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Angioedema
Introduction
Angioedema is defined as " subcutaneous tissues and/or submucosal tissues circumscribed non-pitting edema affecting lips, face, neck, and extremities oral cavity, larynx, and gut." It becomes life-threatening when it involves the larynx, while intestinal angioedema is painful and mimics acute abdomen.[1][2]
Angioedema was first described in 1882 by Quincke, then by Osler in 1888 (hereditary angioedema), and finally in 1963 by Donaldson et al (the role of C1 inhibitor).[3]
Classification of angioedema
Acquired
- Allergic (histaminergic angioedema) associated with anaphylaxis
- Non-allergic (non-histaminergic angioedema), presenting isolated or in combination with urticaria
- Drug-induced, e.g., angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs
- Complement-mediated secondary to acquired deficiency of C1-inhibitor
- Idiopathic which is subdivided into histaminergic and non-histaminergic
Hereditary forms
- C1-Inhibitor deficiency divided into type 1 (lack of C1-inhibitor molecule) and typed 2 (dysfunctional C1-inhibitor molecule) with normal C1 inhibitor.
Etiology
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Etiology
Inherited (hereditary angioedema): Mutations in the gene encoding for C1-inhibitor cause hereditary angioedema and it is an autosomal dominant condition.
Acquired: lymphoproliferative disorders, autoimmune, neoplastic, infection and drug-induced.[1]
Epidemiology
A retrospective study showed angioedema was the second most common disorder after asthma for hospitalization in New York State. African Americans made up 42% of these angioedema admissions.[4] Hereditary angioedema is a rare autosomal dominant condition and affects 1/50,000 individuals.[5][6] A Swedish study showed hereditary angioedema affected females more severely compared to males.[7]
Pathophysiology
In describing pathophysiology, angioedema is classified as histamine-mediated angioedema and bradykinin-mediated angioedema
Histamine-mediated angioedema is the most common and is secondary to mast-cells and basophil activation.
Bradykinin-mediated angioedema (hereditary angioedema, acquired C1-inhibitor deficiency and angiotensin-converting enzyme inhibitor-associated angioedema). Allergic reactions and hives do not trigger this condition. C1-inhibitor is a regulator of complement and the contact system; if deficient or dysfunctional it causes activation of the contact system resulting in uncontrolled production of kallikrein leading to proteolysis of high-molecular-weight kininogen and bradykinin, leading to edema by increasing in vascular permeability. Bradykinin-mediated angioedema is seen in:
- C1 inhibitor deficiency: Excessive production of bradykinin
- Angiotensin-converting enzyme inhibitor-associated angioedema: Decreased degradation of bradykinin[8][9]
- Histamine and bradykinin increase localized microvascular permeability.[1]
- NSAID induced: cyclooxygenase 1 inhibitor affects arachnoid acid metabolism, leukotriene/prostaglandin binding to the receptor or may be IgE mediated[1][8]
Genetics:
Hereditary angioedema can be secondary to F12 gene, angiopoietin-1, and plasminogen or some unknown gene mutation.[2][10]
C1 inhibitor is a serine protease inhibitor (SERPIN) [2] C1 inhibitor deficiency is associated with SERPING 1 mutation or mutated genes which encode for metabolizing and functioning enzymes of bradykinin.[11] Abnormal accumulation of C1 inhibitor in dominant harmful disease affects plasma levels of hereditary angioedema type 1.[12]
History and Physical
The presentation can be acute or chronic.
