Immunology and AllergyTier 1Disease (DEADMAN)

Allergic disorders - drug reactions, adverse

Description

Type A (~80%) - Augmented: dose-dependent, predictable from pharmacology (bleeding on warfarin)
Type B - Bizarre: dose-independent, host-dependent. Includes all true drug allergy
- Only type B is immunologically mediated

Gell and Coombs classification of drug hypersensitivity

Type	Mechanism	Onset	Examples
I	IgE, mast cell	<1h	Anaphylaxis, urticaria, bronchospasm - beta-lactams, NMBAs, chlorhexidine
II	IgG cytotoxic	Days-weeks	Immune haemolysis, drug-induced thrombocytopenia (heparin, quinine)
III	Immune complex	1-3 weeks	Serum sickness, drug-induced vasculitis, hypersensitivity nephritis
IVa-d	T cell	Days to weeks	Morbilliform exanthem, DRESS, AGEP, SJS/TEN, fixed drug eruption

Non-immune direct mast cell activation (MRGPRX2) - vancomycin (red man), opiates, quinolones, radiocontrast
- Clinically identical to type I but skin testing is negative and rechallenge is often possible with premedication and slower infusion

The severe cutaneous adverse reactions (SCARs)

	Latency	Features	Mortality
DRESS	2-8 weeks	Fever, morbilliform rash, facial oedema, eosinophilia, atypical lymphocytes, hepatitis/nephritis, HHV-6 reactivation	~10%
SJS/TEN	4 days - 4 weeks	Mucosal erosions (>=2 sites), skin pain, Nikolsky+, epidermal detachment (SJS <10%, TEN >30% BSA)	TEN 25-35%
AGEP	<4 days	Sterile pustules on erythema, flexural, neutrophilia, fever	<5%

ADRs cause ~3-6% of hospital admissions; occur in ~10-20% of inpatients
Penicillin allergy label in ~10% of the population; <5-10% of those are truly allergic
- -> the single highest-yield delabelling target in medicine
SJS/TEN ~1-2 per million/yr; DRESS ~1:1,000-10,000 exposures for high-risk drugs
F>M for cutaneous drug eruptions
HIV, EBV and CMV infection markedly increase eruption rates (amoxicillin in EBV)

Hapten and p-i concepts

Hapten - small drug binds protein covalently -> neoantigen -> conventional immune response (penicillin)
p-i (pharmacological interaction) - drug binds MHC or TCR non-covalently -> direct T-cell activation, no prior sensitisation required
Altered peptide repertoire - drug binds within the MHC groove and changes which self-peptides are presented (abacavir/HLA-B*57:01)

HLA associations - pharmacogenomic screening

Drug	Allele	Reaction	Population
Abacavir	*HLA-B57:01**	Hypersensitivity syndrome	Mandatory screening before use
Carbamazepine	*HLA-B15:02**	SJS/TEN	Han Chinese, SE Asian - screen
Carbamazepine	HLA-A*31:01	DRESS	European, Japanese
Allopurinol	*HLA-B58:01**	SJS/TEN, DRESS	Han Chinese, Thai, Korean
Flucloxacillin	HLA-B*57:01	Cholestatic hepatitis

Viral reactivation (HHV-6, EBV, CMV) drives the prolonged and relapsing course of DRESS
Granulysin from CD8/NK cells mediates keratinocyte death in SJS/TEN

History is the test

Timing - latency from first dose is the most discriminating feature
- <1h -> IgE. 4-21 days on first exposure -> T cell. 2-8 weeks -> DRESS
Nature: urticaria vs morbilliform vs pustular vs bullous vs mucosal
Sulfonamide reaction is characteristic: 7-10 days after starting, with fever and a pruritic rash
All concurrent drugs with start/stop dates - build a timeline
Prior tolerance of the same or related drug
A childhood label of "rash on amoxicillin" is usually viral, not allergic

Bedside

Mucosal surfaces (eyes, mouth, genitals), Nikolsky sign, skin pain, BSA detachment
Facial oedema, lymphadenopathy, temperature
Bloods: FBE with eosinophil count and atypical lymphocytes, LFT, creatinine, CK

Serum tryptase

Within 3 hours of a suspected acute reaction plus a baseline
Confirms mast cell degranulation but does not distinguish IgE- from non-IgE-mediated mechanisms

