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Why do alpha-gal allergies only occur after a tick bite if alpha-gal is already present in red meat?

Why do alpha-gal allergies only occur after a tick bite if alpha-gal is already present in red meat?


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I just read an NPR article about allergies to red meat being caused by tick bites. That stood out to me because I thought allergies are triggered by an initial exposure to some allergen. In this case, the allergen is alpha-gal, a disaccharide found in cell membranes of most mammals; humans and apes are a notable exception. The article explains that ticks might cause this allergy by transferring alpha-gal from other animals to us when they feed on our blood.

However, we also are exposed to alpha-gal every time we eat red meat. How are we protected from allergic reactions when we eat red meat but not when we eat peanuts? Why does that protection fail after alpha-gal is exposed to our bloodstream?


In order for the immune system to respond to an antigen, beyond recognition of that antigen, there needs to be a signal that there is something wrong. Co-stimulation can take a few different forms, but it requires the involvement of more than just one arm of the immune system, and generally helps prevent our immune system from what I like to call the Dr. Strangelove effect (a psychotic lone general can just decide that there is a problem and launch an attack). Here, costimulation might be from (or downstream of) the tick bite and other invaders associated with the tick bite, or from an allergy to peanuts. You can read about this in the first chapter of Sompayrac's How the Immune System Works, as well as the first chapter of Abbas Basic Immunology.


Alpha-Gal syndrome Trade-off between allergy and protection to infectious diseases

Throughout the natural world there are countless essential interactions between hosts, vectors and pathogens. Vectors carry and transmit microorganisms that cause disease, known as pathogens, and hosts are affected by the pathogen. A common example of this process is the Lyme disease-tick-human relationship where Lyme disease caused by the pathogenic bacterium Borrelia burgdorferi is carried and transmitted by the tick vector to the human host.

The tick affects humans and other animals by biting them, infecting them with pathogens. Tick saliva contains both toxic and pharmacologically active substances which can trigger inflammatory reactions. Environmental factors and increasing levels of human outdoor activities have resulted in greater levels of contact between humans and ticks, and a consequent rise in tick-borne diseases.

Professor José de la Fuente and Dr Alejandro Cabezas-Cruz are unravelling the mysteries behind the allergic reactions that tick bites can cause. Cherries/Shutterstock.com

A tick bite can transmit deadly pathogens, but you might be surprised to hear that these tick bites can also help us understand protective immunity to infectious diseases. Professor José de la Fuente of the Instituto de Investigación en Recursos Cinegéticos, Spain, and Dr Alejandro Cabezas-Cruz of INRA, France, are experts in host-vector-pathogen interactions and their groups are working to develop therapeutic or preventive interventions for the control of allergic and infectious diseases.

Understanding the interactions between hosts, vectors and pathogens can help us to develop vaccines for infectious diseases.

Alpha-Gal syndrome
In addition to Lyme disease, tick bites can lead to Alpha-Gal Syndrome (AGS), a recently discovered allergy resulting in anaphylactic shock to red meat. Allergies occur as a result of hypersensitivity to a particular substance such as pollen, fur or food. In AGS, humans become hypersensitive to a carbohydrate known as α-Gal. Research has shown that α-Gal produced by ticks and introduced into the host by tick bites is responsible for this hypersensitivity as it elicits the production of high levels of an antibody known as immunoglobulin E (IgE). As humans don’t make α-Gal, when someone is bitten by a tick, the levels of anti-α-Gal IgE increase. Then, when a person is exposed to α-Gal through red meat consumption, or certain drugs, pre-existing anti-α-Gal IgE, together with basophils activation, leads to a severe allergic reaction and anaphylaxis.

A typical lesion known as ‘erythema migrans’ produced when a tick bite infects the human host with Borrelia burgdorferi.Photo Credit: James Gathany Content Providers(s): CDC/ James Gathany

Trade-off between AGS and susceptibility to infectious diseases
Obviously, these severe allergic reactions to α-Gal are undesirable. Seemingly paradoxical, immunity to α-Gal appeared during human evolution to protect us against pathogens containing α-Gal on their surface. Immunity to diseases is built up through exposure to pathogens: our immune system has the capacity to remember the pathogens and can produce antibodies faster upon a secondary exposure, so the threat is dealt with quickly. Humans have lost the capacity to produce α-Gal, meaning that no human cells will express this substance on the surface. Until humans are exposed to α-Gal, there are no antibodies present to help fight off pathogens. Exposure to α-Gal, through gut bacteria or pathogen infection allows humans to produce IgM and IgG antibodies. These antibodies provide protection against a lot of disease-causing pathogens that express α-Gal, including Plasmodium (malaria), Mycobacterium (tuberculosis, leprosy), Trypanosoma (sleeping sickness), Borrelia (Lyme disease) and Leishmania (Leishmaniasis). The fact that we have lost the ability to produce α-Gal means that we are better protected against pathogens, as in theory anything that enters our body expressing α-Gal is targeted for destruction. However, this comes at a price – an increased risk of developing AGS. This phenomenon is known as trade-off, when a desirable outcome comes with a detrimental cost. The cost being the increased risk of developing AGS and the desirable outcome the capacity of humans to produce anti-α-Gal antibodies that protect against deadly infectious diseases.