Histaminergic angioedema
Symptoms can involve different systems including skin (Urticaria, flushing, pruritus), Respiratory (bronchospasm), GI symptoms (abdominal pain and vomiting).[1] Onset is within 60 minutes of allergen exposure and may last for one to two days.[1]
Etiologies: Drugs, foods, latex, and insect stings.[13]
While comparing the bradykinin-mediated angioedema with histaminergic angioedema, the former has the following characteristics:
- It is not associated with urticaria
- More severe and longer duration
- Has associated abdominal symptoms [13]
Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor
It clinically presents as angioedema without urticaria or itching[14] It is common in African-Americans.[15] It can develop anytime but common in the first week of exposure.[9]
Nonsteroidal anti-inflammatory disease-induced angioedema
NSAID induced drug reactions include angioedema presenting with urticaria and facial swelling.[16]
Hereditary angioedema begins in childhood or young adulthood, gets worse at puberty and presents as recurrent episodes of swelling or abdominal pain.[17][18][19][20] Patients can develop prominent prodromal symptoms like erythema marginatum (erythematous, serpentine,non-pruritic rash).[21] An acute attack takes one day to peak and resolves in two to three days.[22]
Acquired angioedema with C1 inhibitor deficiency
Acquired C1 inhibitor deficiency presents similarly to hereditary angioedema. However, the low C1 inhibitor in many cases is from an underlying lymphoproliferative disorder which increases protein consumption and an antibody against C1-INH causing overproduction of bradykinin.[13]
Physical examination
Vital signs, level of consciousness, as well as a thorough ski, head, neck, respiratory and abdomen evaluation should be completed.[1]
General monitoring of angioedema in the Emergency room include:
- Oxygen saturation
- Cardiac status
Evaluation
The initial evaluation in the Emergency room
A specific drug and family history is needed along with screening blood work for C4 for hereditary angioedema and tryptase for angioedema with anaphylaxis. These labs when drawn during acute attacks are useful during follow-ups. In the case of anaphylaxis, (tryptase is normal in hereditary angioedema one and two but will be elevated in cases of anaphylaxis and other mast cell disorders associated with angioedema)[13]. Flexible fiberoptic laryngoscopy may be done to evaluate the involvement of tongue and larynx in patients with head, neck and upper airway symptoms.[13]
Clear differentiation between histamine-induced vs. bradykinin-induced angioedema can be life-saving.[23]
Hereditary angioedema type 1: C1 inhibitor function low, C1-Inhibitor level low, and C4 level low
Hereditary angioedema type 2: C1 inhibitor function and C4 level will be low, but the C1 inhibitor level will be normal or high.[24]
Confirm them by repeating the blood test.
Acquired C1-inhibitor deficiency: Low C1-inhibitor antigen and function and low C1q.[1]
Treatment / Management
Antihistamine, corticosteroids, and epinephrine are treatments of histaminergic angioedema.[1][25]
Treatment of Bradykinin-mediated angioedema is often resistant to standard therapies such as epinephrine, glucocorticoids or antihistamines.[13](B3)
Hereditary angioedema (On-demand treatment)
- Treat airway via intubation or surgical airway intervention. Treatment should be as early as possible. Hereditary angioedema attacks should be treated with C1 Inhibitor concentrate, [26] ecallantide (Kallikrein inhibitor) or icatibant (bradykinin-receptor antagonist).[27] Icatibant is an effective home-based, on-demand treatment.[28] (A1)
Pre-procedural (short-term) prophylaxis
Short-term prophylaxis before high-risk procedures in high-risk individuals. [2] Anesthesiologists must be aware of guideline-based treatment for hereditary and acquired angioedema. [29]
Long-term prophylaxis
C1 Inhibitor is the first-line long-term prophylaxis, while the androgens are used as second-line agents.[2]
Hereditary angioedema with mutations in the F12 gene is treated as follows:
- Discontinuing trigger factors (estrogen-containing oral contraceptives, hormonal replacement therapy, angiotensin-converting enzyme inhibitors)
- Treating with plasma-derived C1 inhibitor for acute attacks. Preventing attacks with progestins, tranexamic acid, and danazol.[30]
Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor
Treatment is with antihistamines, epinephrine, and glucocorticoids.[9] Care should be taken to stop the offending ACE inhibitor, and the patient should be not rechallenged with any of the ACE inhibitors in the future.
