THE MANIFESTATION OF PHARMACOGENETIC AND CLINICAL PERSPECTIVES ON MEDICATION-ASSOCIATED EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS): A COMPREHENSIVE EVALUATION OF IMPLICATED AGENTS, RISK FACTORS, AND TREATMENT MANAGEMENTS STRATEGIES IN GENERAL

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a complex, multifaceted, and potentially life-threatening hypersensitivity syndrome associated with a wide spectrum of pharmacologic agents. The syndrome is characterized by delayed onset, typically appearing several weeks after the initiation of the causative drug, and encompasses a constellation of clinical symptoms such as fever, rash, lymphadenopathy, hematologic abnormalities including eosinophilia or atypical lymphocytosis, and involvement of internal organs, most commonly the liver, kidneys, and lungs. DRESS has emerged as a significant challenge in modern pharmacotherapy, not only due to its diagnostic complexity and the variability in clinical manifestations but also because of the underlying pharmacogenetic and immunologic mechanisms that predispose susceptible individuals. The interplay of genetic predispositions, drug metabolism pathways, immune dysregulation, and environmental cofactors makes the management and prediction of DRESS both clinically and scientifically demanding. Pharmacogenetics plays a pivotal role in understanding the individual variability in the onset and severity of DRESS. Specific genetic markers, particularly certain human leukocyte antigen (HLA) alleles, have been closely linked to hypersensitivity reactions associated with particular medications. For instance, the HLA-B15:02 allele has been implicated in carbamazepine-induced DRESS, especially among individuals of Asian descent. Similarly, associations between allopurinol-induced DRESS and HLA-B58:01 have been strongly established. These pharmacogenetic insights have catalyzed efforts toward personalized medicine, where genetic screening before initiating therapy with high-risk drugs can significantly mitigate adverse reactions. In parallel, polymorphisms in genes encoding drug-metabolizing enzymes and transporters, such as cytochrome P450 isoenzymes, have also been implicated, suggesting that impaired detoxification of reactive drug metabolites may provoke an exaggerated immune response. The list of causative agents associated with DRESS is extensive and continues to expand with ongoing pharmacovigilance. Anticonvulsants, including phenytoin, carbamazepine, and lamotrigine, remain among the most commonly implicated drugs. Antimicrobials such as minocycline, vancomycin, and sulfonamides are also frequent offenders. Moreover, the increasing use of biologics and novel cancer immunotherapies has introduced new etiologic agents capable of triggering DRESS, further complicating the landscape of drug safety. The latency period, typically ranging from two to eight weeks, complicates the identification of the responsible drug, especially in polypharmacy scenarios. This underscores the necessity for robust clinical judgment, a detailed patient history, and interdisciplinary collaboration in managing suspected cases. Risk factors for the development of DRESS are multifactorial. In addition to genetic predisposition, factors such as age, ethnicity, comorbid autoimmune diseases, previous hypersensitivity reactions, and certain viral infections, particularly human herpesvirus 6 (HHV-6), play a contributory role. Viral reactivation has been recognized as both a potential trigger and an exacerbating factor, with some studies suggesting that it may drive systemic inflammation and prolong the course of illness. The presence of such cofactors not only amplifies the severity of DRESS but may also delay recovery and increase the risk of long-term complications such as autoimmune sequelae, which have been observed in a subset of patients following acute resolution. Diagnosis of DRESS remains largely clinical, supported by scoring systems such as RegiSCAR, which incorporates parameters including fever, rash, eosinophilia, organ involvement, and the exclusion of alternative etiologies. However, these criteria are not universally applied, and diagnostic delays are common, particularly in atypical or incomplete presentations. Research into the pathogenesis and treatment of DRESS continues to evolve. Advances in immunogenetics, transcriptomics, and systems biology are shedding light on the molecular pathways that mediate hypersensitivity reactions. These insights not only improve diagnostic accuracy but also open the door to novel therapeutic targets. Collaboration between clinicians, pharmacologists, geneticists, and regulatory bodies is essential to translate these discoveries into tangible benefits for patient safety. International registries and multicenter studies are needed to strengthen the evidence base, given the rarity of the condition and the variability in clinical practice. DRESS syndrome epitomizes the complexity of drug-induced hypersensitivity, where pharmacogenetics, immunology, and clinical medicine intersect. The syndrome requires a high index of suspicion, timely intervention, and multidisciplinary coordination to minimize morbidity and mortality. The future of DRESS management lies in personalized medicine, proactive risk stratification, and continued research into safer pharmacological alternatives. A comprehensive understanding of the implicated agents, risk factors, and therapeutic strategies is indispensable to improving patient outcomes and guiding evidence-based clinical decision-making.