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A. Types [1]navigator

  1. Erythema Multiforme Major [2,5]
    1. EMM - mild
    2. Stevens-Johnsons Syndrome (SJS, moderate severity)
    3. Toxic Epidermal Necrolysis (TEN; medical emergency)
  2. Hypersensitivity Reaction ± Vasculitis
  3. Erythroderma
  4. Serum Sickness and Related Reactions
  5. Warfarin-Induced Skin Necrosis
  6. Angioedema / Urticaria

B. Drugs Commonly Associated with Severe Cutaneous Reactionsnavigator

  1. Sulfa (Thiol) Agents
    1. Sulfonamid eantibiotics - TMP/SFX (Bactrim®, Septra®) [3], sulfadiazine, dapsone, others
    2. Less commonly sulfonylureas, celecoxib, others
    3. Thiazide Diuretics
    4. Loop Diuretics - furosemide (Lasix®), bumetanide (Bumex®)
    5. Captopril (Capoten®) - this is the only commonly used ACE inhibitor with a sulfur group
    6. Piroxicam (Feldene®, a NSAID)
    7. Penicillamine (Cuprimine®)
  2. Anticonvulsants [13]
    1. Phenytoin (Dilantin®)
    2. Carbamazepine (Tegretol®) [13,14,] - risk of SJS >3/10,000 whites and >30/10,000 Asians (mainly Chinese) with new users
    3. Valproate (Depokote®)
  3. Penicilllins (less commonly cephalosporins) [3]
  4. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
  5. Allopurinol (Zyloprim®) - dose dependent and independent forms
  6. Antiretroviral Agents (see below)
  7. Overall, antibiotics responsible for 55% of hospitalized patients' cutaneous drug reactions [3]

C. Erythema Multiforme Major and TEN [1,5,8] navigator

  1. Erythema Multiforme (EM)
    1. EM minor - target lesions on body without mucous membrane involvement
    2. EM major - also called Stevens Johnson Syndrome (SJS); mucous membranes involved
    3. Relationship of Erythema multiforme major and TEN is controversial
    4. Severe forms of EM major/SJS can evolve into extensive epidermolysis as in TEN
    5. However, detailed evaluation of EM major versus TEN show distinct differences
  2. Purpuric macules and blisters usually on trunk and face
    1. Mucous membranes involved ~90% of patients
    2. Immunofluorescence of biopsy specimens non-specific with immune complex deposition
    3. CD8+ T cell infiltration may be seen
    4. Biopsy is usually done to exclude other diagnosis
  3. Strongly associated with drug reactions [8]
    1. May be related to metabolism of various drugs
    2. Production of toxic metabolites or inability to detoxify other metabolites
    3. Sulfa drugs, dilantin, carbamazepine [13,], barbiturates, allopurinol, oxicam NSAIDs
    4. Many other drugs are associated with limited number of cases
    5. Risk of SJS >3/10,000 whites and >30/10,000 Asians (mainly Chinese) with carbamazepine
    6. Association of SJS and carbamazepine in Asians found with HLA-B*1502 and genetic testing for this allele is recommended for all Asian patients before initiation carbamazepine []
    7. HIV infected persons at increased risk for development of disease
    8. Idiopathic cases do occur and are not infrequent
    9. Herpes simplex virus and mycoplasma are associated with EM minor and major
    10. These idiopathic reactions may be linked to differential drug metabolism
    11. Glucocorticoids are often recommended, particularly early in course
    12. Corneal epithelial stem-cell transplants may be effective for severe corneal damage [12]
  4. Fever and flu-like illness can occur in EM major and always occurs in TEN
  5. TEN [1,8,14]
    1. SJS involves mucous membrane but limited body involvement
    2. TEN has detachment >30% of body with positive Nikolsky's Sign
    3. TEN behaves like extensive superficial burns
    4. TEN also has conjuctivits (32%), pharyngitis (25%), and pruritus (28%)
    5. In TEN, mucous membranes are affected 1-3 days prior to skin sloughing
    6. Confluent epidermal necrosis occurs with dermal infiltrates
    7. Helper CD4+ and epidermal CD8+ T lymphocytes found
    8. Tumor necrosis factor alpha (TNFa) has been implicated in TEN pathogenesis
    9. Antibody deposits and complement activation are rare
    10. Mortality for TEN >30% (compare with SJS of <5%)
  6. Treatmen of TEN
    1. TEN is best treated as burn injuries in a specialized burn unit [8]
    2. Mechanical ventilation is often required (with permissive hypercapnea)
    3. Skin transplants may be required
    4. Glucocorticoids are not recommended
    5. Thalidomide may exacerbate TEN, probably by increasing TNFa production [11]
  7. Differential Diagnosis
    1. Other skin disease with exfoliation, blistering, desquamation
    2. Exfoliative Dermatitis
    3. Staphylococcal scalded skin syndrome
    4. Acute exanthematous pustulosis
    5. Toxic shock syndromes