In order to better understand AGS and protection to infectious diseases, Professor José de la Fuente and Dr Alejandro Cabezas-Cruz sought to unravel the mysteries behind the allergic reactions that tick bites can cause. Their goal is to obtain a better understanding of AGS leading to better treatment and prevention.

Why is it only some individuals develop AGS in response to tick bites? This is one of the questions that the research teams are aiming to address. Photo Credit:Scott Bauer.

Answering outstanding questions
Professor José de la Fuente and Dr Alejandro Cabezas-Cruz’s latest publication is a consolidation of many years of previous research two key questions were raised by the researchers as grounds for further exploration. Firstly, research shows that only a proportion of the bitten cohort go on to experience symptoms of AGS. Why do only some individuals develop AGS in response to tick bites? Professor José de la Fuente and Dr Alejandro Cabezas-Cruz demonstrated that ticks can synthesise α-Gal carbohydrates, which humans cannot do. This helps to explain why humans can develop a potent immune response to tick bites, as evidenced by the red meat and cetuximab allergies that AGS sufferers’ experience. Although there are several theories as to the possible cause for the discrepancy in response between different people, currently there is no concrete answer. One possible suggestion for this variation is changes in the saliva composition of the tick throughout feeding. This would mean that only some host humans have the correct dose of compounds resulting in AGS. It could also be down to host’s biology – some α-Gal-containing proteins have been shown to be recognised by patients who have anaphylactic shocks to tick bites and not by healthy individuals with a record of tick bites. It’s therefore important that researchers study tick saliva composition across the feeding to better understand discrepancies in people developing AGS.

The team have uncovered some of the mysteries surrounding the trade-off between AGS and protection to infectious diseases.

Another mystery studied by the research groups involves understanding how IgE is produced in humans following a tick bite. There are two suggested mechanisms. The first suggests that α-Gal in tick salvia interacts with human cells involved in the immune response leading to elevated production of IgE. The second suggestion is yet to be demonstrated experimentally but it is proposed that the tick saliva hijacks the host human immune system switching IgM or IgG immune producing cells to produce IgE.

SaBio scientists working on the α-Gal syndrome: new insights into the tick-host conflict and cooperation project.

The second question the researchers sought to explore was whether humans can benefit from the risk of developing AGS. They discovered that the frequency of blood type B was positively correlated with the incidence of malaria and tuberculosis in endemic regions. The relation between blood type B and the incidence of these infectious diseases is the bona fide example of the trade-off intrinsic to the anti- α-Gal immunity. The structure of blood type B [Galα1-3(Fucαl,2)Gal] is very similar to antigen α-Gal because they share the disaccharide Galα1-3Gal (gal2). Accordingly, individuals with blood type B have a reduced antibody response against the related antigens α-Gal, gal2, and the blood antigen B. Therefore, self-tolerance to blood type B affects the immune response to α-Gal, which in turn increases the susceptibility to infectious diseases caused by pathogens carrying α-Gal on their surface and, at the same time, decreases the risk to develop AGS after a tick bite. This protective effect could be harnessed by using the gut bacteria of individuals to develop a probiotic-based vaccine that induces beneficial anti-α-Gal IgM immunity. The potential of a low cost and easy to administer treatment which could provide immunity from a large range of major infectious diseases around the world cannot be overstated.

When a human is bitten by a tick containing α-Gal in the saliva, high levels of anti-α-Gal IgE are produced and ingestion of red meat, that also contains α-Gal, triggers AGS. In a recent study (4), the group searched the Ixodes scapularis genome for the presence of galactosyltransferases and three genes were identified as potentially involved in the synthesis of α-Gal. This conclusion was based on the following evidences. (1) Heterologous gene expression in α-Gal-negative cells induces the cells to produce α-Gal. (2) Gene silencing in ticks reduced the levels of α-Gal. (3) Gene silencing in ticks affected tick feeding, suggesting that α-Gal is essential for tick survival.

The bright future of α-Gal syndrome research
Clearly, there is great potential for many people around the world to benefit from the research conducted by groups led by Professor José de la Fuente and Dr Alejandro Cabezas-Cruz. Any reduction to devastating impact of major infectious diseases would have far-reaching consequences for global health.

The research from this collaborative partnership improves our understanding of AGS and the causes of this potentially deadly disease. Future research into this topic will seek to clarify the specific mechanism between pathogen, vector and host causing AGS. Professor José de la Fuente and Dr Alejandro Cabezas-Cruz will focus on identifying tick proteins involved in the production of IgE antibodies after the tick bite and the immune mechanisms that lead to AGS. As well as treatment development, this research may also help to raise awareness of the symptoms and causes of AGS which will be an important public health benefit. Previous data gathered by the team will be essential to any future work and their theories concerning the importance of gut microbiota may have even further reaching consequences.

Going forward, this consolidation of previous research provides a good foundation for the team to continue to build upon and to develop innovative solutions to treat global infectious diseases.

Personal Response

Of the potential consequences of your research, which do you think has the biggest potential to impact global health? And which excites you most?
The characterisation of the mechanisms triggering the AGS to develop interventions to better monitor, diagnose, treat and prevent this allergic disease. The development of a probiotic-based pan-vaccine that can be used to control major infectious diseases caused by pathogen with α-Gal on their surface.


