Drug hypersensitivity reactions

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Drug hypersensitivity reactions (DHR) are a group of adverse drug effects that resemble an allergy. They are relatively common, and may be classified by underlying pathophysiology (allergic DHR vs nonallergic DHR), or by onset of symptoms (immediate DHR vs non-immediate DHR). Clinical features can vary widely. Diagnosis is typically clinical but there are several methods available for confirmatory testing. Management depends on the underlying mechanism and clinical syndrome suspected, but all patients should stop the suspected offending drug and be provided with supportive care. Severe cutaneous adverse reactions (SCAR) refers to a group of four type IV DHRs that are associated with significant morbidity and mortality, including DRESS, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), all of which require prompt evaluation and management.

See also “Hypersensitivity reactions.”

• 15% of all adverse drug reactions can be attributed to drug hypersensitivity reactions. ^[2]
• Affect > 7% of the general population ^[2]

Epidemiological data refers to the US, unless otherwise specified.

Most DHRs are classified by either mechanism or clinical features; mixed DHRs are ones that do not fit into a single category. ^[2][3]

• Mechanism: allergic DHR (i.e., drug allergy) or nonallergic DHR
• Clinical features
  • Immediate DHRs
    • Mast-cell mediated (IgE-dependent or IgE-independent) ^[3]
    • Onset typically within 1 hour of exposure
  • Nonimmediate DHRs
    • Typically T-cell mediated; can also be non-immune mediated
    • Onset typically > 1 hour after exposure

Immediate DHRs

• Onset: typically occurs within 1 hour of exposure.
• Commonly associated medications ^[4]
  • β-lactam antibiotics
  • Neuromuscular blockers
  • Aspirin
  • NSAIDs
  • Chemotherapeutic agents
  • Vancomycin
  • Morphine
  • Radiocontrast media
• Clinical features: can mimic those of viral infections, although fever is typically absent. ^[2][5][6]
  • Skin/mucosal
    • Urticaria
    • Angioedema
    • Conjunctivitis
    • Flushing
  • Respiratory
    • Bronchospasm
    • Rhinitis
  • Gastrointestinal
    • Nausea
    • Vomiting
    • Diarrhea
    • Abdominal cramping
  • Cardiovascular
    • Hypotension
    • Tachycardia
  • Severe forms manifest as anaphylaxis and anaphylactoid reactions.

Nonimmediate DHRs

• Onset: typically > 1 hour after exposure to the culprit drug
• Commonly associated medications:
  • Antibiotics
  • Anticonvulsants
  • Allopurinol
  • NSAIDs
• Clinical features: typically heterogeneous, ranging from skin reactions to severe extracutaneous syndromes
  • Skin reactions ^[2][5][6]
    • Severe cutaneous adverse reactions
    • Benign cutaneous reactions, e.g.:
      • Allergic contact dermatitis
      • Exanthematous drug eruption
      • Fixed drug eruption
      • Photoallergic dermatitis
  • Extracutaneous syndromes, e.g.:
    • Drug-induced lupus erythematosus
    • Granulomatous drug reaction ^[9]
    • Serum sickness or serum sickness-like reaction
    • Tubulointerstitial nephritis
    • Drug-induced hemolytic anemia
    • Drug-induced liver injury
    • Drug-induced neutropenia ^[10][11]
    • Hypersensitivity pneumonitis ^[12][13]

Immediate DHRs often resemble viral infections; nonimmediate DHRs commonly manifest as drug-induced skin reactions but can cause a variety of syndromes. ^[14]

Diagnosis can often be made on history and clinical findings but occasionally more advanced testing is required to confirm the diagnosis. ^[2]

Confirmatory testing ^[2][5]

• Indications ^[2][5]
  • Clinical history consistent with DHR PLUS a suspected drug that is:
    • Commonly used (e.g., β-lactam antibiotics, NSAIDs)
    • OR required based on individual patient factors (e.g., infection, malignancy)
  • History of severe DHR (e.g., anaphylaxis)
• Testing modalities
  • In vivo allergy skin tests: Obtain if initial DHR was not severe or life-threatening.
  • Hypersensitivity blood tests: Consider if initial DHR was severe or life-threatening. ^[2]
  • Graded challenge test (i.e., drug provocation test): Consider referral to rule out DHR in select cases.

