Acute Angioedema (Non-Allergic)
Your presentation—diffuse pruritic erythematous swelling of the arm, periorbital area, and ankle without obvious lesions, new exposures, or urticaria—is most consistent with acute angioedema, likely histamine-mediated but possibly bradykinin-mediated if antihistamines fail.
Immediate Diagnostic Distinction
The absence of urticaria (wheals) alongside swelling is a critical clue that distinguishes this from typical allergic urticaria 1. Angioedema without urticaria occurs in approximately 10% of angioedema cases and requires different management depending on whether it is histamine- or bradykinin-mediated 2, 3.
Key Clinical Features to Assess Now
- Pain vs. itch dominance: Histamine-mediated angioedema is primarily pruritic, while bradykinin-mediated angioedema (hereditary or ACE-inhibitor-induced) is more painful than itchy 4, 1.
- Duration of individual lesions: Histamine-mediated swelling resolves within 24-48 hours; bradykinin-mediated can persist 48-72 hours or up to 1 week 4, 1.
- Medication history: ACE inhibitors cause angioedema in a small but significant percentage of the 35-40 million patients taking them worldwide, and this can occur even after years of stable use 3. Angiotensin II receptor blockers, fibrinolytics, estrogens, and NSAIDs are also implicated 3.
- Family history: Hereditary angioedema (HAE) presents with recurrent non-pruritic swelling, often triggered by trauma or stress, and may include gastrointestinal colic or laryngeal edema 4.
Immediate Management (First 30 Minutes)
Start treatment empirically for histamine-mediated angioedema while awaiting diagnostic clarification 2, 1:
- Cetirizine 10 mg or fexofenadine 180 mg orally immediately for pruritus control 5, 6.
- Methylprednisolone 125 mg IV or prednisone 40-60 mg orally if swelling is progressing or involves the face/airway 3, 1.
- Epinephrine 0.3-0.5 mg IM (1:1000) only if there are signs of anaphylaxis (hypotension, respiratory distress, tongue/throat swelling) 3.
Critical Airway Assessment
- Examine for tongue, uvula, or pharyngeal swelling by direct visualization 3.
- Ask about dysphagia, voice change, or stridor—these mandate immediate airway protection and ICU-level monitoring 3.
- If airway compromise is imminent and medical management fails, emergency cricothyroidotomy must be performed 3.
Diagnostic Workup (Within 24 Hours)
If Antihistamines and Steroids Are Effective (Histamine-Mediated)
- No further laboratory testing is required if swelling resolves within 24-48 hours and does not recur 1.
- Review all medications for potential triggers (NSAIDs, antibiotics, opiates, radiocontrast media) and discontinue the suspected agent 3, 7.
If Antihistamines and Steroids Are Ineffective (Suspect Bradykinin-Mediated)
Order the following immediately 4, 2:
- Serum C4 level: Low C4 is highly suggestive of hereditary angioedema (HAE types I and II) 4.
- C1-inhibitor (C1-INH) antigen level: Decreased in HAE type I 4.
- C1-inhibitor functional assay: Dysfunctional in HAE type II despite normal antigen levels 4.
- Comprehensive medication review: Specifically ask about ACE inhibitors, ARBs, estrogens, and fibrinolytics 3.
If C4 and C1-INH are normal but bradykinin-mediated angioedema is still suspected (e.g., ACE-inhibitor use), discontinue the offending drug immediately—this is both diagnostic and therapeutic 3.
Cause-Specific Treatment Algorithms
Histamine-Mediated Angioedema (Responds to Antihistamines)
- Continue cetirizine 10 mg or fexofenadine 180 mg daily until swelling fully resolves 5, 6.
- Avoid steroids beyond the acute phase to prevent corticosteroid dependence in chronic cases 1.
- Identify and eliminate the trigger (food, drug, physical stimulus) 1.
Bradykinin-Mediated Angioedema (Does Not Respond to Antihistamines)
ACE-Inhibitor or ARB-Induced
- Discontinue the ACE inhibitor or ARB permanently—this is the single most important intervention 3.
- Antihistamines, corticosteroids, and epinephrine are ineffective for bradykinin-mediated angioedema 2, 3.
- If airway compromise occurs, consider icatibant (bradykinin B2 receptor antagonist) or ecallantide (kallikrein inhibitor) if available 2.
Hereditary Angioedema (HAE)
- Acute attack treatment 4, 2:
- Plasma-derived C1-inhibitor concentrate (first-line).
- Recombinant C1-inhibitor.
- Ecallantide (kallikrein inhibitor).
- Icatibant (bradykinin B2 receptor antagonist).
- Long-term prophylaxis 4:
- 17α-alkylated androgens (e.g., danazol).
- Synthetic antifibrinolytic agents (e.g., tranexamic acid).
- Plasma-derived C1-inhibitor concentrate.
Differential Diagnoses to Exclude
Contact Dermatitis
- Would require a clear history of new topical exposure (soaps, lotions, plants) and typically presents with vesicles, scaling, or weeping 5.
- Your lack of new exposures and absence of vesicles makes this unlikely 5.
Erythema Migrans (Lyme Disease)
- Requires a history of tick exposure and presents as expanding erythematous patches ≥5 cm, often with central clearing 8, 9.
- Your multifocal distribution (arm, eye, ankle) and pruritus without expanding borders argue against this 8.
Non-Bullous Bullous Pemphigoid
- Occurs in elderly patients with severe pruritus preceding blister formation 6, 9.
- Diagnosis requires direct immunofluorescence showing linear IgG/C3 deposits 9.
- Your acute onset without chronic pruritus makes this less likely 9.
Critical Pitfalls to Avoid
- Do not assume all angioedema is allergic—bradykinin-mediated angioedema will not respond to antihistamines, steroids, or epinephrine 2, 3.
- Do not delay discontinuation of ACE inhibitors or ARBs if they are the suspected cause—clinical improvement after drug cessation is both diagnostic and therapeutic 3.
- Do not perform cricothyroidotomy prematurely, but do not hesitate if medical management fails and airway compromise is imminent 3.
- Do not use long-term steroids for chronic urticaria/angioedema—they worsen symptoms through corticosteroid dependence 1.