Alpha Gal, the "tick(?) meat" allergy

I read a couple of articles about the tick meat allergy and have a friend who has tested positive for having it (the test is a scale, not binary--I don't know what her specific results were), but I wasn't convinced that it actually existed until testing positive for it myself (well, there's a lot of uncertainty about it, so I'm still not entirely sure what's going on, though I did test solidly positive for it).

What's particularly strange (aka: created in a lab) about this allergic reaction is that it's delayed (most people experience reactions 3-6 hours after eating mammal meat) and the reaction is to a carbohydrate ("galactose-alpha 1,3-galactose (alpha-gal), an oligosaccharide"1) that exists in the meat, rather than to a protein.

Some background information:

Richmond - The ticks were so bad last summer that Dr. Fred Robinson, a retired cardiologist, could hardly go for a walk in his yard in Midlothian without coming in to find a tick somewhere on his body.

They were a nuisance, but he now suspects they also are to blame for an unusual allergic reaction he has developed to beef.

It sounds improbable, but allergy doctors say patients such as Robinson are cropping up more and more, and research is pinning down a plausible explanation for what may be happening.

Much of that research is being done at the University of Virginia, where studies are also trying to help patients whose only remedy so far is to give up beef or other red meats.
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Cases such as his seem to be becoming more common, said Dr. Scott P. Commins, an assistant professor of medicine and an expert on allergies and immunology. Commins is part of a team overseeing several tick-bite meat-allergy studies at UVa.

Commins and his mentor, Dr. Thomas Platts-Mills, have coauthored several published papers on the topic since 2009. The latest paper, published in the May issue of The Journal of Allergy and Clinical Immunology, suggests that tick bites are a cause - and possibly the only cause - of the allergic reactions to red meat.

"We think there is something in the saliva [of ticks] that triggers some people's immune systems to make an antibody," Commins said.

Antibodies are substances the body makes to defend itself against potentially harmful bacteria, toxins and other harmful invaders. Allergic reactions occur when the allergic class of antibody binds to the substance it recognizes (i.e. the allergen), a process that results in the release of histamine, Commins explained. It is histamine that can cause swelling, hives and breathing problems.

Researchers believe the tick bite causes production of an antibody to a carbohydrate called alpha-gal, which also happens to be present on red meat.

Why do there seem to be more cases now?

Part of it may be that past cases went unrecognized.

"The unique thing is these people react four to six hours after they eat the food, so they don't associate the food ingestion with the allergic reaction," said Dr. Michael Blumberg, a Richmond allergist at Virginia Adult & Pediatric Allergy & Asthma. "I am sure we missed a lot of people . in the last 10 years. We didn't realize this as a probable cause."

There also may be more ticks, and more ticks with the bacterium in their saliva.

"One thought is that the range of ticks, just like the land they occupy, is more now than it was 15 or 20 years ago," Commins said.

For the latest paper, Commins and his coauthors screened hundreds of human blood samples from populations in the United States where tick bites are common and uncommon and from tropical areas in Africa and Central America where tick bites are common. They also created maps that show overlapping areas where meat allergy cases are occurring and where tick populations are increasing, suggesting a correlation.

Commins and his research team are also studying people with the allergy in controlled laboratory conditions.

For some people, any red meat is a trigger.

"It doesn't really matter for patients whether its beef, or pork or lamb or buffalo or venison. And it's hard to think of something that would cross all those different kinds of animals," Commins said. "So it seems that it's really just the fact that these sources of meat all come from mammals."

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"It's so new that we don't know exactly the full story of how people develop this reaction and the history of the allergy," Matos said.
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The Asthma and Allergy Center also has identified patients who have had milder symptoms, such as chronic itching or vague intestinal problems, who test positive for the allergy. In some instances patients had gone decades without knowing the cause of their discomfort.
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Researchers discovered some patients had a bad reaction after taking Erbritux, the anti-cancer drug at the center of the insider trading allegations against Stewart. Some of these patients would have anaphylaxis.

Researchers, who included Commins' boss Dr. Thomas Platts-Mills, ultimately showed the negative reactions to the drug were associated with an allergic reaction to a sugar called galactose-alpha-1,3-galactose, or alpha-gal for short.

A study about it was published in 2008 in the New England Journal of Medicine. Ultimately the drug manufacture changed the way Erbritux was made to stop the problem.

But because nearly all common allergies are reactions to proteins, not sugars, Commins said he was extremely interested in the discovery.

Areas in the Southeast appeared to be unusually hard-hit by the severe reactions to Erbritux, so Commins decided to investigate how common the alpha-gal reaction was among anaphylaxis patients where the cause was unknown. About 20 percent of anaphylaxis patients don't know the cause.
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The connection to ticks

Figuring out why patients had suddenly developed a severe allergy to meats in which alpha-gal was present was the next step.

Commins quickly realized that the geographic range of the Lone Star tick matched the geographic location of people who had developed this allergy. Both were in the Southeast.

"It just fits perfectly," he said.

Commins started asking his patients about their exposure to tick bites and chiggers.

"A lot of science can be serendipity," he said. "My boss [Platts-Mills] goes out in the woods a lot. He got chigger bites or seed ticks. He developed this allergy. So we started to make the connection."

