What is biphasic reaction anaphylaxis?

Biphasic Reaction Anaphylaxis: Definition, Risk Factors, and Management

Biphasic anaphylaxis is a well-recognized complication defined as recurrent anaphylactic symptoms after complete resolution of the initial reaction, occurring between 1 and 78 hours after the initial anaphylactic event, without re-exposure to the trigger. 1

Clinical Characteristics

Biphasic reactions have several key features:

• Occurs after complete resolution of initial anaphylactic symptoms
• Typically happens within 24 hours, but can occur up to 78 hours later
• Must be differentiated from persistent anaphylaxis that doesn't fully resolve
• Requires no additional exposure to the triggering allergen

Contemporary studies using standardized diagnostic criteria show biphasic reactions occur in approximately 4-5% of anaphylaxis cases (range 0.18-14.7%) 1, which is lower than older estimates of up to 20%.

Risk Factors for Biphasic Reactions

Several factors increase the risk of developing biphasic anaphylaxis:

• Severe initial anaphylactic reaction, especially with hypotension (OR 2.18; 95% CI, 1.14-4.15) 1, 2
• Requiring multiple doses of epinephrine during the initial reaction 1, 3
• Delayed administration of epinephrine (60-190 minutes after symptom onset) 3, 4
• Unknown anaphylaxis trigger (OR 2.6; 95% CI, 1.1-6.2) 2
• History of prior anaphylaxis (OR 2.6; 95% CI, 1.1-6.4) 2
• Specific symptoms during initial reaction including diarrhea (OR 4.5; 95% CI, 1.4-14.0) and wheezing (OR 2.6; 95% CI, 1.4-8.9) 2
• History of drug anaphylaxis (OR 14.3; 95% CI, 2.4-85.8) 5

Food-triggered anaphylaxis appears to have a lower risk of biphasic reactions (OR 0.62; 95% CI, 0.4-0.94) compared to other triggers 1.

Clinical Severity and Timing

Important clinical characteristics of biphasic reactions include:

• Biphasic reactions are typically less severe than the initial reaction 1
• The median time between resolution of initial symptoms and onset of biphasic reaction is approximately 7-15 hours 2, 5
• The timing can vary widely, from as little as 1 hour to as much as 72 hours 2, 3

Management Considerations

Observation Period

The optimal observation period remains controversial:

• Studies suggest a 1-hour observation period has a 95% negative predictive value for biphasic reactions 1
• Extended observation (≥6 hours) increases the negative predictive value to 97.3% 1
• For patients with resolved non-severe anaphylaxis who had prompt response to epinephrine and have reliable access to medical care, a 1-hour observation may be reasonable 1
• Extended observation is appropriate for patients with:
  • Severe initial anaphylaxis
  • Requirement for multiple doses of epinephrine
  • Significant comorbidities increasing risk for fatal anaphylaxis 1

Treatment of Biphasic Reactions

• Treatment for biphasic reactions is the same as for the initial anaphylactic reaction 1
• Prompt administration of epinephrine is crucial 6
• No studies have systematically evaluated specific therapies for biphasic reactions 1
• The role of corticosteroids in preventing biphasic reactions remains controversial, with insufficient evidence to recommend their routine use 7

Patient Education

All patients should receive:

• Prescription for self-injectable epinephrine
• Education on how and when to use epinephrine
• Information about the risk of biphasic reactions
• Guidance on trigger avoidance
• Referral for follow-up care with an allergist 1, 8

Important Clinical Pitfalls

• Biphasic reactions can be easily missed if patients are discharged too early
• Neurological symptoms like facial tingling and blurry vision may be the only manifestations of anaphylaxis in 10-20% of cases, with no cutaneous signs 8
• Delayed epinephrine administration is associated with increased mortality and higher risk of biphasic reactions 8, 4
• Patients taking β-blockers may experience more severe and treatment-resistant anaphylaxis 1

By understanding the nature of biphasic reactions and identifying high-risk patients, clinicians can implement appropriate observation periods and ensure patients are equipped with the knowledge and tools to manage potential recurrence of symptoms after discharge.