Drug Reactions Flashcards
Drug induced exanthem
Drugs - PSCAN Penicillin, ampicillin Sulphonamides Carbamazepine, phenytoin Allopurinol NSAIDs
Onset -
1-2 weeks
Features - Itchy Fades with desquamation +/- PIH Trunk, extremities, flexures, palms/soles Spares face, pressure areas
DDx -
Viral exanthem I.e. measles, chicken pox
DRESS
Complications -
Exfoliative dermatitis if drug continued
Mx -
Cease drug
Exclude DRESS I.e. systemic involvement —> bloods
Exclude viral exanthem —> viral PCR, serology
Biopsy if clinical features not characteristic -
- Non specific
- Apoptotic keratinocytes
- Eosinophils
- Papillary oedema
- Perivascular changes
Rx -
Emollients
Mid potency TCS if itchy
Drug-induced pruritus
Drugs - NASSOP NSAIDs ACE-inhibitor Statins Sulphonylureas Opiods Paclitaxel
Onset -
Days
Features - No dermographism (unlike urticaria) Secondary changes I.e. Excoriation, lichenification
Mx -
Exclude causes of itchy without rash
Cease drug
Rx -
0.5% menthol cream
Antihistamines. - but rarely helpful
Systemic allergic contact dermatitis (Drug-induced eczema)
Patient who is sensitised to topical drug develops a rash when the same drug or similar drug is taken systemically
Topical ethylenediamine —> ethylenediamine used as solubiliser for theophylline
Topical parabens —> Drugs containing parabens as preservative
PPD hair dye/PABA sunscreen/benzocaine local anaesthetic —> tolbutamide/chlorpropamide
Topical sulphanilamide —> sulphonylureas
Topical Phenothiazines —> antihistamines
Thiurams in rubber gloves —> disulfiram
OR
Eczematous reaction to systemic drug without prior contact sensitisation
- Penicillin esp beta lactams
Mx -
Cease drug
Patch testing
Oral challenge to confirm/substantiate Dx
Rx -
TCS
May need pred if severe
Endogenic contact eczema (drug induced eczema)
Patient sensitised to systemic drug later develops localised eczema from topicals
Drug - Aminophylline Analgesia - paracetamol, NSAIDs, opiods Antihistamines - cetirizine, diphenhydramine, hydroxyzine 5-FU 8-methoxypsoralen 5-aminosalicylic acid Oestradiol
Onset -
1-2 weeks
Course -
Resolution 1-3 weeks
DDx -
Endogenous eczema
ACD
ICD
Mx -
Cease drug
Patch testing
Oral challenge to confirm/substantiate Dx
Rx -
TCS
May need pred if severe
Symmetrical drug related intertriginous and flexural exanthem SDRIFE (distinct variant of drug induced eczema)
Drug - Penicillin Cephalosporin Clindamycin Erythromycin NSAIDs Telmisartan HCT Terbinafine
Onset -
Hours - days
Features - Symmetrical eczematous sharp erythema Buttock, gluteal, perineal, thighs Flexures - neck, axilla, elbows, knees Spares palms/soles, mucosa, face No systemic symptoms
DDx - Inflammatory - - ACD/ICD - Inverse psoriasis - Hailey-Hailey disease Infection - - Intertrigo - Tinea cruris Other drug eruptions - - AGEP - Chemo- assoc toxic erythema - Neutrophilic eccrine hidradenitis
Mx - Cease drug, avoid in future Patch testing - 50% positive Oral challenge - 80% positive N.B. Prick testing neg
Rx -
Emollients
TCS/pred may speed recovery
Drug induced urticaria, angioedema, anaphylaxis
Urticaria drug - NSAIDs I.e. aspirin
Anaphylaxis drug - NSAIDs Opiods Beta-lactam antibiotics Thiopental anaesthetic Neuromuscular blockers Blood transfusion
Onset -
First exposure 24-36 hrs
Rechallege mins
Anaphylaxis usually occurs after second exposure mins to hrs
Course -
Urticaria/angioedema lasts 24-48 hrs
