Hunting for a Diagnosis

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Posted by Carla Rothaus

What are some of the features of alpha-gal syndrome?

The lone star tick, which is endemic in the East (especially the Southeast) United States, with expansion into the upper midwestern and northeastern United States and eastern Canada, has been associated with the development of allergy to “alpha-gal” (galactose-alpha-1,3-galactose), a carbohydrate moiety that is present in all nonprimate mammals. Tick saliva may contain alpha-gal from other mammals on which the tick has fed, and this exposure appears to trigger the development of alpha-gal–directed IgE antibodies in humans. Once sensitization has occurred, ingestion of red meat triggers hypersensitivity reactions. Read the NEJM Clinical Problem-Solving Article here.

Clinical Pearls

Q: How did the alpha-gal syndrome come to light?

A: Alpha-gal syndrome first came to broad attention in the mid 2000s when a number of patients who had been enrolled in clinical trials of cetuximab had anaphylaxis or urticaria during the first infusion. Although severe hypersensitivity reactions have since been noted to occur in 3% of patients receiving cetuximab overall, 22% of the patients who received it in late-phase trials in Tennessee and North Carolina had severe hypersensitivity reactions. The regional predominance of the reactions prompted the consideration of an environmental factor. Cetuximab includes at least seven distinct alpha-gal epitopes. IgE antibodies against alpha-gal were found to be common in the southeastern United States, where the tick-borne disease Rocky Mountain spotted fever is well recognized; reports of allergies to red meat were also increasingly reported in that area. Alpha-gal is found in the tissues of all mammals except primates. This led to the hypothesis that bites from the Amblyomma americanum (lone star) species of tick deposited stomach contents (from previous mammalian meals) into human skin, leading to the development of IgE against alpha-gal.

Q: Is alpha-gal syndrome seen outside the United States?

A: Associations among tick bites, IgE against alpha-gal, and hypersensitivity reactions to meat have been documented in Asia, Australia, Europe, and the United States. In these geographic regions, various ticks have been associated with alpha-gal syndrome; however, other species of ticks, including Ixodes scapularis, have not been implicated, which suggests that there may be specific tick factors that lead to sensitization.

Morning Report Questions

Q: What are some of the features of alpha-gal syndrome?

A: The most common foods precipitating allergy are mammalian meats, especially beef. Reactions to pork, lamb, rabbit, buffalo, venison, and kangaroo have also been described. Although most patients with alpha-gal syndrome can safely consume dairy products, some have reactions; the removal of cow’s milk from the diet is recommended on an individualized basis. Alpha-gal syndrome may result in myriad symptoms after the ingestion of meat. In a small study, the most common manifestations were pruritus or urticaria (in 70% of patients), gastrointestinal symptoms (in 40%), angioedema, contact urticaria of the oral mucosa, and anaphylaxis. However, symptoms and signs may be more insidious, and cases that involve predominantly gastrointestinal symptoms, presyncope, or syncope may be particularly challenging to recognize.

Q: Describe an unusual feature of alpha-gal allergy.

A: An unusual feature of the IgE-mediated hypersensitivity reaction to alpha-gal is its timing. Symptoms are delayed in onset, often occurring 3 to 6 hours after ingestion. The delay, which can complicate diagnosis, may be related to the fact that the carbohydrate allergen is bound to lipid. Lipids are absorbed into the gut and circulation more slowly than protein allergens, which lead to rapid-onset reactions. Many patients have awoken from sleep with allergic or anaphylactic symptoms after consuming red meat for dinner.

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