Understanding Drug Hypersensitivity Syndrome (DRESS)
Drug Hypersensitivity Syndrome (DHS), more commonly known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), is a severe and potentially life-threatening idiosyncratic drug reaction [1.3.5]. It is characterized by a distinctive triad of symptoms: a widespread skin rash, fever, and internal organ involvement [1.2.2]. Unlike immediate allergic reactions, DRESS has a delayed onset, typically appearing 2 to 8 weeks after starting the culprit medication [1.6.5]. The mortality rate is estimated to be around 8-10%, often due to severe organ damage, particularly liver failure [1.3.5, 1.10.2].
Key Pathophysiology Insights
The mechanisms behind DRESS are complex and not fully understood but are thought to involve a combination of factors [1.2.3]. These include an inability to properly detoxify certain drug metabolites and a subsequent immune response mediated by T-cells [1.2.3]. There is also a strong association with the reactivation of latent viruses, particularly human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), and cytomegalovirus (CMV), which may contribute to the severity and protracted course of the illness [1.6.2, 1.10.2]. Genetic predisposition plays a significant role; for instance, individuals with the HLA-B*58:01 allele have a nearly 100-fold higher risk of developing allopurinol hypersensitivity syndrome [1.5.1].
Primary Drugs That Cause Hypersensitivity Syndrome
A wide range of medications has been implicated in causing DRESS syndrome. However, some classes are more frequently associated with the condition than others [1.2.1].
Aromatic Anticonvulsants
Aromatic antiepileptic drugs (AEDs) are among the most common triggers. This class includes:
- Carbamazepine: Often cited as a leading AED cause of DRESS [1.6.1].
- Phenytoin: Another frequently implicated aromatic anticonvulsant [1.2.2].
- Phenobarbital: Shares a high rate of cross-reactivity (up to 70-80%) with carbamazepine and phenytoin [1.2.2, 1.2.5].
- Lamotrigine: Also a common culprit, its risk increases when co-administered with valproic acid [1.2.3, 1.6.2].
- Oxcarbazepine: Structurally similar to carbamazepine, it carries a risk of cross-reactivity [1.6.1].
Allopurinol
Used to treat gout and high uric acid levels, allopurinol is a well-documented cause of a severe form of the syndrome, often termed Allopurinol Hypersensitivity Syndrome (AHS) [1.5.2]. The risk is significantly elevated in patients with chronic kidney disease and those of certain ethnicities (e.g., Han Chinese, Korean, Thai) who carry the HLA-B*58:01 gene [1.5.1]. AHS has a reported mortality rate between 20% and 25% [1.5.1, 1.5.2].
Antibiotics
Several classes of antibiotics are known triggers:
- Sulfonamides: This class, including sulfamethoxazole (often combined with trimethoprim), is a well-known cause [1.7.1, 1.7.3].
- Minocycline: An antibiotic used for acne and other infections [1.2.5].
- Vancomycin: Implicated in DRESS cases [1.2.1].
- Beta-lactams: Drugs like ampicillin and amoxicillin have also been reported to cause DRESS [1.2.1, 1.8.3].
Other Notable Medications
Other drugs reported to cause DRESS include:
- Dapsone: Used for leprosy and certain skin conditions [1.2.2].
- Sulfasalazine: An anti-inflammatory drug for arthritis [1.2.1].
- Antiretrovirals: Such as Nevirapine, used in HIV treatment [1.2.1, 1.2.5].
- NSAIDs: Some nonsteroidal anti-inflammatory drugs like ibuprofen and celecoxib have been linked to the syndrome [1.2.1].
Clinical Presentation and Diagnosis
The diagnosis of DRESS can be challenging due to its varied presentation [1.6.3]. The onset is typically 1 to 8 weeks after drug exposure [1.3.5]. Key features include:
- Fever: Usually high-grade and one of the first signs [1.3.5].
- Rash: A widespread maculopapular or erythematous eruption is common, often progressing to exfoliative dermatitis. Facial swelling is also a frequent finding [1.3.5, 1.6.5].
- Hematologic Abnormalities: Eosinophilia (high levels of eosinophils) and the presence of atypical lymphocytes are hallmarks of the syndrome [1.3.5].
- Internal Organ Involvement: This is what makes DRESS so dangerous. The liver is the most commonly affected organ (in over 50% of cases), but the kidneys, lungs, heart, and pancreas can also be involved [1.4.5, 1.10.4].
To standardize diagnosis, the RegiSCAR scoring system is often used. It classifies cases as 'no,' 'possible,' 'probable,' or 'definite' based on a point system evaluating fever, eosinophilia, extent of rash, lymphadenopathy, and organ involvement [1.11.2].
| Feature | DRESS Syndrome (DIHS) | Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) |
|---|---|---|
| Onset | 2-8 weeks post-drug exposure [1.6.5] | 1-3 weeks post-drug exposure [1.3.1] |
| Key Features | Fever, eosinophilia, atypical lymphocytes, internal organ involvement [1.3.5] | Mucosal erosions, painful targetoid lesions, significant skin detachment [1.3.1] |
| Skin Rash | Morbilliform, exfoliative dermatitis, facial edema [1.3.5] | Erythematous macules progressing to flaccid blisters and epidermal detachment (<10% for SJS, >30% for TEN) [1.3.1] |
| Mortality Rate | ~10% [1.8.1] | ~10% for SJS, up to 50% for TEN [1.9.1] |
| Common Culprits | Aromatic anticonvulsants, allopurinol, sulfonamides [1.2.2] | Allopurinol, anticonvulsants, sulfonamides, NSAIDs [1.2.3, 1.5.4] |
Management and Long-Term Outlook
The most critical first step in managing DRESS is immediate withdrawal of the suspected causative drug [1.4.5]. Management is then primarily supportive. For severe cases with significant organ involvement, systemic corticosteroids (e.g., prednisone) are the first-line therapy [1.4.1, 1.4.5]. Treatment may be required for weeks or months, with a slow taper to prevent relapse [1.4.4]. In steroid-resistant cases, other immunosuppressants like cyclosporine or intravenous immunoglobulin (IVIG) may be considered [1.4.1, 1.4.5].
Even after recovery from the acute phase, patients can face long-term complications. Autoimmune diseases are a significant concern, with autoimmune thyroiditis, type 1 diabetes, and systemic lupus erythematosus reported as long-term sequelae [1.10.1, 1.10.2]. Permanent organ damage, such as chronic kidney disease or liver dysfunction, can also occur [1.10.3]. Therefore, long-term follow-up for at least two years is often recommended to monitor for these complications [1.10.1, 1.10.4].
Conclusion
Drug Hypersensitivity Syndrome is a complex and serious condition triggered by a specific set of medications, most notably aromatic anticonvulsants and allopurinol. Its delayed onset and mimicry of other conditions can make diagnosis difficult. Prompt recognition, immediate cessation of the offending drug, and supportive care with corticosteroids are the cornerstones of treatment. Given the potential for severe morbidity, mortality, and long-term autoimmune complications, awareness of what drugs can cause hypersensitivity syndrome is crucial for both clinicians and patients.
For more information from an authoritative source, visit the American Academy of Allergy, Asthma & Immunology. [1.4.4]