Masters too has had a lot of tick bites and chigger bites. Last year, prior to her July 4, 2009, reaction, she said she was bitten by about a dozen ticks and hundreds of chiggers.

Commins said outdoor enthusiasts, including hunters and hikers, are often the type of people diagnosed with the allergy. He strongly believes it is related to the seed tick bites that people get by the hundreds. These are the bites from the newly hatched tick larva, as opposed to a mature adult tick. Often, he said, people in this area call these tiny ticks chiggers.

It's unclear what in the seed ticks is causing people to develop the allergy.

"My honest gut feeling is it is something in the saliva," Commins said.

He said that unlike Lyme disease and Rocky Mountain spotted fever, he doesn't think it is an infectious disease carried by the seed tick. Instead he thinks something in the saliva triggers the antigens in the alpha-gal sugar.
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But for now, the only solution to treating the allergy is avoiding meat products. For Masters and many others, this includes avoiding foods made with beef broth.

From these two articles, it doesn't look like they've actually established a causation effect between the ticks and the alpha gal allergic reaction. I've lived in the Southeast USA for a number of years off and on for the last 5 years and been bitten by some, but not what I'd consider a large number of, ticks and what I thought might have been chiggers but may have been the very small ticks that Commins talks about in the roanoke.com (Roanoke is a city in Virginia) article, so I do think there might be something to that.

This is dealing more with the probable conspiracy side:

Significantly, meat-induced anaphylaxis is the first food-induced severe allergic reaction due to a carbohydrate rather than a protein. It is also the first time anaphylaxis has been noted to be delayed rather than occurring immediately after exposure. This was an intentional design by the genetic engineers who have studied population complaint and historical records on insect bites to acute and primary care practitioners knowing that the majority of the population would not suspect the reactions to be caused or born from tick bites if they were sufficiently delayed.

Researcher and entomologist Jaime Lombard says the ticks have been in circulation for a few years however the latest crop released are becoming more potent. "Scientists have been experimenting on ticks since the 1960s because of their ability to spread disease. Since then, genetically engineered ticks have become more potent and scientists can create human disease almost at will," he stated.

This last part may explain why some people have had this allergy for decades (there are just a few comments of people who have had this for a long time in this Huffington Post article: _http://www.huffingtonpost.com/2012/11/09/alpha-gal-meat-allergy-lone-star-ticks_n_2102340.html) and why more people might be getting it now and potentially having more severe reactions.

There's some evidence that doesn't seem to line up well with the Lone Star tick theory (maybe similar to Lone gunmen theories?):

Tick bites have long been synonymous with bad news, responsible for transmitting diseases such as Lyme disease, Ehrlichiosis, and Rocky Mountain spotted fever, but this must be a carnivore or BBQ lover's worst nightmare. A growing body of research suggests that bites from a particular tick are causing an unusual allergic reaction to meat. At an allergy meeting last week, for example, a diagnostics lab presented evidence that the highest prevalence of the allergy is in the southeastern United States, where the tick primarily thrives. Yet American BBQ lovers and carnivores elsewhere may not rest easy the allergy mysteriously afflicts people living in parts of the United States, even Hawaii, where the tick does not live.

The meat allergy, known as alpha-gal for a sugar carbohydrate found in beef, lamb, and pork, produces a hivelike rash - and, in some people, a dangerous anaphylactic reaction - roughly 4 hours after consuming meat. But unlike other common food allergies, the alpha-gal allergy has been found only in people who have been bitten by ticks - specifically the lone star tick, previously best known for causing a condition called southern tick-associated rash illness, the symptoms of which include rash, fatigue, headache, fever, and muscle pains. "You have to have a tick bite to then trigger the immune reaction," Stanley Fineman, an allergist and president of American College of Allergy, Asthma and Immunology (ACAAI).

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Allergy researcher Thomas Platts-Mills of the University of Virginia (UVA) in Charlottesville has been studying the alpha-gal reaction since 2002, when he began investigating an unusual sensitivity to the cancer drug cetuximab, which contains the same alpha-gal sugar as meat. Cancer patients who demonstrated an allergic reaction to the drug were nearly exclusive to the southeastern United States and were also found to have high levels of alpha-gal antibodies, Platts-Mills explains. Furthermore, some of them, along with other noncancer patients in the same region, also reported having severe allergic reactions after eating meat. Platts-Mills later published the relationship between alpha-gal antibodies and the cetuximab allergy in The New England Journal of Medicine.

But Platts-Mills only began to suspect the connection between the alpha-gal antibodies and the ticks after he was bitten by several ticks while hiking and contracted the allergy himself in 2007. His antibody levels jumped significantly after the tick bites, he found. In 2009, he and UVA colleague Scott Commins reported the link between alpha-gal and the meat allergy in The Journal of Allergy and Clinical Immunology - and suggested a possible link between the ticks and alpha-gal based on a more than 80% rate of reported tick bites among the patients before exhibiting symptoms.

