Gemcitabine (Gemzar) (see Gemcitabine, [[Gemcitabine]]): cases of laryngeal edema have been reported
Heparin (see Heparin, [[Heparin]]): anaphylaxis is a manifestation of heparin-induced thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
Omalizumab (Xolair) (see Omalizumab, [[Omalizumab]])
Rituxumab (Rituxan, MabThera, Zytux) (see Anti-CD20 Therapy, [[Anti-CD20 Therapy]])
N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex) (see N-Acetylcysteine, [[N-Acetylcysteine]])
Epidemiology: associated with intravenous administration
Physiology: histamine release has been implicated
Non-Dextran Intravenous Iron
Ferumoxytol (Feraheme) (see Ferumoxytol, [[Ferumoxytol]])
Risk of First-Exposure Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]) [MEDLINE]: 24 per 100k patients
Iron Gluconate (Ferrous Gluconate, Fergon, Ferralet, Simron) (see Iron Gluconate, [[Iron Gluconate]])
Risk of First-Exposure Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]) [MEDLINE]: 24 per 100k patients
Iron Sucrose (Venofer) (see Iron Sucrose, [[Iron Sucrose]])
Risk of First-Exposure Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]) [MEDLINE]: 24 per 100k patients
Cumulative Risk of Anaphylaxis (Over 12 wk Period) [MEDLINE]: iron sucrose has lowest risk of all of the intravenous iron agents
Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]]): NSAID’s rarely cause allergic reactions via this mechanism (in these cases, the reaction is usually to a single NSAID agent)
Pirfenidone (Esbriet) (see Pirfenidone, [[Pirfenidone]]): few cases have been reported (unclear if mechanism involves IgE)
Epidemiology: rare cases of patients with very low levels of IgA and anti-IgA Ab’s, may develop anaphylaxis upon receiving blood with IgA present (these patients need IgA-deficient blood products)
Non-Immunologic Direct Mast Cell/Basophil Activation
Ethanol (see Ethanol, [[Ethanol]]): rarely induces anaphylaxis by itself, but may augment mast cell activation
Foods: these “pseudoallergens” may cause urticaria (or contact urticaria) via IgE-mediated or via non-immunologic mechanisms, especially in children
Stinging Nettle (Urtica Dioica) (see Stinging Nettle, [[Stinging Nettle]]): urticaria was named after this weed (which is commonly found in North America, South Americam Europe, and parts of Africa
Physiology: histamine (and pain-causing mediators) contained in the plant
Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]]): NSAID’s most commonly cause angioedema via this mechanism
Epidemiology: rare disorder (first case reports in 1972 in lymphoma patients)
Age of Onset: typically presents at an older age (4th decade or later in life) than hereditary angioedema
Most Patients Have an Associated Lymphoproliferative Disorder
Etiology
Lymphoma (see Lymphoma, [[Lymphoma]]): lymphatic malignancy is present in 35% of cases
Usually Associated with B-Cell Lymphoma
Monoclonal Gammopathy of Unclear Significance (MGUS) (see Monoclonal Gammopathy of Unclear Significance, [[Monoclonal Gammopathy of Unclear Significance]]): present in 35% of cases
idiopathic Acquired C1 Inhbitor Decifiency: accounts for <10% of cases
Some of These Cases also Lack Anti-C1 Inhibitor Antibodies
Autoimmune Disease: autoimmune disease is present in 8% of cases
Autoimmune Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]])
Epidemiology: 15% of hypereosinophilic syndrome patients have angioedema
Physiology: may involve eosinophil release of mediators or activation of cutaneous mast cells by eosinophil-derived mediators
Idiopathic Non-Histaminergic Angioedema
Clinical: recurrent angioedema without urticaria
Physiology
Mast Cell-Mediated Angioedema
General Comments
Mast Cell-Mediated Angioedema is Pathologically Similar to Urticaria (see Urticaria, [[Urticaria]]): although it occurs in the deeper dermis and subcutaneous tissues
Mast Cell Release of Mediators: resulting in dermal venule vasodilation and increased permeability -> tissue edema
