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Description : Check out this medical presentation on Erythema Multiforme, which is titled "Drug Reactions - Mechanisms and Cutaneous Manifestations", to know about the most common drugs causing immune reactions, to be able to suspect a drug reaction based on clinical and lab findings, to recognize the patient characteristics that put them at risk of a drug reaction, and to be aware of the characteristics of the 3 most Serious Cutaneous Adverse Reactions (SCARs).

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Department of Dermatology Therese Holguin, M.D. Assistant Professor
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Drug Reactions Mechanisms and Cutaneous Manifestations
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Objectives To become familiar with the most common drugs causing immune reactions To be able to suspect a drug reaction based on clinical and lab findings To recognize the patient characteristics that put them at risk of a drug reaction To be aware of the characteristics of the 3 most Serious Cutaneous Adverse Reactions (SCARs)
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How, Why, Who, What
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Epidemiology and Burden of Drug Hypersensitivity 10-20% of hospitalized patients and up to 25% of outpatients Most are Type A Type B around 10-15% of all ADRs* * Adverse Drug Reactions
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Classification of Drug Reactions
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TYPE B: DRUG HYPERSENSITIVITY REACTIONS RESTRICTED TO A SMALL SUBSET OF THE GENERAL POPULATION Intolerance Idiosyncratic Immunologic (allergic)
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Intolerance: Side effects at subtherapeutic doses Reflects altered drug metabolism or end-organ hyperacuity
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Idiosyncratic: Qualitatively distinct from the known pharmacologic toxicity profile May result from defined genetic defect eg., Primaquine-sensitive hemolytic anemia secondary to deficiency of the enzyme glucose-6-phosphate dehydrogenase Reflects a complex interaction of metabolic and constitutional factors eg., reactions to radiocontrast media
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Immunologic Drug Reactions (Allergy): Drug reactions resulting from consequences of a drug-specific immune response Some drug allergies are defined by human leukocyte antigen (HLA) alleles and therefore can be predicted and tested for (personalized medicine). Immediate = onset of symptoms within one hour = IgE mediated Delayed = onset of symptoms later than one hour = T lymphocyte Distinction between idiosyncratic and allergic drug reactions can be difficult to discern.
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Immunologic Drug Reactions (Allergy) Mechanisms Which Drugs Factors influencing immunogenicity of the drug Patient risk factors for developing drug allergy
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Mechanisms Hapten-Prohapten Pharmacoimmune (P-i)
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Hapten- Prohapten: the drug or its metabolite binds to an endogenous peptide and the resultant hapten is recognized by a highly restricted MHC Antigen must be present in the immune system in a multivalent form. Most pharmaceutical agents do not qualify as drug allergens because they are simple structures and small. If less than 1kD can be recognized by the immune system by Directly binding in a covalent fashion with macromolecules on cell surfaces Direct haptenation in plasma to form hapten carrier complexes Conversion into reactive intermediates during drug metabolism followed by haptenation
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P-i Concept: the pharmacoimmune reaction, drug induces formation of drug-HLA complexes that can directly activate T-cell immune responses without the need for a specific peptide ligand Chemically inert drug, unable to covalently bind to proteins or peptides Bind directly and reversibly to HLA molecules on antigen presenting cells or T cell receptors on certain T cells Results in strong T cell immune response of Allergy Cytokine production, proliferation, and cytotoxicity Selective T cell population is stimulated, expands, and infiltrates the skin and other organs
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P-i concept of T lymphocyte activation The drug fits into some TCR with sufficient affinity to cause a signal. This drug-TCR interaction is supplemented by a MHC interaction. Alternatively, the drug binds first to the HLA molecule and the new drug-HLA complex stimulates T cells. APC, Antigen-presenting cell: HLA, human leukocyte allergen: MHC, major histocompatibility complex: SMX, sulfamethoxazole: TCR, T cell receptor
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Gell-Coombs Classification of types of Immune Reactions
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Advances in Immunologic Research The three antibody-dependent types of reactions (I,II,III) require the involvement of helper T (Th) cells. T cells can orchestrate different forms of inflammation. T cell-mediated immunopathology has been further subclassified as types IVa through IVd reactions.
