Three defining features of wheals: (1) Central swelling, (2) Pruritus, (3) Fleeting nature — resolves within < 24 hours ^[1]

Why each feature matters:

• Central swelling: Caused by localized dermal oedema from mast cell degranulation → histamine release → increased capillary permeability
• Pruritus: Histamine stimulates sensory nerve endings (C-fibres) in the superficial dermis
• Fleeting ( < 24 hours): This is the key discriminator from urticarial vasculitis. If a wheal persists > 24 hours, you are dealing with a different pathology

Urticarial vasculitis = painful (not pruritic), lasts > 24 hours, has constitutional symptoms, and leaves post-inflammatory hyperpigmentation ^[1]

Clinical test: Mark the border of a wheal with a pen → reassess at 24 hours → if still present, think vasculitis ^[5].

Angioedema = swelling of the deep dermis/subcutaneous tissue. Painful rather than pruritic. Slower resolution — up to 72 hours. ^[1]

Why it's painful, not itchy: The swelling is deeper (deep dermis and subcutaneous tissue), where there are fewer sensory itch-fibres but more pressure-sensitive nociceptors. Compare this with wheals, which sit in the superficial dermis where histamine-sensitive C-fibres are abundant.

Critical: Angioedema must be classified as with or without wheals — this determines the endotype ^[1]

Anaphylaxis = serious, acute, and life-threatening systemic hypersensitivity reaction ^[1]

Key characteristics (from both GC lecture and the Fundamentals of Allergology lecture) ^[1][2]:

• Acute: rapid onset (typically minutes to hours)
• Life-threatening: can cause cardiovascular collapse and death
• Often multisystem, but not necessarily so: do not require two involved systems when acute hypotension, bronchospasm, or laryngeal involvement follows exposure to a known or highly probable allergen
• Especially significant: cardiac or respiratory involvement

Since 2018, "urticaria" = wheals AND/OR angioedema ^[1]

This is a conceptual shift. Previously, "urticaria" was thought of as just wheals. Now, the umbrella term includes:

• Wheals alone
• Angioedema alone
• Angioedema with wheals

The pattern (with or without wheals) is important to distinguish between different pathomechanisms, different clinical courses, and different management. ^[1] The date and wording above reflect the lecture slide; the current published international urticaria guideline is the 2022 EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline. ^[14]

Mast cell mediated. Activated via FcεRIα. Release of inflammatory mediators including histamine and PAF (platelet activating factor). ^[1]

Downstream effects of histamine ^[1]:

1. Sensory nerve stimulation → pruritus
2. Increased vascular permeability → oedema (wheals/angioedema)
3. Vasodilation → erythema, hypotension (in anaphylaxis)
4. Contraction of bronchial and intestinal smooth muscle → bronchospasm, abdominal cramps/diarrhoea

The organ diagram adds the clinical chain: increased vascular flow/permeability produces oedema and hypotension/shock; narrowed airways plus increased mucus produce cough, wheeze, phlegm, and nasal/ocular symptoms; increased gastrointestinal secretion and peristalsis produce vomiting and diarrhoea. ^[1]

Can be "allergic" or "non-allergic" ^[1]:

• Allergic (IgE-mediated): Allergen cross-links IgE antibodies on mast cells → triggers FcεRI → Type I hypersensitivity. This is the classic pathway in food allergy, drug allergy, venom allergy, allergic rhinitis, allergic asthma
• Non-IgE mechanisms: Direct mast-cell activation or other pathways (e.g., opioids, some radiocontrast reactions, vancomycin infusion reaction, physical stimuli)

Mast cell independent. Bradykinin generated through activation of the plasma contact system. A vasoactive molecule causing vasodilation, swelling, and pain. Regulated by C1-esterase inhibitor. ^[1]

First-principles explanation: The contact system (also called the kallikrein-kinin system) normally generates bradykinin from high-molecular-weight kininogen via kallikrein. C1-esterase inhibitor (C1-INH) normally keeps this in check by inhibiting kallikrein and Factor XIIa. When C1-INH is deficient or dysfunctional, or when its breakdown is accelerated (ACEi blocks bradykinin degradation via a different route), bradykinin accumulates → vasodilation + increased permeability in deep tissues → angioedema.