Anaphylaxis assoc with late phase reactions 5-6 hrs after initial improvement
Drug induced serum sickness like reaction
Drug - Penicillin Cefaclor/cephalosporins Minocycline Infliximab Rituximab Omalizumab Bulpropion
Onset -
1 week
Features - Clinical triad - - Fever - Rash —> migratory itchy urticarial wheals, sometimes with purpuric dusky centres simulating erythema multiforme +/- facial/periorbital oedema - Arthralgias/arthritis —> hands, feet Children Spares mucous membranes Rarely involves kidney/liver
Histo - Urticarial reaction pattern - - Dermal oedema - Superficial + deep perivascular lymphocytes, nests, eosinophils - No vasculitis
Course -
3 days up to 1 week
DDx (urticarial eruption + fever + arthralgias) -
Urticarial vasculitis
Still disease
Schnitzler syndrome
Hereditary inflammatory diseases
Infections - Kawasaki disease, parvovirus B19
Mx -
Cease drug
Drug provocation testing positive (safe to be done if Dx needs confirmation)
Rx -
Antihistamines
Anti-pyretics
Pred
Lichen planus-like lichenoid drug eruption (subtype 1 of lichenoid drug eruptions)
Drug - Antimalarials Penicilliamine NSAIDs Gold Amalgam Thiazides
10% of LP is drug related
Onset -
Months to years
Features -
As in idiopathic LP
Photodistributed variant
Mucosal variant
Histo clues to drug trigger - Less dense infiltrate, but polymorphic I.e. plasma cells, eosinophils Focal parakeratosis Focal interruption to granular layer Night riding apoptotic keratinocytes More apoptotic keratinocytes in clusters
Course -
Weeks to months
Mx -
Cease drug
Biopsy
Rx -
Potent/super potent TCS
Severe cases pred
Drug induced lupus erythematosus lichenoid drug eruptions (subtype 2 of lichenoic drug eruptions)
Drug - ACE-inhibitor I.e. captopril Beta clocker I.e. atenolol Calcium channel blocker I.e. diltiazem Diuretics I.e. thiazides Statins Terbinafine Sulfasalazine Isoniazid
10% of LE is drug related
Onset -
Months to years
Features -
SLE > SCLE
Histo -
Lymphocyte cell poor compared to LP-like lichenoid drug eruption
Histo clues to drug trigger - Less dense infiltrate, but polymorphic I.e. plasma cells, eosinophils Focal parakeratosis Focal interruption to granular layer Night riding apoptotic keratinocytes More apoptotic keratinocytes in clusters
Course -
Weeks to months
Mx -
Cease drug
Biopsy
ANA, ENA, anti-histone antibody
Rx -
Potent/super potent TCS
Severe cases pred
Drug induced pityriasis rosea
Drug - ANGORITV ACE-inhibitor NSAIDs Gold Omeprazole Rituximab Isotretinoin TNF-alpha inhibitors Vaccinations
Onset -
1-6 weeks
Features (comparison to idiopathic pityriasis rosea) - Reaction is dose dependent Fever Oral lesions Itchy No Herald patch Larger lesions Bright red Variable christmas tree distribution Rash > 2 months
DDx (pityriasiform rash) - Classic/idiopathic pityriasis rosea Secondary syphilis Pityriasis lichenoides chronica Guttate psoriasis Nummular (discoid) eczema
Course -
If drug ceased —> 1-2 weeks
If drug not ceased —> more than 8 weeks
Mx -
Cease drug —> resolves w/o Rx
Oral provocation test to confirm Dx (not routinely done)
Rx -
TCS in stubborn cases
Drug induced acneiform eruptions
DRUG Hormones - Steroids Anabolic steroids Androgens Contraceptives
Neuropsych - Tricyclic antidepressants Lithium Valproate Phenytoin
Immunomodulators -
CSA
AZA
Sirolimus
Vitamin B1, B6, B12
G-CSF
Halogens -
Iodine
Bromide
Chlorine
