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Georgian Scientists/ქართველი მეცნიერები ტ. 7 N 3, 2025 141 

 

Georgian Scientists 

ქართველი მეცნიერები 

Vol. 7 Issue 3, 2025 

https://doi.org/10.52340/gs.2025.07.03.13 
 

THE SCIENTIFIC DISCUSSION OF KEY ISSUE ASPECTS OF 
IMMUNOPATHOGENESIS AND PHARMACOLOGICAL PROPERTIES AND PROFILES 

IN RELATION TO ADVERSE DRUG REACTIONS CHALLENGES, FOCUS ON 
MULTIDIMENSIONAL DRUG-INDUCED EOSINOPHILIA AND SYSTEMIC 

SYNDROME 

Nodar Sulashvili1, Rupali Digambar Jadhav2, Margarita Beglaryan3, Luiza 
Gabunia4, Nana Gorgaslidze5, Nato Alavidze6, Natia Kvizhinadze7, Marika 

Sulashvili8 Lela Grigolia9, Kakhaber Robakidze10 

1Scientific Supervisor, MD, PhD, Doctor of Pharmaceutical and Pharmacological Sciences In Medicine, Invited 
Lecturer (Invited Professor) of Scientific Research-Skills Center at Tbilisi State Medical University; Professor of 

Medical and Clinical Pharmacology of International School of Medicine at Alte University; Professor of 
Pharmacology of Faculty of Medicine at Georgian National University SEU; Associate Affiliated Professor of Medical 
Pharmacology of Faculty of Medicine at Sulkhan-Saba Orbeliani University; Associate Professor of Pharmacology of 

Pharmacy Program at Shota Meskhia Zugdidi State University; Associate Professor of Medical Pharmacology at 
School of Medicine at David Aghmashenebeli University of Georgia; Associate Professor of Biochemistry and 

Pharmacology Direction of School of Health Sciences at the University of Georgia; Associate Professor of 
Pharmacology of Faculty of Medicine at East European University; Associate Professor of Pharmacology of Faculty of 
Dentistry and Pharmacy at Tbilisi Humanitarian Teaching University; Tbilisi, Georgia; Researcher of Department of 
Pharmaceutical Management of Yerevan State Medical University after Mkhitar Heratsi, Yerevan, Armenia. Orcid 

https://orcid.org/0000-0002-9005-8577 E-mail: n.sulashvili@ug.edu.ge 
2MD©, 12-th Semester student of MD - Medical Doctor Degree Student of International School of Medicine at Alte 

University; Tbilisi, Georgia; 
3MD, PhD, Doctor of Pharmaceutical Sciences, Academician, Professor of Yerevan State Medical University After 

Mkhitar Heratsi, Head of the Department of Pharmaceutical Management, President of Association PHESA 
(Pharmacy and Pharmacology Education and Science Association), Yerevan, Armenia; https://orcid.org/0000-0003-

3697-6390 
4MD, PhD, Doctor of Medical Sciences, Professor, Director of the Scientific Research-Skills Center at Tbilisi State 

Medical University, Professor, Head of the Department of Medical and Clinical Pharmacology at Tbilisi State 
Medical University, Clinical Pharmacologist of The First University Clinic of Tbilisi State Medical University, Tbilisi, 

Georgia https://orcid.org/0000-0003-0856-2684 
5MD, PhD, Doctor of Pharmaceutical Sciences, Academician, Professor of Tbilisi State Medical University, Head of The 

Department of Social and Clinical Pharmacy, Tbilisi, Georgia. https://orcid.org/0000-0002-4563-5224 
6MD, PhD, Doctor of Pharmaceutical Sciences, Professor of Akaki Tsereteli State University, Faculty of Medicine, 

Department of Pharmacy, Kutaisi, Georgia. Professor, Dean Faculty of Medicine at East European University, Tbilisi, 
Georgia. https://orcid.org/0000-0001-6695-5924 

7MD, PhD, Doctor of Pharmaceutical Sciences, Professor of Tbilisi State Medical University, Department of Social 
and Clinical Pharmacy; Tbilisi, Georgia. 

8MD, Doctor of Family Medicine, Invited Lecturer of Tbilisi State Medical University, Department of Molecular and 
Medical Genetics, Invited Lecturer of Genetics and Molecular Biology of International School of Medicine at Alte 



 

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University; Invited Professor of Biochemistry and Molecular and Medical Genetics at The University of Georgia. 
Tbilisi, Georgia. Orcid https://orcid.org/0000-0002-6338-4262. 

9MD, PhD, Doctor of Medical Sciences, Professor of Faculty of Medicine at Caucasus International University; 
Tbilisi, Georgia; 

10MD, PhD, Doctor of Medical Sciences, Academician, Professor of Faculty of Medicine at Caucasus International 
University; Doctor-Professor of National Health Center Named After Academician O. Gudushauri; Tbilisi, Georgia; 

Corresponding Author: Dr. Professor Nodar Sulashvili 
Mail: n.sulashvili@ug.edu.ge 
Mob: +995-597-12-17-28 

ABSTRACT 

Drug-induced eosinophilia and systemic symptoms (DIES) represent a complex and 
potentially life-threatening spectrum of adverse drug reactions characterized by 
eosinophilic infiltration and multiorgan involvement. This review synthesizes current 
knowledge on the pharmacological, immunological, and clinical aspects of these reactions, 
with particular emphasis on severe manifestations such as drug reaction with eosinophilia 
and systemic symptoms (DRESS). We examine the mechanisms by which specific drug 
classes—including aromatic antiepileptics, antibiotics, and novel biologics—trigger 
eosinophil activation through hapten formation, direct T-cell stimulation, and cytokine 
release. Genetic predispositions, particularly HLA associations, and viral interactions (e.g., 
HHV-6 reactivation) are discussed as critical modulators of individual susceptibility and 
clinical severity. Recent advances in biomarker discovery (e.g., serum Siglec-8, eosinophil-
derived extracellular traps) and imaging modalities (e.g., 68Ga-FAPI PET/CT) are evaluated 
for their diagnostic and prognostic utility. The review highlights emerging therapeutic 
strategies, including targeted biologics against IL-5/IL-33 and pharmacogenomic 
approaches to prevention, while underscoring persistent challenges in management, such 
as corticosteroid dependence and long-term sequelae. By integrating mechanistic insights 
with clinical observations, this work aims to refine diagnostic criteria, optimize therapeutic 
decision-making, and identify future research directions to mitigate the burden of these 
iatrogenic complications. Drug Reaction with Eosinophilia and Systemic Symptoms 
(DRESS) is an uncommon yet serious adverse drug reaction that presents with delayed 
systemic inflammation and multiple organ involvement. It is a member of the spectrum of 
severe cutaneous adverse reactions (SCAR), usually presenting 2–8 weeks post initiation of 
the culprit drug. Nonspecific symptoms, latency, and overlapping clinical findings with 
infections, autoimmune diseases, and other hypersensitivity reactions contribute to a failure 
to diagnose syndrome and worsening morbidity. The objective of this thesis is to conduct 
a comprehensive systematic review with emphasis on the pharmacological characteristics, 
clinical presentation, and genetic risk factors of DRESS syndrome, as well as a range of 
pathological drug classes, including anticonvulsants, antibiotics, allopurinol, and 
nonsteroidal anti-inflammatories (NSAIDs). The article also discusses treatment, long-term 
prognosis and research directions. The leading alternative agents were anticonvulsants 
(e.g., carbamazepine, phenytoin, lamotrigine), antibiotics (e.g., vancomycin, minocycline), 



 

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allopurinol, and NSAIDs including mefenamic acid and ibuprofen. More than 60 % of cases 
had hepatic involvement; involvement of the kidneys (25 %) and the lungs (10–15 %) were 
also important. Nearly all patients presented with cutaneous findings, most commonly a 
diffuse morbilliform rash and facial edema, and frequently had fever and eosinophilia. 
Genetic predisposition is an important factor, with HLA-B58:01 allele in the context of 
allopurinol-induced DRESS, and HLA-A31:01 in the case of carbamazepine. These results 
emphasize the value of pharmacogenetic screening in high-risk population groups. Viral 
reactivation, including human herpesvirus-6 (HHV-6), had been observed in multiple 
patients and has contributed to overall disease severity and duration. Therapy consisted 
mainly in early discontinuation of the inducing agent and systemic corticosteroids. 
Although the majority of patients responded to corticosteroids, some became steroid 
resistant and were treated with medications such as cyclosporine, IVIG, and plasmapheresis. 
There is a lack of standardized treatment protocols, and randomized controlled trials are 
highly desired. Relapses during corticosteroid reduction or autoimmunity (type 1 diabetes, 
thyroiditis, lupus-like syndromes) occurred in some, but not in all patients. Multisystem 
DRESS syndrome mandates a high degree of clinical suspicion for early diagnosis and 
treatment. The underestimation of NSAID-induced DRESS emphasises the necessity for 
better pharmacovigilance tools and public awareness on OTC drug safety. Future advances 
would need to focus on the creation of general diagnostic criteria, useful biomarkers for 
early diagnosis, and the use of evidence-based algorithms for treatment.  
Keywords: Adverse drug reactions, eosinophilia, systemic hypersensitivity, drug safety 
profile, pharmacovigilance, drug-induced immunological response. 
 
 

INTRODUCTION 
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare but 

important hypersensitivity syndrome that can be induced by specific drugs. The syndrome 
presents as a complex and varied clinical picture which may lead to serious multisystem 
organ failure, thereby being associated with a high morbidity and mortality rate. DRESS 
usually occurs 2–8 weeks after starting an offending drug, which complicates its diagnosis 
because of the long lag time between drug exposure and the onset of symptoms. The 
syndrome is most often characterized by a triad of clinical features, including widespread 
cutaneous eruptions, haematological disturbances (e.g., eosinophilia), and organ 
involvement—the liver and kidneys being the most frequently involved. 

Adverse drug reactions (ADRs) remain a significant challenge in pharmacotherapy, 
impacting patient safety, treatment efficacy, and healthcare costs. Among these, drug-
induced eosinophilia and systemic symptoms (DRESS syndrome—Drug Reaction with 
Eosinophilia and Systemic Symptoms) represents a severe hypersensitivity reaction 
characterized by eosinophilia, fever, rash, and multi-organ involvement. Understanding 



 

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the pharmacological properties and mechanistic profiles of drugs associated with DRESS is 
crucial for early detection, risk mitigation, and improved therapeutic outcomes. 

This paper explores the key pharmacological aspects contributing to ADRs, with a 
focus on drug-induced eosinophilia and systemic symptoms, addressing mechanisms, risk 
factors, diagnostic challenges, and management strategies. 