In 2011, Platts-Mills and others were able to confirm that the bites cause an increase in alpha-gal antibodies. But so far, he says, no one is sure exactly which substance in the tick saliva is responsible for the development of alpha-gal antibodies.
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Although the initial cases of alpha-gal allergy were found in lone star tick-laden regions, incidences of the allergy are no longer limited to this tick's favorite haunt, says Michelle Altrich, the clinical laboratory director of Viracor-IBT Laboratories, one of two main reference labs offering a diagnostic assay for the alpha-gal allergy. Last week, at ACAAI's annual scientific meeting in Anaheim, California, researchers from Viracor revealed that although the highest number of reported cases of alpha-gal allergy were found in the southeastern United States, the allergy - which has affected about 1500 people and counting - has also been seen in large numbers well outside known lone star tick areas.

"We were curious to know whether the prevalence of the allergy actually overlaid with the tick or if it was different," Altrich explains. Of the samples submitted for testing, she says, "we saw a trend in positive results to the southeastern U.S. with the tick, but interestingly we also found positive rates varying from 4% to 23% outside of the tick area. We've actually had positives as far west as Hawaii." Why that is isn't clear, Altrich says. One possibility is that those diagnosed with the allergy in places like Hawaii were actually bitten while traveling in a high-tick area like Tennessee, she says.

Another possibility is that the ticks are growing in number and their territory is spreading to adjacent states. The distribution, range, and abundance of the lone star tick has increased steadily in the past 20 to 30 years, according to the U.S. Centers for Disease Control and Prevention - likely concurrent with an explosion of populations of deer, the tick's primary host. Platts-Mills says the increasing number of cases may also be explained in part by the sheer number of bites inflicted by this particular species of tick. "This tick is very aggressive. Its larval forms will bite humans, whereas none of the other American tick larvae will do that," he says.

Preventing the tick bites is the only way to stop the allergy before it starts - but Platts-Mills says once a person has the allergy, there is some evidence that if they don't continue to get bitten they will eventually get better. But until then, it's best to pass on the BBQ.

So they seem pretty certain that tick bites at least cause an increase in antibodies, but still don't have a mechanism for causation and the data for who has the allergy suggests that it may not be exclusively the Lone Star tick, or possibly ticks being the cause at all.

The first time I ate grass fed beef in February or March of 2011 after having not eaten it for 7 years (possibly having eaten no red meat for 7 years, but definitely at least beef--4 of those 7 years I was vegan, no meat at all), I got hives. I don't recall if they were a delayed reaction and I didn't have them again, so I just thought it was some strange reaction after not having eaten beef for so long. Summer of 2011 I was in the Southeast again and got bitten by something at various times (probably some ticks, maybe some other bugs) and started to feel worse without any clear cause. So it's possible that I got the allergy long ago when living in the Southeast, but moved and probably didn't get bitten by many, if any, ticks for around two years, along with being out of the Southeast, and didn't have as much as an allergic reaction as I might have had before, but then got bit more and it got worse. It's hard to really determine the specifics without the mechanism of causation, at least for me.

Some more information:
_http://allergytomeat.wordpress.com/frequently-asked-questions/

When certain people are bitten by ticks or chiggers, the bite appears to set off a chain of reactions in the body. One of these reactions is the production of an allergic class of antibody that binds to a carbohydrate present on meat called galactose-alpha-1,3-galactose, also known as alpha-gal. When a person with the alpha-gal antibody eats mammalian meat, the meat triggers the release of histamine. Histamine is a compound found in the body that causes allergic symptoms like hives, itching and, in the worst case, anaphylaxis (a reaction that leads to sudden weakness, swelling of the throat, lips and tongue, difficulty breathing and/or unconsciousness).

In addition to the classic allergy symptoms, some of our patients report significant gastrointestinal distress or gynecological symptoms. These symptoms can take the form of abdominal cramping and pain, heartburn, diarrhea, nausea or vomiting and in some cases uterine cramping with spotting. It is not uncommon for a patient who has anaphylaxis to lose consciousness while moving their bowels. Some patients have reactions that are characterized almost entirely of GI or gynecological symptoms while others may not experience these types of symptoms at all.

My symptoms mainly consisted of fatigue, rapid heart rate, some difficulty breathing, nausea, reflux, bowel problems, and I think sometimes more classical symptoms like sneezing and possibly mucus production (hard to isolate this with certainty). For some reason, I think magnesium made it worse--I'm really not sure why this might have been the case, but I had really a negative response (very rapid heart rate and felt pretty awful) to it one evening, though something else could have been going on. Cutting out mammal meat and butter has helped quite a bit, though I may still be having lingering effects or some other issue as not everything's cleared up yet. Right now, I'm on chicken and duck, ghee and duck fat, and fish at times. I've been completely off mammal meat for about a month and off butter for about a week.

What I don't understand is the variation of symptoms in different people and why, if it's supposed to be a histamine release, aren't the symptoms more regularly classical allergy symptoms for everyone? I'm not an expert on allergy mechanisms, so perhaps I just don't understand due to lack of knowledge in this area.

No, we do not. During the evolution of our species, the enzyme that leads to the production of alpha-gal was inactivated. The only mammals that do not have it are humans, old world monkeys and great apes.

I think I have this allergy but I only have a reaction after eating beef. Is that possible?

Yes. We have seen many people who only react to only one or two of the mammalian meats. We do not know for sure exactly why this happens. We believe that there is a connection between the fat content of the meat and the way the body reacts to it. Meats with more fat like hamburgers seem to cause more reactions than lean meats like venison.

