Nonallergic angioedema

Last updated Nov. 20, 2024, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

Nonallergic angioedema, also known as drug-induced angioedema, is a type of angioedema that occurs due to an adverse reaction to certain medications. Like other types of angioedema, it is marked by swelling.

This type is one of the most common forms of angioedema. Though its exact prevalence is difficult to determine, it’s estimated to affect as many as 2.5% of individuals treated with certain blood pressure-lowering medicines.

Nonallergic angioedema is more common in people of African descent, and it more often affects women than men. This type of angioedema also tends to be more frequent in individuals who are older or have underlying cardiovascular conditions.

Causes

Nonallergic angioedema is caused by an adverse reaction to certain medications. In some cases, a person who has an allergic reaction to a medicine can experience angioedema, but as its name suggests, nonallergic angioedema is distinct from allergy-related angioedema.

Specifically, acute allergic angioedema is triggered by an aberrant immune reaction against a harmless substance that’s wrongfully recognized as a potential threat. By contrast, the immune system is not activated in nonallergic angioedema. Instead, this form of angioedema typically arises when certain medications lead to higher than normal levels of bradykinin, a signaling molecule that promotes swelling.

High levels of bradykinin also trigger swelling in other forms of angioedema, including hereditary angioedema and acquired angioedema. However, in these other angioedema types, bradykinin levels become dysregulated due to mutations or certain underlying diseases. Nonallergic angioedema is also distinct from idiopathic angioedema, a form of angioedema that lacks a clearly identifiable cause.

Several different types of medications can act as nonallergic angioedema causes. The most notable are angiotensin-converting enzyme inhibitors, commonly abbreviated as ACE inhibitors, which are used to treat high blood pressure. This class of medicines works by preventing the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen.

Nonallergic angioedema is estimated to occur in as many as 2.5% of people who take these drugs. Examples of ACE inhibitors that may potentially cause angioedema include enalapril (marketed as Vasotec and others) and lisinopril (marketed as Zestril and others).

Another class of blood pressure-lowering medicines that can also cause nonallergic angioedema is angiotensin receptor blockers, or ARBs. These medicines do not interfere with the degradation of bradykinin, but the mechanism through which they cause angioedema is not exactly known. Examples of ARBs that have been reported to cause angioedema are losartan (marketed as Cozaar and others) and valsartan (marketed as Diovan and others).

In rarer cases, other types of medications, including nonsteroidal anti-inflammatory drugs — ones commonly used to ease inflammation and pain — can also trigger nonallergic angioedema.

Symptoms

Nonallergic angioedema is characterized by swellings, or large, smooth welts. Unlike other types of angioedema, nonallergic angioedema never appears alongside hives or a rash. Swellings are restricted to the skin and mucosal linings and are generally not painful.

Nonallergic angioedema symptoms usually take some time to develop, generally appearing hours or days after a person starts taking an angioedema-causing medication. Symptoms can also manifest much later, sometimes occurring weeks, months, or even years following the start of treatment.

This delay in symptom onset is one of the key distinctions between nonallergic and acute allergic angioedema. Symptoms in acute allergic angioedema usually set in very quickly after a person has been exposed to an allergen, or a substance capable of triggering an allergic reaction. Moreover, acute allergic angioedema is almost always accompanied by itchiness, hives, and/or rash.

Swelling in nonallergic angioedema can affect any part of the body, though it most often occurs in the face, particularly in the mouth and tongue. In some cases, swelling can block the airway and make it difficult for a person to breathe; this is a life-threatening medical emergency that requires immediate treatment.

Diagnosis

When a patient is experiencing angioedema-like swelling, the first crucial step for establishing a diagnosis is to determine whether or not the swelling is being caused by an allergic reaction. This can usually be accomplished by a detailed examination that assesses whether the patient has been exposed to common allergens and is experiencing signs of allergies, such as hives, rash, and severe itching.

The timing of swelling can also be an important clue, as allergic reactions usually develop fairly quickly following exposure to an allergen, whereas the symptoms of nonallergic angioedema usually take much longer to develop.

If a patient is experiencing angioedema that is not accompanied by signs of an allergic reaction, and the individual is known to have taken medications that can cause angioedema as a side effect, that’s usually an indication of nonallergic angioedema. To confirm the diagnosis, physicians will typically take the patient off of the medication that may be triggering angioedema to see if symptoms resolve.

As a cautionary measure, it’s generally recommended that patients who appear to be experiencing nonallergic angioedema undergo blood tests to rule out hereditary or acquired angioedema.

Treatment

Because it occurs as a side effect of a medication, the most important aspect of nonallergic angioedema treatment is to stop taking the offending medication. This is almost always effective for easing symptoms, though it may take up to several days for swelling to subside after the medication is discontinued. Even after discontinuing treatment, it is possible that a patient may continue to experience mild swelling episodes for a few months.

In the short term, nonallergic angioedema treatment depends largely on the extent and severity of the swelling. Some individuals may have relatively mild swelling and only need monitoring, whereas others may require emergency interventions.

For instance, if the swelling causes breathing problems, it is imperative patients receive interventions to restore breathing. Such measures may include supplemental oxygen, ventilation, or physical interventions to open the airways.

There is no therapy specifically approved to manage swelling in nonallergic angioedema. But because swelling in nonallergic angioedema is typically driven by the excessive activity of bradykinin — also the culprit behind swelling in hereditary angioedema — medicines that are approved for the on-demand treatment of hereditary angioedema may be used in these patients.

Several options are available:

• C1 inhibitor concentrates such as Berinert and Ruconest may be used. These deliver purified forms of C1-INH, which normally regulates the production of bradykinin, the protein that’s missing or abnormal in most people with hereditary angioedema.
• Firazyr (icatibant) can be used to prevent bradykinin from interacting with the receptor to which it normally binds to trigger swelling effects.
• Kalbitor (ecallantide), which blocks the action of an enzyme needed for the production of bradykinin, also can be used.
• Infusions of fresh frozen plasma may be used to temporarily supply patients with C1-INH and other blood components that break down bradykinin.

Importantly, because nonallergic angioedema is not caused by an allergic reaction, it will not respond to standard treatments used for allergic forms of angioedema, such as antihistamines, corticosteroids, and epinephrine (the active agent in EpiPen). Correctly diagnosing nonallergic angioedema is therefore essential to ensure appropriate treatment.

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