Reading the pathway diagram: C1-INH restrains factor XIIa and plasma kallikrein; ACE degrades bradykinin. The drug targets shown are therefore mechanistically distinct: ecallantide inhibits kallikrein, whereas icatibant blocks the bradykinin B2 receptor. ^[1][15]

Bradykinergic angioedema is characterized by: swelling attacks (angioedema), ABSENCE of wheals and pruritus, may involve face, extremities, abdomen, and most dangerously — upper airway. ^[1]

The photographs and imaging translate this into three recurring attack patterns: asymmetric facial/peripheral swelling, bowel-wall/submucosal oedema with free intraperitoneal fluid during abdominal attacks, and tongue/laryngeal oedema on upper-airway examination. The abdominal CT appearance supports the diagnosis in context but is not specific by itself. ^[1]

Why no wheals or pruritus? Because mast cells are not involved. There is no histamine release, therefore no superficial dermal itch or wheal formation. The bradykinin acts on deeper vascular beds.

Can be drug-related (ACEi), hereditary, or acquired. ^[1]

Wheals ± angioedema → usually mast-cell/histamine mediated

Angioedema WITHOUT wheals → could be mast-cell mediated OR bradykinin mediated

This is why the presence/absence of wheals is the pivotal clinical question, but it is a probability clue rather than an absolute rule: CSU can present with angioedema alone, and coincidental CSU can coexist with HAE. ^[15]

Histaminergic differentials ^[1]:

1. "Allergic" Type I hypersensitivity (foods, drugs, venom) — mostly IgE-mediated
2. Spontaneous or autoimmune urticaria and angioedema (CSU) — anti-FcεRIα antibodies on mast cells
3. Inducible urticaria and angioedema
4. Urticarial vasculitis
5. Auto-inflammatory syndromes

Bradykinergic differentials ^[1]:

1. ACEi-induced angioedema — exclude FIRST (~0.1% of ACEi recipients)
2. Hereditary angioedema (HAE) — Type I, II, III and more; 1:10,000 population; reduced level or function of C1-esterase inhibitor
3. Acquired C1-esterase inhibitor deficiency — 1:100,000 population; onset > 40 years old; associated with malignancy; low C1q level

These bullets preserve the slide's historical wording. Current nomenclature replaces “type III” with HAE with normal C1-INH, current global prevalence for HAE-1/2 is about 1:50,000, and acquired C1-INH deficiency should be considered with later-onset disease (especially after age 30), negative family history, lymphoma/MGUS or autoimmune disease; C1q is often, not invariably, low. ^[15]

How to distinguish HAE from acquired C1-INH deficiency:

Acute urticaria: < 6 weeks. Chronic urticaria: ≥ 6 weeks ^[1]

Spontaneous: No specific trigger or eliciting factor. Inducible: Identifiable trigger(s). ^[1]

Causes of acute urticaria (from senior notes) ^[5]:

• Idiopathic (~50%)
• Infection e.g. URTI (~40%)
• Drugs (~10%)
• Food ( < 1%)

Causes of chronic urticaria ^[5]:

• Idiopathic (~50%)
• Autoimmune (antibodies against IgE or FcεRI): 40-50%
• Chronic infection (e.g. parasites): < 5%

The slide calls CSU a chronic “auto-inflammatory” skin disease, but current nomenclature is more precise: CSU is a mast-cell-driven inflammatory disease. Recognized autoimmune endotypes include type I autoimmune (“autoallergic”) CSU, with IgE autoantibodies to self-antigens, and type IIb autoimmune CSU, with mast-cell-directed activating autoantibodies such as IgG against IgE or FcεRI; some cases remain of unknown cause. ^[14]

Why “spontaneous”? Because no definite specific eliciting factor is identified. Some patients have autoimmune CSU, while other cases have no defined cause; this differs from a reproducible IgE-mediated food allergy requiring exposure to the relevant external allergen.

