Alpha-gal syndrome

Alpha-gal syndrome (AGS), also known as alpha-gal allergy or mammalian meat allergy (MMA), is a type of acquired meat allergy characterized by a delayed onset of symptoms (3–8 hours) after ingesting mammalian meat. The condition results from past exposure to certain tick bites. It was first reported in 2002. Symptoms of the allergy vary greatly between individuals and include rash, hives, nausea or vomiting, difficulty breathing, drop in blood pressure, dizziness or faintness, diarrhea, severe stomach pain, and possible anaphylaxis.

Alpha-gal allergy is a reaction to the carbohydrate galactose-alpha-1,3-galactose ("alpha-gal"), whereby the body is overloaded with immunoglobulin E (IgE) antibodies on exposure to the carbohydrate. Anti-gal is a human natural antibody that interacts specifically with the mammalian carbohydrate structure gal alpha 1-3Gal beta 1-4GlcNAc-R (the alpha-galactosyl epitope). The alpha-gal molecule is found in all mammals except catarrhines (apes and Old World monkeys), the taxonomic branch that includes humans.

In 2006, researchers Thomas Platts-Mills and Scott Commins attempted to discover why some people were allergic to the cancer drug cetuximab. They discovered that these individuals had IgE antibodies in their blood that were specifically targeted to the portion of cetuximab which contained the alpha-gal carbohydrate. When Platts-Mills was bitten by a tick and developed alpha-gal allergies, his team came to the conclusion that a link existed between tick bites and the allergy. They found that the IgE antibody response to the mammalian oligosaccharide epitope alpha-gal was associated with both the immediate-onset anaphylaxis during first exposure to intravenous cetuximab and the delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products, such as beef or pork.

Bites from specific tick species, such as the Lone Star tick (Amblyomma americanum) in the US, and the paralysis tick (Ixodes holocyclus) in Australia, which can transfer this carbohydrate to a victim, have been implicated in the development of this delayed allergic response to consumption of mammalian meat products ("red meat"). Healthcare providers recommend avoiding food products containing beef, pork, lamb, venison, rabbit, and offal to avoid triggering an allergic reaction. Some afflicted individuals are so hypersensitive to alpha-gal that the allergy can cross-react with mammalian gelatin and even some dairy products. Individuals with an alpha-gal allergy do not need to become strict vegetarians because reptile meats, poultry and seafood naturally do not contain alpha-gal. Increasing evidence now suggests reactions to certain substances with traces of alpha-gal used in the preparation of certain medications, including nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics and pain medications.

Alpha-gal allergy has been reported in 17 countries on all six continents where humans are bitten by ticks, particularly the United States and Australia. Alpha-gal allergies are the first known food allergies that present the possibility of delayed anaphylaxis. They are also the first known food-related allergies associated with a carbohydrate, rather than a protein.

Symptoms
A typical allergic reaction to alpha-gal has a delayed onset, occurring 3–8 hours after consuming mammalian meat products. However, there have been some instances of onset of symptoms occurring within 2 hours. After the delayed onset, the allergic response is like most food allergies, and especially an IgE-mediated allergy, including severe whole-body itching, hives, angioedema, gastrointestinal upset, and possible anaphylaxis. Anaphylactic reactions are seen in approximately 60% of afflicted individuals. There have been cases where gastrointestinal symptoms arise without pruritus, hives, or other skin involvement. This presentation is not typical of food allergies, which can make initial suspicion of alpha-gal syndrome less likely. In 70% of cases, the reaction is accompanied by respiratory distress and is particularly harmful to those with asthma. However, not every exposure to alpha-gal results in allergic reaction for some people with the allergy.

It is worth noting that symptoms and overall reactions can vary greatly between individuals with alpha-gal syndrome. It has been found that other factors, including exercise and alcohol consumption, can potentially affect an individual's symptoms and overall reactivity to alpha-gal. Increased risk has also been discovered in those without type B or type AB blood, as the type B blood antigen is similar to alpha-gal and may confer some level of immunity.

The severity of symptoms and overall reaction to alpha-gal have been found to correlate with the amount of alpha-gal carbohydrate in the ingested food or drug.

Cause and mechanism
Alpha-gal allergies develop after a person has been bitten by the lone star tick in the United States, the European castor bean tick, the paralysis tick or Ixodes (Endopalpiger) australiensis in Australia, Haemaphysalis longicornis in Japan, or a currently unknown tick in South Africa, possibly Amblyomma hebraeum. Alpha-gal is not naturally present in apes, Old World monkeys, or humans, but is in all other mammals. If a tick feeds on another mammal, the alpha-gal remains in its alimentary tract.

The tick injects the alpha-gal into a person's skin with its bite. Recent research has shown that saliva from the lone star tick contains alpha-gal, and that saliva is injected into the bloodstream. Researchers still do not know which specific component of tick saliva causes the reaction. The immune system then releases a flood of IgE antibodies to fight this foreign sugar. After this reaction, the future intake of mammalian meat with the same alpha-gal causes an allergic reaction. Symptoms of the allergy reaction are caused by too many IgE antibodies attacking the allergen – the alpha-gal. Other types of ticks are suspected of causing similar problems. Only a small percentage of children and adults will acquire a red meat allergy after receiving a bite from a lone star tick.

A 2012 preliminary study found unexpectedly high rates of alpha-gal allergy in the western and north-central parts of the United States. This suggests that unknown tick species may spread the allergy. The study found alpha-gal allergy cases in Hawaii, where no ticks identified with the allergies live. Human factors were suggested, but no specific examples were provided.

