Published: June 2011

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DRESS syndrome: remember to look under the skin

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Prescriber Update 32(2): 12-13
June 2011

DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is an adverse reaction term that is currently used to describe a hypersensitivity reaction with an estimated mortality of up to 10%.¹

Prompt clinical recognition and discontinuing suspected medicines helps to minimise morbidity and mortality associated with this syndrome. DRESS syndrome is a delayed type IVb hypersensitivity reaction thought to be mediated by antiviral T cells.²

It is a severe, idiosyncratic multisystem reaction to a drug, characterised by fever, skin rash, lymphadenopathy, haematological abnormalities and internal organ involvement.

Symptoms and diagnosis

DRESS syndrome most commonly manifests two to eight weeks after starting the offending medicine, with a mean onset of three weeks.¹ Upon re-challenge with the associated medicine symptoms may recur within one day; however symptoms may also flare up three to four weeks after stopping the medicine, even after initial improvement.

Patients routinely develop fever early on in the disease process, followed by the development of rashes. These may vary from a very mild exanthem to extensive blistering and skin loss, but is more often a pruritic, macular erythema which may contain papules, pustules or vesicles. Systemic involvement commonly manifests as lymphadenopathy, hepatitis, pericarditis, interstitial nephritis or pneumonitis. Auto-immunity may develop as a sequalae to DRESS.

If DRESS syndrome is suspected, prescribers are reminded to look beyond the skin as the severity and extent of skin involvement does not always correlate with the extent of internal organ involvement.¹ 

Diagnosis can be difficult due to the variable presentation of the syndrome and is more often obtained by exclusion. Symptoms such as rash, fever, and organ involvement can be attributed to a wide range of other causes. In addition, the long latency period following initiation or after stopping the medicine creates difficulties in diagnosis.

The European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) is a consortium created to reduce the burden of severe cutaneous reactions. This consortium has produced diagnostic criteria to assist in the diagnosis of DRESS syndrome.

RegiSCAR inclusion criteria for potential cases require at least 3 of the following:³

• Hospitalisation
• Reaction suspected to be drug related
• Acute skin rash
• Fever about 38 degrees Celsius
• Enlarged lymph nodes at two sites
• Involvement of at least one internal organ
• Blood count abnormalities such as low platelets, raised eosinophils or abnormal lymphocyte count.

In addition a Japanese group consider human herpes virus 6 (HHV-6) reactivation to be diagnostic. However as this is likely to occur two to three weeks after the onset of the rash, a diagnosis may be missed if reactivation is not measured at the correct time. Experts also debate whether reactivation is part of the syndrome or should be interpreted as a complication.⁴

Differential diagnoses include other cutaneous drug reactions such as Stevens Johnsons Syndrome (SJS) and toxic epidermal necrolysis (TEN). Acute infection, neoplastic and other immunological disorders such as Kawasaki disease or juvenile rheumatoid arthritis also need to be excluded.

Risk factors

Medicines most commonly associated with DRESS syndrome are anticonvulsants, antibiotics (particularly beta-lactams), and allopurinol. Other medications that are known to be associated with DRESS include non-steroidal anti-inflammatory drugs, captopril, mood stabilisers, and antiretrovirals.⁵

The incidence of DRESS with anticonvulsants has been reported at 1 in 1000 to 1 in 10,000 exposures. ⁵ The risk of allopurinol induced DRESS is increased in patients with renal impairment and concomitant use of thiazide diuretics. The syndrome is thought to be caused by an allopurinol metabolite oxypurinol, which increases in concentration in renal impairment or with the use of diuretics. ^6,7

Genetic factors are also important. The risk of DRESS may be as high as 25% for individuals who have a first degree relative who has experienced this syndrome.

Management

Treatment of DRESS involves early recognition followed by prompt cessation of all suspected medicines. Prompt cessation is vital to minimise associated morbidity and mortality. Supportive care is then recommended including local and systemic treatment to relieve symptoms. Systemic corticosteroids have been used in the treatment of DRESS with some researchers reporting dramatic improvement in their patients following treatment.

Systemic steroids may need to be continued for several months, with very slow tapering of the dosage, to avoid flare. However there are no data available from randomised clinical trials to support this treatment. Intravenous immunoglobulin has also been reported as being effective; however again there are no trial data to support this.

References

1. Seth D et al (2008) DRESS syndrome: A practical approach for primary care practitioners. Clinical Paediatrics. 47(9):947-52.
2. Velema M.S. (2009) DRESS syndrome caused by nitrofurantoin
3. Kardun SH et al (2006) Variability in the clinical pattern of cutaneous side effects of drugs with systemic symptoms: doses a DRESS syndrome really exist? Br J Dermatol 156(3):609-11.
4. Shiohara T. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol. 156(3):1045-92.
5. Tas S et al (2003) Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): An update. Dermatology. 206:353-56.
6. Markel A (2005) Allopurinol-induced DRESS syndrome. IMAJ 7:656-60.
7. Apotex NZ Ltd. 11 April 2011. Apo-Allopurinol data sheet www.medsafe.govt.nz/profs/Datasheet/a/apoallopurinoltab.pdf