Concomitant autoimmune thyroid disease in 10% ^[1]

Treat the slide's “10%” as a cohort-level teaching estimate rather than an individual diagnostic rule. Current guideline work-up is intentionally limited: history, examination (including patient photographs), differential blood count, and CRP and/or ESR; in specialist care, total IgE and IgG anti-TPO may help endotyping. Thyroid function, allergy testing, infection testing, biopsy, and other studies are guided by the history, examination, and basic results rather than ordered indiscriminately. ^[14]

Urticaria Activity Score UAS7: number of wheals + intensity of pruritus over past 7 consecutive days ^[1]

This validated scoring tool is used to guide treatment decisions and assess response. Each day scores wheals (0-3) and pruritus (0-3), maximum 6/day, maximum 42/week.

The visual scoring sheet makes the arithmetic explicit: record the maximum wheal count over 24 hours and worst itch intensity once daily, then sum seven daily scores. UAS7 does not capture angioedema; use a control tool such as UCT and, where relevant, the angioedema control test alongside it. ^[1][14]

Identify and eliminate eliciting factors (if any). Pharmacological treatment: 4 lines of treatment. ^[1]

Step 1 (First-line): Second-generation antihistamines

Key principles ^[1]:

• Second-generation only (cetirizine, loratadine, fexofenadine, bilastine — avoid sedating first-gen like chlorpheniramine for chronic use)
• Take regularly (not PRN — you need sustained H1-receptor blockade)
• Avoid different antihistamines at the same time
• Up-dosing up to fourfold (e.g., cetirizine 10mg → up to 40mg daily)
• Safety data available for use of several years continuously

Why second-generation only? First-generation antihistamines (e.g. chlorpheniramine, diphenhydramine) cross the blood-brain barrier → sedation, anticholinergic effects, impaired psychomotor function. Second-generation are peripherally selective, non-sedating, and safer for chronic daily use.

Why up to fourfold? The guideline endorses escalating one modern second-generation H1 antihistamine up to fourfold before moving to other therapies. This is generally off-label, should be individualized, and doses above fourfold are not recommended; avoid relying on unreferenced receptor-occupancy percentages for the clinical decision. ^[14]

Step 2 (Second-line): Increase antihistamine dose to fourfold (if not already done in Step 1)

Step 3 and beyond: Personalized therapy ^[1]

• Omalizumab (anti-IgE monoclonal antibody)

  • Unlike for asthma, a fixed dose approved for CSU: 300mg every month via subcutaneous injection ^[1]

  • Mechanism: Binds free IgE → reduces IgE levels → downregulates FcεRI expression on mast cells/basophils → reduces mast cell activation
  • Indications and dosing may vary from region to region ^[1]

Step 4: Ciclosporin under specialist supervision for severe disease refractory to high-dose second-generation antihistamine plus omalizumab; it is off-label and has a less favourable safety profile. Long-term systemic corticosteroids are not recommended, although a short rescue course may occasionally be considered for an acute exacerbation. ^[14]

Anaphylaxis = acute, systemic, potentially life-threatening hypersensitivity reaction ^[13]. It may be IgE mediated, arise through other immunologic pathways, or follow non-immunologic mast-cell activation.

The WAO 2020 criteria shown in the lecture use either of two routes ^[1][13]:

1. Acute skin/mucosal involvement plus respiratory compromise, reduced blood pressure/end-organ dysfunction, or severe gastrointestinal symptoms (especially after a non-food trigger); or
2. Acute hypotension, bronchospasm, or laryngeal involvement after exposure to a known or highly probable allergen, even without typical skin involvement.