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Immunologic Drug Reactions Most common drug groups: Beta lactam antibiotics Non steroidal anti inflammatory drugs Radiocontrast media Neuromuscular blocking agents Antiepileptic drugs Increasing reports Anticancer drugs such as platins and taxanes Biologic cytokines and anticytokines
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Drug Reaction Quiz: What are the most common drug groups causing immunologic drug reactions? A. Beta lactam antibiotics, Non steroidal anti inflammatory drug, Radiocontrast media, Neuromuscular blocking agents, Antiepileptic drugs B. Beta lactam antibiotics, Acetaminophen, Radiocontrast media, Neuromuscular blocking agents, Antiepileptic drugs
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Drug Reaction Quiz: What are the most common drug groups causing immunologic drug reactions? A. Beta lactam antibiotics, Non steroidal anti inflammatory drug, Radiocontrast media, Neuromuscular blocking agents, Antiepileptic drugs B. Beta lactam antibiotics, Acetaminophen, Radiocontrast media, Neuromuscular blocking agents, Antiepileptic drugs
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Drug Reaction Quiz: What are the two mechanisms of drug recognition by the immune system? A. Hapten Pro Hapten and Fast Acetylator phenotype B. Hapten Pro Hapten and P-i mechanism C. Fast Acetylator phenotype and P-i mechanism D. Fast Acetylator phenotype and Cross reactivity to native or cross reactive epitopes
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Drug Reaction Quiz: What are the two mechanisms of drug recognition by the immune system? A. Hapten Pro Hapten and Fast Acetylator phenotype B. Hapten Pro Hapten and P-i mechanism C. Fast Acetylator phenotype and P-i mechanism D. Fast Acetylator phenotype and Cross reactivity to native or cross reactive epitopes
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Epidemiology Cutaneous reactions such as maculopapular eruptions and urticaria are the most common clinical manifestations of ADRs. Rarely drugs induce more severe and potentially life-threatening reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), Immune hepatitis, and drug-induced hypersensitivity syndromes (DiHS) of which drug reaction with eosinophilia and systemic symptoms (DRESS) is an example.
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Factors that influence Drug immunogenicity
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Factors that influence Drug immunogenicity Genetic Factors: Acetylator phenotype Metabolic Factors: Glutathione levels Drug structure: preformed multivalent Adjuvants Concomitant infections Occult exposure to native or cross-reactive epitopes
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Drug Reaction Quiz: Which is not a patient risk factor for drug hypersensitivity? A. High dose/long term exposure B. Chronic disease states C. HLA phenotype D. HIV status E. Age
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Drug Reaction Quiz: Which is not a patient risk factor for drug hypersensitivity? A. High dose/long term exposure B. Chronic disease states C. HLA phenotype D. HIV status E. Age
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Risk Factors for Drug Hypersensitivity High dose, long term, and frequent drug treatment Existence of naturally occurring cross-reacting epitopes (in children drug exposure in utero or breast milk) Contaminants in drug preparation Chronic disease states eg. Cystic fibrosis (repeated courses of therapy) Allopurinol administered with amino-penicillins Patients with atypical/abnormal lymphocytes with amino-penicillins HIV patients and sulfonamides
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Risk Factors for Drug Hypersensitivity History of allergic drug reaction Atopic background for severe and fatal penicillin anaphylaxis Familial propensity HLA subtypes
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HLA subtypes and Drug Hypersensitivity
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Drug Reaction Concern When to suspect History Physical Exam Laboratory How to approach Timeline Serious Cutaneous Drug Reactions (SCARs)
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Drug Reaction Quiz: The physical characteristics that would make drug reaction a consideration would include: A. Fever, Rash, Adenopathy, Facial swelling B. Fever, Rash, Adenopathy, Fingernail dystrophy C. Fever, Rash, Adenopathy, Alopecia D. Fever, Rash, Adenopathy, Eosinophilia
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Drug Reaction Quiz: The physical characteristics that would make drug reaction a consideration would include: A. Fever, Rash, Adenopathy, Facial swelling B. Fever, Rash, Adenopathy, Fingernail dystrophy C. Fever, Rash, Adenopathy, Alopecia D. Fever, Rash, Adenopathy, Eosinophilia
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When to suspect a drug eruption Cutaneous Findings Confluent erythema Facial edema or central facial involvement Skin pain Palpable purpura Skin necrosis Blisters or positive Nikolsky’s sign Mucous membrane erosions Urticaria Swelling of tongue
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When to suspect a drug eruption General clinical findings High fever (>40C0) Adenopathy Arthralgias/arthritis Shortness of breath/wheezing/hypotension Laboratory Results Eosinophilia (>1000mm3) Lymphocytosis with atypical lymphocytes Abnormal results on liver function tests
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Case # 1 CC: painful rash History : 34 year old woman with a 1 week history painful rash which is located on trunk, extremities, eyes, mouth and genitalia but not palms and soles. Prior to rash had fever and felt unwell. No other family members ill and recently started taking Piroxicam for a sprained ankle. PH/FH/SH: unremarkable PE: skin tenderness; diffuse erythematous, purpuric patches, bullae, erosions, targetoid lesions; ocular, oral, genital erosions, + fever, no adenopathy, BSA >30% Lab: leukocytosis with normal smear, slightly elevated BUN/Cr and LFT
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.
