Drug-induced hypersensitivity syndrome (DIHS) is an immunologic response to a drug received either orally, by injection, or by IV. Although not fully understood, the process is similar to what occurs with skin allergies except that the immune response is activated by the causative agents and their metabolites rather than by a direct effect on the keratinocytes.[1] There are numerous syndromes based on severity, types of lesions, and underlying diseases processes; however, all of them produce generalized (rather than localized) skin lesions, as well as systemic symptoms.
Table 1. DIHS syndromes based on severity of symptoms
Name |
Identifying characteristics |
Maculopapular exanthemas (MPE) |
Generalized, widespread rash with red macular (not elevated) or papular (elevated) skin eruptions |
Erythema multiforme (EM)- minor |
Localized skin eruptions, usually on the lower extremities, that begin to heal in 7 days |
Fixed drug eruption (FDE) |
One or more local annular or oval erythematous patches; resolve with hyperpigmentation; recur at the same location |
Drug rash with eosinophilia and systemic systems (DRESS) |
Three of the following: fever, exanthema, eosinophilia, atypical circulating lymphocytes, lymphadenopathy, hepatitis
|
Stevens-Johnson Syndrome (SJS); also called EM major |
Cutaneous lesions of erythematous papules, vesicles, bullae, or iris lesions covering <10% of the body surface area; mucosal lesions or conjunctivitis |
Toxic epidermal necrolysis (TEN) |
Cutaneous lesions of erythematous papules, vesicles, bullae, or iris lesions covering >30% of the body surface area; mucosal lesions or conjunctivitis |
Adverse drug reactions have been classified as Type A: those that are predictable and dose-dependent reactions, including overdose, side effects, and drug interactions (e.g., a gastrointestinal bleed following treatment with non-steroidal anti-inflammatory drugs [NSAIDs]); and Type B, those that are unpredictable, more likely to be dose independent, and may include immunologically mediated drug hypersensitivity or non-immune-mediated reactions, thus being considered allergic reactions.[2] The most commonly reported medications that cause DIHS are the following:
|
|
|
Drug Class |
Specific Drug |
Latent Period |
Angiotensin-converting enzyme inhibitors Xanthine oxidase inhibitor |
Captopril
Allopurinol |
At any time
2–6 weeks |
Antibiotics |
Beta-lactams (pediatrics) |
Immediate: 1 hour Non-immediate: ³1 hour |
Ceftriaxone |
72 hours |
|
Cyclosporine |
|
|
Dapsone |
Few days to weeks |
|
Isoniazid |
|
|
Levofloxacin |
|
|
Minocycline |
|
|
Penicillin |
|
|
Sulfonamides |
|
|
Trimethoprim |
|
|
Anticonvulsants |
Carbamazepine |
Usually 2–4 weeks; may be to 3 months |
Lamotrigine |
|
|
Phenobarbitone |
|
|
Phenytoin |
|
|
Primidone |
|
|
Antidepressants |
Clomipramine (anafranil) |
|
Antifungals |
Terbinafine |
2–3 days |
Antiretrovirals |
Abacavir |
|
Nevirapine |
|
|
Beta-blocker |
Atenolol |
|
Biologic modifiers |
Infliximab |
|
Murine and humanized monoclonal antibodies |
|
|
Recombinant interferons |
|
|
Drug coloring agents |
Blue dyes |
|
Calcium channel blockers |
Diltiazem |
2–3 days |
Gold salts |
|
|
Antihypertensive |
Hydralazine (apresoline) |
|
Immunosuppressants |
Azathioprine |
|
Non-steroidal anti-inflammatory drugs |
Aspirin |
|
Antiarrhythmic |
Procainamide |
|
Sodium channel blockers |
Mexiletine |
|
Disease-modifying anti-rheumatic drugs |
Sulfasalazine |
|
From Hamm, RL. Drug allergy: delayed cutaneous hypersensitivity reactions to drugs. EMJ Allergy Immunol. 2016. Available at: https://www.emjreviews.com/allergy-immunology/article/drug-allergy-delayed-cutaneous-hypersensitivity-reactions-to-drugs. Accessed July 25, 2018.
Symptoms of DIHS include generalized rash (with or without vesicles) and any of the following: local eruptions, fever (>38ᴼ C), lymphedema, mucosal lesions, conjunctivitis, and epidermal sloughing. Other reported symptoms include liver abnormalities, leukocyte abnormalities (at least one of the following: leukocytosis, atypical lymphocytosis, or eosinophilia) and HHV-6 reactivation.[3]Onset is usually 2–3 weeks after the first exposure to the offending drug, beginning with a fever or sore throat and progressing to the cutaneous/mucosal involvement, at which point the response is either SJS or TEN depending on the amount of body surface involvement. In the younger adult population (20–40 years), the syndrome is termed erythema multiforme. A literature review by Madigan and Fox suggested that “vancomycin-induced cases present with a unique phenotype characterized by a higher burden of renal involvement.”[4] Shiohara reports that approximately 50% of the cases had an episode of infection within the previous month of onset, particularly a virus, consistent with the view in literature that viruses are key in the generation and activation of drug-specific T cells.3 Symptoms can continue to worsen even after withdrawal of the offending drug. The patient in the attached photo developed symptoms 2 weeks after initiating an over-the-counter diet supplement that was ordered online.
Medical management of DIHS begins with identification and cessation of the causative agent, which is usually the last one that the patient has initiated taking. Depending on the severity of the symptoms, systemic corticosteroids are the gold standard to prevent progression and relieve symptoms in the acute phase, beginning with 40-50 mg/day and tapering over 6-8 weeks.3 Supportive care is provided in an intensive care unit or a burn unit for more severe cases such as SJS and TEN.
In minor cases, cessation of the medication may be sufficient to reverse symptoms and no wound care is needed. In more severe cases with epidermal sloughing, treatment is similar to that of a deep superficial burn except that debridement of the detached epidermal tissue is usually not advisable because of potential loss of fluids. Non-adherent antimicrobial dressings are recommended to help prevent infection and to avoid further skin tearing with dressing changes. Prevention of fluid loss and infection are paramount, and as the patient improves, dressings to promote re-epithelialization are recommended.
In summary, DIHS is an allergic reaction to ingested or IV drugs that requires identification and cessation of the offending medication, management of under-lying autoimmune disorders, supportive care to prevent complications, and meticulous wound care to prevent infection.
[1] Hamm RL. Drug-induced hypersensitivity syndrome: Diagnosis and treatment. J Am Coll Clin Wound Spec. 2012;3
(4):77-81.
[2] Wheatley LM, Plaut M, Schwaninger JM, et al. Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy. J Allergy Clin Immunol. 2015;136(2):262-271.e2.
[3] Shiohara T, Mizukawa Y. Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019. Allergology International. 2019;68:301-308.
[4] Madigan LM, Foz LP. Vancomysin-associated drug-induced hypersensitivity syndrome. J Am Acad Derm. 2019;81(1):123-128.
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