Diagnostic criteria are aids, not a prerequisite for treatment: when an evolving systemic hypersensitivity reaction makes anaphylaxis likely, delayed adrenaline is more dangerous than treating before every criterion is fulfilled. ^[16]

~20% of anaphylaxis cases are labelled "idiopathic" ^[1]

HKU study (2020): From 2018-19, > 10% of adult patients referred to QMH Immunology Clinic were for "idiopathic" anaphylaxis. After complete allergist workup, specific causes could be identified in 90%. ^[1]

Despite surviving anaphylaxis, less than 1/3 of patients were prescribed an adrenaline autoinjector (AAI) prior to consultation. ^[1]

Compared to UK patients, HK patients had more urticaria and cardiovascular manifestations. ^[1]

Why this matters: "Idiopathic anaphylaxis" is a diagnosis of exclusion. The lecture stresses to keep looking for triggers/explanations ^[1].

Reading the Hong Kong graphs rather than just the captions ^[1]:

• Paediatric anaphylaxis admissions rose across the 2000s–2010s, while many recorded triggers remained “unspecified”.
• In the 2009–2019 admission series, adrenaline autoinjector prescribing rose from 5.1% to 27.9% but remained incomplete.
• In a selected adult QMH referral cohort initially labelled idiopathic, allergist assessment identified a likely cause in 90%; the pie chart was dominated by wheat/omega-5-gliadin (59%), with smaller shellfish, buckwheat, soy, alpha-gal, exercise, and mastocytosis groups.

These are historical referral/admission datasets, not current population prevalences. The 59% wheat figure should therefore not be generalized to every Hong Kong patient with unexplained anaphylaxis.

The slide's mechanistic figure is broader than this simplified table: non-IgE mechanisms include immune pathways (for example some biologics or contrast reactions) and direct mast-cell activation, while exercise, temperature, alcohol, and medicines may act as triggers or cofactors. “Non-IgE” does not mean “not anaphylaxis”. ^[1][13]

Hidden allergens vs Anaphylaxis mimics: acute urticaria/angioedema, asthmatic attacks, vasovagal syncope, panic attacks, shock and other causes of sudden collapse/respiratory distress ^[1]

How to differentiate vasovagal from anaphylaxis: Vasovagal episodes typically cause pallor, bradycardia, and rapid improvement when supine. Anaphylaxis more often causes tachycardia, flushing/urticaria or angioedema, bronchospasm/upper-airway symptoms, and persistent hypotension—but skin findings may be absent and severe anaphylaxis can occasionally present with relative bradycardia. Use the whole time course and ABC findings, not one sign in isolation.

Co-factors: exercise, NSAIDs, alcohol, menstruation, illness, stress ^[1]

These lower the threshold for anaphylaxis in sensitized individuals. A classic exam scenario: wheat-dependent exercise-induced anaphylaxis (WDEIA) — the patient tolerates wheat when sedentary but develops anaphylaxis when exercising after wheat ingestion ^[2].

Perioperative anaphylaxis (from Crisis Management lecture) ^[7]:

• Cardiovascular collapse (88%), erythema (48%), bronchospasm (40%), angioedema (24%), cutaneous rash (13%), urticaria (8%)
• Note: skin signs may be ABSENT in severe cardiovascular collapse — don't wait for a rash to diagnose anaphylaxis!

First-line treatment: ADRENALINE (epinephrine) ^[1]

Why adrenaline works: It acts on α1 (vasoconstriction → reverses hypotension, reduces oedema), β1 (positive inotrope/chronotrope → improves cardiac output), and β2 (bronchodilation → reverses bronchospasm; inhibits mast cell degranulation → reduces further mediator release) receptors.