The pharmacological properties and profiles of therapeutic agents play a pivotal role 
in determining their efficacy, safety, and overall risk-benefit ratio in clinical practice. While 
modern pharmacotherapy has revolutionized disease management, adverse drug reactions 
(ADRs) remain a significant challenge, contributing to morbidity, mortality, and increased 
healthcare burdens. Among the diverse spectrum of ADRs, drug-induced eosinophilia and 
systemic symptoms (DIES) represent a complex and often underrecognized clinical entity 
that poses diagnostic and therapeutic dilemmas. This discussion delves into the intricate 
interplay between pharmacological mechanisms, host factors, and immunological pathways 
that underlie drug-induced eosinophilia and its systemic manifestations, emphasizing the 
need for heightened clinical vigilance and mechanistic understanding. 

Pharmacological agents, by virtue of their chemical structure, receptor interactions, 
and metabolic pathways, can elicit unintended immune-mediated responses. Eosinophilia, 
characterized by an abnormal elevation in eosinophil count, serves as a biomarker for 
hypersensitivity reactions, parasitic infections, and certain drug-induced pathologies. 
When drug-related, eosinophilia may herald severe systemic involvement, including 
cutaneous eruptions, visceral organ damage, and life-threatening conditions such as drug 
reaction with eosinophilia and systemic symptoms (DRESS) or eosinophilic granulomatosis 
with polyangiitis (EGPA). The pathogenesis of these reactions is multifactorial, involving 
genetic predispositions (e.g., HLA haplotypes), drug-specific properties (e.g., reactive 
metabolites), and dysregulated immune activation (e.g., Th2 cytokine polarization). 

Understanding the pharmacological basis of these adverse events requires a 
thorough examination of drug metabolism, pharmacokinetic variability, and 
pharmacodynamic interactions. Certain drug classes, including antiepileptics (e.g., 
phenytoin, carbamazepine), antibiotics (e.g., sulfonamides, beta-lactams), and allopurinol, 
are frequently implicated in eosinophilic reactions due to their propensity to form hapten-
protein complexes, triggering T-cell-mediated hypersensitivity. Additionally, the role of 
eosinophils themselves extends beyond mere bystanders; these granulocytes release 
cytotoxic granules (e.g., major basic protein, eosinophil peroxidase) and pro-inflammatory 
cytokines (e.g., IL-5, IL-13), contributing to tissue injury and systemic inflammation. 

The clinical presentation of drug-induced eosinophilia varies widely, ranging from 
benign peripheral blood eosinophilia to fulminant multiorgan failure. Early recognition is 
paramount, as delayed diagnosis often exacerbates outcomes. Correlating temporal drug 
exposure with symptom onset, alongside laboratory and histopathological findings, aids in 
establishing causality. However, challenges persist due to the nonspecific nature of 
eosinophilia and overlapping features with other hypersensitivity syndromes. Furthermore, 



 

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the absence of standardized diagnostic criteria for conditions like DRESS complicates 
clinical assessment, necessitating a high index of suspicion and comprehensive drug history 
evaluation. 

Therapeutic management hinges on prompt drug discontinuation, supportive care, 
and, in severe cases, immunosuppressive therapy. The role of corticosteroids remains 
controversial, with debates surrounding optimal dosing and duration. Emerging strategies, 
such as targeted biologic therapies against IL-5 (e.g., mepolizumab), offer promise in 
refractory cases, though further research is needed to define their place in management. 
Pharmacovigilance systems and post-marketing surveillance are critical in identifying at-
risk populations and mitigating future occurrences through risk stratification and 
personalized medicine approaches. 

This discussion aims to synthesize current knowledge on drug-induced eosinophilia 
and systemic symptoms, exploring pharmacological triggers, mechanistic pathways, clinical 
manifestations, and therapeutic challenges. By integrating pharmacogenomic insights, 
immunological advances, and real-world clinical data, we strive to enhance risk prediction, 
improve diagnostic accuracy, and optimize patient outcomes in the face of this formidable 
ADR. 
 

Pharmacological Mechanisms of Drug-Induced Eosinophilia 
 Detailed exploration of hapten hypothesis, p-i concept (pharmacologic interaction with 

immune receptors), and reactive metabolite formation. 
 Role of cytochrome P450 enzymes in generating immunogenic drug intermediates. 
 Genetic susceptibility (e.g., HLA-B*15:02 with carbamazepine, HLA-A*31:01 with aromatic 

antiepileptics). 
 

Immunopathogenesis of Systemic Eosinophilic Reactions 
 Th2 immune response dysregulation and cytokine storm (IL-4, IL-5, IL-13). 
 Eosinophil activation, degranulation, and endothelial damage. 
 Cross-reactivity between structurally unrelated drugs (e.g., aromatic amine drugs). 

 
Clinical Spectrum and Diagnostic Criteria 

 DRESS syndrome: RegiSCAR criteria, latency period, and organ involvement (hepatic, 
renal, cardiac). 

 Differential diagnoses (e.g., viral exanthems, autoimmune eosinophilic disorders). 
 Biomarkers (e.g., eosinophil cationic protein, serum IL-5 levels). 

High-Risk Drug Classes and Case Examples 
 Antibiotics (sulfamethoxazole-trimethoprim, vancomycin). 
 Anticonvulsants (lamotrigine, phenobarbital). 
 Allopurinol and its association with severe cutaneous ADRs. 

 



 

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Therapeutic Interventions and Controversies 
 Corticosteroid regimens: Pulse vs. tapering protocols. 
 Role of IVIG, plasmapheresis, and biologics (e.g., anti-IL-5/Rα therapy). 
 Long-term sequelae (e.g., autoimmune thyroiditis post-DRESS). 

 
Pharmacovigilance and Risk Mitigation Strategies 

 Pre-therapy screening (HLA typing, patch testing). 
 Post-marketing surveillance data (FAERS, WHO VigiBase). 
 Patient education and rechallenge protocols. 

 
Future Directions and Research Gaps 

 In vitro models (Lymphocyte Transformation Test). 
 Personalized medicine approaches (pharmacogenomics). 
 Novel biomarkers for early detection. 

On an epidemiological level, the incidence of DRESS is thought to be 1/1,000 to 
1/10,000 drug exposures, though this is likely an underestimate, probably due to the variable 
presentations and the delayed interval between drug administration and symptom onset. 
The heterogeneous presentation complicates identification and reporting, potentially 
delaying life-saving interventions. In recent years, clinical awareness, diagnostic criteria, 
and understanding of pathophysiology and genetic susceptibility have improved 
recognition and management of the disorder. 

The syndrome is pharmacologically associated with a limited but clinically 
important number of drugs. Anticonvulsants such as carbamazepine and phenytoin remain 
common triggers, likely due to their reactive metabolites inducing immune hypersensitivity 
(Saleem et al., 2025; Thompson et al., 2024). Sulfonamide antibiotics, notably 
sulfamethoxazole, allopurinol, and some NSAIDs including mefenamic acid, are also major 
causative agents. The growing recognition of NSAIDs as causes of DRESS calls for vigilance 
given their widespread use. 
Eosinophilia is the overabundance of eosinophils in the bloodstream. Eosinophils are a 
variety of white blood cell that participates in immune responses -notably those that cause 
allergies, parasitic infections and certain drug reactions, such as DRESS. 

 Eosinophils count range: 0-500 cells/µL (microliter) 
 Mild eosinophilia: 500–1,500 cells/µL 
 Moderate eosinophilia: 1,500–5,000 cells/µL 
 Severe eosinophilia: >5,000 cells/µL 

Eosinophilia (eosinophil count >500 cells/μL) is a classic diagnostic laboratory 
finding in DRESS, and while integral to diagnosis, clinicians should not rely solely on 
eosinophil counts to recognize systemic involvement such as liver or kidney injury that 
may progress rapidly and require emergent treatmen. A combination of cutaneous signs, 



 

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haematological abnormalities, and extracutaneous organ involvement aids in distinguishing 
DRESS from other drug eruptions or systemic diseases (St George-Hyslop et al., 2024). 
The underlying mechanisms responsible for DRESS are complex and involve impaired drug 
metabolism, immune dysregulation, and viral reactivation, particularly human herpesvirus 
6 (HHV-6), as well as other herpesviruses such as Epstein-Barr virus. Reactivation of these 
viruses may amplify immune responses and systemic inflammation characteristic of DRESS. 
Genetic susceptibility also plays a key role, with specific human leukocyte antigen (HLA) 
alleles, such as HLA-B58:01, strongly linked to allopurinol-induced DRESS, especially 
among Asian populations. 

Although DRESS can be life-threatening, timely diagnosis and intervention are 
critical to minimize complications. Standard management involves prompt discontinuation 
of the causative drug and early systemic corticosteroid use to mitigate immune-mediated 
damage (Shakour, Mumtaz, & Abu-Samra, 2025; Shiohara & Mizukawa, 2019). While 
corticosteroids are the mainstay, optimal dosing, duration, and the role of adjunctive 
immunomodulatory therapies remain areas of debate. The variable clinical presentation and 
overlap with other hypersensitivity syndromes often delay diagnosis, underscoring the need 
for clinician awareness of the broad spectrum of DRESS manifestations. 

This project's main objective is to explore drug-related features associated with 
DRESS and its clinical outcomes, with an emphasis on NSAIDs, which are relatively 
underreported in the literature. Other pharmacological classes will also be reviewed. 
Through a systematic review, this thesis aims to identify common clinical features, organ 
involvement, medication triggers, and genetic susceptibilities, providing comprehensive 
insights to improve pharmacovigilance and clinical management protocols in modern 
healthcare. 

The intersection of pharmacology and immunology presents a complex landscape 
where therapeutic efficacy must be carefully balanced against potential adverse reactions. 
Among the myriad challenges in pharmacotherapy, drug-induced eosinophilia and its 
systemic manifestations stand as a particularly intricate and clinically significant 
phenomenon. This condition, often underrecognized in its early stages, can progress to 
severe, sometimes life-threatening systemic involvement, making it a critical area of study 
for clinicians, pharmacologists, and researchers alike. The underlying mechanisms are 
deeply rooted in the pharmacological properties of the drugs themselves, the metabolic 
pathways they engage, and the individual patient's immunological response, creating a 
multifaceted clinical scenario that demands thorough understanding and careful 
management. 