Acquired C1 inhibitor deficiency angioedema
Majority cases are asymptomatic and respond to immunochemotherapy[31] Treatment of acute attacks with icatibant and plasma-derived C1 inhibitor concentrate, and prophylaxis is with rituximab with or without chemotherapy and splenectomy.[32]
Special considerations:
- In pregnancy, the recommended therapy is plasma-derived nano-filtered C1-inhibitor,[33] however, in acute episodes, bradykinin receptor antagonist Icatibant can be used as it is safe with no maternal and fetal adverse effects.[34]
- In the pediatric population, the doses include 500 units (10-25 kg weighed patients), 1000 units and 1500 Units in patients weighing more than 25kg.[35]
- Plasma-derived C1 esterase inhibitor is safe and efficacious in pediatric patients below 12 years.[36]
- Icatibant is a well-tolerated medication in the pediatric group and might have a role in treating angiotensin II receptor blocker induced angioedema.[37]
- Recombinant human C1 esterase inhibitor for acute hereditary angioedema treatment has a persistent response for three days.[38]
- C1 inhibitor is used in the acute management of hereditary angioedema associated pancreatitis.[39]
- Patients with life-threatening orolingual angioedema who are treated with recombinant tissue plasminogen activator infusion, have a rapid response after using icatibant treatment.[40]
- Concurrent use of angiotensin-converting enzyme inhibitors with, dipeptidyl peptidase-4 inhibitors should be monitored closely as dipeptidyl peptidase-4 is also a major enzyme in the degradation pathway of bradykinin like an angiotensin-converting enzyme.[41]
- Use of liquid steroids in patients with severe urticaria associated angioedema in a setting of severe dysphagia secondary to anaphylaxis.[42]
- Use of omalizumab (Anti-immunoglobulin-E antibody) in Idiopathic non-histaminergic acquired angioedema, which is a rare disease resistant to antihistamines.[43][44] (A1)
Differential Diagnosis
- Acute contact dermatitis
- Drug rash with eosinophilia and systemic symptoms
- Dermatomyositis
- Morbus Morbihan
- Superior vena cava syndrome
- Hypothyroidism
- Subcutaneous emphysema
- Orofacial granulomatosis
- Hypocomplementemic urticarial vasculitis syndrome
- Clarkson's disease
- Gleich's syndrome
- A cluster headache
- Idiopathic edema [45]
Angioedema is one of the differential diagnoses in sudden onset of diffuse isolated edema.[46]
C1 inhibitor hereditary angioedema can be misdiagnosed as familial Mediterranean fever.[47]
Prognosis
Histaminergic angioedema clinical course is 1 hour of allergen exposure, and it may last for one to two days.[1]
Hereditary angioedema is a rare disease that often leads to delay in diagnosis as well as a misdiagnosis. Other factors leading to a misdiagnosis are unknown family history, gastrointestinal manifestations of disease without cutaneous involvement.[14]
C1 inhibitor deficiency type 1 and 2 angioedema attacks are worse compared to acquired C1 inhibitor deficiency angioedema.[48]
Complications
- Critical airway occlusion resulting in death
- Acute laryngeal, pharynx and tongue swelling[49]
- Death from asphyxiation[13]
- Hereditary angioedema associated pancreatitis[39]
- Physicians should be mindful of cardiovascular instability including bradycardia after recombinant tissue plasminogen inhibitor in patients who take angiotensin-converting enzyme inhibitors[50]
Deterrence and Patient Education
Patient education for Hereditary angioedema:
Proper training will comfort a patient's intimidating feeling of self-administration of Subcutaneous injections.
For patients
- Individual training for each patient
- Teach them the strategy of planning and scheduling
Train parents/caregivers with the following skills
- C1-inhibitor subcutaneous injection site
- Aseptic technique
- Needle or syringe preparation
- Injection of C1 inhibitor through the subcutaneous route.
Follow-up care
It is important to follow-up closely during the first few months of treatment. Encourage patients to keep a logbook for treatment compliance which should include document and report a breakthrough attack of hereditary angioedema.