Bradykinin is an Immune Mediator Which Induces Vasodilation and Increased Vascular Permeability
Mast Cells are Not Involved: therefore, pruritus and urticaria are notably absent
Bradykinin-Mediated Angioedema Frequently Affects the Gastrointestinal Mucosa, Resulting in Bowel Wall Edema: in contrast to histamine-mediated angioedema
Diagnosis
C4 Level
Indications for Testing
Suspected Acquired C1 Inhibitor Deficiency
Interpretation
Decreased: in most cases of acquired C1 inhibitor deficiency
C1 Inhibitor Level
Indications for Testing
Suspected Acquired C1 Inhibitor Deficiency
Interpretation
Decreased-Normal: in acquired C1 inhibitor deficiency
Interpretation: low result is required for the diagnosis of acquired C1 inhibitor deficiency
Decreased to 50% of Normal*: confirms the diagnosis of acquired C1 inhibitor deficiency
C1q Level
Indications for Testing
Suspected Acquired C1 Inhibitor Deficiency in Patient >30 y/o and Without a Family History of Angioedema
Interpretation
Decreased to <50% of Normal: seen in 70% of acquired C1 inhibitor deficiency cases
However, may be mildly decreased in 30% of cases or normal in rare cases
Plasma Anti-C1 Inhibitor Antibodies
Indications for Testing
Suspected Acquired C1 Inhibitor Deficiency
Interpretation: note that the absence of the antibody does not rule out the diagnosis of acquired C1 inhibitor deficiency
Detectable in approximately 74% of patients with acquired C1 inhibitor deficiency
Detectable in 30% of hereditary angioedema patients
Detectable in 3% of normal controls
Clinical Manifestations
General Clinical Features of Angioedema
Anatomic Sites of Involvement
General Comments: angioedema usually affects body regions with loose connective tissue (face, lips, mouth, throat, pharynx/larynx, uvula, extremities, genitalia, and bowel wall)
Larynx
Difficulty Swallowing/Dysphagia (see Dysphagia, [[Dysphagia]])
Non-Code Blue Situation: IM into thigh is preferred over SQ route
Code Blue Situation: IV route is preferred
Preloaded Epinephrine Injectable Devices
Advantages: patient can keep nearby at home, etc for emergency use
Adult Dose: 0.3 mg IM (1:1000)
Brands
Epipen
Hold like a pen, not like a knife (to avoid inadvertent injection into the thumb)
Remove blue safety cap -> firmly push orange tip against lateral thigh (don’t need to remove clothes to use), until it clicks -> hold in place for 5-10 sec
Auvi-Q: provides verbal instructions
Adrenaclick: pen-like device
Specific Treatment of Angiotensin Converting Enzyme (ACE) Inhibitor-Associated Angioedema
Discontinue ACE Inhibitor
Time Course of Resolution: following discontinuation of ACE inhibitor, angioedema usually resolves within 24-72 hrs
Failure to Discontinue ACE Inhibitor Promptly at the First Sign of Angioedema: may result in spontaneous resolution of angioedema, but an un unpredictable increase in the frequency/severity of future attacks (or even life-threatening angioedema) may occur
After Discontinuation, Do Not Re-Challenge Patient with ACE inhibitors
Recurrent Angioedema Episodes After ACE Inhibitor Discontinuation: patients may experience occasional angioedema episodes in the first few months after ACE inhibitor discontinuation (this may be due to residual effects of the drug vs an alternative etiology of the angioedema)
Although Antihistamines Would Not Be Expected to Be Effective in ACE Inhibitor-Associated Angioedema, There are Some Studies Which Demonstrate Their Efficacy (Otolaryngol Head Neck Surg, 2007) [MEDLINE] (Laryngoscope, 2008) [MEDLINE]
Administration: 30 mg in 3 mL SQ (slowly, preferably in the abdomen)
Cost: $8-9k per dose
Timing of Administration: based on studies in hereditary angioedema, icatibant is most likely to be effective if given in the first few hours of the attack, when the edema is increasing (as compared to when after the angioedema has peaked and stabilized)