When indicated, confirmatory testing should be performed 4–6 weeks after the resolution of a suspected drug reaction to reduce the likelihood of false positive or false negative results.

Graded challenge test ^[2][5][15]

• Description
  • The patient is exposed to increasing amounts of the drug until a full dose has been administered or an HSR occurs.
  • If the drug is tolerated, the patient does not have a DHR.
  • Does not distinguish between allergic and nonallergic reactions
• Indications
  • To rule out DHR in individuals with an inconsistent clinical history or inconclusive evaluation
  • To assess safety in a patient who requires a drug that is related to a known or suspected DHR
• Contraindications
  • Absolute: life-threatening or severe reactions
  • Relative
    • History of anaphylaxis
    • Pregnancy or critical illness

A graded challenge test does not induce drug tolerance and should only be used to demonstrate that a drug is safe for use in patients with a low likelihood of a true drug HSR.

A graded challenge test should only be performed by trained staff with access to resuscitative equipment.

General principles ^[2][5][14]

Management of DHRs varies depending on the underlying etiology and resulting syndrome.

• Life-threatening condition: Provide emergency resuscitation as needed.
  • See “Acute management checklist for anaphylaxis.”
  • See “Acute management checklist for angioedema.”
• Perform a thorough clinical evaluation.
  • Review the onset of clinical features relative to the timing of consumption of medications.
  • Complete skin examination, including mucus membranes
  • Diagnostic studies guided by clinical suspicion
• Identify any red flags for SCAR.
• Stop potential offending drug.
• Start supportive care.
• Consider referral to an allergist for confirmatory testing and/or induction of drug tolerance.

Incorrectly labeling a patient as having drug allergies can lead to avoidance of essential medications, use of less effective or overly broad alternative medications (e.g., antibiotics), and unnecessary desensitization procedures. ^[14]

Supportive care

• Pruritus: consider antihistamine (e.g., cetirizine)
• Systemic or topical glucocorticoids: See “Indications for glucocorticoid therapy.”
• Wheezing: consider bronchodilators (e.g., albuterol; see “Acute asthma treatment”)
• Wound management (see “Treatment” in “Burns”)

Induction of drug tolerance (drug desensitization) ^[5]

See “Allergen immunotherapy” for more detailed information.

• Goal: to enable safe administration of a drug through modification of the patient's immune response
• Indication: offending drug is essential and no satisfactory alternatives exist
• Contraindications: history of severe non-IgE-mediated reaction; history of ACEI angioedema
• Method: administration of incrementally increasing doses of the offending drug
• Outcome: temporary drug tolerance

Prevention of subsequent episodes

• Drug avoidance
• Premedication with antihistamines, glucocorticoids is mainly thought to be helpful for nonallergic DHRs. ^[2]

Contrast allergy premedication ^[16]

• Indication: individuals at high risk for severe repeat DHRs (e.g., anaphylaxis) to radiocontrast media
• Contraindication: history of severe reactions (e.g., SJS/TEN, DRESS) after radiocontrast media
• Example regimen
  • Prednisone (off-label) ^[17]
  • PLUS diphenhydramine (off-label) ^[17]

DHR to contrast can be immediate (IgE-mediated or nonimmunologic) or nonimmediate (T-cell mediated). ^[16]

Severe cutaneous adverse reactions (SCAR)

Definition

A group of four type IV DHRs associated with significant morbidity and mortality: ^[18][19]

• DRESS
• Stevens-Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)
• Acute generalized exanthematous pustulosis (AGEP)

Red flags for SCARs ^[20]

• Clinical features
  • Fever
  • Lymphadenopathy
  • Bullous/pustular lesions
  • Mucosal involvement
  • Positive Nikolsky sign
• Laboratory studies
  • Altered CBC
  • Transaminitis
  • Increased creatinine and/or active urine sediment

Differential diagnosis

See “Overview of blistering skin diseases” and “Rash.”

Management ^[20]

• Identify and discontinue the offending agent (consider all medications started within the last 8 weeks).
• Supportive care (e.g., IV fluid therapy, enteral nutrition, pain management, VTE prophylaxis)
• Prophylactic antibiotics not routinely recommended. ^[20]
• Consider admission to a burn unit or ICU for management of severe cutaneous adverse reactions (SCARs).

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