July 2006

Fig.3

Fig.4

Fig.5

Diagnosis: Drug reaction with eosinophilia and systemic symptoms (DRESS) formerly referred to as drug hypersensitivity syndrome.

Pathology: A 4 mm punch biopsy of a vesiculating papule on her right arm revealed an interface dermatitis with subepidermal blister formation and focal epidermal necrosis (Figs.3, 4, and 5). The infiltrate was mixed, consisting of lymphocytes, neutrophils, and eosinophils. A bacterial swab culture from her face grew abundant staphylococcus aureus.

Discussion:

DRESS is a severe drug reaction characterized by a polymorphic skin eruption, fever, lymphadenopathy, and visceral organ involvement. Bocquet et al, initially coined the term DRESS, and proposed that all three of the following diagnositic criteria be met: (a) drug-induced skin eruption, (b) eosinophilia >1.5 _ 109/l or atypical lymphocytes, and (c) at least one of the following systemic abnormalities: enlarged lymph nodes at least 2 cm in diameter, hepatitis (transaminases > 2 normal), interstitial nephropathy, interstitial lung disease, or myocardial involvement.1

Epidemiology
DRESS occurs 1 to 8 weeks after starting treatment with the inciting medication.2 DRESS most commonly occurs after exposure to aromatic anticonvulsants, such as phenytoin, phenobarbital, and carbamazepime, or sulfonamides.2 The incidence of DRESS after exposure to these medications is estimated to be 1 in 1,000 to 1 in 10,000.2 Other medications that have been implicated in DRESS include lamotrigine, gabapentin, allopurinol, non-steroidal anti-inflammatory medications, captopril, tuberculostatic medications, calcium channel blockers, mood stabilizers, neuroleptics, mexiletine, dapsone, sulfasalazine, terbinafine, methyldopa, minocycline, and antiretroviral medications.

Clinical Features
The cutaneous eruption is typically a pruritic, macular erythema that becomes confluent and may contain papules, vesicles, or pustules. It usually begins on the trunk and face, but often involves the extremities and can involve the mucosa. Facial edema is a characterisitic finding. The clinical appearance can overlap with toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS). In such cases, the patient is best classified as TEN or SJS rather than DRESS. Outside of the skin, the liver is the next most common organ involved with a range of injury varying from mild hepatic enzyme elevation to fulminant hepatic necrosis. Kidney involvement also ranges in severity from hematuria to nephritis to acute renal failure. DRESS can also lead to pancreatitis, colitis, pneumonitis, myocarditis, myositis, arthritis, or encephalitis. Hypothyroidism may manifest several months after the acute phase.

Pathogenesis
In cases involving aromatic anticonvulsants, it has been proposed that this syndrome results from an inherited deficiency of the enzyme epoxide hydrolase.3 Epoxide hydrolase detoxifies reactive intermediates, called arylamines, that are generated during aromatic anticonvulsant metabolism. Patients who develop DRESS secondary to sulfonamides are often slow acetylators who produce toxic hydroxylamine metabolites.3 Patients who develop DRESS secondary to allopurinol often have renal insufficiency and elevated levels of oxypurinol, a metabolite of allopurinol.4 Immunologic injury by T-cells has been implicated in the pathogenesis of DRESS. In vitro analysis of patient with DRESS secondary to lamotrigine and carbamazepime have found T-cell clones specific to these medications.5,6

Recently, human herpes virus 6 and 7 have been implicated in the development of DRESS. A prospective study of 23 patients with DRESS found human herpes virus 6 and 7 DNA and elevated IgG in 7 of the 23 patients compared to controls.7 Human herpes virus 6 has been associated with DRESS by others.8,9 No association with viral infection including HSV, VZV, HHV-8, CMV, EBV, measles, rubella and parvovirus B19 was detected by Oskay et al.7 However, DRESS associated with Epstein Barr virus and cytomegalovirus has been reported.10,11 It has been theorized that viral reactivation may provide an immune stimulus leading to drug hypersensitivity.12

Treatment
The mortality rate is estimated to be 10%. Treatment consists foremost with removing the causitive agent. Most authorities recommend treatment with systemic corticosteroids unless contraindicated.13 However, no controlled trials have been performed to validate this treatment. Because hepatitis from DRESS may last for several months, treatment with systemic corticosteroids can be prolonged. For patients with DRESS secondary to anticonvulsants, it is recommended to use valproic acid or benzodiazepines as these do not cross react.

References:
1. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. 1996;15(4):250-7.
2. Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol. 2005;23(2):171-81.
3. Odom RB, James WD, Berger TG. Andrews' Diseases of the Skin. 9th ed. Philadelphia: W.B. Saunders; 2000: 126.
4. Hamanaka H, Mizutani H, Nouchi N, Shimizu Y, Shimizu M. Allopurinol hypersensitivity syndrome: hypersensitivity to oxypurinol but not allopurinol. Clin Exp Dermatol. 1998;23:32-4.
5. Naisbitt DJ, Farrell J, Wong G, Depta JP, Dodd CC, Hopkins JE, Gibney CA, Chadwick DW, Pichler WJ, Pirmohamed M, Park BK. Characterization of drug-specific T cells in lamotrigine hypersensitivity. J Allergy Clin Immunol. 2003;111(6):1393-403.
6. Naisbitt DJ, Britschgi M, Wong G, Farrell J, Depta JP, Chadwick DW, Pichler WJ, Pirmohamed M, Park BK. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol. 2003;63(3):732-41.
7. Oskay T, Karademir A, Erturk OI.Association of anticonvulsant hypersensitivity syndrome with Herpesvirus 6, 7. Epilepsy Res. 2006 Apr 6; [Epub ahead of print]
8. Zeller A, Schaub N, Steffen I, Battegay E, Hirsch HH, Bircher AJ. Drug hypersensitivity syndrome to carbamazepine and human herpes virus 6 infection: case report and literature review. Infection. 2003;31(4):254-6.
9. Descamps V, Valance A, Edlinger C, Fillet AM, Grossin M, Lebrun-Vignes B, Belaich S, Crickx B. Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. Arch Dermatol. 2001;137(3):301-4.
10. Descamps V, Mahe E, Houhou N, Abramowitz L, Rozenberg F, Ranger-Rogez S, Crickx B. Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection. Br J Dermatol. 2003;148(5):1032-4.
11. Aihara M, Sugita Y, Takahashi S, Nagatani T, Arata S, Takeuchi K, Ikezawa Z. Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus. Br J Dermatol. 2001;144(6):1231-4.
12. Lerch M, Pichler WJ. The immunologic and clinical spectrum of delayed drug-induced exanthems. Curr Opin Allergy Clin Immunol. 2004;4:411-419.
13. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf. 1999;21(6):489-501.

This case was presented by Dr. David Smith.