D. Serum Sickness (Like) Reactions navigator

  1. Hypersensitivity drug reactions
  2. Distinguish between serum sickness and serum sickness-like reactions
  3. Serum Sickness
    1. Severe idiosyncratic reaction mediated by immune complexes
    2. Clinical syndrome with fever, lymphadenopathy, arthralgias
    3. Cutaneous eruptions, gastrointestinal disturbances, mailaise
    4. Commonly with proteinuria but not glomerulonephritis
    5. Immune complexes bind tissues and activate complement
    6. Usually caused by administration of foreign proteins such as antithymocyte globulin
  4. Serum Sickness Like-Reactions
    1. Fever and skin rash (usually urticarial) with arthralgias
    2. Usually occurs 1-4 weeks after drug exposure
    3. Lymphadenopathy and eosinophilia may also be present
    4. Immune complexes, complement activation, vasculitis, and renal disease NOT present
    5. Thus, must rule out hepatitis, renal disease, inflammatory arthritis
    6. Phenytoin, carbamazepine, and phenobarbital most often implicated
    7. Also occurs with cefaclor (mainly in children), with cefprozil and minocycline
    8. Systemic glucocorticoids at least 0.5mg/kg are used unless disease is purely cutaneous
    9. Relapses may occur as glucocorticoids are tapered

E. Hypersensitivity Vasculitis [1,2] navigator

  1. Small vessel vasculitis
  2. Related to serum sickness, cuteaneous leukocytoclastic vasculitis, and HSP
  3. Associations
    1. Drugs
    2. Infections, other exposures
    3. Many cases are idiopathic
  4. Erythema, purpura, hermorrhagic blisters, urticarial vasculitis, ulcers and necrosis
  5. Renal function should be monitored closely
  6. Laboratory
    1. Elevated erythrocyte sedimentation rate (ESR)
    2. C3 and C4 levels are typically reduced in hypersensitivity vasculitis
    3. Patients may become ANA positive
    4. Urinalysis should be obtained
    5. Consider obtaining ANCA levels (differential diagnostic)
  7. Pathology of Skin Lesions
    1. Biopsy shows leukocytoclastic vasculitis, sometimes with eosinophils
    2. IgA deposition occurs in HSP and hypersensitivity vasculitis
  8. Differential Diagnosis
    1. Infection
    2. Henoch-Schonlein Purpura (HSP)
    3. Cryoglobulinemia
    4. Serum Sickness
    5. ANCA Associated Diseases: polyarteritis nodosa, Wegener's Granulomatosis
  9. Drugs Associated with Hypersensitivity Vasculitis
    1. Allopurinol
    2. Antibiotics: Penicillin, aminopenicillins, sulfonamides
    3. Thiazides
    4. Hydantoins
    5. Prophylthiouracil
    6. Pyrazolones
  10. Treatment [6]
    1. Stop suspected drug and provide supportive therapy (fluids, pain control)
    2. NSAIDs may be used for joint symptoms, but caution with renal impairment
    3. Glucocorticoids used for serious reactions, 0.5-2mg/kg per day
    4. These include renal disease, severe skin disease, pericarditis, abdominal pain

F. Cutaneous Reactions in HIV+ Patients [9] navigator

  1. Usually manifests as morbilliform or maculopapular rash
  2. Fever often precedes rash
  3. Fatigue and myalgias
  4. Mucosal ulceration
  5. Features in <5% of Cases
    1. Erythema multiforme major (SJS or TEN)
    2. Anicteric hepatitis
    3. ypotension
    4. Acute interstitial nephritis
    5. Acute interstitial pneumonitis
  6. Drugs Typically Implicated (% indicence with specific drug)
    1. Nevirapine (17%)
    2. Delavirdine (18%)
    3. Efavirenz (10%)
    4. Amprenavir (20%)
    5. Abacavir (3%)

