Angioedema is a dermatologic response that often resembles hives. Most commonly, angioedema appears as a sudden but short-term inflammation of the skin and mucous membranes. There are different types of angioedema with a variety of causes including the amount of C1 inhibitor (C1-INH) present in the bloodstream. Angioedema treatment is dependent upon the causative factor and underlying symptom progression.
WHAT IS ANGIOEDEMA?
Angioedema, caused by vascular leakage, is characterized by significant swelling of the skin, tissues, or mucous membranes. Although any body part can be affected, the swelling generally appears around the periorbital or perioral regions. In serious cases, angioedema can involve the upper respiratory tract or intestines. Approximately 20% of people in the United States are affected by angioedema. Angioedema can be short term or chronic and is usually episodic in nature.
In the majority of instances, angioedema’s cause is not identified. However, it is thought that angioedema is linked to allergic reactions. This is due to the presence of histamine and other allergy related chemicals in the bloodstream. Some potential causes of angioedema are:
- Animal dander
- Exposure to the elements
- Food hypersensitivity
- Bug bites
- Certain Medications
- Infections or autoimmune diseases
- Surgical procedures
SIGNS AND SYMPTOMS
The incidence and severity of angioedema symptoms are inconsistent. Angioedema can involve multiple organ systems but most commonly appears as visible edema. Common symptoms include localized burning feeling, pain, intense itching, and erythema. Other symptoms may include:
- Peripheral swelling
- Abdominal pain
- Nausea and vomiting
- Throat stiffness
- Voice changes
- Difficulty breathing
- Laryngeal swelling (life-threatening)
TYPES OF ANGIOEDEMA
A high number of angioedema cases exist as angioedema alone. In these situations, the symptoms, causes, and treatment may be quite different from those with other types of angioedema. The most common type of angioedema is Acute Allergic followed by Non-Allergic. Rarer forms of angioedema include Hereditary Angioedema (HAE) and Acquired Angioedema (AAE). Types of angioedema are also categorized as either histaminergic or non-histaminergic.
ACUTE ALLERGIC ANGIOEDEMA
Acute allergic angioedema is a common form of angioedema which results from an allergic reaction. The body detects certain substances, for example, food or medications, and treats them as harmful. Chemicals are then released into the blood stream that attack these substances. This results in angioedema and skin swelling.
Non-allergic angioedema, as the name implies, is not caused by an allergic reaction. However, this type of angioedema is a result of a medication reaction. Certain types of medications, such as ACE inhibitors, can cause this type of angioedema. Symptoms can occur days or months after first ingesting the medication.
HEREDITARY ANGIOEDEMA (HAE)
Hereditary Angioedema (HAE) is a rare condition characterized by noninflammatory swelling in subcutaneous tissues, abdominal organs, and the upper airway. HAE is accompanied by episodes of edema formation that can cause significant consequences such as:
- Asphyxiation caused by laryngeal edema
- Abdominal angioedema attacks
- Narcotic dependence resulting from serious pain
- Disfiguring and debilitating cutaneous attacks
ACQUIRED ANGIOEDEMA (AAE)
Acquired angioedema (AAE) is caused by acquired C1-inhibitor (C1-INH) deficiency. Signs and symptoms include non-pitting asymmetric edema,
severe abdominal pain, and life-threatening edema of the upper respiratory tract. There are two types of AAE known as angioedema type I (AAE-I) and acquired angioedema type II (AAE-II). Both occur without urticaria and have characteristic swelling of the skin that is painless, non-pruritic, and non-pitting.
WHO IS AT RISK FOR ANGIOEDEMA?
People with a history of allergies to certain foods, toxins, or medications are at increased risk for angioedema. Other factors include age, gender, and ethnicity.
Although angioedema affects individuals in all age groups, those who are at highest risk of angioedema have more severe and frequent attacks after adolescence. The highest incidence of angioedema occurs in the thirties. However, individuals 65 and over have the highest rate of hospitalizations. Angioedema related to food allergies occurs most often in children.
Angioedema occurs more often in females than males. Estrogen, a hormone found predominately in women, may increase the likelihood of angioedema. Estrogen-containing oral contraceptives can worsen attacks. Women are more likely to suffer from chronic idiopathic angioedema than their male counterparts.
African Americans are at higher risk for angioedema caused by ACE inhibitors. However, there is no other evidence that links ethnicity to the rate or severity of angioedema.
