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.
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).
Classification of angioedema
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.
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. Hereditary angioedema is a rare autosomal dominant condition and affects 1/50,000 individuals. A Swedish study showed hereditary angioedema affected females more severely compared to males.
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 is a serine protease inhibitor (SERPIN)  C1 inhibitor deficiency is associated with SERPING 1 mutation or mutated genes which encode for metabolizing and functioning enzymes of bradykinin. Abnormal accumulation of C1 inhibitor in dominant harmful disease affects plasma levels of hereditary angioedema type 1.
The presentation can be acute or chronic.
Symptoms can involve different systems including skin (Urticaria, flushing, pruritus), Respiratory (bronchospasm), GI symptoms (abdominal pain and vomiting). Onset is within 60 minutes of allergen exposure and may last for one to two days.
Etiologies: Drugs, foods, latex, and insect stings.
While comparing the bradykinin-mediated angioedema with histaminergic angioedema, the former has the following characteristics:
Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor
Nonsteroidal anti-inflammatory disease-induced angioedema
NSAID induced drug reactions include angioedema presenting with urticaria and facial swelling.
Hereditary angioedema begins in childhood or young adulthood, gets worse at puberty and presents as recurrent episodes of swelling or abdominal pain. Patients can develop prominent prodromal symptoms like erythema marginatum (erythematous, serpentine,non-pruritic rash). An acute attack takes one day to peak and resolves in two to three days.
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.
Vital signs, level of consciousness, as well as a thorough ski, head, neck, respiratory and abdomen evaluation should be completed.
General monitoring of angioedema in the Emergency room include:
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). Flexible fiberoptic laryngoscopy may be done to evaluate the involvement of tongue and larynx in patients with head, neck and upper airway symptoms.
Clear differentiation between histamine-induced vs. bradykinin-induced angioedema can be life-saving.
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.
Confirm them by repeating the blood test.
Acquired C1-inhibitor deficiency: Low C1-inhibitor antigen and function and low C1q.
Treatment of Bradykinin-mediated angioedema is often resistant to standard therapies such as epinephrine, glucocorticoids or antihistamines.
Hereditary angioedema (On-demand treatment)
Pre-procedural (short-term) prophylaxis
C1 Inhibitor is the first-line long-term prophylaxis, while the androgens are used as second-line agents.
Hereditary angioedema with mutations in the F12 gene is treated as follows:
Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor
Treatment is with antihistamines, epinephrine, and glucocorticoids. 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 Treatment of acute attacks with icatibant and plasma-derived C1 inhibitor concentrate, and prophylaxis is with rituximab with or without chemotherapy and splenectomy.
Angioedema is one of the differential diagnoses in sudden onset of diffuse isolated edema.
C1 inhibitor hereditary angioedema can be misdiagnosed as familial Mediterranean fever.
Histaminergic angioedema clinical course is 1 hour of allergen exposure, and it may last for one to two days.
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.
C1 inhibitor deficiency type 1 and 2 angioedema attacks are worse compared to acquired C1 inhibitor deficiency angioedema.
Patient education for Hereditary angioedema:
Proper training will comfort a patient's intimidating feeling of self-administration of Subcutaneous injections.
Train parents/caregivers with the following skills
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.
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. Gene therapy in hereditary angioedema may provide an option of durable treatment, but requires further studies for safety and tolerability. Functional polymorphism KLKB1-428G/A with or without functional F12-46C/T polymorphisms may be helpful as prognostic markers of disease. One may monitor 6-keto-prostaglandin F1 alpha as it may be a risk assessment blood marker in ACE inhibitor-induced angioedema. 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.
|||Angioedema and emergency medicine: From pathophysiology to diagnosis and treatment., Depetri F,Tedeschi A,Cugno M,, European journal of internal medicine, 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; [PubMed PMID: 29318628]|
|||Reshef A,Kidon M,Leibovich I, The Story of Angioedema: from Quincke to Bradykinin. Clinical reviews in allergy [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 [PubMed PMID: 16136766]|
|||Andrejević 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; [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; [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; [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; [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; [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; [PubMed PMID: 25952149]|
|||Germenis AE,Speletas M, Genetics of Hereditary Angioedema Revisited. Clinical reviews in allergy [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; [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, 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; [PubMed PMID: 24730413]|
|||Bova 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; [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; [PubMed PMID: 17504659]|
|||Zuraw BL, Clinical practice. Hereditary angioedema. The New England journal of medicine. 2008 Sep 4; [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; [PubMed PMID: 29115243]|
|||Keeney S,Halalau A, Anchoring bias in a case of recurrent abdominal pain. BMJ case reports. 2017 Oct 4; [PubMed PMID: 28978589]|
|||Nanda 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; [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; [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; [PubMed PMID: 29607870]|
|||Hahn J,Bas M,Hoffmann TK,Greve J, [Bradykinin-induced angioedema: Definition, pathogenesis, clinical presentation, diagnosis and therapy]. HNO. 2015 Dec; [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; [PubMed PMID: 28687110]|
|||Busse PJ,Smith T, Histaminergic Angioedema. Immunology and allergy clinics of North America. 2017 Aug; [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; [PubMed PMID: 25680925]|
|||Katelaris CH, Acute Management of Hereditary Angioedema Attacks. Immunology and allergy clinics of North America. 2017 Aug; [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; [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; [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; [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 [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; [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; [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; [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; [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; [PubMed PMID: 26111105]|
|||Strassen U,Bas M,Hoffmann TK,Knopf A,Greve J, Treatment of angiotensin receptor blocker-induced angioedema: A case series. The Laryngoscope. 2015 Jul; [PubMed PMID: 25646708]|
|||Bernstein 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 [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; [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; [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; [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; [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; [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; [PubMed PMID: 27010957]|
|||Andersen 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; [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; [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; [PubMed PMID: 29166502]|
|||Longhurst HJ,Zanichelli A,Caballero T,Bouillet L,Aberer W,Maurer M,Fain O,Fabien V,Andresen I, Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey. Clinical and experimental immunology. 2017 Apr; [PubMed PMID: 27936514]|
|||Gilbert JD,Byard RW, Lethal manifestations of angioedema. Forensic science, medicine, and pathology. 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; [PubMed PMID: 26875969]|
|||Liu J,Qin J,Borodovsky A,Racie T,Castoreno A,Schlegel M,Maier M,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.). 2018 Nov 21; [PubMed PMID: 30463937]|
|||Chen M,Riedl MA, Emerging Therapies in Hereditary Angioedema. Immunology and allergy clinics of North America. 2017 Aug; [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; [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; [PubMed PMID: 28231587]|