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SJS/TEN Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, most commonly triggered by medications, characterized by extensive necrosis and detachment of the epidermis. Spectrum of involvement from SJS (<10%) to TEN (>30%) body surface area. Systemic disease involving the ophthalmic, pulmonary, genitourinary, and gastrointestinal systems, in addition to the skin Skin Biopsy: Necrotic keratinocytes; minimal inflammation; full-thickness epidermal/epithelial necrosis
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Fig. 21.9 Spectrum of disease based upon surface area of epidermal detachment. Adapted from Bastuji-Garin S, et al. Arch Derm. 129:92, 1993 Dermatology Bologna et al, 2nd edition
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Dermatology Bologna et al, 2nd edition
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Stevens-Johnson Syndrome
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Fig. 21.10 Stevens–Johnson syndrome (SJS) versus SJS–TEN overlap. A In addition to mucosal involvement and numerous dusky lesions with flaccid bullae, there are areas of coalescence and multiple sites of epidermal detachment. Because the latter involved >10% body surface area, the patient was classified as having SJS–TEN overlap. B Close-up of epidermal detachment, whose appearance has been likened to wet cigarette paper. Dermatology Bologna et al. 2nd edition
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Fig. 21.7 Cutaneous features of toxic epidermal necrolysis (TEN). Characteristic dusky red color of the early macular eruption in TEN. Lesions with this color often progress to full-blown necrolytic lesions with dermal–epidermal detachment. Dermatology Bologna et al, 2nd edition
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Toxic Epidermal Necrolysis
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Toxic Epidermal Necrolysis
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Fig. 21.8 Clinical features of toxic epidermal necrolysis (TEN). A Detachment of large sheets of necrolytic epidermis (>30% body surface area), leading to extensive areas of denuded skin. A few intact bullae are still present. B Hemorrhagic crusts with mucosal involvement. C Epidermal detachment of palmar skin. A, Courtesy of Francisco Kerdel MD. Dermatology Bologna et al, 2nd edition
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Fig. 21.14 Treatment of toxic epidermal necrolysis (TEN). Facial involvement of a patient with TEN (50% body surface area involvement) before (A) and 3 weeks after (B) treatment with IVIg (0.75 g/kg/day for 4 days) Dermatology Bologna et al, 2nd edition
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Onychomadesis - spontaneous separation of the nail plate from the matrix area and is associated with arrest of nail growth. Onychomadesis has been reported in patients with bullous dermatoses, febrile illnesses, psoriasis, and cutaneous drug eruptions particularly Stevens-Jophnson syndrome and toxic epidermal necrolysis. Symblepharon
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SCORTEN: A Severity-of-Illness Score for Toxic Epidermal Necrolysis Bastuji et al. J Invest Dermatol 2000;115:149-153 SCORTEN should be computed within the first 24 hours after admission and again on day 3
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TEN: Predisposing Factors HIV Genetic factors HLA types Polymorphisms in CYP2C19 gene Malignancy High doses and rapid induction of medications Systemic lupus erythematosus Physical stimuli, e.g. UV light or radiation therapy
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Drugs Associated with SJS/TEN Allopurinol Aromatic anticonvulsants Antibacterial sulfonamides Lamotrigine Nevirapine Oxicam NSAIDs
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Case # 2 CC: facial swelling and rash History : 34 year old woman with a 1 week history of a non-painful rash which is located on trunk, extremities and complains of swelling and redness of her face. Feels unwell and has persistent fever. No other family members ill. Started Lamictal 4 weeks ago for a seizure. PH/FH/SH: unremarkable PE: (-) mucous membrane involvement; erythematous macules, papules, vesicles, bullae; facial erythema, edema, pinpoint pustules; adenopathy Lab: peripheral eosinophilia; + atypical lymphocytsis, and abnl LFTs
