Pathogenesis of DRESS Syndrome
DRESS syndrome is primarily caused by a complex interplay of genetic predisposition, drug metabolism defects, viral reactivation, and immune dysregulation involving T-cell mediated hypersensitivity reactions. 1
Immunological Mechanisms
T-Cell Mediated Response
- DRESS syndrome is fundamentally a T-cell mediated drug reaction 1
- In the acute phase, T-cells infiltrate the skin and following drug stimulation:
Drug Presentation Pathways
Two main hypotheses explain how drugs trigger immune responses:
Hapten-dependent pathway:
- Chemically inert drugs become immunogenic through metabolism
- Reactive intermediates bind covalently with proteins (haptenation)
- These drug-protein complexes are presented via HLA molecules to T-cells 2
Pharmacological interaction (p-i) hypothesis:
- Parent drug interacts directly with T-cells through MHC-restricted but metabolism-independent pathway
- Drugs may activate T-cells by interacting with either MHC-peptide or T-cell receptor 2
"Danger hypothesis" (complementary mechanism):
- Immune response to drug-derived antigens requires co-stimulatory signals including cytokines 2
Genetic Susceptibility
HLA Associations
- Strong genetic predisposition through specific HLA alleles 1
- Different drugs associated with specific HLA types:
Drug Metabolism Defects
- Polymorphisms in drug-metabolizing enzymes contribute to DRESS susceptibility
- For example, with nevirapine hepatotoxicity:
- Associations with CYP2B6 variants
- Associations with ABCB1 gene variants 2
Viral Reactivation
- Viral reactivation (particularly herpesviruses) plays a significant role in DRESS pathogenesis 1
- This distinguishes DRESS from other drug reactions
- Viral reactivation may contribute to the prolonged and relapsing course of DRESS 3
Clinical Progression Factors
Delayed Onset
- Characteristically has a latent period of 2-6 weeks after drug initiation 4
- This delayed onset is a hallmark feature distinguishing it from other drug reactions
Prolonged Course
- DRESS can have persistent progression even after culprit drug withdrawal
- Mechanisms for "long" or "chronic" DRESS reactions may involve:
- Ongoing immunological reactions
- Viral factors
- Corticosteroid dependence 3
Organ Involvement Mechanisms
- Multi-organ involvement occurs through:
- Direct T-cell infiltration of organs
- Cytokine-mediated inflammation
- Eosinophilic infiltration of tissues 2
- Hepatic involvement is common and may present as:
- Early liver enzyme elevation with cutaneous hypersensitivity
- Delayed variant without extrahepatic findings 2
- Pulmonary involvement can progress to severe complications:
- Pneumonitis
- Acute respiratory distress syndrome (ARDS)
- Air leak syndromes (pneumothorax, pneumomediastinum) 5
Special Considerations
Drug-Specific Pathways
- Different drugs may trigger DRESS through distinct pathways
- For example, abacavir hypersensitivity:
- Class I MHC disease mediated by CD8 lymphocytes
- Abacavir can be oxidized to an aldehyde intermediate via alcohol dehydrogenase (ADH) 2
Long-Term Sequelae
- DRESS can lead to serious long-term complications:
- Autoimmune disorders
- Permanent organ damage from initial reaction
- Sequelae from treatment (e.g., long-term steroid complications) 3
Diagnostic Implications
- Understanding the pathogenesis informs diagnostic approaches:
The complex pathogenesis of DRESS syndrome explains its delayed onset, variable presentation, and potential for severe multi-organ involvement, making early recognition crucial for proper management.