type B drug reaction; drug-induced hypersensitivity syndrome; drug rash with eosinophilia & systemic symptoms (DIHS, DRESS)

Introduction

Unpredictable from the known pharmacology of the drug with no apparent dose-response relationship

Etiology

• pharmaceutical agents causing drug reactions
  • beta-lactam antibiotics (most common)
    • penicillins
    • cephalosporins
      • cephalosporin allergy uncommon
      • penicillin allergy not a risk factor for cefazolin hypersensitivity
    • not mentioned among most common agents as cause of drug hypersensitivity in ref
  • sulfonamides allopurinol, anticonvulsants, minocycline most common
  • late onset (> 72 hours)
    • allopurinol, phenytoin, & dapsone most common
    • carbamazepine
  • peri-operative agents
    • consider latex allergy
    • paralyzing agents
      • succinylcholine
      • tubocurarine
  • insulin (human insulin is NOT free from hypersensitivity reactions)
  • ACE inhibitors
    • maculopapular rash
    • cough
    • angioedema
  • ziprasidone
• hypersensitivity reactions
  • type 1 hypersensitivity
    • immediate-type, immunologic, IgE-mediated
    • urticaria (2nd most common)
    • angioedema
    • anaphylaxis
      • mastocytosis
    • more commonly via IV admnistration
  • type 2 hypersensitivity
    • cytotoxic reactions, > 72 hours after administration
    • penicillin, cephalosporins, sulfonamides, rifampin, quinidine, quinine, salicylamide, isoniazid, chlorpromazine, sulfonylurea
  • type 3 hypersensitivity
    • serum sickness, drug-induced vasculitis
    • exanthematous reactions (?)
    • erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
    • vasculitis
    • fixed drug eruption (?)
  • type 4 hypersensitivity
    • morbilliform exanthematous drug eruption (most common)
    • bullous eruptions (?)
    • Stevens-Johnson syndrome ?
    • lichenoid eruptions (?)
    • photoallergic reactions
  • unknown
    • erythema nodosum
    • exanthematous pustulosis
    • red man syndrome

Epidemiology

• most true drug allergies are type-1 hypersensitivity, IgE-mediated
• may occur at any age, but most common age 20-49 years
• 80-90% of patients labeled as penicillin allergic do not have specific IgE to pencillin determinants & if indicated may be safely given
  • testing fails to confirm penicillin allergy in children with parent-reported penicillin allergy & low-risk symptoms (100% of 100 children)
• 4% of patients undergoing skin testing for pencillin allergy without prior history of allergy will be skin test (IgE) positive
• most patients labeled penicillin-allergic are not penicillin intolerant
  • 70% of patients with penicillin allergy will lose that allergy within 10 years
• allergy to cephalosporin in patient allergic to penicillin
  • 1.1% absolute risk, 10-fold increase in relative risk
  • lack of cross-reactivity between cefazolin & penicillin
    • cefazolin has no cross reactivity with any cephalosporin available in the U.S.
  • relative risk of allergy to sulfonamide same as cephalosporin
• more frequent in fall & winter
• more frequent in patients with dark-skin
• no sex bias

Pathology

• cutaneous disease, eosinophilia, fever & lymphadenopathy leading to multi-organ failure occurring within 8 weeks after introduction of a drug
• beta lactams
  • haptenization of protein complexes
  • major determinant results from reaction of beta-lactam ring with protein complex resulting in the penicilloyl moiety
  • minor determinant result include penicilloate & penilloate moieties
  • antibodies to 2nd & 3rd generation cephalosporins are more likely to be directed at side chains

History

• hypotension, tachycardia, dyspnea

Clinical manifestations

• immediate reactions:
  • develop within 1st hour of therapy
  • signs/symptoms
    • urticaria (74%)
    • rhinitis
    • wheezing
    • anaphylaxis
  • parenteral administration associated with early onset
• accelerated reactions:
  • develop over 1-72 hours after onset of therapy
  • may include urticaria
• late reactions:
  • begin > 72 hours after onset of therapy
  • average onset 21 days after starting medication
    • generally 2-8 weeks after starting medication
    • onset < 2 weeks unlikely
  • signs/symptoms
    • maculopapular eruptions
    • burning skin pain, morbilliform exanthem
    • drug fever
    • hemolytic anemia
    • serum sickness
    • nephritis
    • arthralgia (not a feature)
    • leukopenias
    • erythematous exfoliative dermatitis
    • facial swelling
    • erythema multiforme, Stevens-Johnson syndrome (SJS)
    • mucosal involvement can occur in DRESS, but is less severe than with SJS
    • lymphadenopathy
    • pulmonary crackles (see chest X-ray)

* images

Laboratory

• complete blood count (CBC)
  • may show eosinophilia*
  • may show atypical lymphocytosis*
• may show elevated liver function tests*
• specific IgE antibodies
• serum tryptase (released from mast cells,mastocytosis)
  • elevation occurs within 2 hours & is useful for confirming diagnosis of anaphylaxis
  • baseline serum tryptase can identify patients at high risk for anaphylaxis
• pulse oximetry: SaO2 may be low