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DRESS Drug reaction with eosinophilia and systemic symptoms The broad spectrum of clinical features and long latency period in DRESS often results in diagnostic delay Typically, patients present with fever, rash, lymphadenopathy, lymphocytosis (atypical lymphocytes) and abnormal liver tests Skin Biopsy: Superficial perivascular lymphocytes, eosinophils; ± dyskeratotic keratinocytes; ± variable lichenoid inflammation
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Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review . Ganeva et al. Int J Dermatol 2008;47(8):853-860
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DRESS
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© 2009 American Academy of Dermatology, Inc. Fig 1. Generalized maculopapular eruption on patient’s trunk JAAD Volume 60, Issue 1, Pages 146-149 (January 2009) Drug-induced hypersensitivity syndrome: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome induced by aspirin treatment of Kawasaki disease
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DRESS – Drug Reaction with Eosinophilia and Systemic Symptoms Obermoser, Zelger JAAD, Volume 54, Issue 5, Pages 913-914 (May 2006)
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Other Concerns: Liver involvement is the most common visceral manifestation and can lead to fulminant hepatic failure and death. Myocarditis which may progress to acute necrotizing eosinophilic myocarditis (ANEM), interstitial nephritis, pneumonitis, and thyroiditis are other possible complications that require long-term close monitoring.
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Viruses associated with DRESS Herpesviruses Human herpesvirus 6 (HHV6) Human herpesvirus 7 (HHV7) Cytomegalovirus (CMV) Epstein-Barr virus (EBV) Paramyxoviruses Mumps Parainfluenza
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Drugs Associated with DRESS Anticonvulsants Antidepressants Sulfones and Sulfonamides NSAIDs Anti-infectives Ace-inhibitors Beta blockers Allopurinol and others
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Case # 3 CC: face and hands are swollen and rash History : 54 year old man with a 1 day history of rash which started on body fold and face and rapidly spread. The symptoms are itch and burning. Notes swelling on his hands and face. Has fever but otherwise well. No other family members ill. Started amoxicillin 2 days ago for a sore throat. And is complaining of some trouble catching his breath. PH/FH/SH: unremarkable PE: + oral mucosal erosions, diffuse pin head pustules with flexural accentuation, edema of face and hands, a few scattered vesicles and bullae Lab: leukocytosis with neutrophilia, mild abnormalities in LFTs, Bun/Cr
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Acute generalized exanthematous pustulosis (AGEP). A A positive patch test result 4 days following the application of 0.75% metronidazole in a patient with a previous pustular drug eruption to that medication. Diffuse erythema of the buttock (due to cephalosporin, B ) and face (due to metronidazole, C ) studded with sterile pustules. Spongiform pustules are seen within the epidermis of lesional skin ( D ). A & C, Courtesy, Kalman Watsky, MD. Drug Reactions Revuz, Jean, Dermatology, 21, 335-356 Copyright © 2012 © 2012, Elsevier Limited. All rights reserved.
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Acute Generalized Exanthematous Pustulosis Rare, acute eruption characterized by the development of numerous nonfollicular sterile pustules on a background of edematous erythema Fever and peripheral blood leukocytosis are usually present. In approximately 90 percent of cases, AGEP is caused by drugs, most often antibiotics (eg, aminopenicillins and macrolides), the calcium channel blocker diltiazem, and antimalarials. The eruption develops within hours or days of drug exposure and resolves spontaneously in one to two weeks after drug discontinuation.
