74 ALLERGY & HYPERSENSITIVITY

# Allergy & Hypersensitivity

Hypersensitivity is an exaggerated or inappropriate immune response to an antigen that would normally be harmless or only mildly noxious. The damage is done by the immune system, not the antigen itself. The Gell-Coombs classification (I–IV) remains the framework MRCS examiners use, and almost every question in this topic can be answered if you know which type of reaction the clinical scenario describes.

👩‍⚕️ Memory hook — ACID: Allergic/anaphylactic (I), Cytotoxic (II), Immune complex (III), Delayed (IV). Types I–III are antibody-mediated; type IV is T-cell mediated.

Type I — Immediate (IgE-mediated)

A previously sensitised individual re-encounters an allergen. The allergen cross-links IgE bound to FcεRI receptors on mast cells and basophils, triggering degranulation within minutes. Pre-formed mediators (histamine, tryptase, heparin) are released first; newly synthesised leukotrienes and prostaglandins drive the late-phase response 4–12 hours later.

Clinical spectrum: anaphylaxis, allergic asthma, allergic rhinitis (hay fever), food allergy, atopic dermatitis, urticaria, angioedema. Onset is usually under 30 minutes.

➡ The first ever exposure sensitises; the second exposure triggers the reaction — so a "first dose" of penicillin can still kill if there has been previous covert exposure.

➡ Serum mast cell tryptase is the biochemical fingerprint of mast cell degranulation and the test of choice to confirm anaphylaxis retrospectively.

Type II — Cytotoxic (antibody-mediated)

IgG or IgM antibodies bind antigens on the surface of the patient's own cells (or on transfused cells). The bound antibody recruits complement (classical pathway) and triggers antibody-dependent cellular cytotoxicity (ADCC) by NK cells, leading to cell lysis or dysfunction.

High-yield examples:

- ABO-incompatible transfusion — anti-A/anti-B IgM lyses donor RBCs

- Rh haemolytic disease of newborn — maternal anti-D IgG crosses placenta

- Autoimmune haemolytic anaemia, Goodpasture's (anti-GBM), pemphigus vulgaris (anti-desmoglein)

- Myasthenia gravis — anti-AChR antibody (receptor blockade, not lysis)

- Rheumatic fever — molecular mimicry with streptococcal M protein

- Graves' disease — TSH receptor stimulating antibody (variant of Type II)

Type III — Immune complex

Soluble antigen-antibody (IgG) complexes form in the circulation, fail to be cleared, and deposit in small vessels, glomeruli, joints, and skin. Deposited complexes fix complement → C3a/C5a → neutrophil recruitment → tissue damage.

Examples: SLE (DNA/anti-DNA), post-streptococcal glomerulonephritis, serum sickness (7–14 days after foreign protein), farmer's lung (extrinsic allergic alveolitis), Arthus reaction (localised vasculitis at a booster injection site).

➡ Damage in Type III is where the complex lands, not where the antigen lives — hence the multi-organ pattern in SLE.

Type IV — Delayed (T-cell mediated)

No antibody involvement. Pre-sensitised CD4⁺ Th1 cells recognise antigen presented on macrophages, release IFN-γ, and recruit further macrophages → granuloma formation. CD8⁺ cytotoxic T cells contribute in some forms. Onset is 48–72 hours after exposure — the defining feature.

Examples: Mantoux/tuberculin test (prototype), contact dermatitis (nickel, latex, chromate, poison ivy), granulomatous disease (TB, sarcoidosis, leprosy, Crohn's), graft rejection (acute and chronic), GVHD, MS, T1DM, Hashimoto's, IBD.

Comparison table — the four hypersensitivity types

Feature	Type I	Type II	Type III	Type IV
Mediator	IgE	IgG / IgM	IgG (immune complex)	T cells
Target	Soluble antigen	Cell-surface antigen	Soluble antigen	Cell-associated antigen
Effector cell	Mast cells, basophils	Complement, NK cells	Neutrophils, complement	Macrophages, CD8⁺ T cells
Onset	Minutes	Hours	Hours–days	48–72 hours
Classic example	Anaphylaxis	ABO transfusion reaction	SLE	Mantoux, contact dermatitis
Skin test	Wheal & flare (15 min)	—	Arthus (4–8 h)	Induration (48–72 h)

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Atopy, allergy, intolerance — distinguish them

- Atopy — a genetic predisposition to mount an exaggerated IgE response to common environmental allergens. The classic triad is asthma, eczema, allergic rhinitis ("atopic march" in childhood).

- Allergy — a clinical hypersensitivity reaction to a specific allergen, mediated by the immune system (most often Type I IgE).

- Intolerance — a reproducible adverse reaction to a substance that is not immune-mediated (e.g. lactose intolerance from lactase deficiency, IBS triggers). No IgE, no mast cell activation, no risk of anaphylaxis.