Enhancing Healthcare Team Outcomes
Hereditary angioedema: the latest studies indicate that interference RNA mediated knockdown of F12 mRNA ( ALN-F12) is an approach for the prophylactic treatment of hereditary angioedema.[51] Gene therapy in hereditary angioedema may provide an option of durable treatment, but requires further studies for safety and tolerability.[52] Functional polymorphism KLKB1-428G/A with or without functional F12-46C/T polymorphisms may be helpful as prognostic markers of disease.[53] One may monitor 6-keto-prostaglandin F1 alpha as it may be a risk assessment blood marker in ACE inhibitor-induced angioedema.[54] Angioedema is best managed by an interprofessional team as it has very high morbidity and mortality. Patients should be referred to the appropriate specialist as soon as possible. Patients admitted with respiratory distress need ICU monitoring, and the anesthesia staff should be notified. A bedside tracheostomy set is highly recommended.
Media
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Angioedema Image courtesy S Bhimji MD
References
Depetri F, Tedeschi A, Cugno M. Angioedema and emergency medicine: From pathophysiology to diagnosis and treatment. European journal of internal medicine. 2019 Jan:59():8-13. doi: 10.1016/j.ejim.2018.09.004. Epub 2018 Sep 13 [PubMed PMID: 30220453]
Maurer M, Magerl M, Ansotegui I, Aygören-Pürsün E, Betschel S, Bork K, Bowen T, Balle Boysen H, Farkas H, Grumach AS, Hide M, Katelaris C, Lockey R, Longhurst H, Lumry WR, Martinez-Saguer I, Moldovan D, Nast A, Pawankar R, Potter P, Riedl M, Ritchie B, Rosenwasser L, Sánchez-Borges M, Zhi Y, Zuraw B, Craig T. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update. Allergy. 2018 Aug:73(8):1575-1596. doi: 10.1111/all.13384. Epub 2018 Mar 12 [PubMed PMID: 29318628]
Reshef A, Kidon M, Leibovich I. The Story of Angioedema: from Quincke to Bradykinin. Clinical reviews in allergy & immunology. 2016 Oct:51(2):121-39. doi: 10.1007/s12016-016-8553-8. Epub [PubMed PMID: 27287037]
Lin RY, Cannon AG, Teitel AD. Pattern of hospitalizations for angioedema in New York between 1990 and 2003. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2005 Aug:95(2):159-66 [PubMed PMID: 16136766]
Level 2 (mid-level) evidenceAndrejević S, Korošec P, Šilar M, Košnik M, Mijanović R, Bonači-Nikolić B, Rijavec M. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association. PloS one. 2015:10(11):e0142174. doi: 10.1371/journal.pone.0142174. Epub 2015 Nov 4 [PubMed PMID: 26535898]
Nasr IH, Manson AL, Al Wahshi HA, Longhurst HJ. Optimizing hereditary angioedema management through tailored treatment approaches. Expert review of clinical immunology. 2016:12(1):19-31. doi: 10.1586/1744666X.2016.1100963. Epub 2015 Oct 23 [PubMed PMID: 26496459]
Nordenfelt P, Nilsson M, Björkander J, Mallbris L, Lindfors A, Wahlgren CF. Hereditary Angioedema in Swedish Adults: Report From the National Cohort. Acta dermato-venereologica. 2016 May:96(4):540-5. doi: 10.2340/00015555-2274. Epub [PubMed PMID: 26540175]
Stone C Jr, Brown NJ. Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema. Immunology and allergy clinics of North America. 2017 Aug:37(3):483-495. doi: 10.1016/j.iac.2017.04.006. Epub [PubMed PMID: 28687104]