Eosinophilia, defined as an elevated eosinophil count in peripheral blood or tissues, 
serves as a hallmark of various pathological states, ranging from parasitic infections to 
allergic reactions and, notably, adverse drug responses. When drug-induced, eosinophilia 
frequently signals a hypersensitivity reaction, often accompanied by systemic symptoms 
that can affect multiple organ systems. The clinical spectrum of these reactions is broad, 



 

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encompassing conditions such as drug rash with eosinophilia and systemic symptoms 
(DRESS), eosinophilic pneumonia, and even eosinophilic myocarditis, each presenting 
unique diagnostic and therapeutic challenges. The pathogenesis of these reactions is not 
merely a matter of excessive eosinophil production but involves a cascade of immunological 
events triggered by the drug or its metabolites, leading to tissue infiltration and damage. 

The pharmacological basis of drug-induced eosinophilia lies in the intricate 
interplay between a drug's chemical structure, its metabolic fate, and the host's immune 
system. Certain drugs are more prone to inducing these reactions due to their ability to form 
reactive metabolites that act as haptens, binding to endogenous proteins and creating 
neoantigens. These neoantigens are then recognized by the immune system as foreign, 
eliciting a T-cell-mediated response that drives eosinophil activation and recruitment. 
Genetic factors further modulate this risk, with specific human leukocyte antigen (HLA) 
alleles strongly associated with susceptibility to severe cutaneous adverse reactions, 
including those accompanied by eosinophilia. For instance, the HLA-B*15:02 allele has been 
linked to carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal 
necrolysis, often presenting with eosinophilia in the context of systemic involvement. 

Beyond genetic predisposition, the immunological milieu plays a pivotal role in the 
development and progression of drug-induced eosinophilia. Eosinophils are not passive 
bystanders but active contributors to tissue inflammation and damage. Upon activation, 
they release a barrage of cytotoxic proteins, including major basic protein, eosinophil 
peroxidase, and eosinophil-derived neurotoxin, which disrupt cellular integrity and amplify 
inflammatory responses. Additionally, eosinophils secrete cytokines such as interleukin-5 
(IL-5), a key regulator of eosinophil proliferation and survival, further perpetuating the 
cycle of inflammation. This self-sustaining inflammatory cascade underscores the potential 
for rapid clinical deterioration in affected patients, necessitating prompt recognition and 
intervention. 

Clinically, drug-induced eosinophilia and systemic symptoms present a diagnostic 
conundrum due to their variable and often nonspecific manifestations. The latency period 
between drug initiation and symptom onset can range from days to weeks, complicating 
the establishment of a causal relationship. Cutaneous involvement, such as maculopapular 
eruptions or exfoliative dermatitis, is common but not universal, and visceral organ 
involvement—particularly of the liver, kidneys, and lungs—may dominate the clinical 
picture. Laboratory findings typically include peripheral eosinophilia, elevated liver 
enzymes, and occasionally atypical lymphocytes, mimicking viral infections or 
autoimmune disorders. The RegiSCAR criteria have been developed to standardize the 
diagnosis of DRESS, incorporating clinical, laboratory, and histopathological features, yet 
challenges remain in distinguishing these reactions from other hypersensitivity syndromes. 

The management of drug-induced eosinophilia hinges on immediate 
discontinuation of the offending agent, coupled with supportive care tailored to the severity 
of organ involvement. Corticosteroids remain the cornerstone of therapy for moderate to 



 

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severe cases, although the optimal regimen—dose, duration, and route of administration—
remains a subject of debate. In refractory cases, emerging therapies targeting specific 
cytokines, such as anti-IL-5 monoclonal antibodies, have shown promise in mitigating 
eosinophilic inflammation, though their role in acute drug-induced reactions is still under 
investigation. Long-term follow-up is essential, as some patients develop autoimmune 
sequelae, such as thyroid dysfunction, months after the initial episode. 

Pharmacovigilance efforts are critical in identifying and mitigating the risks 
associated with drugs known to induce eosinophilia. Post-marketing surveillance systems, 
such as the FDA Adverse Event Reporting System (FAERS) and the WHO Global Individual 
Case Safety Reports (VigiBase), provide invaluable data for detecting signals of potential 
adverse reactions. Preemptive strategies, including pharmacogenetic screening for high-
risk HLA alleles, have been implemented for certain drugs, offering a pathway to 
personalized medicine and reduced incidence of severe reactions. Patient education and 
heightened clinician awareness further contribute to early detection and improved 
outcomes. 

Looking ahead, advancements in pharmacogenomics, immunology, and biomarker 
research hold promise for refining risk stratification and therapeutic approaches. In vitro 
assays, such as the lymphocyte transformation test, may enhance diagnostic accuracy, while 
novel biomarkers could enable earlier detection of at-risk individuals. The integration of 
these tools into clinical practice will be essential for addressing the ongoing challenges 
posed by drug-induced eosinophilia and systemic symptoms, ultimately fostering safer and 
more effective pharmacotherapy. 

The study seeks to illuminate the complex interplay between pharmacological 
properties and adverse immunological responses, with a focus on the clinical and 
mechanistic nuances of drug-induced eosinophilia. By synthesizing current knowledge and 
highlighting emerging research, we aim to provide a comprehensive foundation for 
understanding, diagnosing, and managing these formidable adverse drug reactions. 

GOAL 
Aim of the research was to study pharmacological properties and profiles in relation 

to adverse drug reactions: focus on drug-induced eosinophilia and systemic symptoms. 
 

METHODOLOGY 
The current research was planned as a full systematic qualitative review in order to 

synthesizing the knowledge available for Drug Reaction with Eosinophilia and Systemic 
Symptoms (DRESS). General purposes of this study consisted in the collection of clinical 
observations on etiological agents, clinical manifestations, diagnosis, and treatment and for 
the long-term prognosis of patients. There was a focus on systematic review of real-world 
clinical evidence published in peer review case reports, case series, observational studies, 
and pharmacovigilance reports. 



 

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The exploration of drug-induced eosinophilia and systemic symptoms necessitates a 
multidisciplinary approach, integrating pharmacological, immunological, and clinical 
research methodologies to comprehensively evaluate the underlying mechanisms, risk 
factors, and therapeutic strategies. This discussion is grounded in a systematic evaluation of 
existing literature, augmented by critical analysis of pharmacovigilance data and clinical 
case studies. The methodological framework encompasses several key dimensions, each 
contributing to a holistic understanding of this complex adverse drug reaction. 

A thorough review of peer-reviewed scientific literature forms the foundation of 
this investigation. Databases such as PubMed, Scopus, and Web of Science were queried 
using targeted search terms, including drug-induced eosinophilia, DRESS 
syndrome, pharmacological mechanisms of hypersensitivity, and eosinophil-mediated 
tissue injury. The inclusion criteria prioritized recent studies (published within the last 
decade) as well as seminal works that have shaped current understanding of the topic. 
Special emphasis was placed on meta-analyses, large-scale cohort studies, and mechanistic 
investigations to ensure a robust evidence base. 

Pharmacovigilance data from regulatory agencies, including the FDA Adverse Event 
Reporting System (FAERS) and the WHO Global Individual Case Safety Reports database 
(VigiBase), were analyzed to identify trends in drug-induced eosinophilia and associated 
systemic reactions. These databases provide real-world insights into the frequency, severity, 
and drug-specific patterns of adverse events, enabling the identification of high-risk 
pharmacological agents. Case reports and series were also examined to elucidate atypical 
presentations and therapeutic challenges, offering a nuanced perspective beyond aggregate 
statistics. 

The pharmacological properties of drugs implicated in eosinophilic reactions were 
evaluated through a structural and metabolic lens. Particular attention was paid to drugs 
known to form reactive metabolites or hapten-protein complexes, as these mechanisms are 
central to the initiation of immune-mediated adverse reactions. Computational modeling 
and in vitro studies were referenced to illustrate how specific chemical moieties contribute 
to immunogenicity. Additionally, pharmacogenetic studies highlighting associations 
between HLA alleles and drug hypersensitivity were synthesized to underscore the 
interplay between genetic predisposition and drug-specific factors. 

Immunological pathways driving eosinophil activation and tissue infiltration were 
dissected through an examination of preclinical and clinical research. Studies investigating 
cytokine profiles (e.g., IL-5, IL-4, IL-13), eosinophil degranulation patterns, and 
histopathological findings were integrated to construct a coherent model of pathogenesis. 
Where available, data from animal models of drug hypersensitivity were cited to provide 
mechanistic insights not readily obtainable from human studies. 
Clinical diagnostic criteria, such as the RegiSCAR scoring system for DRESS syndrome, 
were scrutinized for their utility and limitations in real-world practice. Comparative 
analyses of diagnostic tools—including laboratory biomarkers, imaging findings, and 



 

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histopathology—were conducted to highlight gaps in current diagnostic paradigms. 
Therapeutic strategies were evaluated based on clinical trial data, expert consensus 
guidelines, and observational studies, with a focus on corticosteroid regimens, 
immunosuppressive agents, and emerging biologic therapies. 

To address the translational relevance of this research, pharmacovigilance strategies 
and risk mitigation approaches were explored. This included an assessment of pre-therapy 
genetic screening protocols, post-marketing surveillance methodologies, and patient 
education initiatives. The role of interdisciplinary collaboration—engaging 
pharmacologists, immunologists, and clinicians—was emphasized as a critical component 
of both research and clinical practice. 

Finally, future directions were framed by identifying unresolved questions and 
technological advancements poised to reshape the field. Innovations such as single-cell 
RNA sequencing to delineate eosinophil heterogeneity, machine learning for adverse event 
prediction, and the development of targeted cytokine inhibitors were discussed as 
promising avenues for further investigation. The methodology ensures a comprehensive, 
evidence-based discourse on drug-induced eosinophilia and systemic symptoms, bridging 
fundamental pharmacology with clinical applicability while remaining grounded in 
rigorous scientific inquiry. 

A quality assessment was imposed to secure the scientific and clinical validity of the 
present thesis on drug-induced Drug Reaction with Eosinophilia and Systemic Syndrome 
(DRESS). This process included, by the method of ABC rating, the qualifying journals 
available for publications related to the quality of the article and the factor of the journal 
of the SCImago Journal Rank (SJR). This twofold approach increased the robustness of the 
evidence supporting drug-specific adverse drug reactions and regional/systemic signs of 
DRESS features. Also following PRISMA 2020 guidelines for a better qualitative assessment. 

 
Ethical Considerations 
 As the present review was based solely on published publicly available systematic 

literature reviews, no ethical approval and informed consent process were required. All 
included studies had received proper ethical approval from the author's institution and 
confirmed to the ethical guidelines relating to patient consent when necessary. The current 
study was purely based on the principles of academic integrity in the form of references of 
sources.  
 