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Timeline for Drug Reactions AGEP: less that 4 days DRESS: 1-8 weeks SJS/TEN: 1 day to 3 weeks
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Mortality Incidence SJS 1-5% TEN 25-35% DRESS ~10% AGEP 2-4%
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RegiSCAR http://dermatol-sinica.com/web/data/20091130043801.pdf http://tools.farmacologiaclinica.info/index.php
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Take Home Message: A few medications area associated with a high risk of SJS/TEN. Prescribing one of them requires thorough evaluation of expected benefits. Nevirapine Lamotrigine Carbamazepine Phenytoin Phenobarbital Cotrimoxazole and other anti-infective sulfonamides Sulfasalazine Allopurinol Oxicam NSAIDs Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: Assessment of Medication Risks with Emphasis on Recently Marketed Drugs. The EuroSCAR-Study Journal of Investigative Dermatology (2008) 128, 35–44
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Objectives To become familiar with the most common drugs causing immune reactions To be able to suspect a drug reaction based on clinical and lab findings To recognize the patient characteristics that put them at risk of a drug reaction To be aware of the characteristics of the 3 most Serious Cutaneous Adverse Reactions (SCARs)
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Comparisons of Drug Eruption Subtypes:DRESS (Semin Cutan Med Surg 26:147-154;2007) Onset: 1 to 8 weeks (usually a long latency period) Clinical Presentation: (-) mucous membrane involvement; erythematous macules, papules, vesicles, bullae; facial erythema, edema, pinpoint pustules; + fever; + peripheral eosinophilia; ± atypical lymphocytsis; adenopathy, hepatomegaly, splenomegaly; sialadenitis; myocarditis; pneumonitis; nephritis; hepatitis; thyroiditis Skin Biopsy: Superficial peripheral lymphocytes, eosinophils; ± dyskeratotic keratinocytes; ± variable lichenoid inflammation Mortality: approximately 10%
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Approach to the patient with a suspected drug eruption Testing: CBC with diff, LFTs, kidney function, TFTs, ECHO, BIOPSY Discontinuation of medication Knowledge of association between and drug hypersensitivity All non essential medications Recent additions to patients list especially if timing implicates Treatment: Topical steroids and antihistamines if mild Steroids for DRESS Cyclosporine (and in some cases IVIG) for SJS/TEN Supportive treatment of AGEP
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Comparisons of Drug Eruption Subtypes Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (Semin Cutan Med Surg 26:147-154;2007) Onset: 1 day – 3 weeks Clinical Presentation: (+) mucous membrane involvement; prodrome of malaise, nausea, headache, myalgias, arthralgias; skin tenderness; diffuse erythematous, purpuric patches, bullae, erosions, erythroderma, targetoid lesions; ocular, oral, genital, respiratory erosions; + fever, ± hypotension, respiratory failure, renal failure, hepatitis % of body surface involvement: SJS <10%, TEN >30%, SJS-TEN overlap 10-30% Scalp, palms, soles rarely involved Skin Biopsy: Necrotic keratinocytes; minimal inflammation; full-thickness epidermal/epithelial necrosis
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Comparisons of Drug Eruption Subtypes Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (Semin Cutan Med Surg 26:147-154;2007) Mortality: SJS 1-5%, TEN 25-35% Treatment: Withdrawal of offending medication; transfer to burn unit; cyclosporine, ?biologics, ?IVIG Differential Diagnosis: Staph scalded skin syndrome, GVHD, pemphigus, bullous pemphigoid, AGEP, paraneoplastic pemphigus, Kawasaki disease, erythema multiforme Causative Agents: Sulfonamide antibiotics, beta-lactam antibiotics, anticonvulsants, NSAIDs Special Considerations: Caution HIV patients; patients with brain tumors receiving radiation therapy
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Immunologic mediators in SJS/TEN Cytotoxic T cell immune-mediated disorder leading to massive apoptosis CD8+ T lymphocytes, NK cells Granulysin Fas-FasL Perforin-Granzyme B TNF alpha Immunologic Mediators in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Seminars in Ophthalmology 2016;1(1-2):85-90
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Treatment of Toxic Epidermal Necrolysis Toxic Epidermal Necrolysis. Pereira et al. JAAD 2007;56:181-200 Primary Treatment Discontinuation of offending drug Prognosis correlated to rapidity of cessation of drug Less true of drugs with a long half-life Admission to a burn unit Rapidity is directly proportional to survival Scrupulous attention to eyes, respiratory tract, fluid and electrolyte balance, nutrition, infection and pain control Frequent cultures of skin, urine, blood and IV canulas Staphylococcus aureus and Pseudomonas aeruginosa Empiric or prophylactic use of antibiotics → emergence of resistant organisms and increased mortality