Brown T, Gonzalez J, Monteleone C. Angiotensin-converting enzyme inhibitor-induced angioedema: A review of the literature. Journal of clinical hypertension (Greenwich, Conn.). 2017 Dec:19(12):1377-1382. doi: 10.1111/jch.13097. Epub 2017 Oct 10 [PubMed PMID: 28994183]
Bork K, Wulff K, Witzke G, Hardt J. Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations. Allergy. 2015 Aug:70(8):1004-12. doi: 10.1111/all.12648. Epub 2015 May 22 [PubMed PMID: 25952149]
Germenis AE, Speletas M. Genetics of Hereditary Angioedema Revisited. Clinical reviews in allergy & immunology. 2016 Oct:51(2):170-82. doi: 10.1007/s12016-016-8543-x. Epub [PubMed PMID: 27116602]
Haslund D, Ryø LB, Seidelin Majidi S, Rose I, Skipper KA, Fryland T, Bohn AB, Koch C, Thomsen MK, Palarasah Y, Corydon TJ, Bygum A, Nejsum LN, Mikkelsen JG. Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema. The Journal of clinical investigation. 2019 Jan 2:129(1):388-405. doi: 10.1172/JCI98869. Epub 2018 Dec 10 [PubMed PMID: 30398465]
Moellman JJ, Bernstein JA, Lindsell C, Banerji A, Busse PJ, Camargo CA Jr, Collins SP, Craig TJ, Lumry WR, Nowak R, Pines JM, Raja AS, Riedl M, Ward MJ, Zuraw BL, Diercks D, Hiestand B, Campbell RL, Schneider S, Sinert R, American College of Allergy, Asthma & Immunology (ACAAI), Society for Academic Emergency Medicine (SAEM). A consensus parameter for the evaluation and management of angioedema in the emergency department. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2014 Apr:21(4):469-84. doi: 10.1111/acem.12341. Epub [PubMed PMID: 24730413]
Level 3 (low-level) evidenceBova M, De Feo G, Parente R, De Pasquale T, Gravante C, Pucci S, Nettis E, Triggiani M. Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes. International archives of allergy and immunology. 2018:175(3):126-135. doi: 10.1159/000486312. Epub 2018 Jan 26 [PubMed PMID: 29393169]
Lin RY,Levine RJ,Lin H, Adverse drug effects and angioedema hospitalizations in the United States from 2000 to 2009. Allergy and asthma proceedings. 2013 Jan-Feb [PubMed PMID: 23406938]
Berges-Gimeno MP, Martín-Lázaro J. Allergic reactions to nonsteroidal anti-inflammatory drugs: is newer better? Current allergy and asthma reports. 2007 Apr:7(1):35-40 [PubMed PMID: 17504659]
Zuraw BL. Clinical practice. Hereditary angioedema. The New England journal of medicine. 2008 Sep 4:359(10):1027-36. doi: 10.1056/NEJMcp0803977. Epub [PubMed PMID: 18768946]
Gábos G, Dobru D, Mihály E, Bara N, Dumitrache C, Popa R, Nădășan V, Moldovan D. Recurrent ascites: a need to evaluate for hereditary angio-oedema. Lancet (London, England). 2017 Nov 4:390(10107):2119-2120. doi: 10.1016/S0140-6736(17)32206-7. Epub [PubMed PMID: 29115243]
Keeney S, Halalau A. Anchoring bias in a case of recurrent abdominal pain. BMJ case reports. 2017 Oct 4:2017():. pii: bcr-2017-221027. doi: 10.1136/bcr-2017-221027. Epub 2017 Oct 4 [PubMed PMID: 28978589]
Level 3 (low-level) evidenceNanda MK, Elenburg S, Bernstein JA, Assa'ad AH. Clinical features of pediatric hereditary angioedema. The journal of allergy and clinical immunology. In practice. 2015 May-Jun:3(3):392-5. doi: 10.1016/j.jaip.2014.11.012. Epub 2015 Jan 15 [PubMed PMID: 25609346]
