Allopurinol hypersensitivity syndrome

Overview

Allopurinol Hypersensitivity Syndrome (AHS) is a rare but potentially life-threatening adverse reaction to the drug allopurinol, which is commonly used to treat gout and hyperuricemia. AHS typically presents with a triad of fever, rash, and internal organ involvement, particularly affecting the liver, kidneys, and bone marrow. It is considered a severe cutaneous adverse reaction (SCAR) and shares features with drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

Due to its high mortality rate, estimated between 20–25% in severe cases, early recognition and immediate discontinuation of allopurinol are essential.

Causes

AHS is caused by an idiosyncratic immune-mediated reaction to allopurinol or its active metabolite, oxypurinol. Risk factors include:

• Renal impairment: Reduced kidney function increases oxypurinol levels

• High starting dose of allopurinol

• Use of diuretics (e.g., thiazides)

• HLA-B*58:01 gene variant: Strongly associated with AHS, especially in individuals of Han Chinese, Thai, or Korean descent

• Age > 60 years

Symptoms

Symptoms typically appear within 2 to 6 weeks after starting allopurinol and may include:

Systemic and Constitutional Symptoms:

• High fever

• Malaise and fatigue

• Lymphadenopathy (swollen lymph nodes)

Skin Manifestations:

• Maculopapular rash

• Exfoliative dermatitis

• Stevens–Johnson syndrome or toxic epidermal necrolysis (in severe cases)

Internal Organ Involvement:

• Hepatitis (elevated liver enzymes, jaundice)

• Acute kidney injury

• Eosinophilia and atypical lymphocytosis

• Bone marrow suppression (in rare cases)

Diagnosis

Diagnosis is clinical and based on a history of recent allopurinol use, characteristic symptoms, and exclusion of other causes. Key components include:

• Medication history: Use of allopurinol within the past 2–6 weeks

• Physical exam: To assess skin involvement and systemic symptoms

• Laboratory tests:

  • Complete blood count (eosinophilia, leukocytosis)

  • Liver and kidney function tests

  • Serologic testing to exclude infections or autoimmune diseases

• Genetic testing (HLA-B*58:01): In high-risk ethnic populations to assess susceptibility

• Skin biopsy: May help differentiate from other severe drug reactions if unclear

Treatment

Immediate discontinuation of allopurinol is the first and most critical step. Supportive and symptomatic management may include:

Supportive Care:

• Hospitalization, often in intensive care or burn units for severe cases

• Fluid and electrolyte balance

• Monitoring for organ failure (hepatic, renal)

Medications:

• Systemic corticosteroids: Commonly used in moderate to severe cases

• Immunosuppressants: Such as cyclosporine or IVIG in refractory or severe cases

• Antihistamines: For pruritus (itching)

• Broad-spectrum antibiotics: If secondary infections develop due to skin breakdown

Alternative Uric Acid-Lowering Therapy:

• Febuxostat may be considered, but only after full resolution and with caution

• Uricosuric agents (e.g., probenecid) may be options in select patients

Prognosis

The prognosis of Allopurinol Hypersensitivity Syndrome depends on early diagnosis, prompt discontinuation of the drug, and the severity of systemic involvement. Mild cases may resolve within weeks, while severe cases, particularly those involving Stevens–Johnson syndrome or toxic epidermal necrolysis, carry a mortality rate of up to 25%.

Patients who survive may have lasting complications such as chronic kidney disease, liver damage, or scarring from skin reactions. Long-term avoidance of allopurinol is essential, and affected individuals should carry a medical alert indicating their drug allergy.