Allergy testing

Mechanism	Test
IgE-mediated	Skin prick testing (limited validated reagents - mostly penicillin) then intradermal testing
Non-IgE / delayed	Patch testing, or delayed reading of intradermal tests at 48-72h
Either, to confirm tolerance	Drug provocation (challenge) testing - the reference standard

Test 4-6 weeks to 6 months after the reaction
In vitro basophil activation and specific IgE assays have low sensitivity - a negative result does not clear the drug
Absolute contraindication to challenge/testing: SJS/TEN, DRESS, AGEP, drug-induced organ injury

Penicillin delabelling

Low-risk history (benign childhood rash, no features of anaphylaxis or SCAR, >5 yrs ago) -> direct oral challenge, no skin testing - safe and now standard practice

A. Immediate

Stop the drug. In DRESS and SJS/TEN stop every non-essential drug started in the relevant window
Anaphylaxis -> IM adrenaline (see anaphylaxis note)
Document the reaction accurately - drug, date, latency, manifestation, severity - not simply "allergy"

B. By reaction type

Reaction	Management
Simple morbilliform exanthem	Cease drug, emollients, topical steroid, antihistamine for itch. Often can complete the course under supervision if no red flags
Urticaria/anaphylaxis	Adrenaline, antihistamine; autoinjector if the drug is unavoidable
DRESS	Systemic corticosteroid 0.5-1 mg/kg with a slow wean over 6-12 weeks - abrupt cessation causes relapse. Monitor LFT, creatinine, TFT, glucose
SJS/TEN	Burns unit or ICU. Fluid, thermoregulation, wound and eye care, analgesia. Ciclosporin or etanercept have the best supportive data; IVIg and steroids remain contested. SCORTEN for prognosis
AGEP	Cease drug, topical steroid; self-limiting over 1-2 weeks
Serum sickness-like	Cease drug, NSAID, short steroid course

C. Desensitisation

Induces temporary tolerance only - lost within days of stopping
For IgE-mediated reactions where the drug is essential and irreplaceable
- Penicillin in neurosyphilis or pregnancy, aspirin in AERD, chemotherapy (platinum, taxane)
Never for SJS/TEN, DRESS or AGEP

D. Prevention

*HLA-B57:01 before abacavir - mandatory**
HLA-B15:02 before carbamazepine in at-risk ancestry; HLA-B58:01 before allopurinol in Han Chinese, Thai, Korean
Start allopurinol at 50-100 mg/day and titrate slowly - dose-related hypersensitivity risk
Cross-reactivity
- Penicillin <-> cephalosporin: ~2%, driven by shared R1 side chain, not the beta-lactam ring
- Carbapenems and aztreonam are safe in almost all penicillin-allergic patients
- Aromatic anticonvulsants cross-react (carbamazepine, phenytoin, phenobarbitone, lamotrigine) - switch to levetiracetam or valproate
- "Sulfa" allergy to antimicrobial sulfonamides does not extend to thiazides, sulfonylureas, furosemide or celecoxib

HIV - high rate of cutaneous reactions to sulfonamides and antiretrovirals
EBV/CMV infection - amoxicillin exanthem
Cystic fibrosis - high cumulative antibiotic exposure
Chronic kidney disease - allopurinol hypersensitivity
SLE and Sjogren - increased reaction rate
HLA alleles as above
Penicillin allergy label: associated with more MRSA, C. difficile, VRE, longer stay and higher cost

Most exanthems resolve within 1-2 weeks of cessation with desquamation
IgE sensitivity wanes: ~80% of penicillin-allergic patients lose skin test reactivity by 10 years
- -> the biological basis of delabelling
DRESS: relapsing course over weeks-months; late autoimmune sequelae in 3-5% - thyroiditis, type 1 diabetes, autoimmune hepatitis, up to years later
- Check TFT and glucose at 3, 6 and 12 months
SJS/TEN: mortality by SCORTEN, TEN 25-35%
- Survivors - chronic ocular disease (symblepharon, blindness) in up to 50%, dyspigmentation, nail loss, oesophageal/genital strictures
- Lifelong absolute avoidance of the culprit and its cross-reactors
Provide a written allergy record and MedicAlert; update the electronic record

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