Prematta MJ, Kemp JG, Gibbs JG, Mende C, Rhoads C, Craig TJ. Frequency, timing, and type of prodromal symptoms associated with hereditary angioedema attacks. Allergy and asthma proceedings. 2009 Sep-Oct:30(5):506-11. doi: 10.2500/aap.2009.30.3279. Epub [PubMed PMID: 19843405]
Yigit M, Sogut O, Lisar H, Yigit E. Usefulness of C1 esterase inhibitor protein concentrate in the management of hereditary angioedema of oropharyngeal tissue. Nigerian journal of clinical practice. 2018 Apr:21(4):531-533. doi: 10.4103/njcp.njcp_177_17. Epub [PubMed PMID: 29607870]
Hahn J, Bas M, Hoffmann TK, Greve J. [Bradykinin-induced angioedema: Definition, pathogenesis, clinical presentation, diagnosis and therapy]. HNO. 2015 Dec:63(12):885-93; quiz 894-5. doi: 10.1007/s00106-015-0084-8. Epub [PubMed PMID: 26597136]
Magerl M, Germenis AE, Maas C, Maurer M. Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment. Immunology and allergy clinics of North America. 2017 Aug:37(3):571-584. doi: 10.1016/j.iac.2017.04.004. Epub [PubMed PMID: 28687110]
Busse PJ, Smith T. Histaminergic Angioedema. Immunology and allergy clinics of North America. 2017 Aug:37(3):467-481. doi: 10.1016/j.iac.2017.03.001. Epub 2017 May 13 [PubMed PMID: 28687103]
Li HH, Moldovan D, Bernstein JA, Reshef A, Porebski G, Stobiecki M, Baker J, Levy R, Relan A, Riedl M. Recombinant human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks. The journal of allergy and clinical immunology. In practice. 2015 May-Jun:3(3):417-23. doi: 10.1016/j.jaip.2014.12.013. Epub 2015 Feb 11 [PubMed PMID: 25680925]
Level 1 (high-level) evidenceKatelaris CH. Acute Management of Hereditary Angioedema Attacks. Immunology and allergy clinics of North America. 2017 Aug:37(3):541-556. doi: 10.1016/j.iac.2017.04.002. Epub 2017 May 23 [PubMed PMID: 28687108]
Otani IM, Lumry WR, Hurwitz S, Li HH, Craig TJ, Holtzman NS, Iandoli MI, Tucker J, Riedl MA, Zuraw BL, Banerji A. Subcutaneous Icatibant for the Treatment of Hereditary Angioedema Attacks: Comparison of Home Self-Administration with Administration at a Medical Facility. The journal of allergy and clinical immunology. In practice. 2017 Mar-Apr:5(2):442-447.e1. doi: 10.1016/j.jaip.2016.09.023. Epub 2016 Nov 3 [PubMed PMID: 27818136]
MacBeth LS, Volcheck GW, Sprung J, Weingarten TN. Perioperative course in patients with hereditary or acquired angioedema. Journal of clinical anesthesia. 2016 Nov:34():385-91. doi: 10.1016/j.jclinane.2016.05.010. Epub 2016 Jun 5 [PubMed PMID: 27687418]
Bork K, Wulff K, Witzke G, Hardt J. Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII). Allergy. 2017 Feb:72(2):320-324. doi: 10.1111/all.13076. Epub 2016 Dec 1 [PubMed PMID: 27905115]
Bekos C, Perkmann T, Krauth M, Raderer M, Lechner K, Jaeger U. Acquired C1 esterase inhibitor deficiency in lymphomas: prevalence, symptoms, and response to treatment. Leukemia & lymphoma. 2016 Sep:57(9):2033-6. doi: 10.3109/10428194.2015.1131273. Epub 2016 Jan 21 [PubMed PMID: 26795750]