Clinical Efficacy: decreases time to resolution of angioedema
German Randomized Trial of Icatibant in ACE Inhibitor-Induced Angioedema (NEJM, 2015) [MEDLINE]
Median Time to the Onset of Symptom Relief (By Composite Investigator-Assessed Symptom Score) was Significantly Shorter with Icatibant than with Standard Therapy (2.0 hrs vs 11.7 hrs)
Icatibant Shortened the Time to Complete Resolution of Angioedema, as Compared to Combination Glucocorticoid and Antihistamine Therapy (8.0 hrs vs 27.1 hrs)
Icatibant (Firazyr) (see Icatibant, [[Icatibant]])
Purified C1 Inhibitor Concentrate (Cinryze, Berinert, or Ruconest) (see C1 Inhibitor Concentrate, [[C1 Inhibitor Concentrate]])
Testosterone and Attenuated Androgens (Danazol) (see Danazol, [[Danazol]]): allow the gene (within hepatocytes) to produce enough sufficient functional C1 inhibitor
Effective acutely and as prophylaxis
Specific Treatment of Recurrent, Idiopathic Angioedema
Allergy Evaluation
Antihistamines (H1-Histamine Receptor Antagonists) (see H1-Histamine Receptor Antagonists, [[H1-Histamine Receptor Antagonists]]): may decrease frequency of episodes
Corticosteroids (see Corticosteroids, [[Corticosteroids]]): prednisone may be used (although has not been formally studied) to abort attacks if used early in the course
Dapsone (see Dapsone, [[Dapsone]]): for refractory cases
Icatibant (Firazyr) (see Icatibant, [[Icatibant]]): for refractory cases
Rituximab (Rituxan) (see Anti-CD20 Therapy, [[Anti-CD20 Therapy]]): for refractory cases
Future Use of Other Related Medications Which Have Been Associated with Angioedema
Renin Inhibitors: Aliskiren (see Aliskiren, [[Aliskiren]])
Overall Risk of Angioedema: merits cautious use in patients with prior ACE inhibitor-associated amgioedema (until further studies are performed)
Overall Risk of Angioedema with ARB’s is Believed to Be Lower Than That of ACE Inhibitors
Risk of ARB-Related Angioedema After ACE Inhibitor-Associated Angioedema: 1.5-10% (however, this may be artifactually high due to residual angioedema that may occur after ACE inhibitor discontinuation)
Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012 Nov 12;172(20):1582-9. doi: 10.1001/2013.jamainternmed.34 [MEDLINE]
Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69:602–616 [MEDLINE]
Angioedema induced by cardiovascular drugs: new players join old friends. Allergy. 2015 Oct;70(10):1196-200. doi: 10.1111/all.12680. Epub 2015 Jul 15 [MEDLINE]
Angiotensin-converting enzyme inhibitor-induced isolated visceral angioedema in a liver transplant recipient. Transplantation. 2003;75(5):730 [MEDLINE]
Icatibant
A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015;372:418–425 [MEDLINE]
The role of icatibant—the B2 bradykinin receptor antagonist—in life-threatening laryngeal angioedema in the ED. Am J Emerg Med. 2015 Mar;33(3):479.e1-3. doi: 10.1016/j.ajem.2014.08.055. Epub 2014 Aug 27 [MEDLINE]
Fresh-frozen plasma as a treatment for life-threatening ACE-inhibitor angioedema. J Allergy Clin Immunol. 2002;109(2):370 [MEDLINE]
Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol. 2004;92(5):573 [MEDLINE]
Fresh frozen plasma for progressive and refractory angiotensin-converting enzyme inhibitor-induced angioedema. J Emerg Med. 2013;44(4):764 [MEDLINE]
[C1-esterase inhibitor in ACE inhibitor-induced severe angioedema of the tongue. Anaesthesiol Reanim. 2001;26(5):133] [MEDLINE]
Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate. Acta Anaesthesiol Scand. 2006;50(1):120 [MEDLINE]
[Angiotensin-converting enzyme inhibitor-related angioedema: emergency treatment with complement C1 inhibitor concentrate]. Rev Med Interne. 2008;29(6):516. Epub 2007 Nov 29 [MEDLINE]
ACE-inhibitor induced angio-oedema treated with complement C1-inhibitor concentrate. BMJ Case Rep. 2013;2013 Epub 2013 Oct 4 [MEDLINE]
Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal. Clin Case Rep. 2015 Feb;3(2):126-30. Epub 2014 Dec 05 [MEDLINE]