Chemo -
EGFR inhibitors
Imatinib
Vorinostat
Anti-TB -
Rifampicin
Isoniazid
ONSET
1-2 weeks eGFR inhibitors
<1 month - steroids, androgens, vit B
>1 month - CSA, lithium, antiepileptics, anti-TB
FEATURES
Monomorphic papules, pustules
Lacks comedones/cysts
EGFR inhibitors —> seborrhoeic I.e. neck, chest, shoulders, upper back
Can be widespread and extend beyond seborrhoeic areas I.e. arms, lower back, genitals
DDx -
Acne vulgaris
Gram neg folliculitis
Pityrosporum folliculitis
Mx -
Drug cessation ought to be balanced against drug indication and if an alternative is available
Rx -
Topical + systemic acne vulgaris Rx
Fixed drug eruption
DRUG - NPPPTT NSAIDs (genital + lips) Paracetamol Pseudoephedrine Penicillin Trimethoprim-sulfamethoxazole (genital) Tetracyclines (genital)
Onset 30 mins - 8 hours
DRUG-SPECIFIC VARIANTS NSAIDs - genital + lips Trimethoprim-sulfamethoxazole - genital Metamozole - trunk + extremities Carbocysteine - face
CLINICAL VARIANTS
Lips, genitals, palms, soles
Mucosa only
Generalised bullous fixed drug
DDX MUCOSAL VARIANT HSV Aphthous stomatitis Pemphigus vulgaris SJS
DDX GENERALISED BULLOUS FIXED DRUG
SJS/TEN
Bullous pemphigoid
DDX HEALED FIXED DRUG ERUPTION LESIONS (pigmentation)
Erythema dyschromium perstans
COMPLICATIONS No systemic symptoms No mucosal involvement Denudation associated with 20% mortality rate —> care as in SJS/TEN PIH for several months
IX
Gold standard - Oral provocation test to confirm causality (not performed in generalised bullous fixed drug due to mortality risk)
Alternative - patch testing with reagents placed on skin lesion sites (50% positive)
HISTO
Interface dermatitis (vacuolar degeneration of basal keratinocytes)
Lymphocyte exocytosis
Perivascular lymphocytic infiltrate upper dermis +/- eosinophils
Dermal oedema
Melanin incontinence
MX
General measures -
Cease drug
Manage generalised bullous fixed drug eruption in Burns Unit
Treatment -
TCS
Prednisone if multiple lesions
Drug induced erythema nodosum
DRUG - PSBMIOHAV Penicillin Sulphonamides Bromides Minocycline Isotretinoin OCP HRT AZA Vaccinations I.e. Hep, HPV
Drug induced septal panniculitis w/o vasculitis
Onset -
Few weeks
Features -
Symmetrical red tender subcut nodules/plaques
No ulceration
Anterior limbs LL > UL
Purple —> brown over days
Sometimes systemic involvement I.e. fever, visceral involvement as part of drug hypersensitivity disorder (minocycline, AZA)
Course -
After drug ceased —> 2-4 weeks
Mx -
Cease drug
Exclude other causes of erythema nodosum
Rx -
NSAIDs (reduce pain, inflammation)
Compression (reduce pain, inflammation)
Pred needed very rarely
Acute generalised exanthematous pustulosis (AGEP)
Drug - TADASQ Terbinafine Anti-malarials I.e. HCQ, CQ Diltiazem Aminopenicillins Sulphonamides Quinolones
SCAR (severe cutaneous adverse reaction) syndrome
2-5 days after drug exposure
Prodrome of burning, itching
Rapid onset, rapid resolution
Rapid appearance of sheets of non-follicular sterile pustules Background of oedematous erythema \+/- atypical targets \+/- Purpura \+/- blisters \+/- vesicles Localised to major flexures - neck, axillae, inframammary, inguinal folds \+/- non flexural sites Mucosal involvement rare —> mild, limited to single site usually mouth \+/- Systemic involvement - - fevers - WCC, typically neuts - Agranulocytosis - lungs - liver - renal Self limiting Resolves without sequelae Possible genetic predisposition —> IL36RN gene No personal/fam Hx psoriasis
