ImmunologyTier 1Medical Sciences concept

Mast cell mediators and diagnostic testing in anaphylaxis (tryptase, histamine)

Core concept

Mediators - the timing explains the clinical course

Class	Mediator	Effect	Kinetics
Preformed (granule)	Histamine	H1: itch, flush, bronchospasm, inc permeability; H2: gastric acid, vasodilatation	Peaks <5-10 min, gone by 30-60 min
	Tryptase	Protease; the clinical marker	Peaks 60-90 min, detectable ~5 h
	Chymase, heparin, TNF, carboxypeptidase	Local	Immediate
Newly synthesised (lipid)	Leukotrienes C4, D4, E4 (the old slow-reacting substance of anaphylaxis)	Sustained bronchoconstriction, mucus, permeability	5-30 min
	PGD2	Flushing, bronchospasm, vasodilatation	5-30 min
	PAF	Hypotension, capillary leak; correlates with severity	Minutes
Cytokines	IL-4, IL-5, IL-13, TNF, chemokines	Late-phase eosinophil and lymphocyte recruitment	4-12 h

Early phase = preformed and lipid mediators = STEROID-RESISTANT -> steroids do not treat the acute reaction; adrenaline does
Late phase = cellular infiltration = steroid-responsive -> the rationale for steroids in preventing protracted or biphasic reactions (evidence is weak; do not delay adrenaline for them)
Biphasic reactions in ~5% (up to 20% in some series), typically 4-12 h later

Key detail

Testing

*Anaphylaxis is a clinical diagnosis* - do not wait for a test to treat
Serum mast cell tryptase is the single most useful confirmatory test
- Take at 1-3 hours from symptom onset (ideally also at ~30 min and at 24 h)
- *A BASELINE tryptase at >=24 h, when fully recovered, is essential - the diagnosis rests on the rise*, not the absolute number
- Significant rise = (1.2 x baseline) + 2 mcg/L ("20% + 2")
- Often NOT elevated in food-triggered anaphylaxis (basophil-predominant) - a normal tryptase never excludes anaphylaxis
- Highest yields in drug- and venom-triggered reactions and in hypotensive reactions
Plasma histamine is not clinically useful - peaks within 5-10 minutes and is gone before the patient reaches hospital; requires special handling. Urinary methylhistamine and 11-beta-PGF2alpha are alternatives in research or mastocytosis workup
Persistently elevated baseline tryptase (>8-11.4 mcg/L) -> investigate for
- Clonal mast cell disease - systemic mastocytosis (KIT D816V)
- Hereditary alpha-tryptasaemia - extra germline copies of TPSAB1; ~5% of the population; the commonest cause of a raised baseline tryptase
- Chronic renal failure, myeloid neoplasm
Later allergy workup at >=4 weeks - specific IgE, skin prick and intradermal testing (early testing risks a false negative while mediators are depleted)

Clinical relevance

Treatment: IM adrenaline 0.01 mg/kg (adult 0.5 mg of 1:1000) into the anterolateral thigh, repeat every 5 min
- Alpha-1 reverses vasodilatation and mucosal oedema; beta-1 inotropy/chronotropy; beta-2 bronchodilatation and inhibition of further mediator release
- Lie flat with legs elevated - sitting or standing a hypotensive patient up has caused fatal "empty ventricle" arrest
- IV fluid bolus; adrenaline infusion if refractory; glucagon if on beta-blockers
- Antihistamines treat itch and urticaria only; steroids are adjunctive; neither treats the reaction**
Observation at least 4 h (longer if severe, biphasic risk, protracted, or poor access to care); discharge with two adrenaline autoinjectors, an ASCIA action plan and allergy referral
Mastocytosis - clonal expansion from an activating KIT mutation (D816V) in >90%
- Urticaria pigmentosa, Darier's sign, flushing, diarrhoea, osteoporosis, unexplained syncope
- De novo anaphylaxis with extreme tryptase elevations; particularly severe reactions to hymenoptera stings -> lifelong venom immunotherapy and autoinjectors
- Triggers to avoid: opioids, NSAIDs, radiocontrast, vancomycin, neuromuscular blockers, alcohol, heat, pressure
- Treated with H1/H2 blockade, cromoglicate, montelukast, omalizumab, and avapritinib in advanced disease
Idiopathic anaphylaxis - always measure a baseline tryptase and consider alpha-gal syndrome (delayed 3-6 h after red meat, following tick bite) and exercise-induced/wheat-dependent anaphylaxis

Correlations

Gell and Coombs type I hypersensitivity
Drug hypersensitivity mechanisms; anaphylactoid reactions
Allergen immunotherapy - venom
Asthma and allergic rhinitis; leukotriene pathway drugs
Mastocytosis and myeloid neoplasms; KIT
Hereditary angioedema - the bradykinin mimic

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