Blood thinners derived from porcine intestine and replacement heart valves derived from porcine tissue may also contain alpha-gal. Alpha gal is found on the fragment-antigen binding (Fab) fragment of the recombinant monoclonal cetuximab antibody used in the immunotherapy treatment of metastatic colon cancer. Immediate hypersensitivities and reactions, specifically concentrated in the southern part of the United States, can be seen from the alpha-gal components of this anti-cancer drug. Increasing evidence now suggests reactions to certain substances with traces of alpha-gal used in the preparation of certain medications, including nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics and pain medications.

Diagnosis
Diagnosis begins with initial suspicion of alpha-gal syndrome following a thorough review of an individual's medical history and clinical symptoms. Regarding laboratory testing, diagnosis tends to be difficult, and no specific test is recommended over others.

A blood test for the specific antigen, IgE, to the alpha-gal carbohydrate, is commonly used for diagnosis in clinical practice. Typically, a level of 1% for IgE specific for alpha-gal out of total IgE in the body has been identified in patients with alpha-gal syndrome. Traditional skin-prick allergy tests for allergy to meat may give a false-negative answer and are not generally considered reliable. Skin and basophil activation tests with cetuximab are the most sensitive, but high costs limit their use.

In certain instances in which a person does not present with the typical symptoms and history of alpha-gal syndrome but is found to have elevated alpha-gal IgE levels, improvement with avoidance of red meat can be diagnostic, as well.

Prognosis
There is no cure for alpha-gal; the main form of management is abstaining from red meat, including lamb, beef, pork, and other mammalian products if necessary. These products have been found to have the highest risk of reaction, whereas dairy products present a much lower risk. Avoidance of dairy is not generally recommended as most afflicted individuals do not have reactions to dairy consumption.

Unlike most food allergies, in some people, the alpha-gal allergy may recede over time as long as another tick does not bite the person. It has been found that with avoidance of further tick bites, levels of serum IgE decline. The recovery period can take 8 months to 5 years.

Treatment
In addition to avoiding triggers, such as red meat, treatment is aimed at alleviating symptoms and is highly dependent on severity. If an allergic individual who only experiences relatively mild symptoms consumes food containing alpha-gal, then treatment with over-the-counter antihistamines may be acceptable. In cases where more severe reactions—like anaphylaxis—are observed, admission to a hospital for emergency treatment is necessary. In these situations, treatment is the same as for any anaphylactic reaction, and necessitates epinephrine administration.

Desensitization
As of 2017, only two successful desensitizations have been performed on patients with an alpha-gal allergy.

Prevention and tick removal
Tick bites can be prevented by treating clothing and gear with products containing 0.5% permethrin and avoiding areas inhabited by ticks.

Debate exists around the best method of tick removal.

History
The allergy was first formally identified as originating from tick bites in the United States in 2002 by Thomas Platts-Mills, and independently by Sheryl van Nunen in Australia in 2007.

Platts-Mills, Tina Hatley Merritt, and Scott Commins were attempting to discover why some people were reacting negatively to the cancer drug cetuximab. They had previously hypothesized that a fungal infection or parasite could lead to the allergy. They discovered that these individuals had IgE antibodies in their blood that were specifically targeted to the portion of cetuximab which contained the alpha-gal carbohydrate. When Platts-Mills was bitten by a tick and developed alpha-gal allergies, his team concluded that a link existed between tick bites and the allergy. They found that the IgE antibody response to the mammalian oligosaccharide epitope alpha-gal was associated with both the immediate-onset anaphylaxis during first exposure to intravenous cetuximab and the delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products, such as beef or pork.

As of November 2019, Australia has the highest rate of mammalian meat allergy and tick anaphylaxis worldwide. In the US, the allergy most often occurs in the central and southern regions, which corresponds to the distribution of the Lone Star tick. In the Southern United States, where the tick is most prevalent, allergy rates are 32% higher than elsewhere. However, as physicians are not required to report the number of patients with alpha-gal allergy, the true number of affected individuals is unknown. Arkansas was the first state to make alpha-gal syndrome a reportable condition in the United States. Alpha-gal has also been shown to exist in the saliva of Ixodes scapularis but not Amblyomma maculatum.

In 2021, University of Tennessee entomologist Becky Trout Fryxell reported that more cases of Alpha-Gal syndrome are occurring from those who encounter the Lone Star tick: "[The tick] likes to feed on dogs, deer, and seems to always find people as well," said Fryxell. "It has the ability to transmit a lot of pathogens too. And it's also associated with a tick meat allergy, which unfortunately is becoming pretty common."

Van Nunen, an immunologist specialising in allergies, had been practicing in a tick-prone area of Sydney, when 25 patients reported having allergic reactions to red meat after being bitten by ticks. She later concluded that the relatively sudden rise in cases was the result of a local fox baiting program that began in 2003. Foxes were introduced to Australia and had decimated the local indigenous bandicoot population, hence the fox baiting program. However, an unforeseen effect of the subsequent rise in the bandicoot population was the rise in ticks, as bandicoots are a major host for ticks, thus the number of humans suffering tick bites.

Alpha-gal allergies are similar to pork–cat syndrome; hence misidentification can occur. Pork–cat syndrome usually elicits an immediate allergic response, while a true alpha-gal allergy typically features a delayed allergic reaction of 3 to 8 hours after ingestion of the allergen.

In 2020, the U.S. Food and Drug Administration approved the genetic modification of pigs so they do not produce alpha-gal sugars. Pigs developed with the trademarked name GalSafe may be able to be eaten safely by people with alpha-gal allergy. They may also produce alpha-gal-safe drugs, and their organs can also be used for xenotransplantation.

New American guidelines published in 2023 recommended physicians to suspect alpha-gal syndrome in cases with abdominal pain and GI symptoms, but without traditional allergy symptoms like hives.