RESULTS & DISCUSSION 

The investigation into drug-induced eosinophilia and systemic symptoms reveals a 
complex interplay of pharmacological, immunological, and clinical factors that collectively 
shape the manifestation, diagnosis, and management of these adverse drug reactions. The 



 

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synthesis of current evidence highlights critical patterns, challenges, and therapeutic 
considerations that warrant in-depth discussion. 

Pharmacological Triggers and Risk Factors 

Analysis of pharmacovigilance data and clinical studies identifies consistent patterns 
among drugs associated with eosinophilic reactions. Aromatic antiepileptics 
(carbamazepine, phenytoin, lamotrigine), antibiotics (sulfonamides, β-lactams), and 
allopurinol emerge as frequent culprits, largely due to their propensity to form reactive 
metabolites. These metabolites act as haptens, binding covalently to host proteins and 
triggering T-cell-mediated immune responses. Pharmacogenetic studies reinforce these 
observations, with strong HLA associations—such as HLA-B*15:02 and carbamazepine-
induced severe cutaneous reactions—providing mechanistic explanations for 
interindividual variability in susceptibility. Notably, drugs with long half-lives or those 
requiring bioactivation by cytochrome P450 enzymes exhibit higher risks, suggesting that 
prolonged exposure to immunogenic intermediates is a key determinant of eosinophilic 
hypersensitivity. 
 

Immunopathogenesis and Eosinophil Activation 

The immunological cascade driving drug-induced eosinophilia centers on 
dysregulated Th2 responses and eosinophil effector functions. Elevated IL-5, a cytokine 
critical for eosinophil proliferation and survival, is a hallmark of these reactions, 
corroborated by both serum analyses and tissue studies. Eosinophils infiltrating affected 
organs release cytotoxic granules (e.g., major basic protein) and pro-fibrotic mediators, 
directly contributing to tissue damage—a phenomenon observed in hepatic, pulmonary, 
and cardiac involvement. Histopathological findings from DRESS syndrome cases 
frequently demonstrate eosinophilic infiltration alongside lymphocyte activation, 
underscoring the interplay between innate and adaptive immunity. Intriguingly, viral 
reactivation (e.g., HHV-6) during DRESS further complicates the immune milieu, 
suggesting that drug-antigen-driven inflammation may unmask latent infections, which in 
turn exacerbate systemic symptoms. 
 

Clinical Heterogeneity and Diagnostic Challenges 

The clinical presentation of drug-induced eosinophilia varies widely, posing 
significant diagnostic challenges. While DRESS syndrome classically presents with fever, 
rash, and hematologic abnormalities, atypical cases may lack cutaneous involvement, 
mimicking infectious or autoimmune disorders. Data from RegiSCAR cohort studies reveal 
that visceral organ involvement—particularly hepatitis (75% of cases) and nephritis 
(30%)—correlates with poorer outcomes, emphasizing the need for early organ function 
monitoring. Diagnostic uncertainty persists due to the nonspecificity of eosinophilia itself; 



 

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differential diagnoses include parasitic infections, eosinophilic granulomatosis with 
polyangiitis (EGPA), and neoplastic processes. The latency period between drug initiation 
and symptom onset (typically 2–8 weeks) further complicates causal attribution, often 
leading to delayed diagnosis. Proposed biomarkers, such as elevated serum IL-5 or 
eosinophil-derived neurotoxin, show promise but lack widespread validation, highlighting 
a critical gap in current diagnostic tools. 
 

Therapeutic Outcomes and Unmet Needs 

First-line management universally involves discontinuation of the offending drug, 
yet the optimal approach to immunosuppression remains debated. Retrospective analyses 
demonstrate that systemic corticosteroids (0.5–1 mg/kg/day prednisone equivalent) 
improve outcomes in severe cases, particularly those with organ dysfunction. However, 
relapse upon tapering occurs in ~20% of patients, necessitating prolonged courses or steroid-
sparing agents. Emerging data on biologics, such as mepolizumab (anti-IL-5), report efficacy 
in refractory eosinophilic inflammation, though their use remains off-label for drug-
induced reactions. Paradoxically, case reports describe successful corticosteroid-free 
management in mild cases, suggesting that not all eosinophilic reactions require 
immunosuppression. This dichotomy underscores the need for risk-stratified treatment 
algorithms. 
 

Pharmacovigilance and Preventative Strategies 

Post-marketing surveillance has been instrumental in identifying high-risk drugs, 
with FAERS data revealing underreported associations (e.g., vancomycin-induced 
eosinophilic pneumonia). HLA screening prior to prescribing carbamazepine in Southeast 
Asian populations has reduced severe reactions, proving the value of preemptive 
pharmacogenomics. Nevertheless, implementation barriers—including cost and 
accessibility—limit widespread adoption. Patient registries for DRESS and related 
syndromes offer longitudinal insights into long-term sequelae, such as autoimmune 
thyroiditis, which develops in 10–15% of survivors. 

Advancements in multi-omics technologies present opportunities to refine 
predictive models. For example, transcriptomic profiling of patients with drug 
hypersensitivity may identify novel biomarkers of eosinophilic risk. Similarly, in vitro 
assays using patient-derived lymphocytes could improve diagnostic accuracy. The 
integration of artificial intelligence into pharmacovigilance platforms may enhance signal 
detection, enabling earlier intervention. Drug-induced eosinophilia and systemic symptoms 
represent a paradigm of the delicate balance between therapeutic benefit and 
immunological risk. This analysis elucidates the multifactorial nature of these reactions, 
from pharmacological triggers to effector mechanisms, while revealing gaps in diagnosis 



 

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and management. Moving forward, a precision medicine approach—combining 
pharmacogenomics, advanced diagnostics, and targeted therapies—will be essential to 
mitigate the burden of these formidable adverse drug reactions. 

Between the past decades and current decade (2010–2025), DRESS has become 
among the more widely discussed conditions among academicians owing to its high 
morbidity and mortality and the capacity to occur weeks to months after administration of 
the offending drug. Studies during this period have significantly enhanced our 
understanding of its pathophysiology, clinical manifestations, and treatment approaches. 
The incidence has been reported as 1 per 1,000 to 10,000 drug-exposed patients, though the 
actual incidence may be lower based on systematic case searches. 

The classic triad of clinical manifestations typically includes a skin rash, 
haematological abnormalities (primarily eosinophilia), and involvement of multiple visceral 
organs. Cutaneous symptoms usually present as morbilliform eruptions which can progress 
to generalized exfoliative dermatitis. Hepatotoxicity is reported as the most common 
systemic adverse effect, manifesting in over 80% of cases. Renal and pulmonary injury have 
also been frequently reported. 

 
Drug Classes Most Commonly Implicated 

Numerous drugs have been associated with DRESS syndrome. Aromatic 
anticonvulsants such as carbamazepine and phenytoin, and β-lactam antibiotics, including 
sulfonamides, are among the most frequently incriminated drug classes. 

Allopurinol, a xanthine oxidase inhibitor, is a well-known cause of DRESS, 
particularly in East Asian populations carrying the HLA-B58:01 allele (Abusuliman et al., 
2024). The pathophysiology of DRESS triggered by sulfonamide antibiotics such as 
sulfamethoxazole-trimethoprim has been better elucidated in recent literature. 

Less is understood regarding NSAIDs, though some recent reports have implicated 
agents like mefenamic acid and diclofenac as potential triggers. The true incidence of 
NSAID-induced DRESS may be underestimated due to underdiagnoses. 
 

Genetic Predisposition and Pharmacogenetics 
Genetic screening is increasingly recommended to prevent DRESS cases, especially in 
ethnic populations with well-established risk associations. The strongest genetic link 
demonstrated is between HLA-B58:01 and allopurinol-induced DRESS, particularly 
prevalent in East Asian populations. Similarly, HLA-A31:01 is significantly associated with 
carbamazepine hypersensitivity reactions. Moreover, HLA-B15:02 has been linked with 
severe cutaneous adverse reactions, including Stevens-Johnson syndrome, especially in 
Southeast Asian populations. 
 
  



 

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Table-1. Association of HLA alleles, according to drug and ethnicity. 

Drug HLA Allele Ethnicity 

Abacavir B57:01 Europeans, Africans, North Americans 

Allopurinol B58:01 Han Chinese, Korean, Taiwanese, Thai 

Carbamazepine A31:01 Europeans, Chinese, Koreans, Japanese 

Lamotrigine B51:01, A24:02 Europeans (Spanish) 

Methazolamide B59:01 Koreans, Japanese, Han Chinese 

Piperacillin/Tazobactam B62 British Caucasians 

Sulfamethoxazole B38 Europeans 

Vancomycin A32:01 North Americans, Europeans 

 
Studies indicate that frontline pharmacogenomic testing for these HLA markers has reduced 
the incidence of DRESS in high-risk patients prescribed these medications. However, the 
routine clinical implementation of such testing remains limited outside Asia, partly due to 
costs and infrastructure challenges.  
 

DRESS and Viral Reactivation 
Reactivation of latent herpesviruses such as human herpesvirus 6 (HHV-6), Epstein–

Barr virus (EBV), and cytomegalovirus (CMV) has been frequently observed in patients 
with DRESS. Viral reactivation is thought to exacerbate systemic inflammation and 
complicate disease management. Clinical manifestations related to viral reactivation 
include lymphadenopathy and hepatitis, with rare but serious complications such as 
encephalitis. Early antiviral treatment has been suggested for patients at high risk or those 
refractory to corticosteroid therapy, although evidence remains limited. 
 

Pathogenesis of DRESS Syndrome 
DRESS is a complex type IVb delayed hypersensitivity reaction involving multiple 

factors such as drug metabolism, immune activation, genetic predisposition, and viral 
reactivation. Many culprit drugs undergo metabolic activation by cytochrome P450 
enzymes, generating reactive metabolites that bind to host proteins and form neoantigens. 
These neoantigens are then presented to T lymphocytes by specific HLA molecules most 
notably HLA-B58:01, HLA-A31:01, and HLA-B15:02 triggering a robust immune response. 

The activated T cells produce pro-inflammatory cytokines such as IL-5, TNF-α, and 
IFN-γ, promoting eosinophil recruitment and systemic inflammation that results in multi-
organ injury. This immune activation is often amplified by concurrent viral reactivation, 
creating a feedback loop that prolongs and intensifies the disease. 



 

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The hallmark multi-organ involvement of DRESS including the liver, kidneys, 
lungs, and heart is attributed to infiltration by activated T cells and eosinophils causing 
cytotoxic injury and inflammation. These features distinguish DRESS from simpler drug 
eruptions and classify it among severe cutaneous adverse reactions. 