OTHER RISK FACTORS
Individuals at highest risk for angioedema have experienced past episodes of:
- Body-wide allergic reactions
- Abrupt temperature changes
- Stress or anxiety
- Dental procedures
- Ovarian cysts
Other risk factors for angioedema include:
- History of hives or angioedema
- History of allergic reactions
- Certain illness that cause hives and angioedema (lupus, lymphoma or thyroid problems)
- A family history of hives or angioedema
- Hereditary angioedema
Patients with mild angioedema symptoms may not require treatment. Angioedema treatment varies based on the cause, type, and presenting symptoms. However, the latest advancements in angioedema treatment are making the disorder more manageable. In addition, prophylactic treatments are available to help reduce the incidence and severity of angioedema attacks. The primary goal of angioedema treatment is to minimize and prevent swelling. Common medications prescribed for angioedema treatment include antihistamines, corticosteroids, epinephrine, and inhalers. Immunosuppressants such as cyclosporine can also be used in cases of recalcitrant angioedema. In addition, Intravenous immunoglobulin (IVIg) has had a positive response in patients who are unresponsive to antihistamines.
HISTAMINERGIC ANGIOEDEMA (IH-AAE)
Histaminergic angioedema (IH-AAE) can either be immunoglobulin E (IgE)-dependent or IgE-independent. In most cases, idiopathic and NSAID-related angioedema are treated similarly. Antihistamines are the most often used treatment options. They can decrease the intensity or amount of attacks, and can be given 4 times more than the standard dosage. Common antihistamines used for angioedema treatment include:
For more severe angioedema cases, Diphenhydramine can be given intramuscularly (IM) or intravenously. Other options include Hydrocortisone IV and methylprednisolone IV to reduce the amount of recurrence. When laryngeal swelling or airway obstruction is present, Epinephrine (1:1000) should be administered IM. In severe cases, intubation or tracheostomy may be required.
NONHISTAMINERGIC ANGIOEDEMA (INH-AAE)
In C1-INH-AAE, treating the causative factor usually corrects the condition. Certain patients may benefit from C1-INH containing fresh frozen plasma (FFP). However, in some cases FFP may cause angioedema attacks to get worse due to the presence of substrates. Therefore, emergency measures must be in place prior to starting this type of angioedema treatment. HAE, C1-INH-AAE and some cases of INH-IAE can be treated with antifibrinolytic agents, although the course of action is not known. C1-INH infusions can be used to treat acute HAE.
C1-INH-HAE IN WOMEN
Women with C1INH-HAE require special treatment considerations when dealing with gynecologic or obstetric issues. The following options should be considered:
- Avoid the use of estrogen-containing contraception
- Attenuated androgens should not be used during pregnancy or conception
- Plasma-derived human C1-INH is the preferred angioedema treatment during pregnancy
- Regional anesthesia should be considered for cesarean section
When angioedema causes laryngeal edema, maintaining a patent airway is of utmost importance. Admission to the Intensive Care Unit (ICU) is usually required when intubation is necessary. In severe cases, surgery may be required to create a surgical airway through procedures such as cricothyrotomy or tracheotomy.
Patient education is essential in reducing the incidence and severity of angioedema attacks. Patients with allergies need to be taught allergen avoidance. Consultation with a nutritionist is also recommended to educated individuals about special dietary considerations. When indicated, patients should also be shown the proper technique for administering epinephrine.
The most recent prophylactic angioedema treatment to be approved by the FDA for HAE is lanadelumab, a monoclonal antibody. C1-INH related angioedema has shown positive results with FFP prophylaxis. Attenuated androgens and C1-INH derived from plasma have demonstrated a high degree of success in C1-INH-HAE patients. Other options for prophylactic angioedema treatment include:
- Androgen derivatives for HAE C1-INH-HAE patients
- Patients can be treated prophylactically with Plasma-derived C1-INH
- For patients experiencing angioedema related to ACE inhibitors, angiotensin II receptor blockers (ARB) should be considered
- Antihistamines and H2 antagonists are most commonly used for IH-AAE
Despite the specific type of angioedema, all forms are caused by inflammation. This inflammation leads fluid to ooze deep into the skin, resulting in the swellings. Inflammation-reducing diets may help reduce inflammation and prevent angioedema symptoms. A dietician, nutritionist, or medical doctor should be consulted prior to making any dietary changes. Patients require a nutritionally complete, balanced diet. Permitted foods include fresh milk, non-processed meats, butter, rice, tofu and some vegetables such as broccoli and cauliflower.
Dietary considerations include:
- Excluding certain foods from the diet including nuts, shellfish, processed or cured meats, eggs, black pepper, and sweets
- Avoiding food items that contain flavor enhancers, artificial coloring, preservatives, and additives.
- Avoiding fruits and vegetables in the early stages of the diet
Angioedema is a condition most often characterized by swelling. Many variations of the condition exist. Angioedema treatment can vary dramatically depending on the underlying cause. Angioedema can be regarded as histaminergic or nonhistaminergic. In addition to prophylactic treatments, patient education and dietary changes should be considered.