Histamine-Mediated Angioedema – Symptoms, Treatment

Histamine-Mediated Angioedema/Angioneurotic Edema is a relatively common presentation in the emergency department. It presents as unpredictable frequent edematous episodes of cutaneous and mucosal tissues such as lips, eyes, oral cavity, larynx, and gastrointestinal system. This activity highlights the history, pathogenesis, clinical manifestations, treatment of antineurotic edema, and management of special cases with this condition. It also highlights the importance of the interprofessional team in ensuring the best outcomes in the patients suffering from this condition.

Angioedema is non-pitting edema that involves subcutaneous and/or submucosal layers of tissue that affect 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.

Angioedema is a skin reaction similar to urticaria. It is most often characterized by an abrupt and short-lived swelling of the skin and mucous membranes. All parts of the body may be affected but swelling most often occurs around the eyes and lips. In severe cases, the internal lining of the upper respiratory tract and intestines may also be affected.

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 the acute abdomen.

Classification of angioedema


  • 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.

Causes of Histamine-Mediated 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.
  • 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.
  • C1 inhibitor deficiency – Excessive production of bradykinin
  • Angiotensin-converting enzyme inhibitor-associated angioedema – Decreased degradation of bradykinin
  • Histamine and bradykinin – increase localized microvascular permeability.
  • NSAID induced – cyclooxygenase 1 inhibitor affects arachnoid acid metabolism, leukotriene/prostaglandin binding to the receptor or may be IgE mediated
  • Genetics – Hereditary angioedema can be secondary to the F12 gene, angiopoietin-1, and plasminogen or some unknown gene mutation.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.
  • There are several etiologies of angioedema – most notably angiotensin-converting enzyme inhibitor (ACEI) use. With tens of millions of people taking ACEIs, the incidence of ACEI angioedema is rising. African Americans are at a much higher risk for ACEI angioedema, possibly due to lower endogenous bradykinin and increased sensitivity to ACEI-mediated increases in bradykinin.
  • Other etiologies include IgE-mediated allergic reactions – (such as to food, drug, or environmental triggers), nonsteroidal anti-inflammatory drug (NSAID) use (including aspirin), and chemically-induced histamine release (most commonly opiates, highly cationic antibiotics, and muscle relaxants). A less common cause is hereditary angioedema (HAE) and acquired angioedema (AAE), both caused by a C1-inhibitor (C1-INH) deficiency.
  • HAE and AAE are rare. AAE – is due to an acquired deficiency of (C1-INH), caused by either consumption (type 1) or inactivation (type 2). This increased catabolism can be related to an autoimmune disorder (e.g., systemic lupus erythematosus) or a malignant tumor (e.g., lymphoma). Angioedema recurs unpredictably, lasting from two to five days. It not only presents with edema of the areas mentioned above, but it can also cause severe abdominal pain due to gastrointestinal mucosa edema.

The causes of angioedema depend on the type of angioedema a patient has. Angioedema can be classified into at least four types, acute allergic angioedema, non-allergic drug reactions, idiopathic angioedema, hereditary angioedema (HAE) and acquired C1 inhibitor deficiency.

Angioedema type Causes
Acute allergic angioedema
(almost always occurs with urticaria within 1-2 hours of exposure to the allergen)
  • Food allergy, especially nuts, shellfish, milk, eggs
  • Drug-induced urticaria, eg, to penicillin, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfa drugs, vaccines
  • Radiocontrast media
  • Insect venoms
  • Natural rubber latex, eg, medicinal gloves, catheters, balloons, contraceptive devices
Non-allergic drug reaction
(onset may be days to months after first taking the medication)
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Cascade of effects via kinin production, arachidonic acid metabolism and nitric oxide generation
Idiopathic angioedema
(frequently chronic and relapsing and usually occurs with urticaria)
  • In most cases the cause of angioedema is unknown
  • Recent research indicates that 30–50% of this type of angioedema may be associated with some types of autoimmune disorders including systemic lupus erythematosus (SLE)
Hereditary angioedema
(very rare autosomal dominant inherited disease)
  • Inherited abnormal gene that causes a deficiency of a normal blood protein
  • 3 types: Type 1 and II mutations of C1NH (SERPING1) gene on chromosome 11, encoding C1 inhibitor protein; Type III mutation in F12 gene on chromosome 12, encoding coagulation factor XII.
  • Type 1 results in low levels and function of circulating C1 inhibitor; Type II has normal levels of C1 inhibitor protein but a reduction in function
  • Occurs in 1 in 50,000 males and females; Type III more severe in women.
  • Decreased C1 inhibitor activity leads to excessive kallikrein, which in turn produces bradykinin, a potent vasodilator
Acquired C1 inhibitor deficiency
  • Acquired during life rather than inherited
  • It May be due to B-cell lymphoma or antibodies against C1 inhibitor
Vibratory angioedema
  • A form of chronic inducible urticaria
  • Localized vibratory urticaria is also due to a vibratory stimulus and is considered distinct from vibratory angioedema
AAE recurrence is associated with various conditions such as different forms of lymphoproliferative disorders.
  • 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 

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.