G. Photosensitivity Reactions [4] navigator

  1. Types
    1. Photoxic - nonimmunologic; erythema, pain, edema; burn care required
    2. Photoallergic - immunologic; papulovesicular eruption, pruritus, dermatitis; allergy
    3. Drug Induced Lupus Erythematosus - variant of photoallergic reactions (rarely have rash)
  2. Common Photoxic Reactions
    1. Amiodarone (Cordarone®)
    2. Tetracyclines
    3. Psoralens
    4. Some phenothiazines (such as chlorpromazine)
    5. Sulfanylamide
  3. Common Photoallergic Reactions
    1. Sulfonamides and Sulfonylureas
    2. Thiazide diuretics
    3. Phenothiazines
    4. Nonsteroidal Anti-Inflammatory Agents (NSAIDs)
    5. Griseofulvin
  4. Both Phototoxic and Photoallergic reactions can occur together for some drugs
  5. Drug Induced Lupus Erythematosus (DILE)
    1. Frequently with: procainamide, quinidine, hydralazine, penicillamine
    2. Less commonly: isoniazid, propylthiouracil (PTU), chlorpromazine, minocycline
    3. Also with: alpha-methyldopa, phenytoin, cimetidine, griseofulvin, psoralen-UVA
    4. Also with sulfa agents: hydrochlorothiazide, sulfonamides
    5. Presents with serositis, rash, homogeneous high ANA, anti-histone Abs
    6. Severe SLE manifestations are extremely rare (nephritis, CNS) in drug-induced lupus
    7. Treatment: stop offending agent, short term glucocorticoid therapy for symptoms only

H. Antibiotic Allergies [15] navigator

  1. Most allergic reactions to antibiotics are cutaneous
    1. ~2% of cutaneous drug reactions in hospitalized patients due to antibiotics
    2. Prevalence also estimated as 2 cases per 1000 hospitalized patients per year
  2. Most reactions are Type IV delayed and Type I immediate hypersensitivities
  3. Most common antibiotics associated with ADRs:
    1. Amoxicillin
    2. Trimethoprim-Sulfamethoxazole (TMP-SMX)
    3. Ampicillin
    4. Less common: cephalosporins, macrolides, fluoroquinolones, tetracyclines, vancomycin
  4. Most common skin reactions
    1. Maculopupaular skin eruptions
    2. Urticaria
    3. Pruritus
  5. Usually days to weeks after initial exposure: "sensitization"
  6. On secondary exposure, reaction is within minutes to hours
    1. Secondary exposure may include fever, eosinophilia, other extracutaneous symptoms
    2. Hypotension, bronchospasm, frank anaphylaxis can occur
  7. Increased Risk of Allergic Reactions
    1. HIV Infection
    2. Cystic fibrosis
    3. Infectious mononucleosis
  8. Diagnosis
    1. Skin testing - allergen specific IgE antibodies (mainly for pencillin allergies)
    2. Skin testing not useful for non-IgE drug reactions
    3. Lymphocyte based testing for T cell reactive allergens approved in Europe, not in USA
  9. Treatment and Desensitization
    1. Acute reactions: Supportive, Antihistamines, Glucocorticoids
    2. Desensitization: administer increasing amounts of antibiotics of a period of hours until therapeutic dose is obtained
    3. Desensitization requires continuous presence of drug
    4. Desensitization successful in ~75% of IgE-mediated drug allergies
    5. Patients with sulfonamide antibiotic allergies do not cross react with other sulfur containing drugs such as celecoxib, thiazides, sulfonylureas

References navigator

  1. deShazo RD and Kemp SF. 1997. JAMA. 278(22):1895 abstract
  2. Thaler SJ and Bailey EM. 1996. NEJM. 334(19):1254 (Case Report)
  3. Gruchalla RS and Pirmohamed M. 2006. NEJM. 354(6):601 abstract
  4. Mammen L and Schmidt CP. 1995. Am Fam Phys. 52(2):575 abstract
  5. Knowles SR, Uetrecht J, Shear NH. 2000. Lancet. 356(9241):1587 abstract
  6. Martinez-Taboada VM, Blanco R, Garcia-Fuentes M, Valverde V. 1997. Am J Med. 102(2):186 abstract
  7. Becker DS. 1998. Lancet. 351(9113):1417 abstract
  8. Carr A and Cooper DA. 2000. Lancet. 356(9239):1423 abstract
  9. Vassileva SG, Mateev G, Parisch LC. 1998. Arch Intern Med. 153(18):1993
  10. Wolkenstein P, Latarjet J, Roujeau JC, et al. 1998. Lancet. 352(9140):1586 abstract
  11. Tsubota K, Satake Y, Kaido M, et al. 1999. NEJM. 340(22):1697 abstract
  12. Kaufman DW and Shapiro S. 2000. Lancet. 356(9138):1339
  13. Sheridan RL, Liu V, Anupindi S. 2005. NEJM. 353(19):2057 (Case Record) abstract
  14. Gruchalla RS and Pirmohamed M. 2006. NEJM. 354(6):601 abstract
  15. Genetic Testing for Carbamazepine Induced Stevens-Johnson Syndrome. 2008. Med Let. 50(1284):32