Foundational Principles and Risk Factors in DRESS
Objective
Provide critical care pharmacists with high-yield knowledge of DRESS epidemiology, immunopathology, host factors, and social determinants to enable early identification of at-risk patients.
I. Epidemiology and Incidence
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome affects approximately 1 to 10 per 10,000 new drug exposures. While relatively rare, its severity often necessitates intensive care. An estimated 20–30% of DRESS cases require ICU admission due to multiorgan failure, with mortality rates reaching 10–20%, primarily driven by fulminant hepatic failure, myocarditis, and secondary infections. Early recognition in the ICU is critical to mitigate progression.
Key Epidemiological Data
- Global Incidence: 0.01% to 0.1% of new drug exposures.
- ICU Burden: 20–30% of cases develop organ failure requiring critical care.
- Geographic Variability: Incidence and causative drug patterns vary due to ethnic and geographic differences in pharmacogenomics and prescribing habits.
- Underreporting: Likely common in resource-constrained regions with limited pharmacovigilance systems.
| Drug Class / Agent | Approximate % of ICU Admissions |
|---|---|
| Aromatic Anticonvulsants (phenytoin, carbamazepine) | ~35% |
| Allopurinol | ~20% |
| Sulfonamide Antibiotics | ~15% |
| Selected Antiretrovirals (e.g., abacavir, nevirapine) | Variable |
Case Vignette
A 58-year-old man started on allopurinol for gout presents on day 21 with fever, facial edema, a diffuse morbilliform rash, and an ALT of 350 U/L. His absolute eosinophil count is 2.1 × 10⁹/L. Immediate withdrawal of allopurinol and an ICU consultation for close monitoring prevented progression to fulminant hepatic failure.
Clinical Pearls: Early Recognition
- Any new widespread rash accompanied by systemic signs (fever, lymphadenopathy, organ dysfunction) in a patient on a high-risk drug warrants immediate consideration for DRESS.
- Discontinuation of the suspect drug within 48 hours of recognition is a key intervention to reduce mortality.
- Maintain a high index of suspicion for DRESS syndrome in the typical latency period of 2 to 8 weeks after initiating a high-risk medication.
II. Immune-Mediated Pathophysiology
DRESS syndrome is not a simple allergy but a complex, multi-step immunological event. It arises from the interplay between a causative drug, specific genetic predispositions (HLA alleles), T-cell activation leading to a cytokine storm, and the reactivation of latent viruses, all culminating in widespread tissue injury.
Key Genetic Associations
| HLA Allele | Associated Drug | Key Consideration |
|---|---|---|
| HLA-B*58:01 | Allopurinol | Strong association; screening recommended in high-risk populations (e.g., Han Chinese, Thai). |
| HLA-A*31:01 | Carbamazepine | Associated with DRESS and other hypersensitivities in Northern European and Japanese populations. |
| HLA-B*15:02 | Phenytoin / Aromatic Anticonvulsants | Primarily associated with SJS/TEN but also increases risk for DRESS, especially in Southeast Asian populations. |
Pathophysiology Pearls
- Consider testing for HHV-6 viremia in patients with subacute, refractory, or relapsing DRESS, as its presence may indicate a more severe course and guide potential antiviral therapy.
- Pre-emptive HLA screening in high-risk populations before initiating drugs like allopurinol or carbamazepine can prevent a significant percentage of DRESS cases.
III. Host Risk Factors
Patient-specific factors, including underlying diseases and organ dysfunction, can significantly increase the risk of developing DRESS. These conditions may impair immune regulation, alter drug clearance, and heighten susceptibility to severe outcomes. Pharmacogenomic screening offers a powerful preventive tool, though practical limitations exist.
Influence of Chronic Disease and Organ Dysfunction
- Chronic Kidney Disease (CKD): Renal impairment, particularly in stages 3–5, leads to the accumulation of allopurinol and its active metabolite, oxypurinol, drastically increasing DRESS risk.
- Autoimmune Disorders (e.g., SLE, RA): Baseline immune dysregulation may obscure the early signs of DRESS or predispose patients to a more exaggerated cytokine release upon drug exposure.
- Chronic Infections (e.g., HIV): Impaired control over viral latency (like HHV-6) and baseline immune activation can create a permissive environment for DRESS to develop.
- Hepatic Dysfunction: Cirrhosis or hypoalbuminemia can reduce first-pass metabolism and alter drug distribution, increasing the free fraction and half-life of causative agents.
Pharmacogenomic Screening: Benefits and Limitations
- Benefits: Allows for personalized medicine by identifying individuals with high-risk HLA alleles, enabling clinicians to select safer alternative medications and prevent DRESS.
- Limitations: Practical barriers include cost, insurance coverage, test turnaround time (which may not be feasible in acute settings), and the genetic heterogeneity of admixed populations, which can complicate allele interpretation.
Host Factor Pearls
- In patients with CKD, initiate allopurinol at a low dose (e.g., ≤50 mg daily) and strongly consider pre-emptive HLA-B*58:01 testing where feasible and in at-risk ethnic groups.
- When a patient has a known risk allele for an aromatic anticonvulsant, prioritize non-aromatic alternatives such as levetiracetam or valproic acid.
IV. Social Determinants of Health
Social and economic factors play a crucial role in DRESS outcomes by creating barriers to timely diagnosis and optimal management. Limited access to healthcare, low health literacy, and systemic inequities can lead to delayed recognition and use of higher-risk medications, contributing to increased morbidity and mortality. Integrating social risk assessments into ICU and pharmacy workflows is essential for improving patient outcomes.
Key Barriers and Integration Strategies
- Access and Adherence:
- Limited insurance formularies may compel the use of older, higher-risk drugs (e.g., phenytoin over levetiracetam).
- “Pharmacy deserts,” transportation issues, and high co-pays can delay or prevent access to safer alternatives and necessary diagnostic tests like HLA screening.
- Health Literacy and Delays:
- Low patient awareness of early DRESS symptoms (e.g., dismissing a rash as benign) can lead to continued drug use and late presentation to care.
- Lack of clinician familiarity with DRESS diagnostic criteria or scoring systems can prolong the time to diagnosis and drug withdrawal.
- System-Level Integration Strategies:
- Establish multidisciplinary “Tox-Derm” teams, including pharmacists and social workers, to address medication access barriers.
- Implement Electronic Health Record (EHR) alerts that link high-risk drug orders to a patient’s HLA status or prompt guideline-based monitoring.
- Develop culturally competent patient education materials on the signs of severe drug hypersensitivity reactions.
Social Determinant Pearls
- Deploy EHR-based clinical decision support tools to automatically flag high-risk prescriptions, prompting clinicians to consider HLA testing or safer alternatives.
- Proactively collaborate with hospital social services and case management to expedite prior authorizations and patient assistance programs for safer, more expensive therapies.
References
- Tee S, Abdullah MS, Kristummoonthy R, et al. Severe cutaneous adverse reactions: A 5-year retrospective study at Hospital Melaka, Malaysia, from December 2014 to February 2020. Med J Malays. 2022.
- Hung SI, Mockenhaupt M, Blumenthal KG, et al. Severe cutaneous adverse reactions. Nat Rev Dis Primers. 2024.
- Ramirez E, Ripa M, Burastero SE, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): Focus on the pathophysiological and diagnostic role of viruses. Microorganisms. 2023;11(5).
- Joint Council of Allergy, Asthma & Immunology. Drug allergy: An updated practice parameter. Ann Allergy Asthma Immunol. 2023.