Gobert D, Paule R, Ponard D, Levy P, Frémeaux-Bacchi V, Bouillet L, Boccon-Gibod I, Drouet C, Gayet S, Launay D, Martin L, Mekinian A, Leblond V, Fain O. A nationwide study of acquired C1-inhibitor deficiency in France: Characteristics and treatment responses in 92 patients. Medicine. 2016 Aug:95(33):e4363. doi: 10.1097/MD.0000000000004363. Epub [PubMed PMID: 27537564]
Fox J, Vegh AB, Martinez-Saguer I, Wuillemin WA, Edelman J, Williams-Herman D, Rojavin M, Rosenberg T. Safety of a C1-inhibitor concentrate in pregnant women with hereditary angioedema. Allergy and asthma proceedings. 2017 May 1:38(3):216-221. doi: 10.2500/aap.2017.38.4038. Epub [PubMed PMID: 28441992]
Farkas H, Kőhalmi KV, Veszeli N, Tóth F, Varga L. First report of icatibant treatment in a pregnant patient with hereditary angioedema. The journal of obstetrics and gynaecology research. 2016 Aug:42(8):1026-8. doi: 10.1111/jog.13003. Epub 2016 Apr 19 [PubMed PMID: 27093898]
Lumry W, Soteres D, Gower R, Jacobson KW, Li HH, Chen H, Schranz J. Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2015 Nov:26(7):674-80. doi: 10.1111/pai.12444. Epub 2015 Aug 11 [PubMed PMID: 26171584]
Craig TJ, Schneider LC, MacGinnitie AJ. Plasma-derived C1-INH for managing hereditary angioedema in pediatric patients: A systematic review. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2015 Sep:26(6):537-44. doi: 10.1111/pai.12425. Epub [PubMed PMID: 26111105]
Level 1 (high-level) evidenceStrassen U, Bas M, Hoffmann TK, Knopf A, Greve J. Treatment of angiotensin receptor blocker-induced angioedema: A case series. The Laryngoscope. 2015 Jul:125(7):1619-23. doi: 10.1002/lary.25163. Epub 2015 Feb 3 [PubMed PMID: 25646708]
Level 2 (mid-level) evidenceBernstein JA, Relan A, Harper JR, Riedl M. Sustained response of recombinant human C1 esterase inhibitor for acute treatment of hereditary angioedema attacks. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2017 Apr:118(4):452-455. doi: 10.1016/j.anai.2017.01.029. Epub 2017 Mar 9 [PubMed PMID: 28284978]
Loudin M, Modiano N, Sallay S. Rapid Improvement of Pancreatitis Secondary to Hereditary Angioedema with C1 Inhibitor Administration. The American journal of medicine. 2016 Jul:129(7):e75-6. doi: 10.1016/j.amjmed.2016.02.045. Epub 2016 Apr 4 [PubMed PMID: 27056293]
Cheong E, Dodd L, Smith W, Kleinig T. Icatibant as a Potential Treatment of Life-Threatening Alteplase-Induced Angioedema. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2018 Feb:27(2):e36-e37. doi: 10.1016/j.jstrokecerebrovasdis.2017.09.039. Epub 2017 Oct 31 [PubMed PMID: 29097062]
Scott SI, Andersen MF, Aagaard L, Buchwald CV, Rasmussen ER. Dipeptidyl Peptidase-4 Inhibitor Induced Angioedema - An Overlooked Adverse Drug Reaction? Current diabetes reviews. 2018:14(4):327-333. doi: 10.2174/1573399813666170214113856. Epub [PubMed PMID: 28201967]
Peveling-Oberhag A, Reimann H, Weyer V, Goloborodko E, Staubach P. High-Concentration Liquid Prednisolone Formula: Filling a Therapeutic Niche in Severe Acute Attacks of Urticaria and Angioedema. Skin pharmacology and physiology. 2016:29(1):9-12. doi: 10.1159/000439032. Epub 2015 Oct 15 [PubMed PMID: 26465879]
Faisant C, Du Thanh A, Mansard C, Deroux A, Boccon-Gibod I, Bouillet L. Idiopathic Non-histaminergic Angioedema: Successful Treatment with Omalizumab in Five Patients. Journal of clinical immunology. 2017 Jan:37(1):80-84. doi: 10.1007/s10875-016-0345-7. Epub 2016 Nov 8 [PubMed PMID: 27826875]