Paediatric dosing: use local age/weight guidance and the available autoinjector device. For healthcare professionals, WAO recommends 0.01 mg/kg IM, maximum 0.5 mg; autoinjector strength thresholds vary by product and jurisdiction. ^[13]

The slide says “within 6 hours” and labels either an absolute value > 11.4 ng/mL or a 20% + 2 rise as positive. Current interpretation is more careful ^[16]:

• draw an initial sample as soon as feasible without delaying treatment;
• obtain a timed sample ideally 1–2 hours after symptom onset (no later than 4 hours in the RCUK pathway);
• obtain a baseline sample at least 24 hours after complete resolution or in follow-up;
• compare acute with baseline: an acute value exceeding 1.2 × baseline + 2 ng/mL supports systemic mast-cell activation, but no laboratory threshold diagnoses anaphylaxis by itself. ^[19]

Why tryptase? Tryptase is stored in mast-cell granules and released during degranulation. A paired rise supports mast-cell activation but does not reveal whether the mechanism was IgE mediated. Normal tryptase does not exclude anaphylaxis, especially after food-triggered or normotensive reactions. An isolated value above the assay reference range (often 11.4 ng/mL) is not, by itself, proof that the acute event was anaphylaxis; a persistently raised baseline prompts assessment for causes such as mast-cell disease or hereditary alpha-tryptasemia. ^[19]

Baseline serum tryptase: send blood > 24 hours after the event ^[1]

You need both the acute and baseline tryptase to interpret the change. A persistently elevated baseline deserves contextual assessment for mast-cell disease, hereditary alpha-tryptasemia, and other causes; serum tryptase alone neither confirms nor excludes a clonal mast-cell disorder. ^[19]

The slide's fixed “6–8 hours for respiratory symptoms” and “12–24 hours for hypotension/collapse” reflect its local pathway. Current RCUK guidance uses risk-stratified observation measured from complete resolution ^[16]:

There is no perfectly reliable predictor of biphasic reaction. Greater initial severity, multiple adrenaline doses, and delayed adrenaline increase risk; discharge decisions remain individualized and must include recurrence instructions. ^[16]

1. Comprehensive and targeted allergy history
2. Ensure tryptase taken
3. Patient education
4. Avoidance advice
5. Decision for AAI
6. AAI technique training
7. Return demonstration (patient demonstrates back to you)
8. Trigger Allergist referral (QMH Anaphylaxis Clinic)

The decision-tree graphic adds that AAI prescribing is risk based: previous severe, respiratory, cardiovascular, or multiorgan reactions favour prescription, as do an unavoidable/unknown trigger, relevant comorbidity (especially asthma), occupational exposure, social circumstances, and limited access to emergency help. If indicated, prescribe before discharge, demonstrate technique, require return demonstration, provide a written action plan, and arrange allergy review rather than deferring all of this to a later clinic visit. ^[1][17]

1. Strict allergen avoidance
2. Antihistamines and close observation for mild reactions
3. Adrenaline autoinjector and emergency medical attention for severe reactions

The slide's “Swiss-cheese” graphic is a systems-safety message: no single defence is perfect. Layer trigger avoidance, a written action plan, autoinjector availability, patient/carer training with return demonstration, and specialist review. If severe symptoms emerge—or there is doubt about progression—do not let an antihistamine trial delay adrenaline. ^[1][16]

Device designs and hold times differ. Follow the labelled instructions for the exact autoinjector supplied, inject into the mid-anterolateral thigh (through clothing if necessary), and practise with a trainer device; do not memorize another brand's cap colour or hold time. ^[13]

~0.1% of ACEi recipients. Must be excluded FIRST. ^[1]

Mechanism: ACE (angiotensin-converting enzyme) also degrades bradykinin. When ACEi blocks ACE → bradykinin accumulates → angioedema. This can occur at any time during treatment (even after years of stable use).

Management: Stop the ACE inhibitor immediately and never rechallenge with any ACE inhibitor.

