Continuing Education Activity

Angioedema is non-pitting edema that involves subcutaneous and/or submucosal layers of tissue that affects the face, lips, neck, and extremities, oral cavity, larynx, and/or gut. It becomes life-threatening when it involves the larynx. This activity examines the differential diagnosis of this condition and how to properly evaluate a patient presenting with it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Review the classification of angioedema.
• Describe the presentation of angioedema.
• Summarize the treatment and management options available for angioedema.
• Identify the role of the interprofessional team for improving care coordination and communication to advance the treatment of 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

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]

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]

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] 

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.