Allopurinol-associated Drug Reaction with Eosinophilia and Systemic Symptom Syndrome: A Severe Delayed Drug Hypersensitivity Reaction

Abstract

DRESS syndrome is a rare and life-threatening adverse drug reaction that usually presents with delayed onset rash, Hematalogical abnormality, and multiorgan involvement. In patients with renal impairment, allopurinol is most frequently associated with this syndrome. We report an elderly male in his early 60’s presented with a 35 day history of generalized maculopapular rash with vesicles, scaling, and facial swelling, starting 3–4 weeks after initiating allopurinol (100mg daily) for gout. His medical history includes chronic kidney disease. Using the RegiSCAR scoring system, we confirmed DRESS syndrome. Allopurinol was discontinued immediately, and systemic corticosteroid therapy was started. Patient clinical and laboratory parameters improved progressively, and in 6 weeks, symptoms completely resolved. This case highlights that Clinicians should be extra vigilant in high-risk populations, especially in renal-impaired patients, while prescribing allopurinol.

INTRODUCTION

Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality globally, with delayed hypersensitivity reactions among the most severe.[1] Drug reaction with eosinophilia and systemic symptom (DRESS) syndrome is a rare, life-threatening ADR characterized by delayed onset (2–8 weeks postdrug exposure), fever, rash, eosinophilia, and multiorgan involvement.[2] The pathophysiology involves immune deregulation, cytokine release, and T-cell activation, often linked to genetic predispositions like the HLA-B*5801 allele.[3] Allopurinol, a xanthine oxidase inhibitor for gout management, is a well-documented trigger of DRESS.[4] Genetic screening for HLA-B*5801 is recommended in high-risk populations, particularly Asians.[5] Its metabolite, oxypurinol, accumulates in renal impairment, heightening hypersensitivity risks.[6] Diagnosis is often challenging due to symptom overlap with other hypersensitivity syndromes, necessitating vigilant pharmacovigilance.[2] Here we present a case of allopurinol-induced DRESS, highlighting its clinical presentation, diagnostic nuances, and management strategies, with emphasis on early intervention to prevent severe outcomes.

CASE REPORT

An elderly male in his early 60’s presented with a 35-day history of generalized maculopapular rash with vesicles, scaling, and facial swelling, starting 3–4 weeks after initiating allopurinol (100 mg daily) for gout. His medical history included type 2 diabetes mellitus (15 years), chronic kidney disease (CKD, 4 years), hypertension (2 years), ectopic kidney, and benign prostatic hyperplasia, managed with insulin glargine, telmisartan/chlorthalidone, sodium bicarbonate, and dutasteride/tamsulosin. Symptoms progressed from mild erythema to widespread rash involving the chest, abdomen, trunk, and limbs, with no lymphadenopathy or mucosal involvement. On examination, he exhibited facial puffiness, pallor, bilateral pitting pedal edema, and a maculopapular rash [Figure 1]. Laboratory tests [Table 1] showed progressive eosinophilia (absolute eosinophil count [AEC]: 0.83 × 10⁹/L, white blood cell [WBC] count: 10 × 10⁹/L on day 1; AEC: 4.28 × 10⁹/L, WBC: 10 10⁹/L on day 6), elevated alanine aminotransferase (120 IU/L), reduced total serum globulin (2.0 g/dL), hypoalbuminemia (2.8 g/dL), increased serum creatinine (2.5 mg/dL), hyperkalemia (5.8 mmol/L), hyponatremia (130 mmol/L), and elevated C-reactive protein (50 mg/L). Tests for viral hepatitis and Epstein–Barr virus were negative, ruling out any viral aetiology.

Figure 1.

Generalized maculopapular rash over the abdomen and back with vesicles and scaling, photographed on day 1 of hospital admission

Table 1.