This distinction matters: a peanut-allergic child needs an EpiPen; a lactose-intolerant adult needs a diet review.

Anaphylaxis — recognition and management

Anaphylaxis is a severe, life-threatening, generalised Type I reaction characterised by rapidly developing airway, breathing, and/or circulation problems, usually with skin and mucosal changes.

Clinical features

- Airway: tongue/throat swelling, hoarseness, stridor

- Breathing: dyspnoea, wheeze, hypoxia, fatigue, cyanosis

- Circulation: tachycardia, hypotension, collapse, cardiac arrest

- Skin: urticaria, flushing, angioedema (present in ~80%, absent does not exclude)

Common triggers

- Drugs — penicillin (most common drug cause), NSAIDs, neuromuscular blocking agents (commonest cause under anaesthesia, e.g. suxamethonium, rocuronium)

- Foods — peanut, tree nuts, shellfish, egg, milk

- Venom — wasp, bee

- Latex — sensitised theatre staff and spina bifida patients

Management sequence

1. Remove trigger; ABCDE; call for help

2. Lay flat, raise legs (sit up if airway swelling; left lateral in pregnancy)

3. IM adrenaline 0.5 mg (0.5 mL of 1:1000) anterolateral thigh — repeat every 5 min

4. High-flow O₂, IV crystalloid bolus 500–1000 mL

5. Adjuncts: IV hydrocortisone 200 mg, IV chlorphenamine 10 mg, nebulised salbutamol if wheeze

6. Mast cell tryptase ×3 — immediate, 1–2 h, 24 h

7. Observe 6–12 h for biphasic reaction; allergy clinic referral; two adrenaline auto-injectors

👩‍⚕️ Why IM, not IV? IV adrenaline in a conscious patient risks malignant hypertension and arrhythmia. IM into the vastus lateralis gives rapid, predictable absorption and is safe in untrained hands. IV adrenaline is reserved for cardiac arrest or experienced anaesthetic use with cardiac monitoring.

➡ Adult dose 0.5 mg (1:1000). Child 6–12 yrs: 0.3 mg. Child <6 yrs: 0.15 mg. Commit these to memory.

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Pseudo-anaphylaxis (anaphylactoid reactions)

Clinically indistinguishable from anaphylaxis but not IgE-mediated. Mast cells degranulate directly without prior sensitisation, so reactions can occur on first exposure.

- Vancomycin "red man syndrome" — flushing of face/neck/torso during rapid infusion. Caused by direct mast cell histamine release. Slowing the infusion rate (over ≥60 minutes) and pre-treating with an antihistamine resolves it. Not a true allergy and not a contraindication to future vancomycin.

- Radiocontrast media, opioids (especially morphine), NSAIDs — similar mechanism.

- Treatment of a severe anaphylactoid reaction is identical to anaphylaxis (adrenaline first).

Latex allergy — two distinct mechanisms

Both can occur in healthcare workers and spina bifida patients (early repeated catheterisation).

Type	Mechanism	Onset	Clinical
Type I (immediate)	IgE to latex proteins	Minutes	Urticaria, rhinitis, bronchospasm, anaphylaxis
Type IV (delayed)	T-cell response to rubber accelerators	48–72 h	Contact dermatitis on hands

➡ Latex–fruit syndrome — cross-reactive plant proteins (profilins, chitinases). Patients allergic to latex may react to banana, avocado, kiwi, chestnut, passion fruit. Conversely, allergy to these fruits should prompt latex precautions in theatre.


Test yourself

A female nurse reports developing skin problems over the past 4 years when using latex gloves. What pathological process best explains this condition?

• ((Type I hypersensitivity::IgE-mediated — would cause immediate urticaria or anaphylaxis, not chronic eczema.))
• ((Type II hypersensitivity::Antibody-mediated cytotoxicity — Goodpasture's, AIHA, transfusion reactions.))
• ((Type III hypersensitivity::Immune complex deposition — SLE, serum sickness, farmer's lung.))
• ((Type IV hypersensitivity::☑️ Delayed T-cell mediated; classic latex contact dermatitis evolving over months to years.))

👩‍⚕️ Chronic, eczematous, glove-distribution rash = Type IV. Immediate urticaria with the same gloves = Type I.

A 30-year-old man with cervical lymphadenopathy, weight loss, night sweats, and haemoptysis has a positive Mantoux test. What does this indicate?

• ((T cell-mediated immune response::☑️ Mantoux is the prototypical Type IV delayed hypersensitivity reaction.))
• ((Complement-mediated reaction::Complement drives Type II and III, not the tuberculin response.))
• ((Local anaphylactic reaction::Anaphylaxis is Type I IgE-mediated and occurs within minutes.))
• ((Autoimmune reaction::Mantoux detects sensitisation to TB antigens, not self.))
• ((Functional B and T cell systems::Too broad — the test isolates T-cell memory specifically.))

Which immunoglobulin is primarily associated with anaphylaxis?

