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Drug Hypersensitivity Reaction:Drug Hypersensitivity Reaction:DRESS Syndrome (Drug Reaction DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic with Eosinophilia and Systemic
Symptoms)Symptoms)Christopher CaulfieldChristopher Caulfield
AM ReportAM ReportDecember 1, 2009December 1, 2009
Adverse Drug ReactionsAdverse Drug Reactions Type A reactions are pharmacological effects
that are predictable and dose-dependent and consist of side effects and drug interactions.
Type B reactions are hypersensitivity reactions that are unpredictable and not dose-dependent, usually occurring at normally tolerated doses. Comprise about 10%–15% of all ADRs.
EpidemiologyEpidemiology ADRs occur in roughly 10-20% of
hospitalizations, and approximately 5% of hospitalizations are due to ADRs
Adverse cutaneous reactions to drugs affect about 2 to 3 percent of hospitalized patients.
Estimated that 1 in 1000 hospitalized patients has a serious cutaneous drug reaction.
EpidemiologyEpidemiology Sulfonamides are the most frequent
causes of drug hypersensitivity syndrome.
Aromatic antiepileptic agents (phenytoin, carbamazepine, and phenobarbital) have an estimated incidence of 1 reaction per 5000 patients, possibly a higher rate among black patients.
Medications Involved in DHSMedications Involved in DHS Abacavir Dapsone Nevirapine Allopurinol Diltiazem Oxicam NSAIDs Atenolol Gold salts Phenobarbitone Azathioprine
Isoniazid Phenytoin Captopril Lamotrogine Sulfasalazine Carbamazepine Mexiletine Sulfonamides Clomipramine Minocycline Trimethoprim
PathophysiologyPathophysiology Underlying mechanisms are poorly
understood, but it is proposed that defective detoxification of drug-reactive metabolites results in modification of cellular proteins, targeting an autoimmune response.
Reactive metabolites may also mediate an immune response and induce reactivation or propagation of HHV-6, which results in the systemic effects.
SymptomsSymptoms Rash in DHS occurs 2 to 6 weeks after
drug administration, later than most other serious skin reactions.
Initially presents with a morbilliform eruption that may be indistinguishable from less serious reactions and can eventually develop into erythematous follicular papules, pustules, bullae, or purpura.
SymptomsSymptoms Fever and rash are most frequent presenting symptoms (in
87 percent of cases)
Lymphadenopathy (in about 75 percent) is frequent and usually due to benign lymphoid hyperplasia
Some of these cases resolve with withdrawal of the drug, but lymphoma can develop in cases.
Hepatitis (51 percent)
Interstitial Nephritis (11 percent)
Hematologic abnormalities, especially eosinophilia (30 percent) as well as atypical lymphocytosis
DiagnosisDiagnosis Based on clinical presentation with the
triad of fever, rash, and organ involvement, supported with findings of eosinophilia and abnormal liver function tests.
Hypersensitivity syndrome may be difficult to distinguish clinically from serum sickness or vasculitis
Important to obtain medication history and eventually a skin biopsy may be warranted
TreatmentTreatment Treatment consists of immediate
withdrawal of all suspected medicines, followed by supportive care of symptoms.
Systemic corticosteroids are generally used in more severe DHS cases involving significant dermatitis, pneumonitis and/or hepatitis.
Relapses may occur as corticosteroid doses are tapered, and treatment may need to be continued for several weeks.
Future PreventionFuture Prevention Cross-hypersensitivity reactions are
common and can occur between the three main aromatic anticonvulsants (i.e. phenytoin, carbamazepine and phenobarbitone) as well as NSAIDs
As genetics are suspected in DHS, first-degree relatives may be at increased risk of developing hypersensitivity reactions to similar medicines.