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Treatment of Toxic Epidermal Necrolysis Toxic Epidermal Necrolysis. Pereira et al. JAAD 2007;56:181-200 Adjuvant Treatments Cyclosporine – immunosuppressive and anti-apoptotic (↓NF-κB) Plasmapheresis Cyclophosphamide - not currently used for treatment of TEN Corticosteroids – CONTROVERSIAL, BEST AVOIDED Steroids given 48 hrs or more PTA associated with ↑ mortality No effect in stopping TEN progression once reaction is initiated Don’t stop if patient is taking steroids for another condition High-dose pulse steroids may be beneficial in early TEN
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Treatment of Toxic Epidermal Necrolysis Toxic Epidermal Necrolysis. Pereira et al. JAAD 2007;56:181-200 Adjuvant Treatments, continued TNF-α inhibitors Thalidomide Prospective trial suspended due to excess mortality Infliximab Pentoxifylline Intravenous Immune Globulin (IVIG) Recommended dose of 1 g/kg/day for 3 days In vitro evidence provides rational basis for treatment Small studies show improved survival rates (88-100%) A number of studies show no benefit of IVIG (doses 0.4 g/kg/day) Granulocyte Colony Stimulating Factor (G-CSF)
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Breathnach SM. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook's Textbook of Dermatology. 7th ed. Oxford: Blackwell-Science; 2004. p. 74.1-74.20. Long-term consequences of TEN
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Drug reaction with eosinophilia and systemic symptoms (DRESS)
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Comparisons of Drug Eruption Subtypes:DRESS (Semin Cutan Med Surg 26:147-154;2007) Onset: 1 to 8 weeks (usually a long latency period) Clinical Presentation: (-) mucous membrane involvement; erythematous macules, papules, vesicles, bullae; facial erythema, edema, pinpoint pustules; + fever; + peripheral eosinophilia; ± atypical lymphocytsis; adenopathy, hepatomegaly, splenomegaly; sialadenitis; myocarditis; pneumonitis; nephritis; hepatitis; thyroiditis Skin Biopsy: Superficial peripheral lymphocytes, eosinophils; ± dyskeratotic keratinocytes; ± variable lichenoid inflammation Mortality: approximately 10%
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Comparisons of Drug Eruption Subtypes:DRESS (Semin Cutan Med Surg 26:147-154;2007) Treatment: Withdrawal of offending medication Prolonged course of systemic steroids (6-8 weeks at 0.5-1 mg/kg) Differential Diagnosis: Morbilliform drug eruption, early SJS or TEN, viral exanthem, hypereosinophilic syndrome, Still’s disease Causative Agents: Aromatic anticonvulsants, non-aromatic anticonvulsants, allopurinol, dapsone Special Considerations: Caution allopurinol use in patients on thiazide diuretics with renal insufficiency, serologic testing for HHV4, HHV6, HHV7, CMV, EBV
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The broad spectrum of clinical features and long latency period in DRESS often results in diagnostic delay. Typically, patients present with fever, rash, lymphadenopathy, leucocytosis and abnormal liver tests which, understandably, may suggest an infectious illness.
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Copyright restrictions may apply. Drug-Induced Eosinophilia and Systemic Symptoms: Hypersensitivity or Peripheral T-Cell Lymphoma? Schleinitz, N. et al. Arch Dermatol 2005;141:395-396. Extensive erythematous eruption
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DRESS-associated myocarditis Myocarditis is a fatal and under-recognized manifestation of DRESS, which may occur long after the initial diagnosis. Each of the reported DRESS-associated myocarditis cases had a nonspecific rash along with cardiac manifestations, including hypotension, tachycardia, dyspnea and/or chest pain. The onset of the myocarditis after the appearance of the rash ranged from immediate to a delay of 4 months.
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Table 1 Diagnostic criteria for drug-induced hypersensitivity syndrome (DIHS) established by a Japanese consensus group6 The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Shiohara et al. Br J Dermatol 2007;156(5):1083-1084 Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int 2006; 55:1–8
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Table 1.Clinical features of drug-hypersensitivity syndrome, serum sickness–like reaction, Stevens-Johnson syndrome, and toxic epidermal necrolysis Recognition and Management of Severe Cutaneous Drug Reactions Dermatologic Clinics, Volume 25, Issue 2, Pages 245-253 (April 2007)
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Beware of cross-reactions Cross-reactions are common between the three main aromatic anticonvulsant drugs (phenytoin, carbamazepine and phenobarbital), and patients who have experienced Drug Hypersensitivity Syndrome with any one of these medicines must avoid all three. Because genetic factors are suspected in Drug Hypersensitivity Syndrome, first-degree relatives should be alerted to their elevated risk of developing hypersensitivity reactions to the same medicine(s).