Current safety note: acute management prioritizes airway evaluation and stabilization, with early expert airway intervention when swelling progresses. Stop the ACE inhibitor permanently because this is a class effect. Antihistamines, steroids, and adrenaline do not target bradykinin; however, treat as possible anaphylaxis when the mechanism is uncertain. Evidence is insufficient to recommend routine icatibant, ecallantide, C1-INH concentrate, tranexamic acid, or fresh frozen plasma specifically for ACE-inhibitor angioedema. Choice of any future ARB should be individualized rather than described as automatically safe. ^[18]

The slide quotes 1:10,000; the 2021 WAO/EAACI guideline estimates HAE due to C1-INH deficiency/dysfunction at about 1 in 50,000 globally. ^[15]

Why C4 is often low: C1-INH also inhibits activated C1 (C1r and C1s) in the classical complement pathway. Without C1-INH → unchecked C1 activation → consumption of C4. However, C4 has limited sensitivity and specificity and must not be the sole screening or exclusion test. Measure C4, C1-INH antigen, and C1-INH function together; repeat initially positive/inconsistent testing to confirm the diagnosis without delaying treatment. ^[15]

1:100,000 population. Onset > 40 years. Associated with malignancy. Low C1q level. ^[1]

Clues favouring acquired C1-INH deficiency over HAE are later onset without a family history, an associated lymphoproliferative/monoclonal gammopathy or autoimmune disorder, and an often low C1q. None should be used alone as an absolute discriminator. ^[15]

For confirmed HAE-1/2, antihistamines, adrenaline, and steroids do not treat the bradykinin pathway. Treat attacks early, and treat every attack affecting or potentially affecting the upper airway; progressive upper-airway swelling requires early intubation/surgical-airway planning in parallel with specific therapy. ^[15]

Recommended on-demand treatments for HAE-1/2 are:

• C1-INH concentrate (plasma-derived or recombinant): replaces the missing inhibitor
• Icatibant: bradykinin B2 receptor antagonist — blocks the action of bradykinin directly
• Ecallantide: kallikrein inhibitor — prevents bradykinin generation
• Lanadelumab: anti-kallikrein monoclonal antibody (prophylaxis)
• Berotralstat: oral kallikrein inhibitor (prophylaxis)

Where first-line on-demand therapy is unavailable, solvent-detergent-treated plasma—and only if that is unavailable, safe-source fresh frozen plasma—are fallback options. Tranexamic acid and attenuated androgens are not recommended for on-demand treatment. ^[15]

Answer: Chronic spontaneous urticaria (CSU) ^[9]

• Duration > 6 weeks → chronic
• No obvious triggers → spontaneous
• Responds to antihistamines → histaminergic
• NOT hereditary angioedema (he has HIVES, and it responds to antihistamines)
• NOT acute urticaria (duration > 6 weeks)
• NOT food allergy (no trigger identified, chronic course)

Answer: Mast cells ^[9]

• Anaphylaxis = IgE-mediated → allergen cross-links IgE on mast cells → FcεRI activation → degranulation → histamine release
• NOT B-lymphocytes (they produce the IgE but don't degranulate)
• NOT T-lymphocytes (Type IV, delayed)
• NOT neutrophils (innate immunity, not primary in IgE-mediated reactions)

Answer: Hen's egg ^[10]

• 8 major food allergens: milk, egg, soy, wheat (outgrown), nuts, peanuts, fish, shellfish (persistent)
• In young children, egg and milk are the most common food allergens
• Immediate onset (15 min) → IgE-mediated

• Immediate reactions ( < 1 hour): IgE-mediated → urticaria, angioedema, anaphylaxis
• Delayed reactions ( > 1 hour, usually 2-4 days): T-cell mediated → maculopapular rashes, SCAR (SJS/TEN, DRESS, AGEP)
• False penicillin allergy labels are a major public health issue → 1 in 50 of HK population may need de-labelling

• For acute urticaria control: non-sedating antihistamines first-line
• Up to 4 tablets (fourfold dose) before escalating
• Pre-bullous pemphigoid can mimic urticaria → always ask if individual wheals resolve within 24 hours ^[12]

• Perioperative anaphylaxis: cardiovascular collapse is the most common manifestation (88%), not skin signs