Variant —> Acute localised exanthematous pustulosis (ALEP)
- Pustules confined to single body site, typically neck
Assoc - Infections - - Mycoplasma pneumoniae - Coxsackie virus - Parvovirus - CMV Spider bite Mercury exposure
DDx PUSTULAR PSORIASIS (Von Zumbusch variant)
Hx of psoriasis
More generalised distribution pattern
Longer duration of pustules
Longer duration of fever
Arthritis
Uncommon history drug
Less frequent recent drug administration
Subcorneal/intraepidermal pustules + papillomatosis + acanthosis
Other DDx -
Subcorneal pustular dermatosis (Sneddon Wilkinson disease) —> less acute, flaccid pustules
DRESS —> may feature pustules, but less numerous, organ involvement
Candidosis —> pustules in flexures, yeast on MCS
Histo -
Marked spongiosis
Subcorneal/Intraepidermal spongiform pustules, vesicles
Perivascular infiltrate —> neuts +/- eos
Infrequent necrotic keratinocytes
Papillary dermal oedema
Leukocytoclasis
Classic psoriasis histo features I.e. papillomatosis, acanthosis ABSENT
Ix -
Careful drug Hx
Skin biopsy of early lesions
FBC - Neutrophilic, eosinophilia
ELFTs - rule out liver, renal dysfunction, hypocalcaemia
CRP - distinguish infection from systemic involvement in AGEP
+/- septic screen if highly suspect infection I.e. fevers
Mx -
Avoid culprit drug
Emollients until full skin integrity restored
Limited disease, systemically well —> TCS
Extensive disease + fever + systemic involvement —> Pred
Renal/liver dysfunction —> monitor, IVF
Empiric ABs pending septic screen, if can’t exclude infection
ICU/organ support not required
Drug reaction with systemic symptoms and eosinophilia (DRESS)
DRUGS - AAASIFO Anticonvulsants —> carbamazepine, phenytoin, lamotrigine Allopurinol Antibiotics —> amoxicillin, piperacillin/tazobactam, vancomycin, minocycline Sulpha drugs —> sulphasalazine, dapsone Ibuprofen Furosemide Omeprazole
ASSOC
Anticonvulsants —> neuro/neurosurgical patients —> carbamazepine reactions —> general population (HLA-DR3, HLA-DQ2), south East Asians (HLA-B1502), white + Chinese + Japanese (HLA-B3101)
Allopurinol —> Rheum patients —> Han Chinese + Portuguese (HLA-B5801)
Antibiotics —> patients with fever
Antivirals I.e. abacavir —> white HIV patients (HLA-B5701)
Latent herpesvirus reactivation in sequential fashion d/t drug induced immunosuppressed state characterised by hypogammaglobulinaemia —> HHV-6 + EBV (detected early in course of disease), HHV-7 + CMV (detected later in disease) ? Bystander phenomenon vs direct cause rash, fever, haem, solid organ dysfunction
Family Hx esp carbamazepine in white + Chinese + Japanese (HLA-B*3101)
Severe cutaneous drug reaction (SCAR) syndrome @ drug induced hypersensitivity syndrome Idiosyncratic Multisystem Onset 2-6 weeks post culprit drug
PRODROMAL PHASE Asthenia Malaise Fatigue \+ Fever
ACUTE PHASE
+ Rash of variable morphology —> urticated papular exanthem (widespread papules and plaques with skin oedema) > morbiliform (pink macules) > Erythroderma (widespread exfoliative erythema) > EM-like (dusky/purpuric atypical targets, more commonly assoc with more severe liver dysfunction)
+/- pustules
+/- Facial (head and neck) swelling esp ears
Cheilitis
Sequential Systemic involvement
+ LN x 2 nodal basins