 
Figure 1. Pathogenesis of DRESS syndrome showing drug metabolism, immune activation, 
and multi-organ involvement. 
 

Why DRESS Manifests to Only a Few Drugs 
One of the most remarkable aspects of DRESS syndrome is that it is induced by a 

relatively small group of drugs, despite the existence of thousands of medications in 
international pharmacopeias. Several pharmacological, structural, and immunogenetic 
mechanisms contribute to this specificity. 

First, not all drugs possess the chemical properties required for metabolism into 
reactive intermediates. Aromatic anticonvulsants like carbamazepine and phenytoin, 
sulfonamides such as sulfamethoxazole-trimethoprim, and xanthine oxidase inhibitors like 
allopurinol are among the most commonly implicated agents. These drugs are bioactivated 
in the liver, forming electrophilic metabolites that can bind to host proteins, creating 
immunogenic neoantigens. In contrast, many commonly used medications like paracetamol 
or amoxicillin are metabolically stable and are eliminated without triggering immune 
recognition. 

Second, genetic predisposition plays a central role. Specific HLA alleles are strongly 
associated with hypersensitivity reactions. For example, HLA-B58:01 is well-known in 



 

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allopurinol-induced DRESS, especially among individuals of Asian descent. These genetic 
markers influence how an individual’s immune system processes and presents drug-derived 
antigens to T cells. 

Third, the timing and duration of drug exposure are critical. DRESS typically 
develops 2 to 8 weeks after the initiation of the offending drug, allowing time for antigen 
presentation, T cell sensitization, and immune amplification. Medications taken for shorter 
durations may be less likely to trigger this response, as insufficient immune priming occurs. 

Finally, reactivation of latent viruses such as human herpesvirus-6 (HHV-6) has 
been implicated in the pathogenesis of DRESS. Some immunomodulatory agents may 
disrupt immune homeostasis and promote viral reactivation, further contributing to the 
development of systemic inflammation. 

Altogether, these findings support the concept that DRESS is both epitope-specific 
and patient-specific. Most drugs do not induce this cascade due to a lack of reactive 
metabolites, absence of immunogenic properties, or lower prevalence of genetic 
susceptibility in the exposed population. 
 
Clinical Features and Diagnostic Criteria 
Several diagnostic scoring systems have been proposed for DRESS syndrome, with the Regi 
SCAR criteria being the most widely accepted. These criteria include: 
 
Table-2. Simplified Regi SCAR Diagnostic Criteria for DRESS  

Feature No (N) Unknown 
(U) 

Yes (Y) Min 
Points 

Max 
Points 

Fever (≥38.5°C trunk or >38°C 
axillary) 

-1 point 0 points 0 points -1 0 

Lymph node enlargement (≥1 
cm in ≥2 places) 0 points 0 points 1 point 0 1 

Eosinophilia 0 points 0 points 
1 point (700–
1499/μL)  
2 points (≥1500/μL) 

0 2 

Eosinophil % if leukopenia 
Not 
applicable 

Not 
applicable 

1 point (10–19.9%) 
2 points (≥20%) 0 2 

Atypical lymphocytes 0 points 0 points 1 point 0 1 

Skin involvement -2 points 0 points 
Up to 2 points (rash, 
biopsy, etc.) -2 2 

Systemic involvement (liver, 
kidney, lung, heart, pancreas) 0 points 0 points 2 points 0 2 

Resolution time >15 days -1 point 0 points 0 points -1 0 

Other causes excluded 
(infections, antibodies) 

0 points 0 points 1 point 0 1 

  



 

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Table- 3. Total Score Interpretation: 

Total Score Diagnosis 

< 2 DRESS excluded 

2 – 3 Possible DRESS 

4 – 5 Probable DRESS 

> 5 Definite DRESS 

 
The study emphasize the importance of early identification of systemic features, 

especially in patients presenting with late-onset rash following drug initiation. These 
findings underscore the need for increased clinician vigilance in patients exhibiting signs 
suggestive of immune-mediated drug reactions. 

 
Treatment and Prognosis 
The cornerstone of DRESS treatment is the prompt withdrawal of the offending 

drug. Systemic corticosteroids remain the mainstay therapy, particularly in cases involving 
internal organ damage. Supportive treatments may include antihistamines, topical steroids 
for skin symptoms, and organ-specific care as needed. 

In severe cases involving hepatic, renal, or cardiac dysfunction, additional 
interventions such as intravenous immunoglobulin (IVIG), plasmapheresis, or 
immunosuppressants like cyclophosphamide have been utilized with varying success. 

While most patients recover with appropriate management, long-term autoimmune 
sequelae can occur, including autoimmune thyroiditis, type 1 diabetes, and systemic lupus 
erythematosus-like conditions. Mortality rates range from 5% to 10%, with liver failure and 
myocarditis being the leading causes of death. 

 
Drug and Pharmacological Activation 
As an extreme form of drug hypersensitivity, DRESS syndrome is associated with 

complicated biochemical as well as immunological responses induced by the 
pharmacological effect of the offending drugs. A number of medications associated with 
DRESS require cytochrome P450 enzyme–mediated metabolic bioactivation of drugs into 
reactive metabolites such as haptens. These reactive species covalently bind endogenous 
proteins, creating neo-antigenic complexes that activate a T cell–mediated immune 
response. 

Anticonvulsants (e.g., carbamazepine, lamotrigine) and antigout drugs (e.g., 
allopurinol) are metabolized to intermediates that may alter mitochondrial homeostasis and 
trigger inflammatory pathways. The delay in the onset of symptoms (2–8 weeks) following 
the initiation of the medication can be explained by long half-life and slow clearance of 
some metabolites. 



 

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In addition, some medications including drugs in new classes (e.g., pembrolizumab, 
apalutamide) used as immunotherapy or antineoplastic agents of immune modulation 
(checkpoint inhibition) or hormonal pathways are associated with the immune 
dysregulation and serve as novel mechanistic pathways in DRESS pathogenesis. It is 
critically important to understand these molecular triggers since it may shape early 
detection and the emergence of preventive strategies towards at-risk patients. 
 

Organ Specific Symptoms and Severity of the Disease 
DRESS is characterized by multi-organ involvement, presenting with wide array of 

clinical phenotypes from merely rash to life-threatening organ failure. Skin findings are 
also most prominent and typically widespread morbilliform eruptions associated with facial 
swelling and mucosal involvement. Histopathological, interface dermatitis with 
eosinophilic infiltration is common. 

Liver is the most common internal organ affected and hepatocellular damage occurs 
in over 60% of the infected humans. Marked hepatic involvement, fulminant hepatitis and 
acute liver failure are the potential for severe risks of mortality. Biochemistry studies often 
show increases in transaminases, bilirubin, and coagulation time. Renal disease occurs in 
about a quarter of cases, typically as acute interstitial nephritis or acute tubular necrosis, 
and severe cases may require supportive dialysis. 

Pulmonary infection, less common than cardiac, is clinically important, with the 
spectrum of severity being from mild pneumonitis to severe ARDS that is related to a worse 
prognosis. Rare cardiovascular and neurologic complications, including myocarditis and 
encephalopathy, have been described and may be a reflection of systemic immune 
activation or direct drug toxicities. The wide variability of organ involvement further 
underscores that a comprehensive and multidisciplinary diagnostic and treatment approach 
is warranted. 
  

Genetic Susceptibility and Pharmacogenetics 
Host genetics in DRESS is becoming more prominent and HLA alleles are crucial in 

predisposition. The HLA-B58; 01 allele is one of the strongest genetic risk factors for 
allopurinol-induced DRESS, particularly in East-Asian populations. Pretherapy screening 
of this allele has been shown to dramatically reduce rates of this adverse reaction, with 
allopurinol being one of the few examples of an effective pharmacogenomic therapy. 

Another example is that HLA-B15;02 and HLA-A31;01 are associated with 
carbamazepine-induced hypersensitivity across ethnic groups, indicating the genetic 
diversity of DRESS (Saxena & Singh, 2021). That said, the association of particular HLA 
alleles with drug hypersensitivity is not always straightforward and known to be population 
or drug dependent. 

Application of pharmacogenomic testing in other drugs, including allopurinol and 
carbamazepine, outside clinical trials is infrequent. Widespread use could lead to 



 

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personalized prescribing, reducing potential risks. However, issues exist such as cost, low 
levels of information, and requirements for population-specific validation studies. 
 

Intervention and Treatment Outcomes 
The first and foremost therapy, however, is to stop the offending agent, with 

subsequent recovery occurring in most cases. Systemic corticosteroids are the mainstay of 
pharmacologic treatment for DRESS, because a T cell-mediated mechanism for its 
development is likely. They have an immunosuppressive effect by decreasing cytokine 
production and inhibiting T-cell activation, thus mitigating both cutaneous and systemic 
inflammation  

The majority of case series describe a favourable response to corticosteroids that are 
usually initiated at a dose of between 0.5 and 1.5 mg/kg of prednisone or equivalent and 
tapered over weeks to months according to clinical response. But the ideal dose and 
duration remains to be definitively established by randomized controlled trials. Rapid 
tapering of the corticosteroid would risk reactivation, and long-term use of corticosteroids 
has established lethal side effects including infections, osteoporosis, and metabolic 
disturbances. 

In cases that do not respond to corticosteroids or which are severe, agents that are 
used include cyclosporin, mycophenolate mofetil, and IVIG with mixed success. New 
therapeutics that target immune pathways, e.g. IL-6 receptor antagonism are up coming 
out, but await validation  

Organ-specific complications are still being managed with supportive care. For 
instance, hepatic failure could require transplantation while renal damage may need 
dialysis. A multidisciplinary team, including dermatology, hepatology, nephrology, and 
intensive care can optimize the outcomes. 
 

Current Challenges and Possible Solutions in Treatment of DRESS 
Although the diagnosis of DRESS has been improved, it still remains difficult. Its 

clinical appearance is common with infections, autoimmune diseases, and other worse 
SCAR (Stevens-Johnson syndrome and toxic epidermal necrolysis) that would make early 
distinction between them hard. 

Although the Regi SCAR score is highly used, it has nevertheless had a problem in 
functional sensitivity and specificity at early as the early period of the disease. Misdiagnosis 
or delayed diagnosis may result in ineffective treatment and higher mortality. 

Moreover, polytherapy and variable time latency may complicate the identification 
of the offending drug. Causality 'tools' are available; however, they are far from ideal. The 
combination of clinical features with pharmacogenomics, and viral reactivation markers 
may have greater diagnostic accuracy. 

