DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe, potentially life-threatening reaction to a medication that affects not just the skin but internal organs like the liver, kidneys, and heart. It typically appears 2 to 6 weeks after starting a new drug, which makes it tricky to recognize because most people don’t connect a rash appearing a month later to a pill they started weeks ago. The mortality rate is approximately 5 to 7%, with multi-organ failure, respiratory complications, and liver or kidney damage as the leading causes of death.
How DRESS Syndrome Develops
Unlike a simple allergic rash that shows up within hours, DRESS has an unusually long delay. Symptoms typically begin 2 to 6 weeks after the first dose of the triggering medication, though it almost always appears within the first two months. For specific drugs, the timing is somewhat predictable: phenytoin (an anti-seizure medication) triggers symptoms after roughly 17 to 21 days, while carbamazepine (another anti-seizure drug) typically causes a reaction between 21 and 28 days.
If someone has been sensitized by a previous reaction, a second exposure to the same drug can trigger DRESS within a single day.
One of the more unusual aspects of this condition is the role of dormant viruses. Most people carry certain herpes-family viruses (particularly Human Herpesvirus 6, or HHV-6) in a dormant state without any problems. In DRESS, the immune system’s overreaction to the drug appears to “wake up” these latent viruses. The drug binds to immune receptors and triggers a massive expansion of immune cells, including some that target cells harboring these dormant viruses. When those cells are destroyed, viral particles are released into the bloodstream. HHV-6 reactivation occurs in roughly 45 to 60% of DRESS cases and has been linked to disease flares and greater severity.
Which Medications Cause It
At least 44 medications have been linked to DRESS syndrome. The most common culprits fall into a few major categories:
- Anti-seizure medications: Carbamazepine, lamotrigine, phenytoin, phenobarbital, and oxcarbazepine. These “aromatic anticonvulsants” are the single most frequently implicated drug class.
- Antibiotics: Amoxicillin, ampicillin, azithromycin, minocycline, vancomycin, and trimethoprim-sulfamethoxazole (a common sulfa antibiotic).
- Allopurinol: Used to treat gout, this is one of the most commonly reported triggers worldwide.
- Anti-tuberculosis drugs: Isoniazid, rifampin, ethambutol, and pyrazinamide.
- NSAIDs: Ibuprofen, diclofenac, piroxicam, aspirin, and celecoxib.
- Others: Dapsone, hydroxychloroquine, certain cancer drugs like imatinib, the antidepressant amitriptyline, and the HIV medication nevirapine.
Genetics and Who Is at Higher Risk
Your genetic makeup plays a significant role in whether a particular drug will trigger DRESS. Specific immune system genes (called HLA alleles) make certain people more vulnerable to specific drugs. For example, people carrying the HLA-B*58:01 gene variant face a higher risk of DRESS from allopurinol and sulfa antibiotics. The HLA-A*32:01 variant increases risk from lamotrigine, vancomycin, and carbamazepine. And HLA-B*53:01 has been linked to reactions from allopurinol, phenytoin, and sulfasalazine.
For some of these high-risk combinations, genetic testing before prescribing the drug is now recommended in certain populations. This is especially common with allopurinol, where HLA-B*58:01 testing is advised for patients of Southeast Asian, African American, or Korean descent before starting the medication.
Signs and Symptoms
DRESS usually begins with a fever and an itchy rash, often accompanied by noticeable swelling of the face. The rash is typically raised, red, and widespread, eventually covering more than half the body. It often starts on the extremities and face (unlike Stevens-Johnson syndrome, which tends to begin on the trunk). Over time, the rash may develop a thickened, infiltrated texture and peel in a pattern resembling psoriasis. Purplish spots may appear on areas beyond the legs.
Swollen lymph nodes in multiple areas of the body are another hallmark. But the real danger lies beneath the skin. The liver is the most commonly affected internal organ. Elevated liver enzymes appear in most cases, and in severe situations, liver inflammation can progress to liver failure. The kidneys are involved in roughly 10 to 20% of cases. Less commonly, the heart, lungs, and pancreas can also be affected.
Blood tests reveal a distinctive pattern: a high white blood cell count, elevated eosinophils (a type of immune cell that normally fights parasites but runs rampant in DRESS), and unusual-looking lymphocytes circulating in the bloodstream. These blood abnormalities, combined with organ involvement, are what distinguish DRESS from a garden-variety drug rash.
How It Differs From Stevens-Johnson Syndrome
DRESS is sometimes confused with Stevens-Johnson syndrome (SJS), another serious drug reaction, but the two conditions look and behave quite differently. SJS causes blistering, skin peeling, and necrosis (tissue death), with a positive Nikolsky sign, meaning the skin slides off with gentle pressure. DRESS does not cause this kind of skin destruction.
Mucous membrane involvement is another key difference. In SJS, painful erosions of the lips, mouth, eyes, and genitals occur in about 90% of patients. DRESS rarely affects mucous membranes. SJS also tends to appear on the trunk first, while DRESS typically starts on the face and extremities. And while both can involve internal organs, DRESS is defined by eosinophilia and organ inflammation, whereas SJS is primarily a skin and mucosal disease with less prominent blood abnormalities.
The early warning signs also differ. DRESS patients typically experience intense itching, fever, and facial puffiness before the rash spreads. SJS patients more commonly report fever and general malaise before developing the characteristic blisters and skin sloughing.
How DRESS Is Diagnosed
Diagnosis relies on a validated scoring system called the RegiSCAR criteria, which assigns points based on several features: the characteristics of the rash, the number of internal organs involved, blood cell abnormalities, whether lymph nodes are swollen in multiple body regions, and whether other conditions (like hepatitis or bacterial infections) have been ruled out. A score of 6 or higher is considered a definite diagnosis. Scores of 4 to 5 indicate a probable case, while 2 to 3 suggest a possible one.
The scoring system gives the most weight to high eosinophil counts (above 1,500 cells per cubic millimeter), involvement of two or more organs, and a rash with features specifically suggestive of DRESS, such as facial swelling, infiltrated lesions, and peeling skin. Ruling out infections through blood cultures and hepatitis testing also adds to the diagnostic score, because these conditions can mimic DRESS.
Treatment and Recovery
The first and most critical step is stopping the offending drug immediately. Because of the long delay between starting a medication and developing symptoms, identifying the correct culprit sometimes requires detective work, especially if a patient started multiple new drugs in the preceding weeks.
For moderate to severe cases, corticosteroids are the standard treatment. Oral doses are typically started and then gradually tapered over at least 2 to 3 months, sometimes considerably longer. Tapering too quickly is a well-known cause of relapse, as the underlying immune activation can persist long after the drug has been cleared from the body. In the most severe cases, high-dose intravenous steroids may be used initially before switching to an oral taper.
Recovery from DRESS is slow. Even after the offending drug is stopped and treatment begins, symptoms can wax and wane for weeks or months. The reactivation of dormant viruses like HHV-6 can cause disease flares during recovery, complicating the picture. Liver and kidney function need to be monitored throughout the recovery period, and some patients develop autoimmune conditions (particularly thyroid disease or type 1 diabetes) in the months following a DRESS episode. Long-term follow-up is important even after the rash clears and blood counts normalize.
Anyone who has experienced DRESS should be carefully counseled about which drugs to avoid permanently, since re-exposure can trigger a rapid and potentially more severe reaction. Cross-reactivity between related drugs (for instance, between different aromatic anticonvulsants) is also a concern, so alternatives need to be chosen carefully.