Because I wasn't entirely convinced about this alpha gal allergy when I got tested, I asked to be tested to beef and pork via blood as well (both positive) and beef, pork, and lamb via skin. The skin tests weren't as clear--beef was the largest and they determined it was positive, but the pork and lamb were smaller and the doctor considered them negative. I didn't get a blood test for lamb.

And another question comes up with this--why do some people who have tested positive for alpha gal react to some meats, but not others?

It's also interesting that, anecdotally, leaner meats cause fewer reactions.

It can go away over time with avoiding tick bites? Really strange.

What do the test results mean?

You will receive a number that indicates the amount of alpha-gal specific antibody you have in your blood. Any number above 0.35 is considered to be positive. A higher number does not necessarily indicate worse symptoms but, in general, people with lower numbers (2-3 IU/mL) seem to be able to tolerate small amounts of lean meat without much difficulty.

My result was 6.5. Viracor (one of the testing companies) gives a range here:

There is a small amount of alpha-gal in dairy products (milk, yogurt, cheese, butter, cream, etc.). Most people who test positive for this allergy are still able to eat dairy without problems. However, if you have any lingering symptoms or just do not feel “right” after giving up mammalian meat, you might consider avoiding dairy as well. Some people with really bad reactions have found that to be helpful. If you are feeling fine, we suggest keeping milk in your diet as it may offer some amount of tolerance to alpha-gal.

Gelatin is a substance made from animal products. It is in many foods including certain candies, marshmallows and other desserts. Some medications are also put in gelatin capsules. Gelatin does have alpha-gal in it. We have heard from at least one person who had a reaction after eating candy with gelatin in it. If you are particularly sensitive to mammalian meat products, you might consider avoiding gelatin.

I think I can confirm at this point that butter is also a problem for me. Ghee seems to be doing well for me so far, for the most part, but I'm not entirely certain about it, especially whether it's entirely free of the alpha gal. There aren't really many options for fat left without ghee, though, as it's not really easy or affordable to buy duck fat in america, as far as I'm currently aware.

Is it possible that the allergy is caused by hormones, pesticides or other chemicals found in meat?

While certain people with this allergy report having fewer or less severe reactions after eating all natural meat, we have also heard from people who have had severe reactions after eating wild meat from animals they hunted or all natural meat from reputable sources. It is possible that the chemicals found in industrially produced meat exacerbate certain people’s reactions but the connection is unclear at this time.

I suspect that being paleo and ketogenic probably help (since they help with basically everything else) along with eating healthy meat, but I was also eating healthy meat, in ketosis, eating bone broth, and still having problems.

So at this point, I'm pretty sure that this allergy actually exists and that I have it. I think ticks probably play some role in it, but it's really quite a strange thing with a lot of questions still unanswered, as far as I can tell. I'm also still pretty early in the testing phase of this hypothesis, so I don't have a very conclusive set of n=1 results yet.


Finally, A Diagnosis

I was back in my doctor’s office and after I described my symptoms, he recommended I see an Allergist/Immunologist. I am also a three-time cancer survivor, so my health history sometimes complicates medical visits and seeing a specialist at that point felt like the right move.

I was lucky enough to find Dr. Tina Merritt in Bentonville, Arkansas, who happened to also have Alpha-gal syndrome. When I described my symptoms [which can vary for each individual], she was the first medical provider who did not greet me with skepticism or a “you’ll have to live with it” mentality. In fact, she listened intently and told me that what I was describing sounded like Alpha-gal syndrome. I had never heard of it before, but I was grateful for some sort of hope that I may just be getting answers soon. Dr. Merritt began with skin prick testing which showed a reaction to a number of things like wheat, peanut and several types of grasses and trees. She sent me to the lab for bloodwork the very same day, and two days later I had the answers I’d been waiting on for two years. Dr. Merritt’s suspicions were confirmed. I was AGS positive. The bloodwork also confirmed peanut, wheat, soy and a number of other allergies that were never present prior to my diagnosis. While it wasn’t the most optimal answer, it was an answer. And that is more than I’d had previously. While I had eliminated peanut, dairy, wheat and soy six months prior to my diagnosis, I was still eating beef and other mammalian meat like pork and venison. And then it hit me. Every time I ate those things, angioedema and severe gastric issues occurred. AGS reactions are often delayed since food takes time to go through the entire digestive system. My life changed that day. And it was all caused by a tick…


Symptoms of Tickborne Illness

Many tickborne diseases can have similar signs and symptoms. If you have been bitten by a tick and develop the symptoms below within a few weeks, a health care provider should evaluate the following before deciding on a course of treatment:

  • Your symptoms
  • The geographic region in which you were bitten
  • Diagnostic tests, if indicated by the symptoms and the region where you were bitten

The most common symptoms of tick-related illnesses are:

  • Fever/chills: With all tickborne diseases, patients can experience fever at varying degrees and time of onset.
  • Aches and pains: Tickborne disease symptoms include headache, fatigue, and muscle aches. With Lyme disease you may also experience joint pain. The severity and time of onset of these symptoms can depend on the disease and the patient&rsquos personal tolerance level.
  • Rash: Lyme disease, southern tick-associated rash illness (STARI), Rocky Mountain spotted fever (RMSF), ehrlichiosis, and tularemia can result in distinctive rashes:
    • In Lyme disease, the rash may appear within 3-30 days, typically before the onset of fever. The Lyme disease rash is the first sign of infection and is usually a circular rash called erythema migrans or EM. This rash occurs in approximately 70-80% of infected persons and begins at the site of a tick bite. It may be warm, but is not usually painful. Some patients develop additional EM lesions in other areas of the body several days later.
    • The rash of (STARI) is nearly identical to that of Lyme disease, with a red, expanding &ldquobulls eye&rdquo lesion that develops around the site of a lone star tick bite. Unlike Lyme disease, STARI has not been linked to any arthritic or neurologic symptoms.
    • The rash seen with Rocky Mountain spotted fever (RMSF) varies greatly from person to person in appearance, location, and time of onset. About 10% of people with RMSF never develop a rash. Most often, the rash begins 2-5 days after the onset of fever as small, flat, pink, non-itchy spots (macules) on the wrists, forearms, and ankles and spreads to the trunk. It sometimes involves the palms and soles. The red to purple, spotted (petechial) rash of RMSF is usually not seen until the sixth day or later after onset of symptoms and occurs in 35-60% of patients with the infection.
    • In the most common form of tularemia, a skin ulcer appears at the site where the organism entered the body. The ulcer is accompanied by swelling of regional lymph glands, usually in the armpit or groin.
    • In about 30% of patients (and up to 60% of children), ehrlichiosis can cause a rash. The appearance of the rash ranges from macular to maculopapular to petechial, and may appear after the onset of fever.

    Tickborne diseases can result in mild symptoms treatable at home to severe infections requiring hospitalization. Although easily treated with antibiotics, these diseases can be difficult for physicians to diagnose. However, early recognition and treatment of the infection decreases the risk of serious complications. So see your doctor immediately if you have been bitten by a tick and experience any of the symptoms described here.

    &ldquoTarget&rdquo lesion on patient with Lyme disease.

    1. Site of tick bite
    2. Red, radial, expanding edge of rash
    3. Central clearing

    Photograph used with permission from the Journal of Infectious Diseases.

    Late (petechial) rash on hand and forearm in patient with Rocky Mountain spotted fever.


    Meat allergy caused by tick bites turns comforts of home into a deadly terrain

    It is early morning in early summer, and I am tracing my way through the woods of central North Carolina, steering cautiously around S-curves and braking hard when what looks like a small rise turns into a narrow bridge. I am on my way to meet Tami McGraw, who lives with her husband and the youngest of their kids in a sprawling development of old trees and wide lawns just south of Chapel Hill. Before I reach her, McGraw emails. She wants to feed me when I get there:

    “Would you like to try emu?” she asks. “Or perhaps some duck?”

    These are not normal breakfast offerings. But for years, nothing about McGraw’s life has been normal. She cannot eat beef or pork, or drink milk or eat cheese or snack on a gelatine-containing dessert without feeling her throat close and her blood pressure drop. Wearing a wool sweater raises hives on her skin inhaling the fumes of bacon sizzling on a stove will knock her to the ground. Everywhere she goes, she carries an array of tablets that can beat back an allergy attack, and an auto-injecting EpiPen that can jolt her system out of anaphylactic shock.

    McGraw is allergic to the meat of mammals and everything else that comes from them: dairy products, wool and fibre, gelatine from their hooves, char from their bones. This syndrome affects some thousands of people in the USA and an uncertain but likely larger number worldwide, and after a decade of research, scientists have begun to understand what causes it. It is created by the bite of a tick, picked up on a hike or brushed against in a garden, or hitchhiking on the fur of a pet that was roaming outside.

    The illness, which generally goes by the name “alpha-gal allergy” after the component of meat that triggers it, is a trial that McGraw and her family are still learning to cope with. In much the same way, medicine is grappling with it too. Allergies occur when our immune systems perceive something that ought to be familiar as foreign. For scientists, alpha-gal is forcing a remapping of basic tenets of immunology: how allergies occur, how they are triggered, whom they put in danger and when.

    Recommended

    For those affected, alpha-gal is transforming the landscapes they live in, turning the reliable comforts of home ­– the plants in their gardens, the food on their plates – into an uncertain terrain of risk.

    In 1987, Dr Sheryl van Nunen was confronted with a puzzle. She was the head of the allergy department at a regional hospital in the suburbs of Sydney, Australia, and had a reputation among her colleagues for sorting out mysterious episodes of anaphylaxis. This time, a man had been sent to see her who kept waking up, in the middle of the night, in the grip of some profound reaction.

    Van Nunen knew at once that this was out of the ordinary, since most allergic reactions happen quickly after exposure instead of hours later. She also knew that only a few allergens affect people after they have gone to bed. (Latex, for instance – someone sensitive to it who has sex using a latex condom might fall asleep and wake up in the midst of an allergy attack.) She checked the man for the obvious irritants and, when those tests came up negative, took a thorough look at his medical history and did a skin test for everything he had eaten and touched in the hours before bedtime. The only potential allergen that returned a positive result was meat.