Staubach P, Metz M, Chapman-Rothe N, Sieder C, Bräutigam M, Canvin J, Maurer M. Effect of omalizumab on angioedema in H1 -antihistamine-resistant chronic spontaneous urticaria patients: results from X-ACT, a randomized controlled trial. Allergy. 2016 Aug:71(8):1135-44. doi: 10.1111/all.12870. Epub 2016 Mar 31 [PubMed PMID: 27010957]
Level 1 (high-level) evidenceAndersen MF, Longhurst HJ, Rasmussen ER, Bygum A. How Not to Be Misled by Disorders Mimicking Angioedema: A Review of Pseudoangioedema. International archives of allergy and immunology. 2016:169(3):163-70. doi: 10.1159/000445835. Epub 2016 Apr 22 [PubMed PMID: 27100932]
Laccourreye O, Rubin F, Delort J, Bonfils P. Diagnostic approach to sudden onset of diffuse isolated oedema of the lips. European annals of otorhinolaryngology, head and neck diseases. 2017 Oct:134(5):357-359. doi: 10.1016/j.anorl.2016.12.007. Epub 2017 Jan 9 [PubMed PMID: 28082136]
Akoglu G, Kesim B, Yildiz G, Metin A. Outcomes of long term treatments of type I hereditary angioedema in a Turkish family. Anais brasileiros de dermatologia. 2017 Sep-Oct:92(5):655-660. doi: 10.1590/abd1806-4841.20175899. Epub [PubMed PMID: 29166502]
Longhurst HJ, Zanichelli A, Caballero T, Bouillet L, Aberer W, Maurer M, Fain O, Fabien V, Andresen I, IOS Study Group. Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey. Clinical and experimental immunology. 2017 Apr:188(1):148-153. doi: 10.1111/cei.12910. Epub 2017 Feb 9 [PubMed PMID: 27936514]
Level 3 (low-level) evidenceGilbert JD, Byard RW. Lethal manifestations of angioedema. Forensic science, medicine, and pathology. 2019 Sep:15(3):494-497. doi: 10.1007/s12024-018-0045-0. Epub 2018 Nov 3 [PubMed PMID: 30390279]
Kageyama T, Okanoue Y, Takai R, Suenaga T. Cardiovascular Instability Preceded by Orolingual Angioedema after Alteplase Treatment. Internal medicine (Tokyo, Japan). 2016:55(4):409-12. doi: 10.2169/internalmedicine.55.4772. Epub 2016 Feb 15 [PubMed PMID: 26875969]
Liu J, Qin J, Borodovsky A, Racie T, Castoreno A, Schlegel M, Maier MA, Zimmerman T, Fitzgerald K, Butler J, Akinc A. An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema. RNA (New York, N.Y.). 2019 Feb:25(2):255-263. doi: 10.1261/rna.068916.118. Epub 2018 Nov 21 [PubMed PMID: 30463937]
Level 2 (mid-level) evidenceChen M, Riedl MA. Emerging Therapies in Hereditary Angioedema. Immunology and allergy clinics of North America. 2017 Aug:37(3):585-595. doi: 10.1016/j.iac.2017.03.003. Epub [PubMed PMID: 28687111]
Gianni P, Loules G, Zamanakou M, Kompoti M, Csuka D, Psarros F, Magerl M, Moldovan D, Maurer M, Speletas MG, Farkas H, Germenis AE. Genetic Determinants of C1 Inhibitor Deficiency Angioedema Age of Onset. International archives of allergy and immunology. 2017:174(3-4):200-204. doi: 10.1159/000481987. Epub 2017 Nov 9 [PubMed PMID: 29130992]
Bas M, Storck K, Strassen U. Potential Biomarkers for the Diagnosis of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema. ORL; journal for oto-rhino-laryngology and its related specialties. 2017:79(1-2):85-92. doi: 10.1159/000455803. Epub 2017 Feb 24 [PubMed PMID: 28231587]