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Acute Generalized Exanthematous Pustulosis (AGEP)
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AGEP Epidemiology 1-5 per million per year Mean age 56 Slight female predominance Genetics: HLA-B5, -DR11 and -DQ3 have been found more frequently in patients with AGEP. Recessively inherited mutations in IL36RN gene found in pustular psoriasis, also found in small proportion of AGEP patients Onset: hours to days Clinical Presentation Rapid development of hundreds of sterile pinhead pustules on edematous erythema with flexural accentuation with burning and pruritus Begins on face or intertriginous areas Edema of hands and face, purpura, vesicles, bullae Involvement of mucous membranes 50% 17% have at least one organ involvement: liver, kidney, respiratory distress. Leukocytosis with marked neutrophilia.
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AGEP: Skin biopsy Intra- or subcorneal spongiform pustules Eosinophils in the pustules or dermis Necrotic keratinocytes Superficial, interstitial, and mid-dermal infiltrate rich in neutrophils Absence of tortuous, dilated blood vessels
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Acute generalized exanthematous pustulosis (AGEP). A A positive patch test result 4 days following the application of 0.75% metronidazole in a patient with a previous pustular drug eruption to that medication. Diffuse erythema of the buttock (due to cephalosporin, B ) and face (due to metronidazole, C ) studded with sterile pustules. Spongiform pustules are seen within the epidermis of lesional skin ( D ). A & C, Courtesy, Kalman Watsky, MD. Drug Reactions Revuz, Jean, Dermatology, 21, 335-356 Copyright © 2012 © 2012, Elsevier Limited. All rights reserved.
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AGEP 90% drug-related Antibiotics are the primary drugs implicated in AGEP. Beta-lactam antibiotics (e.g. penicillins, aminopenicillins, cephalosporins) and macrolides are the most frequently responsible medications, followed by calcium channel blockers (in particular diltiazem) and antimalarials. Immunologic mechanisms: AGEP is a T cell mediated neutrophilic inflammation involving drug-specific CD4 T cells, cytotoxic CD8 T cells, and inflammatory cytokines and chemokines. Drug-specific CD4 T cells produce large amounts of CXCL8 and GMCSF. CXCL8, a chemokine inducing neutrophil chemotaxis, and GMCSF, which reduces neutrophil apoptosis, are both involved in tissue accumulation of neutrophils [1824]. T helper 17 (Th17) cells also may be involved in the recruitment, activation, and migration of neutrophils in AGEP
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AGEP Mortality: 2-4% reported AGEP resolves spontaneously without sequelae in the majority of patients. Treatment: topical steroids for symptomatic relief
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Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: Assessment of Medication Risks with Emphasis on Recently Marketed Drugs. The EuroSCAR-Study Journal of Investigative Dermatology (2008) 128, 35–44
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Ann Allergy Asthma Immunol. 2010 Oct;105(4):259-273. doi: 10.1016/j.anai.2010.08.002. Drug allergy: an updated practice parameter. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Collaborators (52) Abstract Adverse drug reactions (ADRs) result in major health problems in the United States in both the inpatient and outpatient setting. ADRs are broadly categorized into predictable (type A and unpredictable (type B) reactions. Predictable reactions are usually dose dependent, are related to the known pharmacologic actions of the drug, and occur in otherwise healthy individuals, They are estimated to comprise approximately 80% of all ADRs. Unpredictable are generally dose independent, are unrelated to the pharmacologic actions of the drug, and occur only in susceptible individuals. Unpredictable reactions are subdivided into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions. Both type A and B reactions may be influenced by genetic predisposition of the patient.