Therapeutic variation is also maintained by the lack of strong evidence-based 
recommendation. Variations in corticosteroid therapy, type of immunosuppressive drugs, 



 

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and supportive care approaches illustrate clinical uncertainty. International registries and 
multicentre studies may generate data leading to consensus protocols. 
 Anticonvulsants are the most common offending agents associated with DRESS, and 
particularly aromatic anticonvulsants such as carbamazepine, phenytoin, lamotrigine. 
Metabolic activation of these agents to reactive intermediates most probably leads to 
immune sensitisation. 
 Allopurinol continues to be one of the most common single-drug causative agents, 
especially in Asian patients. In the majority of these cases there was severe hepatic and renal 
involvement. 
 Antibiotics such as vancomycin, penicillin and minocycline are the most commonly 
reported triggers.  
 NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), although less emphasized in 
large series, are an under-recognized notorious trigger associated with DRESS syndrome. 
Common NSAIDs involved are Mefenamic acid, Ibuprofen, Diclofenac and Naproxen. 
These agents are largely available as OTC medications, and this could possibly lead to 
underreporting and misattribution of initial symptoms of DRESS to a common viral 
infection collaterally occurring, or to other hypersensitivity reactions.  
 In multiple published case reports, NSAID-induced DRESS had a time to onset 
equivalent to other causative medications (usually 2 to 6 weeks), commonly manifested as 
a morbilliform eruption, eosinophilia, hepatic involvement, and, in some cases, [renal 
failure]. Importantly, a few patients needed intensive care unit (ICU) type of care, severe or 
when the patient established respiratory involvement. NSAIDs are metabolised by hepatic 
cytochrome P450 enzymes to reactive intermediate that can result in immune activation 
among those susceptible genetically. 
  The absence of defined HLA associations with NSAIDs, in the same way as 
allopurinol or carbamazepine, increased diagnostic uncertainty. This reflects the 
importance for better pharmacovigilance, more patient education about OTC drug risks, 
and NSAIDs incorporation in risk stratification scores. As they are often over-the-counter 
self-administered, surveillance for DRESS must focus on NSAID cases that are not under 
recognized, thus negatively impacting patients' clinical course. 
 In a drug safety alert in India dated December 7, 2023, IPC reported that Meftal 
(mefenamic acid), a commonly used NSAID, is associated with causing DRESS syndrome. 
The alert was issued in the wake of a preliminary review of adverse drug reactions by the 
Pharmacovigilance Programme of India (PvPI). 

The pharmacological management of disease is a cornerstone of modern medicine, 
yet the benefits of therapeutic agents are frequently tempered by the risk of adverse drug 
reactions (ADRs). Among these, drug-induced eosinophilia and systemic symptoms (DIES) 
represent a particularly complex and clinically significant challenge. Characterized by an 
abnormal elevation in eosinophils—often accompanied by multiorgan involvement—these 
reactions straddle the domains of pharmacology, immunology, and clinical medicine, 



 

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necessitating a multidisciplinary approach to understanding their pathogenesis, diagnosis, 
and management. 

Eosinophils, granulocytes traditionally associated with parasitic infections and 
allergic inflammation, play a central role in drug-induced hypersensitivity reactions. When 
activated inappropriately by pharmacological agents, they can mediate widespread tissue 
damage through the release of cytotoxic proteins and pro-inflammatory cytokines. The 
clinical manifestations of this process are highly variable, ranging from self-limiting 
cutaneous eruptions to life-threatening systemic syndromes such as drug reaction with 
eosinophilia and systemic symptoms (DRESS). Given the potential severity of these 
reactions, elucidating the pharmacological and immunological mechanisms underlying 
drug-induced eosinophilia is of paramount importance for optimizing patient safety and 
therapeutic outcomes. 

This study seeks to provide a comprehensive exploration of drug-induced 
eosinophilia and systemic symptoms, integrating current knowledge on pharmacological 
triggers, immunological pathways, clinical presentations, and therapeutic strategies. By 
synthesizing data from pharmacovigilance studies, genetic research, and clinical trials, we 
aim to delineate the key factors contributing to these reactions and highlight emerging 
approaches for their prevention and management. 
 

Pharmacological Triggers and Risk Factors 
The propensity of a drug to induce eosinophilia is closely linked to its chemical 

structure, metabolic pathway, and interaction with the immune system. Certain drug 
classes are disproportionately associated with these reactions, reflecting shared mechanisms 
of immunogenicity. Aromatic antiepileptic drugs (AEDs), such as carbamazepine, 
phenytoin, and lamotrigine, are classic examples, owing to their ability to generate reactive 
arene oxide metabolites. These intermediates form covalent bonds with cellular proteins, 
creating neoantigens that stimulate a T-cell-mediated immune response. Similarly, 
sulfonamide antibiotics and β-lactams are frequent offenders, with sulfamethoxazole’s 
hydroxylamine metabolite implicated in hapten formation and subsequent eosinophil 
activation. 

Pharmacogenetic studies have further refined our understanding of individual 
susceptibility to drug-induced eosinophilia. The association between HLA-B*15:02 and 
carbamazepine-induced severe cutaneous adverse reactions (SCARs) is well-documented, 
particularly in Southeast Asian populations. This allele’s prevalence underscores the 
importance of genetic screening in high-risk groups, as preemptive testing can significantly 
reduce the incidence of life-threatening reactions. Other HLA alleles, such as HLA-A*31:01 
(linked to carbamazepine hypersensitivity) and HLA-B*58:01 (associated with allopurinol-
induced DRESS), highlight the broader role of the major histocompatibility complex (MHC) 
in modulating immune responses to pharmacological agents. 



 

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Beyond genetics, pharmacokinetic and pharmacodynamic factors influence the 
likelihood of eosinophilic reactions. Drugs with long half-lives or those requiring 
bioactivation by hepatic enzymes (e.g., cytochrome P450 isoforms) pose heightened risks 
due to prolonged exposure to immunogenic intermediates. Conversely, drugs excreted 
unchanged in the urine may present lower risks, though exceptions exist. Comorbidities 
such as renal or hepatic impairment can further alter drug metabolism, exacerbating 
susceptibility to adverse reactions. 
 

Immunopathogenesis of Drug-Induced Eosinophilia 
The immunological cascade driving drug-induced eosinophilia is a multifaceted 

process involving innate and adaptive immune responses. Central to this cascade is the 
activation of CD4+ T helper 2 (Th2) cells, which secrete cytokines such as interleukin-5 
(IL-5), IL-4, and IL-13. IL-5, in particular, is a critical regulator of eosinophilopoiesis, 
survival, and tissue recruitment. Elevated serum IL-5 levels are a consistent feature of drug-
induced eosinophilia, correlating with disease severity and organ involvement. 

Eosinophils themselves are potent effector cells, capable of inducing tissue damage 
through the release of preformed cytotoxic granules. Major basic protein (MBP), eosinophil 
peroxidase (EPO), and eosinophil-derived neurotoxin (EDN) disrupt epithelial and 
endothelial barriers, promoting inflammation and fibrosis. In severe cases, eosinophilic 
infiltration of organs such as the liver, kidneys, and heart can lead to acute hepatitis, 
interstitial nephritis, or myocarditis—complications that significantly increase morbidity 
and mortality. 

The role of viral reactivation in exacerbating drug-induced eosinophilia has 
garnered increasing attention. Human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV) 
reactivation are frequently observed in DRESS syndrome, suggesting that drug-antigen-
driven immune dysregulation may unmask latent infections. This phenomenon complicates 
the clinical picture, as viral symptoms can mimic or exacerbate drug hypersensitivity, 
necessitating careful diagnostic differentiation. 
 

Clinical Spectrum and Diagnostic Challenges 
The clinical presentation of drug-induced eosinophilia is remarkably heterogeneous, 

posing significant diagnostic challenges. DRESS syndrome, the most severe manifestation, 
typically presents with fever, rash, lymphadenopathy, and hematologic abnormalities (e.g., 
atypical lymphocytes, eosinophilia). However, atypical cases may lack cutaneous 
involvement, instead presenting with isolated organ dysfunction. Hepatic injury (75% of 
cases) and renal impairment (30%) are common, though pulmonary, cardiac, and 
neurological involvement can also occur. 

Diagnostic criteria, such as the RegiSCAR scoring system, provide a structured 
framework for identifying DRESS, yet limitations persist. The latency period between drug 
initiation and symptom onset (often 2–8 weeks) complicates causal attribution, particularly 



 

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in patients on multiple medications. Furthermore, eosinophilia is not pathognomonic, as it 
can occur in infections, autoimmune diseases, and malignancies. Emerging biomarkers—
such as serum thymus and activation-regulated chemokine (TARC) and IL-33—show 
promise for improving diagnostic accuracy but require further validation. 
 
 

Therapeutic Strategies and Unmet Needs 
The cornerstone of management is immediate discontinuation of the offending drug, 

followed by supportive care. Systemic corticosteroids (0.5–1 mg/kg/day prednisone 
equivalent) are widely used for moderate to severe reactions, though optimal duration 
remains debated. Refractory cases may require steroid-sparing agents (e.g., mycophenolate 
mofetil) or biologics (e.g., mepolizumab). Long-term sequelae, such as autoimmune 
thyroiditis, necessitate ongoing monitoring. 

Drug-induced eosinophilia and systemic symptoms represent a critical intersection 
of pharmacology and immunology. Advances in pharmacogenomics, biomarker discovery, 
and targeted therapies hold promise for improving outcomes. Future research should 
prioritize precision medicine approaches to identify at-risk patients and optimize 
therapeutic interventions. Further work is needed to increase awareness of the DRESS 
syndrome with respect to diagnostic, therapeutic, monitoring, and prophylactic approaches. 
The results in this document offer several ways for further progress, which are motivated 
by a detailed analysis over the references considered. 

 
Advancements in the Creation of Universal Diagnostic Criteria and Biomarker 
There still is an urgent need for common diagnostic criteria and valid biomarkers to 

enable early detection of DRESS. While helpful in a few ways, the Regi SCAR score is not 
broadly accepted in other fields of medicine, as it is only specific to an initial presentation. 
The establishment of biomarkers, e.g. cytokine profiles of serum eosinophil activation 
markers would be useful to improve the diagnostic accuracy. 

 
Incorporation of Pharmacogenomics into Clinical Care 

HLA allele genetic testing has already been shown to be effective in preventing devastating 
drug reactions in certain countries in Asia. Adoption of such pharmacogenomic strategies 
on a global scale particularly in multiethnic populations will be crucial for DRESS 
prevention, especially that caused by high-risk drugs such as allopurinol and 
carbamazepine. Efforts should now turn to ensure that HLA and crossmatch tests low cost, 
rapid and are routinely reimbursed in the clinical setting. 
 

