Categories of Delayed-type Hypersensitivity Drug Rashes



Common (>80%)
Exanthematous drug eruptions (aka morbilliform or maculopapular drug eruptions)
  • Appear 4-21 days after starting the drug
  • Patients with HIV or BMT are at increased risk
  • Rash appearance variable
    • Maculopapular or morbiliform eruptions - often characterized by pink-to-red macules and papules (often pruritic) that spread rapidly and may coalesce; scaling/peeling can occur with resolution of the exanthem
    • Usually begins on trunk, spreads to extremities, typically symmetric
    • Urticarial lesions, angioedema, fixed drug eruptions, photosensitivity are less common manifestations of drug eruptions
Less Common
Urticaria and/or angioedema
  • These symptoms can also be non-IgE-mediated
  • Urticaria is the most common skin manifestation of serum sickness; however, the presence of maculopapular lesions on the sides of the fingers and toes or a serpiginous distribution of such lesions along the lateral aspects of both soles might be more specific
Fixed drug eruptions
  • Can present as eczematous lesions, papules, vesicles, or urticaria and occasionally involve the oral mucosa
    • Common anatomic locations include the lips, hands, and genitalia (especially males)
  • Often appear round or oval, sharply demarcated, red to livid, slightly elevated plaques ranging from a few mm to cm in diameter
  • Typically occur within 1-2 wks of drug exposure but might recur more rapidly with re-exposure
Erythema multiforme major
  • Target lesions with or without blisters
  • Compared to SJS, causes symmetric, mainly acral lesions, and mucosal involvement is less severe and less frequently involves 2 or more mucosal lesions
  • Occurs mainly after HSV infection and less frequently is drug induced, and the prognosis is usually benign
Acneiform

Pruritus

Uncommon
  • Acanthosis nigricans
  • Alopecia
  • Aphthous stomatitis
  • Black hairy tongue
  • Bullous eruptions
  • Erythema nodosum
  • Exfoliative dermatitis
  • Gingival hyperplasia
  • Lichenoid eruptions
  • Lupus erythematosus
  • Phototoxic/photoallergic
  • Pigmentation
  • Pityriasis rosea–like eruptions
  • Psoriasis
  • Purpura
  • Vasculitis
Severe
AGEP
  • Rare, begins with erythema or edema in the intertriginous areas or face followed by generalized fine nonfollicular sterile pustules. Fever, neutrophilia, and eosinophilia can also be present.
  • Should be distinguished from other causes of infectious pustules, such as candidiasis, gonococcemia, impetigo, and bacterial folliculitis
SJS/TEN
  • Large scale epidermal death (mucous membrane erosions, target lesions, and epidermal necrosis with detachment), almost always drug-induced
    • Hallmarks include fever (universal), conjunctivitis, pharyngitis, pruritis, painful skin
    • SJS is usually classified as <10% BSA involvement, TEN >30% BSA, 10-30% is overlap syndrome
    • Multi-organ involvement can occur
    • Mortality 5-10% for SJS, 30-50% for TEN
DRESS



Comparison

Delayed drug comparison.png


Onset of Delayed Drug Rashes (Pichler)

Onset of Delayed Drug Rash.png


Drug-HLA-Severe Rash Associations

Pharmacogenomic biomarkers drug allergy.png
HLA drug rash associations.png
High = point estimate relative risk ≥ 10 and significant and/or incidence ≥1 per 10,000 users
Mid = point estimate of relative risk ≥ 5 and < 10 and significant
SA = Suspected association based on detection of genetic association of increased risk of hypersensitivity reactions to this drug which is highly likely to include cases of DRESS with this drug or ≥ 5 suspect cases
†Whites ‡Han Chinese and/or other non-Japanese Asians §Japanese ¶ pooled estimate for all antiepileptic drugs listed below




