Adverse Drug Reactions — Written Clinical Reasoning

SAQ 1 — DRESS to Allopurinol in a Patient with Chronic Kidney Disease (20 marks, 30 minutes)

Prompt: Outline your structured assessment and management of this patient, including the clinical diagnosis and its classification, the causality assessment, the pharmacological reasoning for the dose error, the immediate and definitive management, the monitoring plan, the communication with the patient and family, and the discharge and follow-up plan. Justify each decision with reference to evidence and guideline recommendations. [1]

Model Answer

Diagnosis and classification (3 marks): [1]

This is Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) — a severe Type B (bizarre, idiosyncratic, dose-independent) adverse drug reaction. The diagnostic triad is met: fever, rash with facial oedema, and internal organ involvement (hepatitis and acute kidney injury), accompanied by marked eosinophilia (1.6 times ten to the ninth per litre). The timeline — onset four weeks after starting allopurinol — is the classical 2 to 8 week latency of DRESS, and allopurinol is one of the five canonical triggers (alongside aromatic anticonvulsants, minocycline, sulfonamides and dapsone). The RegiSCAR scoring system would classify this as probable or definite DRESS (fever, generalised lymphadenopathy, eosinophilia above 1.5, visceral involvement of liver and kidney, and the exclusion of alternatives all score positively). The reaction is not simple urticaria (which appears within hours to days, not weeks, and lacks visceral involvement) and is not SJS/TEN (no painful blistering, no mucosal involvement, no epidermal detachment). [1]

A critical iatrogenic contribution: allopurinol was started at 300 mg daily in a patient with an eGFR of 28. Allopurinol's active metabolite oxypurinol is renally cleared, and the dose must be reduced in renal impairment (starting at 50 to 100 mg daily, not 300 mg). The failure to dose-adjust is a Type A prescribing error that increased the oxypurinol exposure and therefore the risk of the Type B hypersensitivity reaction. The HLA-B*5801 allele, prevalent in Han Chinese, Thai and Korean populations and increasingly screened in ANZ practice before starting allopurinol, is a further risk factor that should be checked if relevant. [1]

Causality assessment (2 marks): [1]

Applying the Naranjo Adverse Drug Reaction Probability Scale: there are previous conclusive reports of allopurinol-induced DRESS (plus 1); the reaction appeared after allopurinol was administered (plus 1); the reaction is expected to improve on discontinuation (plus 1); rechallenge is ethically barred in severe Type B reactions so cannot be tested; there is no convincing alternative cause — the eosinophilia, hepatitis and timing all point to the drug (plus 1 for no alternative cause, scored as not minus 1); the reaction was more severe with a higher-than-appropriate dose (plus 1); objective evidence includes the eosinophilia and transaminitis (plus 1). The total score is in the probable range (5 to 8). Causality is probable rather than definite because rechallenge is not performed. The Naranjo scale assesses causality, not severity — the severity here is severe (visceral involvement, hospitalisation). [1]

Immediate management (5 marks): [1]

1. Stop the allopurinol immediately and permanently — the patient must never take it again. Document the reaction in the medication record and the adverse-reaction field, naming the drug, the reaction (DRESS), the date and the severity.
2. Admit for observation and supportive care — daily liver function tests and renal function for the first week, because DRESS can progress to fulminant hepatic failure, and the hepatitis and AKI may worsen before they improve.
3. Systemic corticosteroids for visceral involvement — the hepatitis and AKI justify oral prednisolone 0.5 to 1 mg per kg per day (approximately 50 mg per day), tapering slowly over weeks to months to prevent the relapses that characterise DRESS (partly driven by human herpesvirus 6 reactivation). Intravenous methylprednisolone would be used if the hepatitis were fulminant or the patient were haemodynamically unstable.
4. Stop any cross-reactive or interacting drugs — review the atorvastatin (a rare cause of DILI and a contributor to transaminitis) and hold it temporarily while the hepatitis is characterised; resume only if the DRESS attribution to allopurinol is clear.
5. Exclude alternative causes — viral hepatitis A, B, C and E serology, EBV and CMV, HIV, autoimmune hepatitis screen (ANA, SMA, immunoglobulins), and an abdominal ultrasound to exclude biliary obstruction.
6. Investigations to confirm — eosinophil count trend, liver function trend, renal function trend; consider a skin biopsy (lymphocytic infiltrate with eosinophils) if the diagnosis is uncertain; tryptase if there is any anaphylactoid component (not expected here). [1]

Monitoring and complications (3 marks): [1]

DRESS relapses in the first weeks in a substantial proportion of patients, even after the drug is stopped, partly via HHV-6 reactivation. The taper of corticosteroids must be slow and supervised. Long-term autoimmune sequelae — autoimmune hepatitis, type 1 diabetes, and autoimmune thyroiditis — are described and warrant follow-up for months. The acute complications to monitor for are: fulminant hepatic failure (a falling ALT with a rising INR and encephalopathy signals decompensation and the need for transplantation referral per the King's College criteria); superimposed infection from the immunosuppression; and the renal and hepatic recovery trajectory. [1]

Communication, discharge and follow-up (4 marks): [1]