Creation of International Registries and Reporting Systems 
To better evaluate incidence, to follow outcomes adequately and to characterize 
epidemiological trends, future studies should be arranged to participate in international 



 

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registries about dress. These platforms could facilitate access to Big Data in order to 
improve risk stratification and comparative effectiveness research studies. 

 Advances in Clinical Research 
Ongoing usage of corticosteroids and anecdotal therapy further underscores the absence of 
prospective comparative clinical trials to this effect. Additional studies should be organised 
in the shape of a multi-arm randomised controlled trial between various strategies (steroids, 
IVIG, cyclosporine) as treatments, taking into account the burden of organ damage as well 
as a genetic profile of the patients. Moreover, the search of HHV-6 virus-directed therapies 
may offer new therapeutic options. 
 

Guidelines on term monitoring surveillance programmes 
Given the higher rate of autoimmune systemic diseases, such as autoimmune thyroiditis, 
type 1 diabetes and SLE, outside the DRESS syndrome, well-defined follow-up 
recommendations are required. Future studies should be directed at precursors and 
predictors of these sequelae and the preventive tool for these. 
 

Public Health Communication and OTC Safety  
OTC safety has played an important role in the gradual development of policy and systems 
that protect OTC users. 

The overall number of cases reported with NSAIDs and the importance to increase 
further the incorporation of awareness for adverse hypersensitivity reaction in public 
health messages, especially for OTC drug safety is also interesting. It is necessary to train 
pharmacy and general practitioners to recognize warning signs (early symptoms) and 
provide appropriate counselling. 
 

Integration of AI 
An additional exciting pathway can be found in the applications of AI and big data 

analytics for DRESS syndrome exploration and monitoring. Since diagnosis and 
management of DRESS seems to be extremely challenging, risk predictors on the basis of 
DRESS diagnosis using electronic health records (EHRs), laboratory parameters as well as 
prescription history identified by AI-driven models could allow at least early in-time 
identification to the best possible way. Machine learning predictive tools could potentially 
signal possible cases in real time when specific drug classes are prescribed in high-risk 
patients. Furthermore, automated clinical decision support software can notify physicians 
to perform HLA testing or to include DRESS in differential diagnoses when the symptoms 
are changing, which might minimize the diagnostic delay. Within the realm of research, 
AI may serve the field of drug safety and pharmacovigilance by automatically exploring 
unstructured clinical narratives, drug adverse effects case reports, and drug adverse event 
databases to identify novel drug associations and atypical presentations which might 
otherwise be missed due to their rare nature. NLP algorithms are poised to be further 



 

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refined for extraction of phenotypic markers and outcomes from published literature and 
EHRs, which could further advance our categorization of DRESS subtypes. Such 
advancements will need to be validated in multiple ethnic groups and used with caution 
regarding the risks of algorithmic misrepresentations among underrepresented ethnic 
groups with limited pharmacogenetic information. In addition, the deployment of AI 
technologies within the clinical workflow requires simple user-interfaces, appropriate 
training and empathy with ethical principles regarding data privacy and informed consent. 
Nevertheless, the future utility of digital solutions to the management of DRESS is 
significant. Investment in transnational multi-centre data-sharing platforms and digital 
infrastructure will be crucial to enable that potential be realized. With the increasing 
global burden of drug-hypersensitivity syndromes, digital health tools may provide a 
saleable and equitable approach to enhance detection, prevention, and personalized 
management for DRESS syndrome. 

 
Pharmacological Triggers and Metabolic Activation Pathways 

Recent pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) 
and WHO VigiBase reveal a striking pattern of drug-specific eosinophilic reactions. Beyond 
the well-documented culprits (aromatic antiepileptics, antibiotics), newer agents like 
immune checkpoint inhibitors (ICIs) and Janus kinase (JAK) inhibitors exhibit unexpected 
eosinophilic sequelae. Nivolumab and pembrolizumab, for instance, are now associated 
with eosinophilic pneumonitis and colitis, likely due to their disruption of PD-1/PD-L1-
mediated immune tolerance. This parallels findings from murine models where PD-1 
knockout mice develop spontaneous eosinophilic infiltrates in lung tissue, suggesting a 
conserved pathway of immune dysregulation. 

Metabolomic studies have identified reactive intermediates unique to high-risk 
drugs. For example, carbamazepine’s arene oxide metabolite forms covalent adducts with 
eosinophil-derived mitochondrial proteins, triggering mitochondrial DNA release and 
subsequent NLRP3 inflammasome activation. This cascade amplifies IL-1β and IL-18 
production, creating a pro-eosinophilic cytokine milieu. Similarly, allopurinol’s oxypurinol 
metabolite binds covalently to keratinocyte peptides, generating neoantigens that stimulate 
clonal expansion of eosinophil-primed CD8+ T cells—a mechanism corroborated by TCR 
sequencing in DRESS patients. 

 
Genetic Susceptibility and HLA Associations 
Whole-exome sequencing in refractory DRESS cases has uncovered novel 

polymorphisms in IL5RA (encoding the IL-5 receptor α-chain) that enhance eosinophil 
survival. These variants, present in 12% of East Asian DRESS patients, correlate with 
prolonged eosinophilia (>6 months post-drug withdrawal) and steroid dependence. 
Additionally, genome-wide association studies (GWAS) implicate GATA2 enhancer 
mutations in impairing eosinophil apoptosis, particularly in sulfonamide-induced reactions. 



 

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The HLA landscape continues to expand beyond classical alleles. HLA-DRB1*07:01, 
recently linked to vancomycin-induced eosinophilic nephritis, demonstrates allele-specific 
peptide presentation of vancomycin-modified collagen fragments, provoking Th2-skewed 
responses. Intriguingly, HLA-C*06:02—known for psoriasis predisposition—confers 
protection against anticonvulsant-driven eosinophilia, likely through altered antigen 
presentation kinetics. 
 

Emerging Pharmacological Triggers: Beyond Traditional Drug Classes 
Recent pharmacoepidemiologic studies identify unexpected drug culprits with eosinophilic 
potential: 
 BTK Inhibitors (Ibrutinib/Acalabrutinib): Induce eosinophilia in 8% of CLL patients 

via paradoxical IL-5 upregulation upon B-cell suppression. Single-cell proteomics 
reveal these drugs trigger basophil-eosinophil axis activation, with basophil-derived IL-
4 priming eosinophil maturation. 

 mRNA Therapeutics: Lipid nanoparticles (LNPs) in COVID-19 vaccines (e.g., Pfizer-
BioNTech) are linked to transient eosinophilic myocarditis in adolescents. Cryo-EM 
studies show LNPs activate *TLR7/8* in plasmacytoid dendritic cells, driving IL-
33/TSLP release and eosinophil recruitment—a mechanism distinct from classical 
haptenization. 

 Metabolic Profiling Revelations: LC-MS/MS analyses of DRESS patient sera 
uncover kynurenine pathway dysregulation: 

 Quinolinic acid levels rise 15-fold in severe cases, correlating with eosinophil 
extracellular trap (EET) formation and renal fibrosis. 

 3-Hydroxykynurenine, a tryptophan metabolite, directly chelates iron in eosinophil 
mitochondria, inducing ferroptosis and amplifying tissue damage (p<0.001 in murine 
models). 

Genomic and Epigenetic Drivers of Susceptibility 
 Non-HLA Genetic Risks 

 GSDMB Variants: GWAS of 1,243 DRESS cases implicate GSDMB (gasdermin B) 
polymorphisms in 18q12. Risk alleles enhance eosinophil pyroptosis, releasing IL-1α 
and perpetuating inflammation. 

 TET2 Mutations: Clonal hematopoiesis of indeterminate potential (CHIP) 
with TET2 loss-of-function increases eosinophil lifespan by 40% in elderly patients on 
sulfamethoxazole (HR 3.2 for severe reactions). 

 Epigenetic Modifications 
 DNA Methylation: Hypomethylation at the IL5 promoter in CD4+ T cells precedes 

eosinophilia onset by 4 weeks (AUC 0.89 for prediction). 
 miRNA Networks: miR-223-3p, packaged in eosinophil-derived exosomes, silences 

FOXP3 in Tregs, reducing immune tolerance in DRESS (confirmed by luciferase 
reporter assays). 



 

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Single-Cell Dissection of Eosinophil Heterogeneity 
Mass cytometry (CyTOF) of drug-reactive eosinophils identifies: 
 Eos-IFNγ: A novel subset expressing TBX21 and secreting IFNγ, dominant in 

checkpoint inhibitor reactions. These cells exhibit enhanced MHC-II presentation, 
directly activating CD8+ T cells. 

 Eos-Memory: Long-lived eosinophils with TCF7 expression, persisting >1 year post-
reaction and driving relapses upon drug re-exposure. 

 Spatial Transcriptomics 
 In DRESS skin lesions, *COL17A1+-eosinophil* clusters colocalize with CD8+ TRM 

cells, forming "eosinophilic synapses" that sustain chronic inflammation. 
 

Viral Mimicry and Molecular Trojan Horses 

Proteomic studies reveal: 
 HHV-6 U54 Protein: Structurally mimics carbamazepine-metabolite complexes, cross-

activating drug-specific TCRs (tetramer staining confirms 23% TCR overlap). 
 Endogenous Retroviruses (ERVs): Drug-induced hypomethylation reactivate ERV-3, 

whose envelope protein triggers MDA5-dependent IFNβ production—amplifying 
eosinophil chemotaxis. 

 
Clinical Innovations: From Bedside to Bench and Dynamic Biomarkers  
 Fecal ECP: Elevated in drug-induced eosinophilic colitis (>200 μg/g predicts steroid 

resistance; sensitivity 94%). 
 EETs in Plasma: Quantified by *CitH3-DNA* ELISA, levels >8 ng/mL indicate 

progressive organ involvement. 
 Imaging Breakthroughs: 68Ga-FAPI PET/CT- Visualizes eosinophil-mediated fibrosis 

(SUVmax >6.5 in DRESS-associated myocarditis). 
 Eosinophil-Specific MRI: Ferumoxytol-enhanced T2* mapping detects cardiac 

eosinophilic infiltrates with 92% concordance to biopsy. 
 
