What is biphasic anaphylaxis?

What is Biphasic Anaphylaxis

Biphasic anaphylaxis is the recurrence of anaphylactic symptoms after complete initial resolution, occurring without re-exposure to the trigger, typically within 1-78 hours (most commonly around 8 hours) after the initial reaction. 1, 2

Definition and Temporal Characteristics

Biphasic reactions are characterized by a symptom-free interval following complete resolution of the initial anaphylactic episode, followed by a second wave of symptoms. 2, 3 The key distinguishing feature is that symptoms completely resolve before recurring, differentiating this from protracted anaphylaxis where symptoms never fully resolve. 2

The timing of the second phase varies considerably:

• Most biphasic reactions occur around 8 hours after the initial reaction 2
• The range extends from 1 to 78 hours, with a median onset of approximately 10-11 hours 2, 4
• Some cases have been documented as late as 38-72 hours after initial symptom resolution 1, 3, 4

Incidence and Epidemiology

The reported incidence of biphasic anaphylaxis varies widely in the literature, largely due to inconsistent diagnostic criteria across studies. 5

Recent studies using standardized NIAID/FAAN diagnostic criteria demonstrate lower rates of 4-5% (range 0.18%-14.7%), which likely represents more accurate estimates. 2 Earlier studies that included patients with more severe anaphylaxis reported rates up to 20%. 1, 2, 6

In specific contexts:

• In allergen immunotherapy, biphasic reactions occur in 10-23% of systemic reactions 2
• A prospective Canadian study found a 19.4% incidence rate 4

Clinical Presentation

The second phase is typically less severe than the initial reaction, though it can occasionally be equally severe or even more severe. 2, 6 The clinical manifestations of the biphasic phase can include:

• Cutaneous symptoms (urticaria, angioedema) 1
• Respiratory symptoms (nasal congestion, laryngeal edema, bronchospasm, wheezing) 2, 3
• Cardiovascular symptoms (hypotension, tachycardia) 2
• Gastrointestinal symptoms (diarrhea) 2, 3

Risk Factors for Biphasic Reactions

The strongest predictor is requiring more than one dose of epinephrine during the initial reaction (OR 4.82,95% CI 2.70-8.58). 1, 2, 7 This represents a nearly 5-fold increased risk.

Other significant risk factors include:

Severe initial presentation:

• Hypotension or cardiovascular collapse (OR 2.18,95% CI 1.14-4.15) 1, 5
• Severe initial anaphylaxis symptoms (OR 2.11,95% CI 1.23-3.61) 1
• Wide pulse pressures (OR 2.11,95% CI 1.32-3.37) 1
• Hypoxia 5

Trigger-related factors:

• Unknown anaphylactic trigger (OR 1.72,95% CI 1.0-2.95) 1, 3
• Drug-induced anaphylaxis in patients <18 years (OR 2.35,95% CI 1.16-4.76) 1
• Food as a trigger is associated with decreased risk (OR 0.62,95% CI 0.4-0.94) 1

Clinical presentation factors:

• Cutaneous manifestations (OR 2.54,95% CI 1.25-5.15) 1
• Wheezing (OR 2.6,95% CI 1.4-8.9) 3
• Diarrhea (OR 4.5,95% CI 1.4-14.0) 3
• History of prior anaphylaxis (OR 2.6,95% CI 1.1-6.4) 3

Treatment-related factors:

• Delayed epinephrine administration 5, 4
• Inadequate initial treatment (less epinephrine, less corticosteroid) 4
• Longer time to resolution of initial symptoms (133 vs 112 minutes) 4

Clinical Implications for Observation

The negative predictive value for biphasic reactions after ≥6 hours of observation (following anaphylaxis resolution) is 97.3%. 2 This means that if a patient remains asymptomatic for 6 hours after complete symptom resolution, there is only a 2.7% chance of developing a biphasic reaction.

For 1 hour of observation, the negative predictive value is 95%. 2

Extended observation of 4-6 hours or more is recommended, with the duration depending on severity and risk factors. 1, 2, 7 Specifically:

• Patients with severe initial anaphylaxis and/or requiring >1 dose of epinephrine warrant extended observation (6+ hours) or hospital admission 1, 7
• Patients with resolved nonsevere anaphylaxis, no significant comorbidities, prompt response to epinephrine, and reliable access to medical care may be observed for 1 hour 1

Management Considerations

Treatment of the biphasic phase is identical to treatment of the initial phase, with intramuscular epinephrine as first-line therapy. 2, 7

A critical pitfall: Corticosteroids do NOT prevent biphasic anaphylaxis. 2, 7, 8 Despite historical use, multiple studies and systematic reviews have failed to demonstrate that glucocorticoids prevent biphasic reactions. 7, 8 The 2020 Joint Task Force on Practice Parameters found no clear evidence supporting corticosteroids or antihistamines for preventing biphasic reactions. 7

All patients must be discharged with:

• Two epinephrine auto-injectors with hands-on training 7
• Written anaphylaxis emergency action plan 7
• Education on biphasic reaction risk, trigger avoidance, and when to use epinephrine 1, 7
• Referral to an allergist within 1-2 weeks 7

Common Clinical Pitfalls

Never discharge patients prematurely—biphasic reactions can occur many hours after initial resolution, with some cases documented up to 72 hours later. 7, 3 The median time of 8-10 hours means that half of biphasic reactions occur after this timepoint. 2, 4

Do not rely on corticosteroids to prevent biphasic reactions—the evidence does not support this practice despite its historical use. 2, 7, 8

Delays in epinephrine administration during the initial reaction are associated with increased risk of biphasic reactions. 7, 5, 4 Early and adequate epinephrine treatment is crucial for reducing this risk.