Drug-Reaction Associations

Drugs rarely causing cutaneous eruptions
  • Antacids
  • Antihistamines (oral)
  • Atropine
  • Benzodiazepines
  • Corticosteroids
  • Digoxin
  • Ferrous sulphate
  • Insulin
  • Laxatives
  • Local anaesthetics (other than topical)
  • Muscle relaxants
  • Nitrates
  • Nystatin
  • Oral contraceptives
  • Propranolol
  • Spironolactone
  • Theophylline
  • Thyroid hormones
  • Vitamins

Drugs commonly causing exanthematous reactions
  • Allopurinol
  • Antimicrobials: cephalosporins, penicillins, chloramphenicol, erythromycin, gentamicin, amphotericin, antituberculous drugs, nalidixic acid, nitrofurantoin, sulfonamides
  • Barbiturates
  • Captopril
  • Carbamazepine
  • Furosemide
  • Gold salts
  • Lithium
  • Phenothiazines
  • Phenylbutazone
  • Phenytoin
  • Thiazides

Drugs commonly causing fixed drug eruption
  • ACE inhibitors
  • Allopurinol
  • Antimicrobials: co-trimoxazole, sulfonamides, tetracyclines, cephalosporins, penicillin, clindamycin, trimethoprim, metronidazole
  • Barbiturates
  • Benzodiazepines
  • Calcium channel blockers: amlodipine, diltiazem
  • Carbamazepine
  • Dextromethorphan
  • Diltiazem
  • Fluconazole
  • Lamotrigine
  • NSAIDs, including aspirin
  • Paclitaxel
  • Paracetamol
  • Phenolphthalein
  • Proton pump inhibitors: omeprazole, lansoprazole
  • Quinine
  • Salicylates
  • Terbinafine

Drugs commonly causing psoriasiform eruptions or exacerbate psoriasis
  • ACE inhibitors
  • Beta-blockers
  • Chloroquine and hydroxychloroquine
  • Digoxin
  • Gold
  • Granulocyte colony-stimulating factor (G-CSF)
  • Interferons
  • Lithium
  • NSAIDs
  • Penicillamine
  • Terbinafine
  • Tetracyclines
  • TNF-alpha antagonists

Drugs commonly causing cutaneous vasculitic reactions
  • Allopurinol
  • Aspirin
  • Beta-lactam antibiotics
  • Carbamazepine
  • Carbimazole
  • Co-trimoxazole
  • Diltiazem
  • Erythromycin
  • Furosemide
  • Gold
  • Haemopoietic growth factors (G-CSF and GM-CSF)
  • Hydralazine
  • Interferons
  • Methotrexate
  • Minocycline
  • NSAIDs
  • Penicillamine
  • Propylthiouracil
  • Retinoids
  • Sulfasalazine
  • Sulfonamides
  • Thiazides
  • Thrombolytic agents

Drugs commonly causing EMM, SJS, TEN
  • Allopurinol
  • Anti-tuberculous drugs
  • Barbiturates
  • Beta-lactam antibiotics*
  • Carbamazepine*
  • Chlorpropamide
  • Co-trimoxazole
  • Gold
  • Griseofulvin
  • Histamine H2-antagonists
  • Lamotrigine*
  • Leflunomide
  • Macrolides
  • Mefloquine
  • Nevirapine*
  • Nitrofurantoin
  • NSAIDs (expecially oxicams)*
  • Pantoprazole*
  • Phenothiazines
  • Phenytoin*
  • Rifampicin
  • Salicylates
  • Sertraline*
  • Sulfonamides*
  • Tetracyclines
  • Thiazides
  • Tramadol*
*Higher risk for SJS/TEN

Drugs commonly causing blistering drug eruptions
Pemphigus
  • Captopril
  • Cephalosporins
  • Penicillin
  • Penicillamine
  • Piroxicam
  • Gold/sodium aurothiomalate
Bullous pemphigoid
  • Furosemide
  • ACE inhibitors (captopril, enalapril)
  • Penicillin
  • Penicillamine
  • Chloroquine
  • Sulfasalazine
IgA bullous dermatosis
  • Captopril
  • Ceftriaxone
  • Co-trimoxazole
  • Furosemide
  • G-CSF
  • Interleukin-2
  • Lithium
  • NSAIDs
  • Penicillin
  • Rifampicin
  • Vancomycin
Pseudoprophyria cutanea tarda
  • NSAIDs
  • Tetracycline
  • Thiazides
  • Furosemide

