How should I evaluate and test a patient with a suspected drug allergy?

Evaluating and Testing a Patient with Suspected Drug Allergy

Start with a Detailed Allergy History

The cornerstone of drug allergy evaluation is obtaining a comprehensive allergy history that documents the specific drug name, timing of reaction onset relative to drug administration, nature and severity of symptoms, duration of symptoms, and whether the reaction was observed by healthcare personnel. 1

Document these critical elements:

• Exact drug name and dose - patients who cannot recall the specific drug name have a 98.4% negative predictive value for true IgE-mediated allergy 1
• Timing: Reactions within 1 hour of first dose suggest IgE-mediated mechanism; delayed reactions (>24 hours) suggest T-cell mediated mechanisms 1
• Symptom pattern: Single organ system (non-severe) versus multi-system involvement (severe) 1
• Time elapsed since reaction: Reactions >5 years ago for immediate-type or >1 year for delayed-type have significantly lower risk of true allergy 1
• Healthcare observation: Reactions documented by medical personnel are more likely to represent true allergy 1

Classify Reaction Severity Immediately

Severe reactions include anaphylaxis (respiratory compromise, hypotension, multi-organ involvement), Stevens-Johnson syndrome/toxic epidermal necrolysis, DRESS syndrome, acute generalized exanthematous pustulosis, or organ-specific reactions like hemolytic anemia or acute interstitial nephritis. 1

Non-severe reactions involve single organ systems: isolated urticaria, maculopapular rash without organ involvement, or mild gastrointestinal symptoms. 1

Blood Testing During Acute Reactions

For suspected anaphylaxis, draw serum tryptase as soon as feasible during resuscitation, then at 1-2 hours after symptom onset, and obtain a baseline sample at 24 hours or during convalescence. 1, 2 An increase above 1.2 × baseline + 2 mg/L confirms mast cell degranulation. 1, 3

Draw allergen-specific IgE during the acute reaction or shortly afterward, but repeat at 4-6 weeks if initially negative, as IgE antibodies may be temporarily consumed during the acute reaction. 4, 2 However, recognize that approximately 23.6% of allergic reactions are non-IgE-mediated and will have negative blood tests despite true clinical allergy. 4, 2

Referral Criteria for Specialist Allergy Testing

Refer patients to specialist allergy/immunology centers for skin testing and drug provocation testing if they have: 1

• Unexplained cardiac arrest during drug administration 1
• Unexplained hypotension requiring treatment (>30 mmHg mean arterial pressure decrease) 1
• Severe or resistant bronchospasm with oxygen desaturation 1
• Widespread rash, flushing, urticaria, or angioedema 1
• Any severe immediate-type reaction regardless of time elapsed 1
• Non-severe immediate-type reactions that occurred <5 years ago 1
• Suspected severe delayed-type reactions (never re-expose without specialist evaluation) 1

Skin Testing Protocol (Performed by Specialists)

Skin testing should be performed as soon as the patient has clinically recovered and antihistamine effects have worn off, using both skin prick tests and intradermal tests with appropriate positive (histamine) and negative (saline) controls. 1, 5

For beta-lactam antibiotics, test at validated non-irritating concentrations: 1

• Cefazolin: 200 mg/mL (prick), 2.0 mg/mL and 20 mg/mL (intradermal) 1
• Ceftriaxone: 100 mg/mL (prick), 1 mg/mL and 10 mg/mL (intradermal) 1
• Cefepime: 2 mg/mL (both prick and intradermal, as 20 mg/mL is irritating) 1

Skin testing is most reliable for latex, beta-lactam antibiotics, neuromuscular blocking agents, chlorhexidine, and protamine. 1 Skin tests are not useful for NSAIDs, dextrans, or iodinated contrast media because reactions are typically non-IgE-mediated. 1

Critical Interpretation Pitfalls to Avoid

Never diagnose drug allergy based solely on positive specific IgE or skin testing without clinical correlation - this is the most common diagnostic error. 4, 3, 2 Positive tests indicate sensitization, not clinical allergy; many patients with positive tests tolerate the drug without symptoms. 4, 3

A negative skin test does not rule out allergy - sensitivity varies by drug and timing of testing, and some reactions are not IgE-mediated. 5

Low-Risk Patients Who Can Avoid Testing

Remove the allergy label directly without testing if: 1

• The non-severe, skin-only reaction occurred in remote childhood/adolescence 1
• The patient cannot recall any details of the reaction 1
• Non-severe immediate-type reactions occurred >5 years ago (can receive therapeutic dose in controlled setting) 1
• Non-severe delayed-type reactions occurred >1 year ago 1

Drug Provocation Testing (Final Step)

When skin tests and specific IgE are negative or unavailable, drug provocation testing (graded challenge) is the definitive test to confirm tolerance. 1 This involves gradual administration of increasing doses in a monitored setting and is particularly important for drugs where IgE-mediated mechanisms are unlikely (opioids, NSAIDs). 1

For low-risk patients (negative history features, remote reactions, non-severe symptoms), direct drug provocation without prior skin testing is appropriate. 6, 7

Beta-Lactam Cross-Reactivity Assessment

Cross-reactivity between penicillins and cephalosporins is primarily determined by R1 side chain similarity, not the beta-lactam ring itself. 1 Cefazolin has a unique side chain and shows very low cross-reactivity with penicillins despite being a first-generation cephalosporin. 1

For patients with confirmed penicillin allergy, cephalosporins with dissimilar R1 side chains (cefazolin, cefpodoxime, ceftriaxone, ceftazidime, cefepime) have only 2.11% cross-reactivity risk. 1 Aminocephalosporins (cephalexin, cefadroxil) sharing R1 side chains with aminopenicillins have 16.45% cross-reactivity. 1