Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction that presents with rash, fever, lymphadenopathy, as well as hematologic (eosinophilia) abnormalities and end-organ dysfunction.

Diagnosis can be challenging due to variable clinical presentations, but important to identify as mortality has been reported as high as 10%. DRESS should be on the differential diagnosis in patients who develop rash 2-6 weeks after initiation of a new medication, especially aromatic anticonvulsants (carbamazepine, phenobarbital, phenytoin) or sulfonamides. Other documented medications associated with the development of DRESS include (but are not limited to) trimethoprim, minocycline, metronidazole, allopurinol, azathioprine, nevirapine, and abacavir.

The pathogenesis of DRESS is not completely understood but appears primarily related to a drug-specific immune response and reactivation of latent herpes virus. Active viral replication of HHV-6 has been demonstrated by PCR assays and an increase of convalescent antibody titers. These findings have led to differing theories of whether the initial insult in DRESS is a drug-specific immune response that causes viral replication or whether viral reactivation induces T-cell proliferation that then reacts with the drug.

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Similar drug-virus interactions causing cutaneous symptoms are well known such as that after ampicillin administration in an Epstein-Barr virus (EBV) infected patient. There is also evidence of TH1 and TH2 cytokine involvement targeting subcellular structures at the sites of enzymatic drug bio-activation but the significance of these immune changes are not known.

DRESS is also known as: Drug-induced Delayed Multi-organ Hypersensitivity Syndrome (DIDMOHS), Drug-induced Hypersensitivity Syndrome (DIHS), and Anticonvulsant Hypersensitivity Syndrome.

Diagnosis is made with a combination of clinical and hematologic abnormalities. Clinical features include new onset diffuse rash, fever, lymphadenopathy, and facial edema within weeks of new drug exposure.

Diagnostic Criteria (5 are required for diagnosis):

  • Maculopapular rash developing >3 weeks after drug initiation

  • Clinical symptoms persisting more than 2 weeks after stopping drug

  • Lymphadenopathy at multiple sites

  • Fever (>38°C)

  • Leukocytosis (>11 x 109/L), atypical lymphocytes (>5%), OR eosinophilia (>1.5 x 109/L)

  • Hepatitis (ALT >100)

  • HHV-6 reactivation

Diagnostic scoring systems have also been published to classify cases as definite, probable, possible, or no case.

Typical symptoms occur 2-6 weeks after exposure to an inciting medication and begin with fever followed by development of a diffuse rash and lymphadenopathy. Facial edema and hepatosplenomegaly may be evident on physical exam. Laboratory evaluation often reveals eosinophilia, atypical lymphocytosis, as well as signs of end-organ involvement – hepatitis (60-80% of patients), nephritis (10-30% of cases), pneumonitis (10% of cases). Less commonly, thyroiditis, rhabdomyolysis, encephalitis, diabetes mellitus, myocarditis, and pericarditis have been reported.

Incidence is 1 in 1000 to 1 in 10000 drug exposures. DRESS occurs most commonly in adults, and has no predilection based on sex. Patients who develop DRESS are believed to have a genetic predisposition related to ineffective drug metabolism and accumulation of active metabolites leading to the delayed symptom onset. At this time, there is no screening test available to identify those individuals at increased risk for developing DRESS, but an association between HLA haplotypes and DRESS susceptibility has been identified. Familial cases have been reported, so counseling is indicated for family members after diagnosis.

  • Stevens-Johnson syndrome (SJS)

  • Toxic Epidermal Necrolysis (TEN)

  • Hypereosinophilic syndrome

  • Kawasaki Disease

  • Stills Disease

  • Severe bacterial or viral infection

  • Autoimmune disease

  • Measles

  • Infectious mononucleosis

  • Serum sickness

  • Drug-induced Lupus

  • Acute generalized exanthematous pustulosis

  • Staphylococcal scalded skin syndrome

  • Fever (38°C-40°C)

  • Rash (morbilliform, papulopustular, or exfoliative dermatitis)

  • Usually no mucocutaneous involvement (in contrast to SJS/TEN)

  • Lymphadenopathy cervical or generalized

  • Facial edema

  • +/- Hepatosplenomegaly

  • Icteric hepatitis associated with poorer prognosis

There are no specific diagnostic tests performed to aid in diagnosis of DRESS. Skin biopsy is non-specific revealing lymphocytic infiltrate of the papillary dermis that may contain eosinophils or band-like infiltrate of atypical lymphocytes with epidermotropism.

