The History of Alpha-gal Syndrome 

Written by Linda P

Alpha-gal syndrome has an interesting history, as it actually begins in the
cancer/oncology world. In 2004, a new cancer drug, called cetuximab, came onto the market. As with any new drug, some people had bad reactions to it. At first, only one or two out of every 100 cancer patients who had cetuximab infused into their veins had a hypersensitivity reaction (drop in blood pressure and difficulty breathing).

However, as cetuximab was given to larger and larger groups, those statistics
changed drastically. In clinics in North Carolina and Tennessee, 25 out of 88 patients became hypersensitive. Some became so sick that they needed emergency shots of epinephrine and hospitalization. About that same time, a patient in Bentonville, Arkansas collapsed and died after receiving their first dose of cetuximab.

A nurse working at the Bentonville clinic mentioned the death to Dr. Tina Hatley, an immunologist in Bentonville. Hatley had recently finished postgraduate training at the University of Virginia’s allergy center. She mentioned the death to her former supervisor, Dr. Thomas Platts-Mills. Since the responses to the drug appeared to be allergic reactions, and there seemed to be no explanation for why they had occurred, Dr. Platts-Mills put together a team, which included Hatley, Dr. Scott Commins, and several others.

The research team was able to identify the cause of the reaction, the sugar galactose-alpha-1,3-galactose, also known as alpha-gal. Alpha-gal is present in all mammals, except humans and some other primates.

Knowing the source of the allergic reaction, however, did not completely solve the puzzle. In order to have an allergic reaction, someone needs to have been primed with a prior exposure to a substance, but the cetuximab patients who reacted badly had all done so on their very first dose.

Team members looked for any common denominators that could explain the problem. The reactions happened in Arkansas, North Carolina and Tennessee, but not in Boston and northern California, suggesting that they were regional.

Dr. Christine Chung, a member of the team, began checking neighbors of the patients and discovered that almost one in five also had antibodies to alpha-gal.

Dr. Jacob Hosen, another researcher in Platts-Mills’s lab, found a map from the Center for Disease Control (CDC) that showed the prevalence of Rocky Mountain spotted fever. He realized that it exactly overlapped the hot spots of the cetuximab reactions. Since Rocky Mountain spotted fever is transmitted by the bite of ticks, researchers began to wonder if ticks could be linked to the alpha-gal reactions as well.

Patients began coming to Platts-Mill’s clinic with sudden allergic symptoms: swelling, hives and sometimes anaphylactic shock. They too had high levels of IgE antibodies to alpha-gal. While none of them were cancer patients, some told the doctors that they thought their reactions had something to do with eating meat. Dr. Commins began calling all the new patients and asking them if they had ever been bitten by a tick. Almost all had.

Around this same time, Platts-Mills took a hike in the woods and was bit by a nest of larval Lone Star Ticks. He sent them to an entomologist and began checking his own IgE levels, which were rising. Eventually he experienced a bad reaction of hives a few hours after eating lamb chops.

Meanwhile, in Australia, Dr. Sheryl van Nunen, was researching unknown causes of anaphylaxis. In 2007, she discovered a link between ticks and the red meat allergy. In 2009, the Virginia team learned of her research. It was then that they realized Alpha-gal syndrome was not limited to the southeastern United States but was instead a global problem. Alpha-gal reactions have now been linked to bites not only from the Lone Star Tick in the U.S., but from at least nine other tick species, in every part of the world except the Arctic and Antarctica.

A lab test for the allergy has been on the market since 2010 (Platts-Mills and Hatley share the patent.). Yet patients still struggle to be diagnosed because of the unusual delayed symptoms and variance in allergic reactions between patients.


Time course of the alpha-gal story
Year: Events leading to our understanding of red meat allergy
∼2000: At least 2 groups reported cases of meat allergy that started after tick bites.
2003: IgE to cat allergens is common in an African village but not related to symptoms.
2005: There are reports of hypersensitivity reactions to first infusion of cetuximab in clinical trials.
2007: Severe reactions to cetuximab are common in Tennessee, North Carolina, Arkansas, Missouri, and Virginia.
2007: Two cases in Virginia of adult-onset delayed anaphylaxis occurring 3 to 6 hours after eating beef are reported.
2008: Alpha-gal is identified as the epitope on cetuximab.
2009: Twenty-four cases of delayed anaphylaxis to red meat are found in the United States.Multiple cases of meat allergy after tick bites are reported in Sydney, Australia.
2010: There is a range of evidence that ticks are responsible for the IgE response in the United States.
2011: There is extensive evidence that the IgE response is not related to asthma, despite cross-reactions with dog and cat.
2014: Open challenge tests confirm the delay in reactions to red meat.
Source: The alpha-gal story: Lessons learned from connecting the dots. Steinke, John W. et al. Journal of Allergy and Clinical Immunology, Volume 135, Issue 3, 589–596. Republished with permission.

Click below to download a copy of a presentation created by Dr. Tina (Hatley) Merritt, describing the history of alpha-gal:

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