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Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity. Chen, C.-B., Abe, R., Pan, R.-Y., Wang, C.-W., Hung, S.-I., Tsai, Y.-G., & Chung, W.-H. (2018). An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity. Journal of Immunology Research, 2018, 6431694. http://doi.org/10.1155/2018/6431694
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Gell and Coombs Classification of Drug Hypersensitivity Reactions
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Approach to the Patient with a Suspected Drug Eruption J Cotliar, MD New-onset skin eruption: excluding mimickers of drug eruption by history and ROS (viral exanthem, connective tissue disease, autoimmune disease, malignancy Building a suspicion of a drug eruption: taking extensive patient history (all Rx and non-Rx medications) creating timeline of medication intake and appearance of eruption searching literature for documented cases of specific agents causing adverse reactions. (www.drugeruptiondata.com) Characterizing the type of drug eruption: primary skin lesion (morbilliform, bullous, erosive) distribution of the lesions (diffuse, acral, photodistribution) mucous membrane involvement systemic symptoms (fever, hypotention, adenopathy, facial edema, hepatosplenomegaly) laboratory abnormalities (eosinophilia, abnormal liver function tests, renal dysfunction, thyroid dysfunction) Semin Cutan Med Surg 2007;26:147-154
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Approach to the Patient with a Suspected Drug Eruption J Cotliar, MD Testing to confirm the presence of drug eruption: a) skin biopsy (presence of eosinophils, epidermal necrosis) b) in vivo testing (patch test, pinprick, intradermal injection, rechallenge) c) in vitro testing (lymphocyte transformation, IFN gamma assay) Discontinuing the offending drug(s): a) recognizing certain drug eruptions as unique to specific agents b) discontinuation of all non-essential medications c) discontinuation of newest medications in relation to onset of eruption. Treating drug eruptions: topical steroids Antihistamines systemic steroids (DRESS) IVIG (Stevens-Johnson syndrome, toxic epidermal necrolysis) Semin Cutan Med Surg 2007;26:147-154
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Severe Adverse Cutaneous Reactions to Drugs Roujeau J and Stern R. N Engl J Med 1994;331:1272-1285 Clinical and Laboratory Findings That Should Alert Clinicians That a Drug Induced Cutaneous Eruption May Be Serious
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From “Approach to the Patient With a Suspected Drug Eruption” Semin Cutan Med Surg 2007;26:147-154 It is important for the clinician to distinguish between self-limited exanthematous drug eruptions, which may resolve solely with cessation of the offending agent and more severe presentations of drug reactions such as drug hypersensitivity syndromes or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), which are associated with significant mortality and may necessitate treatment beyond just the withdrawal of the inciting medication.
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Erythema Multiforme Younger males Frequent recurrences Less fever Milder mucosal lesions Principal risk factor: recent or recurrent herpes Lack of association with collagen vascular disease, HIV, or cancer
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Copyright restrictions may apply. Correlations Between Clinical Patterns and Causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Auquier-Dunant, A. et al. Arch Dermatol 2002;138:1019-1024.
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Correlations Between Clinical Patterns and Causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Auquier-Dunant, A. et al. Arch Dermatol 2002;138:1019-1024.
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Copyright restrictions may apply. Teraki, Y. et al. Arch Dermatol 2008;144:232-235. Biopsy specimen obtained from an erythematous macule on the dorsum of the foot shows prominent eosinophilic necrosis of the keratinocytes and a subepidermal blister (hematoxylin-eosin, original magnification x100)
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Drugs Associated with Stevens Johnson Syndrome and Toxic Epidermal Necrolysis Severe Adverse Cutaneous Reactions to Drugs Roujeau J and Stern R. N Engl J Med 1994;331:1272-1285 Allopurinol Aromatic anticonvulsants Antibacterial sulfonamides Lamotrigine Nevirapine Oxicam NSAIDs
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Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) - History First described by Chaiken et al in “Dilantin sensitivity; report of a case of hepatitis with jaundice, pyrexia and exfoliative dermatitis” in N Engl J Med. 1950 Jun 8;242(23):897-8 Shear and Spielberg first use the term “anticonvulsant hypersensitivity syndrome” to recognize this constellation of symptoms related to the aromatic anticonvulsants carbamazepine, phenytoin and phenobarbital in “Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1988;82:1826-1832 In 1997 Roujeau et al. propose the term “DRESS” in Rev Fr Allergol Immunol Clin 1997;37:651-659 In 1998 Sontheimer et al. propose a consensus nomenclature for syndrome – DIDMOHS (drug-induced delayed multiorgan hypersensitivity syndrome) in Arch Dermatol 1998;134:874-875
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Table 1. Criteria used in the classification of severe drug eruptions Physiopathology and treatment of severe drug eruptions Bachot, Nicolas; Roujeau, Jean-Claude Current Opinion in Allergy and Clinical Immunology: Volume 1(4)August 2001pp 293-298
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Beware of cross-reactions
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Drugs associated with DRESS syndrome Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review . Ganeva et al. Int J Dermatol 2008;47(8):853-860
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SJS/TEN in setting of HIV