9.5 Hypersensitivity Reactions in Dental Practice

1. Coombs and Gell Classification of Hypersensitivity in Dental Practice

Robin Coombs and Philip Gell (1963) established the definitive immunological framework categorising hypersensitivity into four distinct mechanistic classes:

Type I: Immediate Hypersensitivity & Dental Anaphylaxis

Type I hypersensitivity occurs in two distinct phases:

1. Sensitisation Phase: An environmental allergen (e.g., penicilloyl-protein conjugate from amoxicillin, or hevein proteins from latex) is sampled by dendritic cells, which present it to naive CD4+ T cells. Driven by IL-4 and IL-13, these differentiate into Th2 cells, which stimulate B cells to undergo immunoglobulin class-switching to IgE. Synthesised IgE binds via its constant region with picomolar affinity to high-affinity receptors (FcεRI) on tissue mast cells and circulating basophils, rendering the host "sensitised".
2. Challenge (Effector) Phase: Upon re-exposure, the bivalent or multivalent allergen cross-links adjacent FcεRI-bound IgE molecules on the mast cell membrane. This cross-linking activates Lyn and Syk tyrosine kinases, mobilising intracellular calcium (Ca²⁺) and triggering:
   • Immediate release (within minutes): Pre-formed granular mediators, predominantly histamine (acting via H1 receptors to cause smooth muscle bronchoconstriction, arteriolar vasodilation, and increased venular permeability) and tryptase (a clinical biomarker for mast cell degranulation).
   • De novo lipid mediator synthesis (within 10–30 mins): Cleavage of arachidonic acid yielding Leukotrienes LTC₄, LTD₄, LTE₄ (which induce intense, prolonged bronchoconstriction and microvascular leakage 1,000-fold more potent than histamine) and Prostaglandin PGD2.
   • Late-phase reaction (4–8 hours): Secretion of cytokines (IL-4, IL-5, TNF-α) driving tissue eosinophil and neutrophil infiltration.

UK Resuscitation Council Anaphylaxis Protocol in Dental Practice

Acute anaphylaxis is a medical emergency characterised by rapid-onset, life-threatening compromised Airway (pharyngeal/laryngeal oedema, hoarseness, stridor), Breathing (bronchospasm, wheezing, tachypnoea), and/or Circulation (profound hypotension, tachycardia, collapse), frequently accompanied by cutaneous manifestations (pruritus, urticaria, angioedema).

[Recognise Acute Anaphylaxis: Airway / Breathing / Circulation Compromise]
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[1. Stop administration of suspected allergen immediately]
[2. Call 999 for emergency medical assistance (state 'Anaphylaxis')]
[3. Position patient flat with legs elevated (unless breathing is impaired; NEVER stand)]
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[4. Administer INTRAMUSCULAR (IM) ADRENALINE (1:1000, 1 mg/mL) into mid-outer thigh]
       • Adult / Child >12 years: 500 micrograms (0.5 mL)
       • Child 6–12 years:       300 micrograms (0.3 mL)
       • Child <6 years:         150 micrograms (0.15 mL)
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[5. High-flow Oxygen (15 L/min via non-rebreather reservoir mask)]
[6. Repeat IM Adrenaline after 5 minutes if no clinical improvement]
[7. Secondary non-emergency adjuvants (Chlorphenamine, Hydrocortisone) once stabilized]

[!CAUTION] Critical Clinical Pearls — UK Anaphylaxis Management:

• Route of Choice: Adrenaline must be administered intramuscularly (IM) into the anterolateral aspect of the middle third of the thigh (vastus lateralis). The vastus lateralis has superior vascularity compared to the deltoid, ensuring rapid, reliable peak plasma concentrations within minutes. Subcutaneous injection is too slow; intravenous adrenaline is strictly reserved for specialist intensive care / anaesthetic teams due to lethal cardiac arrhythmia risks.
• Patient Posture: Never allow an anaphylactic patient to stand or sit up suddenly. Sudden upright positioning causes catastrophic venous pooling in the lower extremities, leading to empty-ventricle pulseless electrical activity (PEA) and death ("empty heart syndrome").

Type IV: Delayed-Type Hypersensitivity in Dentistry

Unlike Types I–III, Type IV reactions are entirely cell-mediated and independent of antibodies:

• Pathomechanism: Small lipophilic chemicals (<1,000 Da) known as haptens are not immunogenic on their own. Upon contacting oral mucosa, they penetrate the epithelial barrier and covalently conjugate with endogenous host tissue proteins. Intraepithelial Langerhans cells (CD1a+) internalise these haptenated neoantigens, migrate to regional lymph nodes, and prime antigen-specific CD4+ Th1 and CD8+ cytotoxic T cells.
• Upon subsequent re-challenge, memory T cells infiltrate the mucosa and release pro-inflammatory cytokines, notably Interferon-gamma (IFN-γ) and TNF-α. IFN-γ activates tissue macrophages, resulting in localized release of reactive oxygen species, lysosomal proteases, basal cell liquefactive degeneration, and epithelial vesiculation over 24 to 72 hours.
• Common Dental Culprits:
  • Residual Methylmethacrylate Monomer: Inadequately cured polymethylmethacrylate (PMMA) acrylic dentures release unpolymerised free monomer, causing intense contact stomatitis characterised by fiery red erythema strictly demarcated beneath the denture-bearing area.
  • Nickel, Cobalt, and Chromium: Released from base-metal orthodontic archwires and partial denture cobalt-chromium frameworks. Nickel is the single most common contact allergen in the UK population.
  • Eugenol: Found in zinc oxide-eugenol temporary dressings and impression pastes, causing contact cheilitis or localized mucosal ulceration.
  • Cinnamic Aldehyde (Cinnamon) & Flavourings: Additives in toothpastes and confectionery; contact cinnamon stomatitis presents with deep mucosal erythema, shaggy white keratosis, and ulceration resembling plasma cell gingivitis.
  • Oral Lichenoid Contact Lesions (OLCL): Type IV cell-mediated delayed hypersensitivity to corrosion products (mercury, copper) leaching from dental amalgam restorations. Lesions present with reticular white striae and erythema strictly confined to oral mucosal sites in direct physical contact with the offending amalgam restoration, resolving completely following replacement with composite resin or glass ionomer.
• Diagnostic Investigation: The definitive diagnostic gold standard is Cutaneous Patch Testing (read at 48 hours and 72–96 hours). Skin prick testing evaluates immediate Type I IgE responses and is useless for Type IV delayed stomatitis.

The clinically important point is that the type of reaction determines both the time course and the emergency response. A type I reaction develops within minutes and may require adrenaline; a type IV reaction develops over one to three days and does not. This is why a patient who reports that a rash appeared two days after starting amoxicillin has a delayed reaction, which is unpleasant but not immediately dangerous, whereas one who reports facial swelling and wheeze within minutes has an immediate reaction and must never receive a penicillin again. Taking a history that establishes the timing, the symptoms and the outcome is therefore more useful than recording the single word "allergy".