Can you have a delayed allergic reaction to Angiotensin-Converting Enzyme (ACE) inhibitors?

Delayed Allergic Reactions to ACE Inhibitors

Yes, delayed allergic reactions to ACE inhibitors can occur weeks, months, or even years after starting therapy, with angioedema being the most serious delayed reaction that can be life-threatening.

Types of Delayed Allergic Reactions to ACE Inhibitors

Angioedema

• Angioedema is the most concerning delayed allergic reaction to ACE inhibitors
• Can occur at any time during treatment, from days to years after initiation
• Characterized by swelling of face, extremities, lips, tongue, glottis, and/or larynx
• May involve intestinal tissue (intestinal angioedema)
• Can be life-threatening when affecting the airway 1, 2

Timing of Delayed Reactions

• While reactions are more common shortly after starting therapy, delayed onset is well-documented
• Reactions can occur from 3 weeks to more than 8 years after starting an ACE inhibitor 3
• One case report documented life-threatening angioedema after 11 years on lisinopril 4
• Delayed reactions may be less well recognized than immediate reactions 3

Pattern of Delayed Reactions

• Patients may experience multiple episodes with long symptom-free intervals
• Some patients have had up to 12 episodes before the association with ACE inhibitors was recognized 3
• Reactions can occur without any preceding symptoms or as part of a biphasic reaction 5

Mechanism of Delayed Reactions

• ACE inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin 1, 2
• The primary mechanism involves:
  • Accumulation of bradykinin and substance P due to reduced degradation by ACE
  • Stimulation of prostaglandin production by bradykinin
  • Sensitization of sensory nerves in the respiratory tract 6
• In angioedema cases, very high levels of bradykinin have been found during attacks 7

Risk Factors

• Higher incidence in women, non-smokers, and people of Chinese origin 6
• African American patients may be at increased risk 4
• Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk 2
• Concomitant use of other medications that can cause angioedema may increase risk 4

Management of Delayed Allergic Reactions

For Angioedema

• Immediate discontinuation of the ACE inhibitor is essential 1, 2
• For severe reactions involving the airway:
  • Subcutaneous epinephrine (1:1000 solution)
  • Measures to ensure patent airway
  • Close monitoring 1, 2
• Complete resolution typically occurs within 1-4 weeks but may take up to 3 months 6

Alternative Medications

• The best alternative for patients with ACE inhibitor-induced reactions is an angiotensin receptor blocker (ARB) 6
• ARBs have a significantly lower incidence of cross-reactivity (estimated at 10% or less) 8
• When ARBs are used after ACE inhibitor-induced angioedema, reactions tend to be less severe 8

Important Clinical Considerations

• Delayed recognition is common due to the irregular pattern of recurrence
• ACE inhibitors seem to facilitate angioedema in predisposed individuals rather than causing it through an allergic or idiosyncratic mechanism 7
• Fatal cases of angioedema have been reported, highlighting the importance of prompt recognition and management 9
• Patients should be educated about the possibility of delayed reactions and instructed to seek immediate medical attention if they experience unexplained shortness of breath or swelling of the throat or tongue 9

Pitfalls to Avoid

• Don't assume all reactions in patients on ACE inhibitors are due to the medication; consider other common causes
• Don't fail to consider ACE inhibitors as the cause of reactions that develop months or years after starting therapy
• Don't restart the same or different ACE inhibitor after a serious reaction has occurred
• Don't delay discontinuation of the ACE inhibitor if angioedema is suspected