For many people with hereditary angioedema (HAE), swelling that doesn’t improve with antihistamines may be a clue that the swelling isn’t caused by an allergy.

When HAE swelling is misdiagnosed as an allergic reaction, the correct diagnosis may be delayed for years, sometimes a decade or longer. Getting the right diagnosis is important for treating HAE and preventing life-threatening complications.

How HAE Swelling Differs From Allergic Swelling

HAE and allergic angioedema can cause similar signs and symptoms. They’re both types of angioedema, which is swelling in the deeper layers of your skin and the tissue beneath it.

Although the swelling can look very similar, the causes are completely different. There are also subtle differences in the symptoms and how quickly HAE and allergic angioedema symptoms begin.

Histamine-Mediated Angioedema

Allergic angioedema is more common than HAE. Also called histamine-mediated angioedema, it happens in some people who have allergies as part of an allergic reaction. You might experience allergic angioedema during allergic reactions to foods, medications, or insect stings.

Histamine, the chemical that causes histamine-mediated angioedema, is released by cells in your immune system. During an allergic reaction, a chain of events begins when you’re exposed to an allergen and leads to the release of histamine. Histamine causes allergy symptoms, which can include swelling, hives, and flushing.

Symptoms of Histamine-Mediated Angioedema

Histamine-mediated angioedema typically develops in just one area of your body. The most common areas for histamine-mediated angioedema are the face, lips, tongue, and throat.

Many people with histamine-mediated angioedema also have hives during the allergic reaction. Hives are itchy bumps or welts that appear on the skin. They can be the same color as the surrounding skin, or appear red or darker depending on your skin tone. Each hive from an allergic reaction usually lasts no longer than 24 hours.

Onset of Histamine-Mediated Angioedema

Histamine-mediated angioedema usually starts quickly. In most cases, you’ll start to see swelling within minutes of being exposed to something you’re allergic to. Sometimes, it can take a couple of hours for swelling and hives to appear.

Bradykinin-Mediated Angioedema

Bradykinin-mediated angioedema is the type of swelling you experience with HAE. Bradykinin is a chemical that widens blood vessels and causes inflammation and swelling.

During an HAE attack, your body releases too much bradykinin. In type 1 and type 2 HAE, a protein called C1 inhibitor (C1INH) is too low or doesn’t work properly. When there isn’t enough working C1INH, the kallikrein-kinin system can produce too much bradykinin.

Symptoms of Bradykinin-Mediated Angioedema

HAE attacks involve swelling that can look like allergic angioedema and affect many of the same areas. The most common areas for swelling in an HAE attack are the hands, feet, face, and gastrointestinal (GI) tract.

Unlike allergic angioedema, HAE swelling doesn’t come with hives or itchy skin. However, if the swelling affects the GI tract, you might have additional symptoms like diarrhea or severe cramping.

Onset of Bradykinin-Mediated Angioedema

Bradykinin-mediated angioedema starts more slowly than allergic angioedema. It often gets worse over 24 hours, reaches its peak, and then gradually goes away over two to three days. It doesn’t happen because of exposure to an allergen, but it can be triggered by emotional stress, hormone changes, or even trauma from a minor dental procedure.

In most cases, an HAE attack happens spontaneously without any clear cause or trigger. But if you have HAE, you may not be able to take certain medications. ACE inhibitors and any medications that contain estrogen can trigger HAE attacks for some people.

Why Antihistamines, Steroids, and Epinephrine Don’t Work for HAE

HAE attacks are caused by bradykinin, so antihistamines and other allergy medicines won’t work.

Antihistamines don’t work for HAE because they block histamine, which causes swelling during some allergic reactions. Because histamine isn’t involved in bradykinin-mediated angioedema, they won’t do anything to stop the HAE attack.

HAE attacks also won’t improve with corticosteroids or epinephrine, which are used to treat allergic angioedema. Like antihistamines, they’re not effective in targeting the excess bradykinin that causes an HAE attack.

Treatments That Work for Swelling During HAE Attacks

If you have HAE and experience bradykinin-mediated angioedema, you’ll need HAE-specific treatments to manage swelling. Some HAE treatments help prevent swelling attacks, while others are used to rapidly reduce swelling during attacks.

Your doctor can help choose the best option based on your attack history, health needs, and treatment preferences.

C1 Inhibitor Replacement

C1INH replacement therapy supplies the body with working C1INH. This helps the kallikrein-kinin system work more normally. Some are taken regularly to prevent attacks, while others are used as needed to treat acute attacks. An acute attack is one that is currently happening.

Bradykinin Receptor Antagonists

Your doctor may recommend bradykinin receptor antagonists, also called bradykinin receptor blockers, to treat acute bradykinin-mediated swelling episodes. These HAE medications work by blocking bradykinin receptors to stop bradykinin from causing swelling.

Kallikrein Inhibitors

Kallikrein inhibitors are also available to either prevent HAE attacks or treat them while they’re happening. They work by blocking an enzyme called kallikrein, which is involved in making bradykinin.

Talk to Your Doctor

If you have signs of angioedema, talk to your doctor about what causes it and how you can treat it. If you’ve had swelling episodes that didn’t improve with antihistamines or other treatments for allergic angioedema, your doctor may want to test you for HAE.

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