What is the best approach to diagnose the cause of recurrent allergic reactions in a hospitalized patient with no known allergy, who has been treated with epinephrine (EpiPen), intravenous (IV) steroids, and antihistamines, but continues to experience symptoms?

Diagnostic Approach to Recurrent Allergic Reactions in Hospitalized Patients

In a hospitalized patient with recurrent hives despite epinephrine, IV steroids, and antihistamines, immediately discontinue all non-essential medications and systematically eliminate potential hospital-based allergens while obtaining serum tryptase levels and referring to an allergist for comprehensive diagnostic testing. 1

Immediate Actions to Identify the Trigger

Stop All Non-Essential Exposures

• Discontinue all medications that are not immediately life-sustaining, as drugs are among the most common triggers of anaphylaxis in hospitalized patients 1, 2
• Review and eliminate potential culprits including:
  • Antibiotics (especially beta-lactams like penicillins and cephalosporins) 3
  • NSAIDs and other analgesics
  • IV contrast agents if recently administered
  • Any newly introduced medications in the past 72 hours 1
• Document all suspected allergens prominently in the medical record to prevent re-exposure 3

Obtain Diagnostic Laboratory Testing

• Collect serum tryptase levels at multiple time points: one sample immediately during or within 1 hour of symptoms, a second sample 2-4 hours after symptom onset, and a baseline sample 24 hours or later for comparison 1, 2
• Tryptase elevation reflects mast cell degranulation and helps confirm the diagnosis when clinical presentation is unclear 2
• Elevated acute tryptase compared to baseline supports IgE-mediated anaphylaxis 1

Systematic Environmental Assessment

Identify Hospital-Based Allergens

• Examine all materials in direct patient contact: latex gloves, adhesives, antiseptics (chlorhexidine, iodine), tape, wound dressings 1
• Review cleaning products and disinfectants used in the patient's room 1
• Consider food allergens if the patient is eating, including hidden ingredients in hospital meals 1, 2
• Evaluate IV fluids and additives, including preservatives like benzyl alcohol 4

Document Temporal Patterns

• Record the exact timing of each reaction in relation to medications, procedures, meals, and environmental changes 1
• Note whether reactions occur at consistent times of day or in relation to specific activities 1
• This temporal correlation often reveals the trigger even before formal testing 2

Escalate Treatment for Persistent Symptoms

Optimize Antihistamine Therapy

• Increase H1 antihistamine dosing up to 4 times the standard dose (e.g., cetirizine 40 mg daily) if hives persist despite standard dosing 3
• Add H2 antihistamine therapy (ranitidine 50 mg IV or equivalent) as combined H1/H2 blockade is superior to either alone 3, 5
• Continue antihistamines around-the-clock rather than as-needed to maintain steady therapeutic levels 3

Consider Continuous Epinephrine Infusion

• For persistent Grade I severe allergic reactions unresponsive to intermittent intramuscular epinephrine, consider continuous low-dose IV epinephrine infusion (0.05-0.1 mcg/kg/min) under continuous cardiac monitoring 1, 6
• This approach is safe and effective for preventing biphasic or worsening reactions when symptoms persist despite standard treatment 6
• Monitor heart rate, blood pressure, and cardiac rhythm continuously during infusion 1, 6

Definitive Allergy Evaluation

Urgent Allergist Consultation

• Request immediate allergist consultation while the patient is still hospitalized and symptomatic 1
• The allergist can perform skin testing or in vitro testing for suspected allergens once acute symptoms are controlled 1
• Consultation is particularly critical when the diagnosis is doubtful, symptoms are recurrent, or the trigger remains unidentified 1

Post-Acute Diagnostic Testing

• Skin prick testing and intradermal testing should be performed 4-6 weeks after the acute reaction to allow mast cell recovery 1
• Serum-specific IgE testing can identify sensitization to suspected allergens including drugs, foods, and latex 1
• Drug provocation testing may be necessary under controlled conditions to definitively identify or exclude medication triggers 1

Critical Management Considerations

Observation and Monitoring

• Observe the patient in a monitored setting for a minimum of 6 hours after symptom resolution, or longer if severe features were present or multiple epinephrine doses were required 1
• Risk of biphasic reactions (recurrence without re-exposure) is highest in patients requiring multiple epinephrine doses, those with severe initial reactions, and those with unknown triggers 1, 5
• Continue monitoring vital signs and watch for recurrent symptoms until complete resolution 1

Common Pitfalls to Avoid

• Do not assume steroids and antihistamines alone will prevent recurrence—they do not reliably prevent biphasic reactions and should never replace epinephrine for anaphylaxis 1, 7
• Do not discharge the patient without identifying the trigger, as re-exposure in an unmonitored setting could be fatal 1
• Do not continue suspected allergen exposure while waiting for allergy testing results 1, 3
• Avoid administering epinephrine IV bolus outside of cardiac arrest without appropriate monitoring, as this can cause dangerous arrhythmias 1, 8

Discharge Planning

• Prescribe an epinephrine auto-injector and provide hands-on training in its use before discharge 1
• Provide written emergency action plan with clear instructions on when to use epinephrine and seek emergency care 3
• Schedule outpatient allergist follow-up within 1-2 weeks for comprehensive evaluation 1
• Continue oral antihistamines for 2-3 days after discharge to prevent late-phase reactions 3