+ Haem disturbance —> eosinophilia (fluctuates over initial phase, but settles in tandem w/ overall clinical improvement), WCC, atypical lymphocytes on blood film, lymphocytosis, lymphopenia (? Viral induced), thrombocytosis, thrombocytopenia
+ Liver (esp phenytoin, minocycline, dapsone) —> hepatocellular, obstructive patterns —> spectrum of mild transient hepatitis to fulminant liver failure
+/- Lung —> pleural effusion, pleuritis, Acute interstitial pneumonitis
+/- cardiac/pericardial —> myocarditis, pericarditis —> beware Acute Necrotising Eosinophilic Myocarditis (ANEM) —> 50% mortality
+/- spleen
+/- Kidney (esp allopurinol) —> interstitial nephritis
+/- GI —> intestinal, pancreas —> diarrhoea
+/- CNS
MX ACUTE PHASE
Identify and withdraw culprit drug
Exclude unnecessary drugs
Surveillance for co-exisiting infection I.e. skin, other organs —> no ABS if no signs of infection
IVF for dehydration
Thermoregulation for fevers
Urinary catheter for fluid balance
Oxygen
Derm —> skin directed Rx —> emollients, TCS
CS Rx - topical/PO/IV as guided by severity of disease
Refractory cases —> steroid sparred I.e. CSA
Hepatology if involved
Cardiology if involved
Renal med if involved
Resp med if involved
FIRST LINE RX
PO pred 1mg/kg/d tapered over 1-3 months
If PO pred failed to produce satisfactory improvement —> Methylpred IV 1g daily for 3 days
Limited severity, minimal skin involvement + can’t have systemic CS —> Potent TCS
SECOND LINE RX
Refractory to CS I.e. persistent liver dysfunction, chronic exfoliative dermatitis —> CSA
IVIg (conflicting evidence)
THRID LINE RX Plasmapheresis Cyclophosphamide Rituximab Valganciclovir NAC as adjunct —> helps detoxify anticonvulsants
PROGNOSIS typically < 4 weeks duration Few/no sequelae Mortality usually from liver dysfunction Diabetes secondary to systemic CS
CHRONIC PHASE
minority enter chronic phase I.e. persistence of skin rash/systemic involvement
? D/t persistence of viral reactivation
SEQUELAE —> autoimmune phenomena —> ? Protective role of systemic CS against this
thyroid —> autoimmune hyper/hypothyroidism —> reg TFT monitoring for 1 yr after acute event
Type 1 DM —> fasting gluc
Alopecia areata
SLE
Chronic exfoliative dermatitis
IX
Haem - FBC + diff, blood film
Liver - LFT, LDH, ferritin (acute phase reactant), coag screen, Hep BC (exclude cause of hepatitis), EBV, CMV, HHV6, HHV7
Cardiac - ECG, CK, tropnonin +/- ECHO
Lung - CXR +/- PFT
Renal - UEs, calcium, urinalysis (proteinuria, haematuria) +/- USS
GI (pancreatitis) - amylase +/- lipase, triglycerides
Infection - blood cultures, mycoplasma serology
CNS - CSF MCS +/- CT/MRI head, EEG
Autoimmune (SLE) - ANA, ENA, C3C4, ANCA
Endocrine (thyroid, diabetes) - TSH, TFT, blood glucose
HISTO (varies widely)
Spongiosis
Superficial perivascular lymphocytic + eosinophilia infiltrate
+/- lichenoid infiltrate
+/- basal cell vacuolar degeneration, necrotic keratinocytes
DIAGNOSTIC CRITERIA —> RegiSCAR DRESS scoring system
> 50% BSA rash
Rash suggestive of DRESS
Systemic -
- LN x 2 sites at least 1 cm diameter
- Eos
- Atypical lymphocytosis
- Organ involvement —> liver, creat, echo pericarditis
- at least 3 Relevant neg serological tests —> Hep ABC, mycoplasma/chlamydia, ANA, Blood cx
DDX
sepsis/infection
Epidermal loss/Purpura/target lesions —> EM, SJS/TEN, systemic vasculitis
Pustules —> AGEP
Erythroderma/exfoliative erythema —> CTCL/sezary, Acute eczema, acute psoriasis