* may also be seen with Stevens-Johnson syndrome (SJS) or morbilliform drug eruption

* absence of eosinophilia does not rule out DRESS

Diagnostic procedures

• skin testing
  • rapid & sensitive testing to evaluate true penicillin allergy
  • major determinant
    • penicilloyl polylysine moiety
    • type 2 hypersensitivity
    • cytotoxic reactions > 72 hours after administration
  • penicillin G included for minor determinants
    • reactivity to minor determinants is more predictive of risk of anaphylaxis
    • responsible for type 1 hypersensitivity
    • ref suggests skin testing not available
  • repeat skin testing may be necessary
• RAST & ELISA unable to identify all patients who have a positive skin test to major determinant
• skin biopsy if SJS-TEN suspected
• point-of-care beta-lactam allergy skin testing (pocBLAST)
• oral challenge consisting of 1/10 the standard drug dose followed by full dose 1 hour later with subsequent 2-hour observation safe for low-risk patients

Radiology

• chest X-ray
  • bilateral interstitial infiltrates
  • lower lobe atelectasis

Complications

• labeling a patient with penicillin allergy is associated with
  • longer hospital stays
  • increased antibiotic use
  • use of less safe, less effective, more expensive antibiotics
  • development of more infections with resistant organisms
• delabeling a patient with penicillin allergy associated with cost savings on antibiotics & reduced exposure to broad-spectrum antibiotics
• self-reported penicillin allergy associated with increased risk for surgical site infection
  • less likely to receive cefazolin (12. vs 92%)
  • more likely to receive clindamycin (49 vs 3%), vancomycin (35 vs 3%), gentamicin (24 vs 3%), or fluoroquinolone (7 vs 1%)
• patients whose medical records list a penicillin allergy are at increased risk for MRSA & C difficile colitis
• electronic alerts to avoid cephalosporin use in patients with history of penicillin allergy reduces use of cephalosporins

Differential diagnosis

• Mycoplasma pneumoniae
  • not associated with eosinophilia
• erythema mutiforme
  • suddent appearance
  • sharply demarcated
  • predilection for dorsum of hands, palms & soles, feet, face, elbows, knees, penis (50%) & vulva

Management

• drug hypersensitivity is a severe, life-threatening reaction
  • stop offending agent
  • systemic glucocorticoids
  • antihistamines for pruritus
• avoid offending agent if history suggests true allergy (see history)
  • < 10% of patients labeled penicillin-allergic are truly allergic to penicillin
  • cefazolin allergy was rare in those reporting penicillin allergy
• hemolytic anemia, thrombocytopenia, Stevens-Johnson syndrome & exfoliative dermatitis preclude re-administration of offending agent
• administration of beta lactam antibiotic to skin-test negative patients will not preclude development of non-IgE reactions such as most non urticarial & maculopapular rashes (not life-threatening)
• history penicillin allergy characterized by mild non-puritic rash is not a contraindication to use of cephalosporin or 3rd generation penicillin
• beta-lactam antibiotic may be safely continued with monitoring with most non urticarial & maculopapular rashes
• history of allergy to 1 beta-lactam antibiotic is not a reason to avoid all beta-lactam antibiotics
  • in patients with gram-negative sepsis, benefits of appropriate empirical antibacterial therapy outweigh risk for allergic reactions
• preferred beta-lactam therapy may reduce adverse outcomes in patients with reported beta-lactam allergy
• inadvertant administration of penicillin to a skin-test positive individual results in allergic reactions in 67%
• low risk pencillin allergy defined as benign, immediate, or delayed rash (without angioedema, mucosal ulceration, or systemic symptoms) > 1 year prior
• select alternative pharmaceutical agent
  • avoid cephalosporin in patients with penicillin allergy
    • cephalosporin reaction occurs in 50% of patients who are allergic to penicillin
    • skin testing for penicillin does not predict cephalosporin allergy
  • cefazolin allergy is rare in those reporting penicillin allergy
  • avoid carbapenem in patients with penicillin allergy
  • caution with sulfonamide in patients with penicillin allergy
• skin testing if penicillin is necessary for life-threatening infection
• oral provocation challenge to amoxicillin safe & more accurate than skin testing
• Pen-Fast tool predicts likelihood of significant allergic response
• drug desensitization (protocol for penicillin desensitization (ref)

More general terms

• adverse drug reaction (ADR)

More specific terms

• drug eruption with eosinophilia & systemic symptoms
• drug eruption; drug rash
• sulfa allergy

Additional terms

• anaphylactoid reaction
• anaphylaxis
• antigen desensitization; allergen immunotherapy
• hypersensitivity
• PEN-FAST Penicillin Allergy decision tool
• penicilloate moiety (minor determinant)
• penicilloyl moiety (major determinant)

Patient information

drug rash with eosinophilia & systemic symptoms (DRESS) patient information