Drugs commonly causing photosensitivity reactions
Frequent
  • Amiodarone
  • NSAIDs
  • Phenothiazines (particularly chlorpromazine)
  • Retinoids
  • Sulfonamides
  • Tetracyclines (particularly demeclocycline)
  • Thiazides
Less frequent
  • Antidepressants (tricylic, MAOIs)
  • Antifungals
  • Antimalarials
  • Benzodiazepines
  • Beta-blockers
  • Carbamazepine
  • Griseofulvin
  • Oral contraceptives
  • Quinine
  • Quinolones
  • Retinoids
  • St John’s Wort
  • Sulphonylureas

Drugs associated with other integumentary changes
  • Pigmentation
    • Amiodarone (slate grey)
    • Chloroquine (blue-grey or brown)
    • Chlorpromazine (blue-grey)
    • Cytotoxic agents
    • Gold (blue-grey)
    • Hydroxychloroquine
    • Imatinib
    • Mepacrine (yellow)
    • Minocycline
    • Oral contraceptives (brown)
    • Phenytoin (brown)

  • Alopecia
    • Amphetamines
    • Anticoagulants (warfarin, heparin, heparinoids)
    • Antidepressants
    • Antithyroid drugs
    • Beta-blockers
    • Carbamazepine
    • Cimetidine
    • Cytotoxic agents
    • Hypolipidaemics
    • Interferons
    • Leflunomide
    • Lithium
    • Oral contraceptives
    • Phenytoin
    • Retinoids
    • Tamoxifen
    • Valproate

  • Hypertrichosis
    • Androgens
    • Ciclosporin
    • Diazoxide
    • Methoxsalen
    • Minoxidil
    • Nifedipine
    • Penicillamine
    • Phenytoin
    • Verapamil

  • Nail disorders
    • Captopril
    • Chloramphenicol
    • Chlorpromazine
    • Cytotoxic agents
    • Fluoroquinolones
    • Gold
    • Lithium
    • Methoxsalen
    • Penicillamine
    • Phenytoin
    • Retinoids
    • Tetracyclines
    • Thiazides

Drugs commonly causing eczematous reactions
  • Gold: lichenoid features, may progress to erythroderma
  • Bleomycin
  • Penicillin
  • Chloramphenicol
  • Quinine
  • Beta-blocker
  • Methyldopa
  • Clonidine


Diagnosis

  • H&P alone is often sufficient
  • Signs of a serious drug rash that should always be identified:
drug allergy alert signs.png

Lab Testing (Pichler)

  • LFTs - in patients with severe/generalized maculopapular rashes, 25% will have liver inflammation
  • CBC/diff
    • Eosinophilia (>0.6 g/L) is common (50%) and typical for delayed drug hypersensitivity
    • Presence of activated atypical lymphocytes is a sign of severe delayed drug hypersensitivity reaction (also seen in acute EBV, acute HIV, acute Still's disease)
  • BUN/Cr may demonstrate renal involvement
  • CRP may be normal or elevated
  • Lymphocyte transformation tests are specific but not sensitive


Skin Biopsy

  • When diagnosis is less clear, biopsies can aid in differentiating vasculitis, bullous diseases, and contact dermatitis
    • Note that there are no absolute histologic criteria for the diagnosis of drug-induced eruptions, and biopsy might not definitively exclude alternative causes
    • Histopathologic features of interface dermatitis, spongiosis, and tissue eosinophilia are not specific and can be seen with other cutaneous diseases.
  • Best lesions to biopsy are evolving or recent skin lesions, and the biopsy should be performed at the edge of the lesion
  • Immunofluorescence stains are important in the evaluation of bullous lesions


Drug Challenge



Drug Rash Likelihood Algorithm (Stern)

Drug rash likelihood algorithm.png



References