  • Complete blood count (CBC) with differential and peripheral smear

  • Liver function tests (LFT)

  • Basic metabolic panel (BMP)

  • Urinalysis

  • TSH

  • PCR for HHV 6,7, EBV

Eosinophilia is a hallmark of DRESS. End-organ dysfunction is believed to be related to a rising eosinophil count and infiltration in those affected systems. Atypical lymphocytosis may also be present. Liver and renal function studies should be ordered to evaluate hepatitis and interstitial nephritis.

Autoimmune thyroiditis has been reported with DRESS usually as a late finding, thus thyroid studies should be evaluated at the time of admission, and 2-3 months after discharge. Co-infection with Human Herpes Viruses have been associated with DRESS and although the role in pathogenesis remains unclear, many authors recommend testing for these viruses, especially HHV-6 as evidence of reactivation has been associated with a more severe disease course.

Generally, there are no specific imaging studies indicated in the work-up of DRESS; however, some imaging tests, such as chest radiograph or CT, may be indicated if organ involvement is suspected.


  • Identify and discontinue offending drug

  • Supportive care

  • Antipyretics

  • Skin care as needed

  • Corticosteroids (prednisone 0.5-2 mg/kg/day or prednisone equivalent tapered slowly over 6-8 weeks. Rapid taper or discontinuation of corticosteroids has been associated with return of symptoms and can cause marked deterioration)

Second-line therapies (patient may require a combination of the therapies below):

  • Pulse dose IV methylprednisolone 30mg/kg for 3 days if clinical picture continues to deteriorate despite initial prednisone therapy

  • Plasmapheresis

  • IVIG

Removal of the offending drug is critical in the management of DRESS. The variable presentations of this condition make other immediate management decisions specific to the clinical features of each individual case. Antibiotics and NSAIDS are often started early in the disease course due to fever and concern for infectious etiology of symptoms. These medications should be discontinued as soon as the diagnosis of DRESS is established to avoid confusing or worsening the clinical picture.

Patients without severe organ involvement are generally managed with high-potency topical steroids rather than systemic steroids. Systemic corticosteroids are recommended for DRESS with severe organ involvement, particularly if there is renal or pulmonary involvement.

Fever and rash should resolve quickly after initiation of systemic corticosteroids.

After removal of the offending agent, improvement in end organ dysfunction should follow. Resolving hepatitis (LFT) or nephritis (creatinine) should be documented by daily laboratory values trending toward the normal or baseline range. There may be an initial trend up in these values after drug therapy has been discontinued related to decreased clearance. Lack of improvement after the addition of corticosteroids warrants expert consultation to evaluate for an alternative diagnosis (e.g. renal biopsy for rising creatinine despite appropriate management).

Other appropriate daily labs include complete blood count with differential to monitor for a downward trend in the eosinophil count.

Continued supportive care and outpatient laboratory monitoring is required for those patients who are slower to recover from the initial insult of DRESS. Patient education on drug avoidance and family counseling is also indicated.

The most common pitfall in management of DRESS is a delay in diagnosis which leads to continuation of inciting medication and further multi-organ damage.

No specific change in management. If renal insufficiency is a result of DRESS, renal dosing medications until glomerular filtration rate (GFR) has recovered.

No specific change in management. If hepatitis is a result of DRESS, consider avoiding medications known to be metabolized in the liver until acute inflammation has resolved. Hepatology consultation may be warranted, particularly if acute liver failure develops, which can manifest with rising bilirubin and INR.

No specific change in management.

No specific change in management.

No specific change in management. Management of diabetes will likely need to be adjusted for high dose or long-term corticosteroid therapy.