I will explain to the patient and his family in plain language that the gout medication caused a serious allergic-type reaction affecting his skin, liver and kidneys, that the drug has been stopped permanently, and that he must never take allopurinol again. I will document the reaction clearly in the medication record, the adverse-reaction field, and a written alert letter for the patient to carry. I will report the reaction to the Therapeutic Goods Administration (TGA) via the Blue Card (or the MHRA Yellow Card in the UK) because it is a severe reaction to a marketed drug, and I will tell the patient I have done so. For his gout, I will arrange an alternative — colchicine for acute flares, and a uricosuric (probenecid) or a pegloticase infusion if he has severe tophaceous gout, weighing the renal function and the options. I will arrange follow-up with clinical immunology or dermatology for the slow corticosteroid taper and surveillance for autoimmune sequelae. I will review the prescribing error that started allopurinol at 300 mg in renal impairment as a systems-level lesson for the team. [1]

Insight (3 marks): [1]

The two systems-level errors here were: (1) starting allopurinol at full dose in significant renal impairment without dose adjustment, contrary to the gout guideline recommendation to start at 50 to 100 mg and titrate; and (2) not screening for HLA-B*5801 in a patient of an at-risk ethnic background. The lesson is that every prescription in a patient with renal impairment must be dose-adjusted, and that pharmacogenomic screening before high-risk drugs is increasingly standard of care. The patient's underlying gout will need a different strategy, and the communication must support his confidence in future medical care. [1]

SAQ 2 — Severe Cutaneous Adverse Reaction and SCORTEN (15 marks, 20 minutes)

Prompt: A 54-year-old woman with epilepsy (on lamotrigine for six weeks) presents with a two-day history of painful skin, blistering of the lips and oral mucosa, and conjunctivitis. On examination there is a confluent erythematous rash with flaccid bullae and sheet-like epidermal detachment over 15 per cent of the body surface area, with a positive Nikolsky sign. Her heart rate is 128 beats per minute, her temperature is 39.2 degrees, her serum urea is 12 mmol per litre, glucose 8 mmol per litre, and bicarbonate 18 mmol per litre. She has no malignancy. Calculate the SCORTEN, give the predicted mortality, and outline the immediate management. [1]

Model Answer

Diagnosis and classification (2 marks): [1]

This is Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) overlap — epidermal detachment of 10 to 30 per cent of body surface area, with the characteristic painful skin, mucosal involvement of two sites (oral and conjunctival), flaccid bullae, and a positive Nikolsky sign. The trigger is lamotrigine, an aromatic anticonvulsant started six weeks ago, which is within the classical 1 to 8 week latency. This is a severe Type B adverse drug reaction with mortality of 10 to 30 per cent. [1]

SCORTEN calculation (3 marks): [1]

Each of the seven components scores one point. Applied to this patient: [1]

Total SCORTEN = 5. A score of 5 carries a predicted mortality of approximately 90 per cent (SCORTEN 4 is about 58 per cent, 5 or more is above 90 per cent). The score should be recalculated at 48 hours as it can change. [1]

Immediate management (7 marks): [1]

1. Stop all suspected drugs immediately, especially the lamotrigine (started within the 1 to 8 week latency window) and any other drug that could plausibly be a trigger. This is the single most important intervention.
2. Transfer to an ICU or specialist burns unit — a SCORTEN of 5 mandates intensive care, and the management is the same as for severe thermal burns.
3. Fluid resuscitation using the burn formula (Parkland or modified Brooke), titrated to urine output and haemodynamics; the fluid losses from extensive epidermal detachment are large.
4. Nutritional support early — enteral feeding via a nasogastric tube; the catabolic state is profound.
5. Analgesia — these patients are in severe pain from denuded skin; opioid analgesia is usually required.
6. Infection surveillance and source control — daily clinical review, blood cultures as indicated, and narrow-spectrum antibiotics only for documented infection; prophylactic antibiotics are not recommended.
7. Meticulous eye care with urgent ophthalmology review — conjunctival involvement can progress to corneal ulceration, synechiae and blindness; topical lubricants, antibiotics and sometimes amniotic membrane grafting are used.
8. Skin care with biological dressings, silver-impregnated dressings, and careful handling.
9. Immune therapy is controversial — IVIG has been used historically but recent meta-analyses show no clear mortality benefit; corticosteroids are generally avoided in extensive disease because of the infection risk. The decision is made by the treating unit.
10. Prevent long-term sequelae — early ophthalmology, urology (for urethral strictures) and dermatology input; the patient will need prolonged rehabilitation. [1]

Reporting and follow-up (3 marks): [1]

Report the reaction to the TGA (Blue Card) or MHRA (Yellow Card) — this is a severe reaction to a marketed drug and is exactly the kind of signal that pharmacovigilance depends on. Document the reaction in the medication record and the adverse-reaction field permanently. The patient must never take lamotrigine again and, because of the cross-reactivity among aromatic anticonvulsants, should avoid carbamazepine, phenytoin and phenobarbital as well; levetiracetam or sodium valproate are the usual alternatives, chosen with the neurologist. Long-term follow-up addresses the ocular, skin, urological and psychological sequelae that follow severe SJS/TEN. [1]