• ((IgE::☑️ Cross-linking of IgE bound to mast cell FcεRI receptors triggers degranulation.))
• ((IgA::Mucosal immunity; secretory dimer.))
• ((IgD::B-cell receptor function; no role in anaphylaxis.))
• ((IgG::Drives Type II cytotoxic and Type III immune complex reactions.))
• ((IgM::First antibody in primary response; Type II and III reactions.))

In anaphylaxis, which cell type is predominantly responsible for the release of mediators?

• ((Mast cells::☑️ Tissue-resident; degranulate on IgE cross-linking releasing histamine, tryptase, leukotrienes.))
• ((Eosinophils::Late-phase allergic response and antiparasitic immunity.))
• ((Basophils::Contribute but vastly outnumbered by tissue mast cells.))
• ((Neutrophils::Acute bacterial inflammation; not the anaphylaxis effector.))

A patient receives IV ampicillin and within minutes develops stridor, wheeze, and hypotension. What is the first-line treatment?

• ((IV hydrocortisone::Adjunct only; works over hours, does not reverse the acute crisis.))
• ((IV chlorphenamine::Adjunct antihistamine; no longer routinely recommended.))
• ((☑️ IM adrenaline 0.5 mg 1:1000::First-line in adults — vasoconstriction, bronchodilation, mast cell stabilisation.))
• ((Nebulised salbutamol::Useful for residual bronchospasm but not first-line.))
• ((IV fluid bolus::Supportive for hypotension but secondary to adrenaline.))

👩‍⚕️ Penicillin is the commonest drug cause of anaphylaxis; neuromuscular blockers are the commonest under anaesthesia.

A patient develops flushing of the face, neck, and torso during rapid infusion of vancomycin. What is the most appropriate next step?

• ((Stop vancomycin permanently and label as allergic::Not a true allergy — future vancomycin is safe with slow infusion.))
• ((Slow the infusion and give an antihistamine::☑️ "Red man syndrome" is direct mast cell histamine release, not IgE-mediated.))
• ((IM adrenaline 0.5 mg::Reserved for true anaphylaxis with airway/circulatory compromise.))
• ((Switch to teicoplanin immediately::Unnecessary — infusion rate is the cause.))
• ((Send mast cell tryptase::Tryptase rise is variable and not the immediate priority.))

A patient develops acute haemolysis after receiving an ABO-incompatible blood transfusion. Which type of hypersensitivity reaction is this?

• ((Type I::IgE-mediated; would cause urticaria and bronchospasm, not haemolysis.))
• ((Type II::☑️ Pre-formed anti-A/anti-B IgM bind donor RBC antigens → complement-mediated lysis.))
• ((Type III::Soluble immune complexes; not the mechanism in ABO mismatch.))
• ((Type IV::T-cell mediated, delayed by 48–72 h — far too slow for an acute haemolytic reaction.))

A 35-year-old woman with a malar rash, arthralgia, and proteinuria has anti-dsDNA antibodies. The renal damage in SLE is mediated by which type of hypersensitivity?

• ((Type I::IgE-mediated immediate reaction; not relevant to lupus nephritis.))
• ((Type II::Some lupus features are Type II, but glomerulonephritis is driven by complexes.))
• ((Type III::☑️ DNA/anti-DNA immune complexes deposit in glomeruli → complement activation and nephritis.))
• ((Type IV::T-cell mediated; not the primary mechanism in lupus nephritis.))

When should serum mast cell tryptase be sampled to confirm anaphylaxis?

• ((A single sample on admission::Single samples miss the peak and the return to baseline.))
• ((Three samples — immediate, 1–2 hours, and 24 hours::☑️ Captures rise and return to baseline, confirming mast cell degranulation.))
• ((Daily for one week::Tryptase normalises within hours; daily sampling is wasteful.))
• ((Only if adrenaline fails::Tryptase is diagnostic, not a measure of treatment response.))

Revision summary

➡ I = IgE/mast cells (min) — anaphylaxis, asthma, atopy.

➡ II = IgG/IgM vs cell-surface antigen — ABO, Rh HDN, AIHA, Goodpasture's, myasthenia, pemphigus.

➡ III = immune complexes — SLE, post-strep GN, serum sickness, farmer's lung, Arthus.

➡ IV = T cells (48–72 h) — Mantoux, contact dermatitis, graft rejection, GVHD, granulomas.

➡ Anaphylaxis: IM adrenaline 0.5 mg of 1:1000 first; then O₂, fluids, hydrocortisone 200 mg, chlorphenamine 10 mg.

➡ Tryptase: immediate, 1–2 h, 24 h.

➡ Commonest drug cause = penicillin; under anaesthesia = neuromuscular blockers.

➡ Red man syndrome = direct histamine release; slow the vancomycin infusion.

➡ Latex cross-reacts with banana, avocado, kiwi, chestnut.