Revised: 12 June 2013
Website: October 2003
Prescriber Update 2003;24(2):22-23
Marius Rademaker, Hon. Associate Professor, Dermatology Department, Waikato Hospital, Hamilton; and Tim Maling, Associate Clinical Professor of Internal Medicine and Clinical Pharmacology, Wellington Hospital.
Drug Hypersensitivity Syndrome is potentially life-threatening with significant morbidity. It is characterised by fever, rash and internal organ involvement. Prompt diagnosis is vital, along with identification and early withdrawal of suspect medicines. Avoidance of re-exposure to the responsible agent is essential. Cross-reactivity to structurally-related medicines is common. First-degree relatives may be predisposed to developing this syndrome.
Drug Hypersensitivity Syndrome (DHS) is sometimes called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). This syndrome is a severe, idiosyncratic multi-system reaction defined by the clinical triad of fever, rash and internal organ involvement (e.g. hepatitis, myocarditis, nephritis or pneumonitis), which may occur 1 - 8 weeks after medicine exposure.1 Fever is a common early feature, usually preceeding a widespread and long-lasting papulopustular or erythematous skin eruption, which often progresses to exfoliative dermatitis. The severity of the skin-related changes does not correlate with the extent of internal organ involvement, which may remain asymptomatic or be life-threatening.1 DHS mortality is estimated at around 8%.2 Consequently, in patients presenting with fever and rash, blood tests should be done as soon as possible. Eosinophilia and atypical lymphocytosis are common, occurring in up to 30% of cases.2 Allopurinol, anticonvulsants (particularly carbamazepine, phenobarbitone and phenytoin) and sulphonamides are amongst the most frequent causative agents.1,2 The incidence of DHS with anticonvulsants has been estimated at 1 in 10,000 exposures.2
The underlying mechanisms causing DHS are poorly understood.1 Defective detoxification of reactive oxidative metabolites1 and a genetic predisposition4 have been implicated in the pathophysiology of this syndrome, as has slow acetylator status.1 A role of viral co-infection is also suspected - specifically, a reactivation of the human herpes virus 6 (HHV6).5
The variable presentations of DHS lead to considerable diagnostic confusion and a high index of suspicion of a medicine-related cause is essential. Diagnosis is based on clinical presentation (i.e. the triad of fever, rash and organ involvement), supported by a finding of eosinophilia and abnormal liver function tests. Treatment consists of immediate withdrawal of all suspect medicines, followed by supportive care of symptoms.
As DHS can occur up to eight weeks post-exposure, a great degree of care is required when determining the responsible medicine. A temporal relationship between medicine use and the onset of the syndrome is the most important indicator of causality. Patients who develop DHS must avoid re-exposure to the causative medicine/s.
Systemic corticosteroids are generally used in the more severe DHS cases involving significant exfoliative dermatitis, pneumonitis and/or hepatitis.3 Relapses may occur as corticosteroid doses are tapered, and treatment may need to be continued for many weeks. The effect of corticosteroids on prognosis is unknown as controlled clinical trials are lacking.2
Cross-hypersensitivity reactions are common between the three main aromatic anticonvulsants (i.e. phenytoin, carbamazepine and phenobarbitone), and all three must be avoided by patients who have experienced DHS with any one of these medicines.1,4 Cross-reactions may also occur with non-steroidal anti-inflammatory agents (NSAIAs) such as the oxicams, e.g. piroxicam, tenoxicam. The evidence for this is based on limited case reports. Because genetic factors are suspected in DHS, first-degree relatives should be alerted to their elevated risk of developing hypersensitivity reactions to the same medicine/s.1 Prescribers are reminded to report cases of DHS to the Centre for Adverse Reactions Monitoring (CARM) in Dunedin.
Competing interests (authors): none declared.
Correspondence to Dr Marius Rademaker, Dermatology Department, Waikato Hospital, Private Bag 3200, Hamilton. E-mail: Rademakm@waikatodhb.govt.nz