1.1.3.3 Drug related rash with eosinophilia and systemic symptoms (DRESS)

DRESS is a rare disease with an incidence of ten cases per million in one year. Due to the wide diversity of individual symptoms, many cases are not diagnosed correctly. The real incidence therefore might be higher. There has been reported a slight female prevalence (male/female ratio 0.8), the median age at diagnosis is 53 years.

DRESS is defined as a drug induced rash with blood eosinophilia and involvement of internal organs. It is a T-cell mediated delayed-type hypersensitivity reaction like Stevens-Johnsons syndrome (SJS) or Toxic Epidermal Necrolysis (TEN).

Drugs frequently inducing DRESS are (selection):

Antiarrhythmic Mexiletin

Anticonvulsants Carbamazepine, Phenytoin, Lamotrigine, Phenobarbital, Zonisamid

Anti-retroviral Abacavir, Nevirapine

Antibacterial Amoxicillin, Levofloxacin, Minocycline

Other Dapsone, Sulfonamide, Allopurinol, Vemurafenib, Cobimetinib

Drugs with the highest risk of inducing DRESS are anticonvulsants and allopurinol.

DRESS is associated with the infection or reactivation of human herpesvirus 6/7, Epstein-Barr virus and cytomegalovirus. Viral replication has been detected during all phases of the drug hypersensitivity reaction. Viral replication and T-cell mediated responses against viruses are thought to contribute to the clinical symptoms and may even worsen the disease.

Risk genes from alleles of human leukocyte antigen (HLA) class I and II have been shown to be associated with a higher risk to develop DRESS.

A transient blood eosinophilia (>1500/µl) and leukocytosis (>11x109/L) with atypical lymphocytes appears in the early course of disease. Liver involvement is reported in about 70% of patients with a massive increase of liver enzymes. Signs of an acute hepatitis with jaundice may develop. Depending on the involvement of other organs, there is an increase of creatinine kinase, creatinine, amylase and lipase.

An acute onset of symptoms for up to six weeks after taking the drug is characteristic for DRESS. Cutaneous lesions start as disseminated, symmetrical reddish macules on the trunk, arms and legs. Patients often show facial edema. Later a generalized maculopapular rash develops and in the course of disease, an exfoliative dermatitis or erythroderma may develop.

Mucosal involvement is very rare. In general, patients present feeling unwell with fever and lymphadenopathy. There is involvement of at least one internal organ (liver > kidney > lung, heart, pancreas).

To enable a quick diagnosis the following scoring system is proposed by the RegiSCAR group:

1. Acute rash

2. Reaction suspected drug-related

3. Hospitalization

4. Fever (>38°C)

5. Laboratory abnormalities (at least 1 present)

     a. Lymphocytes above or below normal

     b. Low platelets

     c. Eosinophilia

6. Involvement of >1 internal organ

7. Enlarged lymph nodes >2 sites

DRESS is diagnosed if 1-3 and three out of 4-7 apply.

After the culprit drug is withdrawn, symptoms may worsen after three or four days. If there are no sure signs for an infection, physicians should not treat the patient empirically with antibiotics to avoid cross- reactivity.

• Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)

• Acute generalized exanthematous pustulosis (AGEP)

• Hypereosinophilic syndromes

• Angioimmunoblastic T-cell lymphoma

• Acute cutaneous lupus erythematosus

The suspected drug has to be withdrawn immediately. Patients must be treated with systemic glucocorticoids 40-50 mg/d. Slowly reduce steroids over up to eight weeks to avoid relapse.