Change in laboratory values

Test	Result	Normal range	Rationale
AEC (day 1)	0.83×109/L	0.04–0.4×109/L	Assess eosinophilia
AEC (day 6)	4.28×109/L	0.04–0.4×109/L	Monitor progression
WBC	10×109/L	4–11×109/L	Contextualize eosinophilia
ALT	120 IU/L	7–56 IU/L	Detect hepatic injury
Albumin	2.8 g/dL	3.5–5.0 g/dL	Assess liver synthetic function
Total globulin	2.0 g/dL	2.5–3.5 g/dL	Evaluate protein status
Creatinine	2.5 mg/dL	0.7–1.2 mg/dL	Monitor renal function
Potassium	5.8 mmol/L	3.5–5.0 mmol/L	Assess electrolyte imbalance
Sodium	130 mmol/L	135–145 mmol/L	Detect hyponatremia
CRP	50 mg/L	<10 mg/L	Confirm systemic inflammation

AEC=Absolute eosinophil count, WBC=White blood cell, CRP=C-reactive protein, ALT=Alanine aminotransferase

The RegiSCAR score was 6 (definite DRESS), based on rash, eosinophilia, and organ involvement.[2] The WHO-UMC causality assessment classified the reaction as “probable/likely,”[7] and Hartwigs et al.’s severity assessment rated it as “severe” (Level 5).[8] Allopurinol was discontinued, and oral prednisolone (40 mg daily) was initiated to reduce systemic inflammation, tapered to 5 mg over 6 weeks.[9] Supportive measures included ranitidine (150 mg twice daily) for gastric protection, intravenous chlorpheniramine (10 mg every 8 h) for pruritus, and antihistamine lotion. Insulin was adjusted for glycemic control. By day 10, the rash and swelling resolved [Figure 2], and AEC normalized (0.075 × 10⁹/L) with the day-wise progression summarized in Table 2. Liver and kidney functions returned to baseline over 6 weeks, with no symptom recurrence. The patient was advised to avoid allopurinol and other high-risk drugs (e.g., phenytoin and carbamazepine) due to potential cross-reactivity.[10]

Figure 2.

Resolution of rash and facial swelling by day 10 post-treatment

Table 2.

Daywise eosinophil count progression

Day	Eosinophils’ count (%)
1	42.8
2	26.9
3	13.2
4	18.8
5	13.2
6	8.3

DISCUSSION

DRESS syndrome is a complex drug-induced hypersensitivity reaction with multiorgan involvement, often triggered by allopurinol.[1] This elderly male patient developed DRESS 3–4 weeks postallopurinol, presenting with maculopapular rash, eosinophilia, and hepatic dysfunction, consistent with cohort studies.[2,10] His existing CKD likely exacerbated oxypurinol accumulation, increasing hypersensitivity risk.[6] Renal manifestations, such as acute kidney injury or interstitial nephritis, are common in DRESS and were evident here with elevated serum creatinine.[11] Diagnosis is challenging due to symptom overlap with Stevens–Johnson syndrome, viral exanthemas, or hypereosinophilic syndrome. The RegiSCAR criteria (fever, rash, eosinophilia, and organ involvement) distinguished DRESS in this case.[2] Pertinent negatives (e.g., no lymphadenopathy and negative viral serologies) ruled out alternatives. Pharmacovigilance is critical, as delayed recognition increases mortality risk (3%–10%).[1] Patient education on early ADR symptoms can facilitate timely intervention. HLA-B*5801 is strongly associated with allopurinol-induced DRESS, particularly in Asians.[4] HLA typing was not performed due to resource limitations but could have confirmed genetic predisposition, aiding risk stratification. Cohort studies advocate pretreatment screening in high-risk populations.[10] Treatment involved allopurinol withdrawal and corticosteroids, with prednisolone resolving symptoms rapidly.[9,10] However, evidence for steroids is limited; alternatives such as cyclosporine or intravenous immunoglobulin are emerging but lack robust trials.[12] Supportive measures (antihistamines and emollients) alleviated symptoms, while monitoring prevented complications. Visceral involvement (e.g., pneumonitis and myocarditis) correlates with higher mortality, necessitating comprehensive organ assessment.[2]

CONCLUSION

This case highlights the complexity of allopurinol-induced DRESS in a patient with CKD. Early recognition using RegiSCAR criteria, prompt drug withdrawal, and corticosteroid therapy ensured recovery. Clinicians should monitor eosinophilia, liver, and renal function and consider genetic screening in high-risk populations. Differential diagnosis requires excluding viral and other hypersensitivity syndromes. Long-term follow-up is essential to detect autoimmune sequelae. Future research should explore targeted therapies to reduce DRESS morbidity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.