No specific change in management.

Early expert consultation recommended for patients on long-term steroids as pulse dosing or second-line agents may be indicated as initial therapy.

No specific change in management.

No specific change in management, though may consider a proton pump inhibitor while on glucocorticoids if the patient is on a nonsteroidal anti-inflammatory drug (NSAID).

No specific change in management.

Use high dose corticosteroids with caution if psychiatric illness is a comorbidity.

Slight worsening of laboratory values for several days after discontinuation of inciting medication is to be expected.

Worsening symptoms (e.g. return of rash after it had resolved) or laboratory values after initial improvement may be indicative of a need to step up therapy or of steroids being tapered too rapidly.

At least 3 days.

It is suggested that all patients with DRESS be hospitalized until response to therapy can be determined. The clinical picture and laboratory abnormalities may worsen 3 days after discontinuation of the offending medication. Therefore, length of stay is variable but can be as short as 3 days in mild disease, which is likely to resolve in 1-2 weeks and can be tracked on an outpatient basis. A patient can safely be discharged when clinically stable and a downward trend in laboratory values toward the normal range is documented, which indicates resolving organ involvement.

  • Internal medicine

  • Allergy immunology

  • Nephrology follow-up if kidney function has not normalized at the time of discharge

A trend in laboratory values toward the normal range in addition to clinical improvement should be documented prior to discharge. Final laboratory values (CBC with differential, LFTs if hepatitis was present, renal panel if nephritis was present) should be documented on the day of or day prior to discharge. Outpatient testing can then be compared to these values.

End-organ dysfunction and inpatient laboratory tests should guide outpatient testing. For hepatic or renal involvement, liver function tests and a renal panel should be monitored until levels have normalized. Thyroid studies should be followed for several months after discharge to monitor for autoimmune thyroiditis, which is a late complication. Other autoimmune diseases, such as type I diabetes and autoimmune hemolytic anemia, have also been described.


Mortality rates up to 10% have been described and correlate most with hepatic involvement. Prognosis is dependent on disease severity and time of diagnosis. The majority of patients will recover with corticosteroids and supportive care after the inciting drug has been discontinued. Late diagnosis has a poorer prognosis, likely due to more extensive end-organ involvement.

Counseling should include medication avoidance and education on both brand name and generic names of the inciting medication. Familial cases have been reported and family members should be cautious if starting a similar class of medications.


Stress ulcer prophylaxis with a proton pump inhibitor is indicated during long-term corticosteroid therapy if the patient is also on an NSAID.

Steroid therapy should be tapered slowly, over months, as documented relapses have been attributed to the medication being tapered too quickly. If recurrence of the rash or other symptoms that were present during the hospitalization for DRESS return, the patient should be evaluated by the primary care physician so laboratory evaluation and medication adjustments can be made which may prevent readmission.

Cacoub, P,, Musette, P,, Descamps, V. “The DRESS syndrome: a literature review.”. American Journal of Medicine. vol. 124. 2011. pp. 588-597.

Tas, S,, Simonart, T. “Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update.”. Dermatology. vol. 206. 2003. pp. 353-356.

Sullivan, JR,, Shear, NH. “The drug hypersensitivity syndrome: What is the pathogenesis?”. Arch Dermatol. vol. 137. 2001. pp. 357-364.

Shiohara, T,, Inaoka, M,, Kano, Y. “Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses.”. Allergol Int. vol. 55. 2006. pp. 1-8.

Rosenbaum, J,, Alex, G,, Roberts, H. “Drug rash with eosinophilia and systemic symptoms secondary to sulfasalazine.”. J Paediatr Child Health. vol. 46. 2009. pp. 193-196.

Kumar, A,, Goldfarb, JW,, Bittner, EA. “A case of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome complicating airway management.”. Can J Anaesth. vol. 59. 2012. pp. 295-298.

Kano, Y,, Shiohara, T. “The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug.”. Immunology and Allergy Clinics of North America. vol. 29. 2009. pp. 481-501.