Symptoms of Histamine-Mediated Angioedema

Symptoms and signs of angioedema may vary slightly between the different types of angioedema but in general, some or all of the following occur.

  • Marked swelling, usually around the eyes and mouth
  • Throat, tongue, hands, feet and/or genitals may be affected too
  • The skin may appear normal, i.e. no hives or another rash
  • Swellings may or may not be itchy
  • Swellings may be painful, tender or burning
  • In severe angioedema swelling of the throat and/or tongue may make it difficult to breath
  • Swelling of the lining of the intestinal tracts may cause gastrointestinal pain and cramps

Some features specific to the different types of angioedema are listed below.

Angioedema type Clinical features
Acute allergic angioedema
  • Almost always occurs with urticaria
  • Angioedema and urticaria both usually occur within 1-2 hours of exposure to an allergen (exception is ACE inhibitor-induced angioedema that usually occurs within the first week of treatment but can occur weeks to months later)
  • Reactions are usually self-limiting and subside within 1-3 days
  • Reactions will recur with repetitive exposures or exposure to cross-reactive substances
Non-allergic drug reaction
  • ACE inhibitor-induced angioedema occurs without urticaria
Idiopathic/chronic angioedema
  • Similar to acute allergic but angioedema keeps on recurring and often no known cause is found
Hereditary angioedema
  • Patients often experience no symptoms until they reach puberty
  • Swellings can occur without any provocation or induced by precipitating factors, including local trauma, vigorous exercise, emotional stress, alcohol, and hormonal factors (menstruation, pregnancy, estrogen)
  • Some patients may get a transitory prodromal non-itchy rash, headache, visual disturbance or anxiety
  • Face, hands, arms, legs, genitals, digestive tract, and airway may be affected; swellings spread slowly and may last for 3-4 days
  • Abdominal cramps, nausea, vomiting, difficulty breathing, and rarely urinary retention from swelling of internal tracts
  • Urticaria (wealing) does not occur
  • The tendency to angioedema is less pronounced in adults

Swellings that can look like angioedema

  • Contact allergy – from animals or plants is usually localized to the site of direct contact. It is often itchy, short-lived, does not cause internal swelling, and causes blistering rashes that weep and peel after a few days.
  • Animal allergy – can cause itchy hives (urticaria) and angioedema, but occurs mostly with severe hay fever (allergic rhinitis) and/or asthma.
  • Insect stings  – from bees, wasps, and some ants can cause severe local and temporary swelling.
  • Palindromic rheumatoid arthritis – is a rare form of arthritis that causes swellings that last a few days at a time, mainly over joints and affecting the limbs. Swellings are usually painful and hot rather than itchy. Some people with this condition will eventually go on to develop rheumatoid arthritis.

Less common mimics of angioedema – include the following causes of swelling that tend to persist:

  • Dermatomyositis (muscle weakness, facial redness, and swelling).
  • Blockage of the superior vena cava (a major vein in the chest that can result in fixed fluid accumulation in the neck and face and arms).
  • Underactive thyroid gland (which can cause puffiness of the face and lips known as myxoedema).
  • Facial rosacea (causing non-specific puffiness of the face, redness, flushing, and pimples).
  • Orofacial granulomatosis (fixed facial and lip swelling sometimes associated with inflammation of the bowel).
  • Subcutaneous emphysema (leakage of air into the soft tissues, often occurring after trauma or surgery).
  • Cluster headache (severe one-sided headache associated with puffiness around the eye on the same side).

Diagnosis of Histamine-Mediated Angioedema

History and Physical

The presentation can be acute or chronic. 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 includes Oxygen saturation and Cardiac status.

Histaminergic angioedema

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:

  • It is not associated with urticaria
  • More severe and longer duration
  • Has associated abdominal symptoms 

Lab Test

  • Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor – It clinically presents as angioedema without urticaria or itching It is common in African-Americans. It can develop anytime but common in the first week of exposure.
  • 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.
  • 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 the 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 Histamine-Mediated Angioedema

Initially, the cause of angioedema is likely to be unknown, the mainstays of initial medical management include supplemental oxygen, a parenteral H-blocker, a parenteral steroid, and intramuscular epinephrine. Unfortunately, in AAE standard regimens of epinephrine, corticosteroids and antihistamines do not have much effect and are not recommended for AAE. Administration of plasma-derived or recombinant C1-INH can resolve acute attacks, but some patients will become non-responsive.

