Adverse Drug Reactions — Viva Defence

Long Case Viva — DRESS to Allopurinol in a Complex Elderly Man

Examiner's opening question

"You have 90 seconds to present this patient. A 66-year-old man with chronic kidney disease (eGFR 28), gout, hypertension and ischaemic heart disease was started on allopurinol 300 mg daily four weeks ago for recurrent gout flares. He now presents with fever, a morbilliform rash with facial oedema, generalised lymphadenopathy, eosinophils 1.6 times ten to the ninth per litre, ALT 280 U per litre, bilirubin 36 micromol per litre, and creatinine 195 micromol per litre. His medications are amlodipine, atorvastatin, aspirin, frusemide and allopurinol. Present." ^[1]

Candidate's opening statement (SASPOP format)

"A 66-year-old man with a five-day history of fever, rash and dark urine (symptoms), aged 66 (age), male (sex), presenting acutely unwell to the emergency department (presentation), who is a retired engineer (occupation), with the following problems: (1) Drug Reaction with Eosinophilia and Systemic Symptoms — DRESS — to allopurinol, a severe Type B adverse drug reaction with hepatitis and acute kidney injury; (2) chronic kidney disease stage 4 with an eGFR of 28; (3) gout; (4) ischaemic heart disease on secondary prevention; (5) hypertension; and (6) a prescribing error — allopurinol started at 300 mg in significant renal impairment without dose adjustment, which increased the risk of this reaction. The immediate threats to life are the hepatitis, which may progress to fulminant hepatic failure, and the acute kidney injury. My immediate plan is to stop the allopurinol permanently, admit for observation, and start systemic corticosteroids for the visceral involvement." ^[1]

Examiner probe 1 — diagnosis and classification

"Defend your diagnosis of DRESS. What is DRESS, and how does it differ from Stevens-Johnson syndrome?" ^[1]

"DRESS — Drug Reaction with Eosinophilia and Systemic Symptoms — is a delayed, immune-mediated, multi-organ hypersensitivity reaction that typically occurs 2 to 8 weeks after first exposure to a culprit drug. The culprits are the aromatic anticonvulsants (phenytoin, carbamazepine, lamotrigine, phenobarbital), allopurinol, minocycline, the sulfonamide antibiotics, dapsone and abacavir. The clinical picture is a triad of fever, a morbilliform rash with facial oedema, and internal organ involvement — most often the liver but also the kidney, lung and heart — accompanied by a marked eosinophilia and generalised lymphadenopathy. This patient has the full picture: the latency of four weeks, the fever, the morbilliform rash with facial oedema, the lymphadenopathy, the eosinophilia of 1.6 times ten to the ninth, and the hepatitis and acute kidney injury. On the RegiSCAR scoring system this would be probable or definite DRESS. ^[1]

The distinction from Stevens-Johnson syndrome is the pattern of the skin and mucosa. SJS and TEN present with painful blistering, target lesions, flaccid bullae, sheet-like epidermal detachment and mucosal involvement of at least two sites — the patient is in pain, the skin sloughs, and the Nikolsky sign is positive. DRESS presents with a morbilliform rash and facial oedema, with no blistering, no detachment and a negative Nikolsky sign, but with eosinophilia and visceral involvement. The two share some triggers — allopurinol can cause either — but the clinical signatures are distinct. The classification matters because the management and the prognosis differ: SJS/TEN has a mortality of 10 to 30 per cent and is managed in a burns unit, while DRESS has a mortality of 5 to 10 per cent and is managed with corticosteroids." ^[1]

Examiner probe 2 — causality and the prescribing error

"How confident are you that allopurinol caused this? And why was the dose an error?" ^[1]

"I would apply the Naranjo Adverse Drug Reaction Probability Scale. There are previous conclusive reports of allopurinol-induced DRESS (plus 1); the reaction appeared after the drug was started (plus 1); the reaction will improve when the drug is stopped (plus 1); rechallenge is ethically barred in a severe Type B reaction so cannot be tested; there is no convincing alternative cause — the eosinophilia, hepatitis and timing are all consistent with the drug (plus 1 for no alternative cause); the reaction was more severe because the dose was too high for the renal function (plus 1); and there is objective evidence in the eosinophilia and transaminitis (plus 1). The total is in the probable range. In practice, causality in severe Type B reactions rests on the temporal relationship, dechallenge, and exclusion of alternatives, because rechallenge is not done. ^[1]