Return to Our CaseReturn to Our Case Biopsy not diagnostic as it showed a mixed
picture with some possible vasculitis
Clinical presentation and initial laboratory data helpful in diagnosis
As an aside, some studies have shown an association between the use of Singulair and the development of Churg-Strauss syndrome, but never in hypersensitivity syndrome/DRESS
Review of Skin Reactions Review of Skin Reactions
Morbilliform Drug Eruption Drug eruptions are most often
morbilliform or exanthematous, and usually fade in a few days.
This is often the initial presentation of more serious reactions including toxic epidermal necrolysis, hypersensitivity syndrome, and serum sickness
Morbilliform Drug Eruption
Erythema Multiforme MajorErythema Multiforme Major Typical target lesions that
predominate on the extremities, and usually occurs after infections, especially herpes simplex and mycoplasma, and has a benign course
Erythema Multiforme MajorErythema Multiforme Major
Stevens-Johnson SyndromeStevens-Johnson Syndrome Widely distributed purpuric macules and
blisters and prominent involvement of the trunk and face are likely to have Stevens-Johnson syndrome, which is usually drug-induced
Generalized eruption of lesions that initially had a target-like appearance but then became confluent, brightly erythematous, and bullous.
Stevens-Johnson SyndromeStevens-Johnson Syndrome
SJS vs. TENSJS vs. TEN Limited areas of epidermal detachment are usually
labeled Stevens-Johnson syndrome and those with extensive detachment toxic epidermal necrolysis.
Stevens-Johnson syndrome is characterized by sloughing of less than 10 percent of the epidermis
Toxic Epidermal Necrolysis is characterized by sloughing of more than 30 percent of he epidermis
About 90 percent of patients with each disorder have mucosal lesions, including painful erosions and crusts on any surface
Hypersensitivity VasculitisHypersensitivity Vasculitis Cutaneous vasculitis is palpable
purpuric papules, classically located on the lower extremities, although any site may be involved
The results of direct immunofluorescence are often positive, with deposits of IgM and C3 complement on capillary walls
Hypersensitivity VasculitisHypersensitivity Vasculitis
Warfarin-induced Skin Warfarin-induced Skin NecrosisNecrosis
A rare and devastating effect of warfarin therapy is skin necrosis, a consequence of occlusive thrombi in vessels of the skin and subcutaneous tissue, and typically begins three to five days after therapy is initiated.
Red, painful plaques evolve to necrosis with hemorrhagic blisters or necrotic scars, frequently in areas with large quantities of adipose tissue, including the breasts, hips, and buttocks.
Warfarin-induced Skin Warfarin-induced Skin NecrosisNecrosis
Take Home Points in Take Home Points in DHS/DRESSDHS/DRESS
Rash occurs 2 to 6 weeks after drug administration, which is later than most other serious skin reactions.
Initially presents with a non-specific morbilliform eruption
Take Home Points in Take Home Points in DHS/DRESSDHS/DRESS
Diagnosis based on clinical presentation with triad of fever, rash, and organ involvement, supported with findings of eosinophilia and abnormal liver function tests.
Treatment consists of stopping suspected medicines, providing supportive care, and administration of systemic corticosteroids in more severe cases.
ReferencesReferences Sullivan J.R., Shear N.H. The drug hypersensitivity syndrome: What
is the pathogenesis? Archives of Dermatology, 2001, 137:357-364.
Descamps V., Valance A., Edlinger C., et al. Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. Archives of Dermatology, 2001, 137:301-304.
Eshki M., Allanore L., Musette P., Milpied B., Grange A., Guillaume J., Chosidow O., Guillot I. Paradis V., Joly P., Crickx B., Ranger-Rogez S., Descamps V. Twelve-Year Analysis of Severe Cases of Drug Reaction With Eosinophilia and Systemic Symptoms: A Cause of Unpredictable Multiorgan Failure. Archives of Dermatology, 2009; 145: 67-72.
Roujeau J.C., Stern R.S. Severe adverse cutaneous reactions to drugs. New England Journal of Medicine, 1994, 331: 1272-1285.
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