Q/ What is your presumptive diagnosis?
Allopurinol hypersensitivity syndrome
Allopurinol hypersensitivity syndrome (AHS) is a diffuse vasculitis induced by a type III hypersensitivity reaction, possibly to oxypurinol, allopurinol’s toxic metabolite. The exact pathophysiology is unknown, but oxypurinol levels correlate positively with the risk of AHS.1 Thiazides may increase oxypurinol levels.2
Signs and symptoms of AHS include fever, erythematous skin rash, eosinophilia, hepatitis, progressive renal insufficiency, and leukocytosis. Case reports have also attributed septic shock, myocardial infarction, and Guillain-Barré syndrome to AHS.3-6 The incidence of AHS is 0.1% to 0.4% of patients treated with allopurinol; mortality approaches 25%.1
Q/ What are the diagnostic criteria for AHS?
Singer and Wallace have outlined diagnostic criteria for AHS,7 the first being a clear history of exposure to allopurinol.
Second, the clinical profile usually takes one of the following forms:
- The patient exhibits at least 2 of the following major features: worsening renal function, acute hepatocellular injury, or a rash (toxic epidermal necrolysis, erythema multiforme, or diffuse maculopapular or exfoliative dermatitis) or
- The patient exhibits just one of the major features and at least one of the following minor features: fever, eosinophilia, or leukocytosis.
Third, there is no history of exposure to another drug that may cause a similar clinical picture.
Q/ What is the accepted treatment for ahS?
Although there is no well-established treatment plan, the standard of care is to discontinue allopurinol, administer parenteral corticosteroids followed by oral taper, and offer supportive management. Desensitization protocols are difficult and hypersensitivity reactions may recur. Early withdrawal of steroids has been reported to result in recurrence of symptoms. However, no strong data exist for determining an optimal length of corticosteroid therapy, or the number of days that constitutes “early” withdrawal of steroids. Mortality is high, even with seemingly adequate treatment.
Q/ Which patients are most at risk for ahS?
Definite risk factors for AHS include recent onset of allopurinol therapy, the presence of HLA-B5801 allele in patients of Han Chinese and European ancestry, and chronic kidney disease.1,8,9 Suggested risk factors include concomitant use of thiazide diuretics with allopurinol, treatment of asymptomatic hyperuricemia, and high allopurinol dose relative to renal function.
Q/ What are the indications for allopurinol therapy?
Indications for allopurinol therapy:1,10
- Failure of uricosuric drugs or contraindications to their use
- Frequent attacks of gouty arthritis (≥3 per year)
- Nephrolithiasis
- Marked overproduction of urate, such as seen in tumor lysis syndrome
- The presence of tophi.
For patients with appropriate indications for allopurinol therapy, treat with the minimum effective dose. Initiation of allopurinol is controversial for a patient with a single lifetime episode of gout. However, most patients with one episode of gout will develop recurrent gout.8
In patients with creatinine clearance >60 mL/min, allopurinol is usually started at 100 mg oral daily and titrated every 2 to 3 weeks until reaching the desired effectiveness.8 One retrospective study suggests that initiating allopurinol at a dose of 1.5 mg per unit of estimated GFR may reduce the risk of AHS.11
Our patient’s case: Treatment, discharge, readmission
With our patient, we started intravenous normal saline fluid boluses and parenteral methylprednisolone, 60 mg q6h. We discontinued triamterene/hydrochlorothiazide due to his hyperuricemia, and irbesartan and glyburide due to renal failure. Basal and rapid-acting insulins maintained good glycemic control. To control his wheezing and dyspnea, we began albuterol/ipratropium nebulizer treatments and oxygen delivery via nasal cannula. Nephrology, pulmonology, and rheumatology consultants agreed with these management decisions.
Over the next 9 days, the patient’s renal function improved and his rash started to resolve. His wheezing fluctuated but persisted throughout the hospital stay. We stopped nasal oxygen delivery, and his oxygen saturation remained normal (96%-98%) on room air. He was subsequently discharged in stable condition on a 2-week prednisone taper starting at 30 mg bid.
Thirteen days later, he was readmitted with a right frontoparietal cerebrovascular accident (CVA). He developed respiratory distress, which led to respiratory arrest, and was ventilated. He became hypotensive, lapsed into shock, and died a few days later (approximately one month after initial presentation).
The appropriate use of allopurinol—a second look
This case raised many questions for our inpatient team concerning not just AHS, but the appropriate use and dosing of allopurinol. Allopurinol is widely used for hyperuricemia and gout because it is effective for all causes of hyperuricemia and is inexpensive. Given that 3.9%12 of the general population has gout and that its prevalence has increased with rising rates of obesity, the importance of AHS is not abstract.
Revisiting initial treatment choices. Our patient was at risk for this syndrome due to his Chinese ancestry, recent onset of allopurinol therapy, concomitant use of triamterene/hydrochlorothiazide, and impaired renal function. Although his uric acid level was >10 mg/dL when treatment was started, his risk factors may have precluded initiation of allopurinol. Furthermore, the prescribed dose of allopurinol (300 mg) was too high for his baseline GFR; 100 mg daily would have been more appropriate. It could be argued that hydrochlorothiazide would not be an antihypertensive of choice due to its hyperuricemic effects. Switching the thiazide to a loop diuretic would offer no benefit, because loop diuretics also cause hyperuricemia. (More on which antihypertensive agent would have been appropriate in a bit.)