The dose was an error because allopurinol's active metabolite oxypurinol is renally cleared, and the dose must be reduced in renal impairment. In a patient with an eGFR of 28, the starting dose should have been 50 to 100 mg daily, titrated upward against the serum urate — not 300 mg. Starting at 300 mg produced a higher oxypurinol exposure and increased the probability of the Type B hypersensitivity reaction. This is an example of a Type A prescribing error (a dose-related mistake) that increased the likelihood of a Type B reaction. In addition, the HLA-B*5801 allele, prevalent in Han Chinese, Thai and Korean populations, strongly predicts allopurinol-induced SJS/TEN and DRESS, and screening is increasingly standard of care in those populations in ANZ practice." ^[1]

Examiner probe 3 — immediate management

"Take me through your immediate management in detail." ^[1]

"First, I stop the allopurinol immediately and permanently, and document the reaction in the medication record and the adverse-reaction field, naming the drug, the reaction, the date and the severity. The patient must never take allopurinol again. ^[1]

Second, I admit him for observation and supportive care, with daily liver function tests and renal function for the first week, because the hepatitis can progress to fulminant hepatic failure and the acute kidney injury may worsen. I monitor for a falling ALT with a rising INR and encephalopathy, which would signal decompensation and trigger a liver transplantation referral per the King's College criteria. ^[1]

Third, because he has visceral involvement — hepatitis and acute kidney injury — I start systemic corticosteroids. I would use oral prednisolone 0.5 to 1 mg per kg per day, approximately 50 mg per day, and plan a slow taper over weeks to months to prevent the relapses that characterise DRESS. If the hepatitis were fulminant or he were haemodynamically unstable, I would use intravenous methylprednisolone. ^[1]

Fourth, I exclude alternative causes — viral hepatitis A, B, C and E serology, EBV and CMV, HIV, an autoimmune hepatitis screen (ANA, smooth muscle antibody, immunoglobulins), and an abdominal ultrasound to exclude biliary obstruction. I hold the atorvastatin temporarily because it can contribute to transaminitis and rarely to DILI, and I resume it only when the DRESS attribution to allopurinol is secure. ^[1]

Fifth, I will report this reaction to the Therapeutic Goods Administration via the Blue Card, because it is a severe reaction to a marketed drug, and I will tell the patient I have done so." ^[1]

Examiner probe 4 — follow-up and the long view

"What are the long-term issues, and how will you manage his gout going forward?" ^[1]

"DRESS can relapse for weeks after the drug is stopped, partly via human herpesvirus 6 reactivation, so the corticosteroid taper must be slow and supervised. Long-term autoimmune sequelae are described — autoimmune hepatitis, type 1 diabetes and autoimmune thyroiditis — and I would arrange follow-up with clinical immunology or dermatology for the taper and for surveillance for these sequelae over the following months. ^[1]

For his gout, allopurinol is now contraindicated permanently. The alternatives are colchicine for acute flares (with dose adjustment for the renal function), a uricosuric such as probenecid (which is less effective in significant renal impairment), or pegloticase infusions for severe tophaceous gout. I would involve a rheumatologist. The broader lesson is a systems-level one: the prescribing error that started allopurinol at 300 mg in renal impairment should be reviewed with the team, and I would reinforce the practice of dose adjustment for renal function and the consideration of HLA-B*5801 screening in at-risk populations." ^[1]

Examiner probe 5 — the ABCDEF classification

"Give me the ABCDEF classification with one example each." ^[1]

"Augmented — Type A — an exaggerated normal pharmacology, dose-dependent and common; example, beta-blocker bradycardia. Bizarre — Type B — idiosyncratic, dose-independent, rare, high mortality; example, DRESS, SJS/TEN, anaphylaxis. Chronic — Type C — cumulative dose over time; example, bisphosphonate osteonecrosis of the jaw. Delayed — Type D — time-related, including teratogenesis and carcinogenesis; example, thalidomide phocomelia, diethylstilboestrol and clear-cell vaginal carcinoma. End-of-use — Type E — a withdrawal syndrome; example, adrenal suppression after long-term steroids. Failure — Type F — unexpected therapeutic failure; example, oral contraceptive failure with rifampicin." ^[1]

Examiner probe 6 — a high-yield discriminating question

"A patient on long-term prednisolone for polymyalgia rheumatica is admitted hypotensive, hyponatraemic and hyperkalaemic after a gastrointestinal illness. What is the diagnosis and what do you do?" ^[1]

"This is adrenal suppression — a Type E withdrawal reaction — unmasked by the stress of the gastrointestinal illness. The long-term exogenous steroid has suppressed the hypothalamic-pituitary-adrenal axis, and the patient cannot mount a cortisol response to the illness. I would give empirical intravenous hydrocortisone 100 mg and intravenous fluid resuscitation immediately, without waiting for a cortisol level — adrenal crisis is fatal if untreated and the empirical steroid is safe. I would send a 9 am cortisol and a short synacthen test before the first dose if it can be obtained immediately, but treatment must not wait. The HPA axis may take months to a year to recover, and the patient will need a slow supervised steroid taper." ^[1]