  • Icatibant, a bradykinin B2 receptor antagonist –  has been shown to provide symptoms relief in AAE and was well tolerated. Icatibant is an effective home-based, on-demand treatment. Before any high-risk procedure in high-risk patients, it is essential to give short-term prophylaxis. Anesthetists must be aware of the guidelines for HANE and AANE. C1 esterase inhibitor is the first-line long-term prophylaxis and androgens are used as second-line prophylaxis. The majority of AANE cases are asymptomatic and respond to immunochemotherapy.
  • Ecallantide, a potent bradykinin pathway inhibitor – has also shown promise in the treatment of AAE, providing another alternative in the treatment of patients with resistance to C1-INH replacement.
  • Fresh frozen plasma (FFP) – may be used. Although effective (at least in HAE), it at times will lack efficacy or even cause a sudden worsening of the patient’s symptoms. There is also the risk of viral transmission to consider.
  • Rituximab  – efficacy has been shown to be inconstant in AAE. It is also important to consider that treatment of an underlying causative condition can result in improvement of AAE.
  • Antihistamine, corticosteroids, and epinephrine – are treatments of histaminergic angioedema.Treatment of Bradykinin-mediated angioedema is often resistant to standard therapies such as epinephrine, glucocorticoids, or antihistamines.
  • 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,  ecallantide (Kallikrein inhibitor), or icatibant (bradykinin-receptor antagonist). Icatibant is an effective home-based, on-demand treatment.
  • Pre-procedural (short-term) prophylaxis – Short-term prophylaxis before high-risk procedures in high-risk individuals.  Anesthesiologists must be aware of guideline-based treatment for hereditary and acquired angioedema. 
  • Long-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 – 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.
  • 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  – The majority of 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.
  • Antifibrinolytics and androgens – Two other therapies, which have recently fallen out of favor, include antifibrinolytics and androgens. Androgens induce the production of C1-inhibitor and are very effective in preventing attacks, but have no benefit in treating an attack. Short-term prophylaxis is tolerated well and is effective for pre-procedure of other short-term events; however, the toxicity of androgens limits their use for long-term prophylaxis. Most experts recommend not exceeding 200 mg of Danocrine a day. Adverse effects include hyperlipidemia, obesity, androgenic effects in females, and disposition problems.
  • Antifibrinolytics – include tranexamic acid and aminocaproic acid, and both have minimal effect in the prevention and treatment of attacks. Presently, multiple other therapies are in the investigation including an oral kallikrein inhibitor and a monoclonal antibody that inhibits kallikrein. Table one includes the drugs that are currently available, and that may be available in the next few years.

Special considerations

  • In pregnancy, the recommended therapy is plasma-derived nano-filtered C1-inhibitor, however, in acute episodes, bradykinin receptor antagonist Icatibant can be used as it is safe with no maternal and fetal adverse effects.
  • 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.
  • Plasma-derived C1 esterase inhibitor is safe and efficacious in pediatric patients below 12 years.
  • Icatibant is a well-tolerated medication in the pediatric group and might have a role in treating angiotensin II receptor blocker-induced angioedema.
  • Recombinant human C1 esterase inhibitor for acute hereditary angioedema treatment has a persistent response for three days.
  • C1 inhibitor is used in the acute management of hereditary angioedema-associated pancreatitis.
  • Patients with life-threatening orolingual angioedema who are treated with recombinant tissue plasminogen activator infusion, have a rapid response after using icatibant treatment.
  • 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.
  • Use of liquid steroids in patients with severe urticaria-associated angioedema in a setting of severe dysphagia secondary to anaphylaxis.
  • Use of omalizumab (Anti-immunoglobulin-E antibody) in Idiopathic non-histaminergic acquired angioedema, which is a rare disease resistant to antihistamines.

Hereditary angioedema

Acute episodes of hereditary angioedema do not respond to adrenaline, antihistamine and corticosteroids. Most acute episodes of Type I and II hereditary angioedema are not life-threatening.

  • The mainstay of emergency medical treatment is intravenous C1 inhibitor concentrate (a blood product).
  • If this is unavailable, fresh frozen plasma can be infused, but this occasionally exacerbates angioedema.
  • Icatibant, a synthetic peptidomimetic drug, and bradykinin B2 receptor antagonist can be used in emergencies for the symptomatic treatment of acute attacks of hereditary angioedema in adults with C1-esterase-inhibitor deficiency. It was approved by the FDA in 2011. In New Zealand, it is available for home use on Special Authority application.
  • Ecallantide is a potent and selective human plasma kallikrein inhibitor that is also indicated for the symptomatic treatment of hereditary angioedema, approved for use by the FDA in 2009. It is a protease that is responsible for liberating bradykinin from its precursor kininogen. Ecallantide has been reported to cause anaphylaxis in 4% of cases and thus has a black box warning in the USA.

The chance of an attack can be reduced with the following medications

  • C1 inhibitor concentrate infused an hour before a surgical procedure
  • Anabolic steroids (stanazolol, oxandrolone, and danazol) increase circulating levels of normal functional C1 inhibitor. These have ‘male-like hormonal activity, so may cause weight gain, menstrual irregularities, and virilism.
  • Tranexamic acid has been used in pre-pubertal children and may be effective in Type III hereditary angioedema.
  • A monoclonal antibody, lanadelumab, which inhibits active plasma kallikrein, has been approved in the USA for the prevention of hereditary angioedema attacks.


  • Critical airway occlusion resulting in death
  • Acute laryngeal, pharynx, and tongue swelling
  • Death from asphyxiation
  • Hereditary angioedema associated pancreatitis
  • Physicians should be mindful of cardiovascular instability including bradycardia after recombinant tissue plasminogen inhibitor in patients who take angiotensin-converting enzyme inhibitors


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