Can medications cause delayed anaphylaxis?

Delayed Anaphylaxis with Medications: Recognition and Management

Yes, medications can cause delayed anaphylaxis, which is defined as anaphylactic reactions occurring more than one hour after exposure to the triggering medication. 1

Types of Delayed Medication Reactions

• Delayed anaphylaxis is classified under non-immediate hypersensitivity reactions, which can occur from 1 hour to many days after drug administration according to the European Network for Drug Allergy (ENDA) 1
• While most anaphylactic reactions occur within minutes to 2 hours of exposure, delayed reactions can develop later without re-exposure to the allergen 1, 2
• A prospective study of anaphylaxis cases in Australian emergency departments found delayed deterioration (worsening of the reaction while under observation) in 17% of reactions, with 69% of these starting within 4 hours of ED arrival 1

Specific Medications Associated with Delayed Anaphylaxis

• Omalizumab (an anti-IgE monoclonal antibody) has been documented to cause delayed anaphylaxis, with 36% of reactions occurring >1 hour after administration and 7% occurring >12 hours later 1
• Chemotherapeutic agents can cause both immediate and delayed hypersensitivity reactions, with delayed reactions typically occurring 6-24 hours after administration 1
• Certain excipients (inactive ingredients) in medications can also trigger delayed hypersensitivity reactions 1

Mechanisms of Delayed Anaphylaxis

• Delayed anaphylaxis is associated with elevated levels of histamine, tryptase, IL-6, IL-10, and TNF-receptor 1 1
• These are the same mediators found to be correlated with severe anaphylaxis, suggesting that the severity of the initial reaction may be linked to protracted symptoms 1
• Both IgE-mediated and non-IgE immunologic mechanisms can be involved in delayed anaphylactic reactions 1, 3

Risk Factors for Delayed Anaphylaxis

• Delay in administration of epinephrine or inadequate dosing during the initial reaction 1
• Severity of the initial reaction 1
• Known risk factors for severe anaphylactic reactions include: age-related factors, concomitant diseases (chronic respiratory diseases, cardiovascular diseases, mastocytosis), severe atopic disease, and concurrent medications that increase risk (β-adrenergic blockers, ACE inhibitors) 1

Diagnosis of Delayed Anaphylaxis

• Diagnosis is based on clinical signs and symptoms occurring after the expected timeframe for immediate reactions 1
• Measurement of biochemical mediators can be helpful:
  • Plasma histamine (elevated for 15-60 minutes after onset) 1
  • Urinary histamine metabolites (detectable for up to 24 hours) 1
  • Tryptase levels (optimally obtained 15 minutes to 3 hours after onset) 1
• Serial measurement of tryptase levels during an anaphylactic episode followed by a baseline measurement after recovery is more useful than a single measurement 1

Management of Delayed Anaphylaxis

• Epinephrine remains the first-line treatment for all anaphylactic reactions, including delayed ones 1, 4
• Antihistamines and glucocorticoids are considered second-line therapies and should never delay epinephrine administration 1
• Patients should be monitored for 4-12 hours after the initial reaction, depending on risk factors for severe anaphylaxis, due to the possibility of biphasic reactions 2
• Extended observation periods should be considered for patients at higher risk of delayed or biphasic reactions 1

Prevention Strategies

• For patients with a history of delayed anaphylaxis to a specific medication, that medication should be avoided 1
• In cases where the medication is essential, desensitization protocols may be considered under specialist supervision 1
• Premedication with antihistamines and glucocorticoids has not been proven to prevent delayed anaphylaxis and should not be relied upon as a substitute for appropriate monitoring 1
• Patients with a history of delayed anaphylaxis should be prescribed epinephrine auto-injectors and educated on their use 2

Clinical Pitfalls and Caveats

• Normal levels of tryptase or histamine do not rule out the clinical diagnosis of anaphylaxis 1
• Delayed anaphylaxis may be misdiagnosed as a new reaction rather than a continuation of the initial reaction 1
• The "optimal" timeframe for epinephrine delivery to prevent delayed deterioration has not been established 1
• Antihistamines alone are insufficient for treating anaphylaxis as they do not relieve all pathophysiological symptoms, particularly serious complications like airway obstruction, hypotension, and shock 4