules) - Oral food challenge