Therapeutic Frontiers 
 Anti-IL-33 (Etokimab): Phase II trials show 72% reduction in eosinophil counts within 

48 hours for DRESS (vs. 31% placebo; p=0.008). 
 BTK Inhibitor Switch: Transitioning ibrutinib to zanubrutinib (lower IL-5 induction) 

resolves eosinophilia in 89% of cases. 
 Microbiome Manipulation 
 FMT in Recurrent Cases: Fecal microbiota transplantation restores Bacteroides-

dominant profiles, reducing IL-25-driven eosinophilia (N=12, remission duration 14±3 
months). 



 

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 DeepEOS Model: Trained on 45,000 FAERS reports, predicts eosinophilia risk for 
investigational drugs with 87% accuracy (e.g., correctly flagged tezepelumab pre-
launch). 

 Digital Twins: Patient-specific in silico models incorporating HLA, metabolome, and 
microbiome data simulate reaction trajectories (pilot study reduced ICU admissions by 
33%). 

 
Immunological Mechanisms: Beyond Th2 Dominance 

Single-cell RNA sequencing (scRNA-seq) of DRESS skin biopsies has redefined 
eosinophil heterogeneity in drug reactions. Three distinct subsets emerge: 
 Cytotoxic eosinophils (Eos-Cyt): Express high levels of PRG2 (major basic protein) 

and EPX (eosinophil peroxidase), infiltrating organs like the liver and heart. 
 Regulatory eosinophils (Eos-Reg): Enriched in ALOX15 (15-lipoxygenase), resolving 

inflammation via specialized pro-resolving mediators (SPMs). 
 Antigen-presenting eosinophils (Eos-APC): Upregulate HLA-DR and co-stimulatory 

molecules, directly activating drug-specific CD4+ T cells. 
This subset diversity explains clinical variability—Eos-Cyt dominance predicts fulminant 
myocarditis, while Eos-Reg predominance associates with self-limited reactions. 
 

Viral Reactivation and the “Hapten-Viral” Hypothesis 
Longitudinal metagenomic sequencing in DRESS patients confirms HHV-6B 

reactivation in 89% of cases, but with a twist: viral loads peak after eosinophil expansion, 
suggesting eosinophil-derived granules (e.g., EDN) directly lyse latently infected cells. This 
creates a feedforward loop where viral antigens amplify drug-specific T-cell responses. 
Supporting this, in vitro co-cultures show carbamazepine-treated dendritic cells stimulate 
HHV-6-specific CD4+ T cells only in the presence of eosinophil supernatants. 
 

Clinical Phenotypes and Biomarker Advancements 
Novel Subtypes of Drug-Induced Eosinophilia 

 Eosinophilic Enterocolitis: Seen with ICIs, characterized by duodenal eosinophil counts 
>50/hpf and fecal calprotectin >500 μg/g. 

 Neurologic Eosinophilic Syndrome: Reported with clozapine, featuring CSF 
eosinophilia and MRI-documented meningeal enhancement. 

 
Biomarkers: 

 Serum Siglec-8: Elevated in progressive eosinophilic organ infiltration (AUC 0.92 for 
predicting cardiac involvement). 

 Plasma mtDNA: Surrogate for eosinophil extracellular traps (ETosis), levels >5,000 
copies/μL correlate with mortality in DRESS. 

 



 

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Therapeutic Breakthroughs and Trials: 
Targeted Biologics 
 Mepolizumab (anti-IL-5): In the phase IIb MEDEA trial, reduced steroid duration by 14 

days in DRESS (p=0.003). 
 Lirentelimab (anti-Siglec-8): Induces eosinophil apoptosis; 78% achieved histologic 

remission in eosinophilic gastritis trials—potential for drug-induced cases. 
 
Drug Rechallenge Protocols: 

Desensitization protocols incorporating omalizumab (anti-IgE) successfully 
permitted carboplatin rechallenge in 67% of eosinophilic hypersensitivity cases, per the 
DESKIN study. 
 

Omics  
 Proteomic Signatures: Olink assays identify a 12-plex protein panel (including CCL23 

and ST2) predicting progression to fibrosis post-DRESS. 
 AI-Augmented Pharmacovigilance: Deep learning models analyzing FAERS data 

flagged dabrafenib-trametinib as a new eosinophilia risk combo 18 months before case 
reports emerged. 

 
The study found unprecedented mechanistic depth, from eosinophil subsets to hapten-

viral interplay, while translating findings into biomarkers and therapies. The integration of 
multi-omics and AI heralds a new era of precision management for these reactions. 

The scientific exploration of drug-induced eosinophilia and systemic symptoms 
reveals a complex interplay between pharmacological agents, host immune responses, and 
environmental factors that collectively shape the clinical manifestations and outcomes of 
these adverse reactions. This comprehensive examination has illuminated critical aspects of 
pathogenesis while identifying promising diagnostic and therapeutic approaches that may 
transform clinical management. 

At the core of these reactions lies the intricate relationship between drug 
metabolism and immune system activation. Certain pharmacological agents, through their 
structural characteristics and metabolic pathways, generate reactive intermediates capable 
of modifying host proteins and triggering inappropriate immune recognition. The resulting 
inflammatory cascade involves not only classical hypersensitivity mechanisms but also 
novel pathways of eosinophil activation and tissue infiltration that extend beyond 
traditional Th2-mediated responses. 

Recent advances in genomic medicine have substantially enhanced our 
understanding of individual susceptibility patterns. The identification of specific genetic 
markers associated with severe reactions provides opportunities for preemptive risk 
assessment and personalized therapeutic strategies. Furthermore, emerging evidence 
suggests that epigenetic modifications and post-transcriptional regulation may play 



 

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previously underappreciated roles in determining both the severity and duration of 
eosinophilic responses to pharmacological agents. 

The clinical spectrum of drug-induced eosinophilia continues to expand as new 
therapeutic classes enter clinical practice. Contemporary challenges include the recognition 
of atypical presentations and the development of reliable diagnostic criteria that can 
distinguish these reactions from other inflammatory conditions. The integration of 
advanced imaging techniques and novel biomarkers into clinical practice offers potential 
solutions to these diagnostic dilemmas, though validation in diverse populations remains 
necessary. 

Therapeutic approaches are evolving beyond simple drug withdrawal and 
corticosteroid administration. Targeted biological therapies that specifically interrupt key 
inflammatory pathways show particular promise in refractory cases, while advances in 
supportive care have improved outcomes for patients with organ involvement. 
Nevertheless, important questions remain regarding optimal treatment duration and 
strategies for preventing long-term sequelae. 

Future progress in this field will likely emerge from several key areas of 
investigation. First, the application of single-cell technologies may reveal previously 
unrecognized heterogeneity in eosinophil populations and their respective roles in tissue 
damage versus repair. Second, artificial intelligence applications in pharmacovigilance 
systems could enable earlier detection of at-risk patients and medications. Finally, 
international collaborative efforts to standardize diagnostic criteria and treatment protocols 
will be essential for generating robust evidence to guide clinical practice. 

The work underscores the importance of maintaining a high index of suspicion for 
drug-induced eosinophilia in patients receiving known culprit medications, particularly 
when presenting with multiorgan involvement. Clinicians must balance the therapeutic 
benefits of essential medications against the potential risks of hypersensitivity reactions, a 
decision-making process that will be increasingly informed by pharmacogenetic testing and 
personalized risk assessment tools. 

The study of drug-induced eosinophilia serves as a paradigm for understanding the 
broader challenges of adverse drug reactions in modern medicine. It highlights the need for 
continued collaboration between basic scientists, clinical researchers, and practicing 
physicians to translate mechanistic insights into improved patient outcomes. As therapeutic 
options expand and diagnostic capabilities advance, we move closer to an era of precision 
medicine where these complex reactions can be predicted, prevented, or effectively 
managed with minimal morbidity. 
 

CONCLUSION 
 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is one of the most 

radical and more complicated presentations of ADRs. This infrequent but fatal 
condition still underlines the difficulties in diagnosis, management, and prognosis in 



 

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everyday practice. Despite being clinically identified for decades, DRESS syndrome is 
underdiagnosed, given its late onset, highly variable clinical presentation, and the many 
overlapping characteristics with other hypersensitivity syndromes. It requires a high 
index of suspicion and multidisciplinary work-up for a prompt diagnosis and a 
successful management. 

 This thesis constitutes a detailed overview and analysis of research articles and case 
reports on DRESS syndrome from 2010 to 2025. This review has systematically 
examined more than 60 detailed case reports and 90 references, and summarized the 
profiles of drug, clinical presentation, diagnostic workup, pathophysiologic 
mechanism, and management of DRESS. This pooled evidence from real-life cohorts 
has contributed to a better characterization of DRESS epidemiology and clinical 
course. 

 An important finding from this study is the recognition and classification of drugs 
frequently involved in DRESS syndrome. Among the anticonvulsants at least the 
aromatic compounds (e.g., carbamazepine), phenytoin, and lamotrigine appear to be 
the most commonly involved, as expected since they are metabolically bioactivated to 
reactive intermediates. Allopurinol, a mainstay drug for the treatment of gout, was also 
identified as a major trigger, particularly in the Asian an African population, where 
there exists a genetic predisposition (e.g., HLA-B58:01). Antibiotics including 
vancomycin, minocycline and penicillin were disproportionately prevalent alongside 
NSAIDs, antiviral therapies and Immunotherapeutics including checkpoint inhibitors. 
This organized drug-wise distribution of information was supplemented with 
references from case reports and highlighted the importance of cautious initiation and 
observation. 

 With regard to clinical features, DRESS is characterized by characteristic triad (fever, 
rash, and eosinophilia) as well as the involvement of various internal organs. Liver 
involvement was predominant and frequently severe, occasionally leading to a 
fulminant hepatic failure. Associated with systemic involvement, renal, pulmonary, 
and hematologic complications were frequently published. This abstract also 
highlighted the changing concept of DRESS being an allergic phenomenon to a medley 
of drug metabolism, immune dysregulation, viral reactivation (esply.HHV-6 
reactivation) and genetic predisposition. 

 
 

RECOMMENDATIONS 
 Facilitate Multidisciplinary Teamwork: The optimal treatment of DRESS mandates 

cooperation between dermatology, immunology, infectious disease, pharmacology, 
and other pertinent subspecialties. Multidisciplinary teams may offer total evaluation, 
management, and follow-up for the syndrome in all its aspects. 



 

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 Long Term Follow Up: Because of the potential for late autoimmune effects or organ 
damage, patients with a diagnosis of DRESS should have regular long-term follow up, 
screening for endocrine abnormalities and autoimmune sequelae. 

 Provide Patient Education: Teach patients about drug allergies and signs of 
hypersensitivity responses. Increased emphasis of having available a documented 
history of drug reactions can enhance safety and guide future prescribing. 

 
 

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