    This was weird (and dismaying, in barbecue-loving Australia). But it was the only such case van Nunen had ever seen. She coached the patient on how to avoid the meals that seemed to be triggering his reactions, put it down mentally to the unpredictability of the human immune system, and moved on.

    Then a few more such patients came her way. There were six additional ones across the 1990s by 2003, she had seen at least 70, all with the same problem, all apparently affected by meat they had eaten a few hours before. Groping for an explanation, she lengthened the list of questions she asked, quizzing the patients about whether they or their families had ever reacted to anything else: detergents, fabrics, plants in their gardens, insects on the plants.

    “And invariably, these people would say to me: ‘I haven’t been bitten by a bee or a wasp, but I’ve had lots of tick bites,’” van Nunen recalls.

    In her memory, Tami McGraw’s symptoms began after 2010. That was the year she and her husband Tom, a retired surgeon, spied a housing bargain in North Carolina, a development next to a nature reserve whose builder had priced the big houses to sell. The leafy spread of streams and woodland pockets was everything she wanted in a home. She didn’t realise that it offered everything that deer and birds and rodents, the main hosts of ticks, want as well.

    She remembers one tick that attached to her scalp, raising such a welt the spot was red for months afterwards, and a swarm of baby ticks that climbed her legs and had to be scrubbed off in a hot bath laced with bleach. Unpredictably, at odd intervals, she began to get dizzy and sick.

    “I’d have unexplained allergic reactions, and I’d break out in hives and my blood pressure would go crazy,” she told me. The necklines of all her T-shirts were stretched, because she tugged at them to relieve the feeling she couldn’t take a deep breath. She trekked to an array of doctors who diagnosed her with asthma or early menopause or a tumour on her pituitary gland. They prescribed antibiotics and inhalers and steroids. They sent her for MRI scans, pulmonary function tests, echocardiograms of her heart. Nothing yielded a result.

    Looking back, she realises she missed clues as to the source of her problem. She always seemed to need to use an asthma inhaler on Wednesdays – the day she spent hours in her car, delivering steaming-hot dinners for Meals on Wheels. She would feel short of breath, and need to visit an urgent-care clinic, on Saturdays – which always started, in her household, with a big breakfast of eggs and sausages.

    Then a close friend had a scary episode, going for a run, arriving home and passing out on the hot concrete of her driveway. Once she was recovered, McGraw quizzed her. Her friend said: “They thought I got stung by a bee while I was running. But now they think maybe I have a red-meat allergy.”

    McGraw remembers her first reaction was: That’s crazy. Her second was: Maybe I have that too.

    She Googled, and then she asked her doctor to order a little-known blood test that would show if her immune system was reacting to a component of mammal meat. The test result was so strongly positive, her doctor called her at home to tell her to step away from the stove.

    That should have been the end of her problems. Instead it launched her on an odyssey of discovering just how much mammal material is present in everyday life. One time, she took capsules of liquid painkiller and woke up in the middle of the night, itching and covered in hives provoked by the drug’s gelatine covering.

    When she bought an unfamiliar lip balm, the lanolin in it made her mouth peel and blister. She planned to spend an afternoon gardening, spreading fertiliser and planting flowers, but passed out on the grass and had to be revived with an EpiPen. She had reacted to manure and bone meal that were enrichments in bagged compost she had bought.

    She struggled with the attacks’ unpredictability, and even more with the impact on her family. “I think I’m getting better, and then I realise I’m not,” she says. “I’m more knowledgeable about what I can and can’t do.”

    The discovery of new diseases often follows a pattern. Scattered patients realise they are experiencing strange symptoms. They find each other, face to face in a neighbourhood or across the world on the internet. They bring their experience to medicine, and medicine is sceptical. And then, after some period of pain and recalcitrance, medicine admits that, in fact, the patients were right.

    That is the story of the discovery of CFS/ME and Lyme disease, among others. But it is not the story of alpha-gal allergy. An odd set of coincidences brought the bizarre illness to the attention of researchers almost as soon as it occurred.

    The story begins with a cancer drug called cetuximab, which came onto the market in 2004. Cetuximab is a protein grown in cells taken from mice. For any new drug, there are likely to be a few people that react badly to it, and that was true for cetuximab. In its earliest trials, one or two of every 100 cancer patients who got it infused into their veins had a hypersensitivity reaction: their blood pressure dropped and they had difficulty breathing.

    That 1-2 per cent stayed consistent as cetuximab was given to larger and larger groups. And then there was an aberration. In clinics in North Carolina and Tennessee, 25 of 88 recipients were hypersensitive to the drug, with some so sick they needed emergency shots of epinephrine and hospitalisation. At about the same time, a patient who was receiving a first dose of cetuximab in a cancer clinic in Bentonville, Arkansas, collapsed and died.

    The manufacturers, ImClone and Bristol-Myers Squibb, checked every obvious thing about the trial: the drug’s ingredients, the cleanliness of the manufacturing plants, even the practices at the medical centres where cetuximab had been administered. Nothing stood out. The most that researchers could guess at the time was that the unlucky recipients might have some kind of mouse allergy.

    Then the first coincidence occurred: a nurse whose husband worked at the Bentonville clinic mentioned the death to Dr Tina Hatley, an immunologist in private practice in Bentonville. Hatley had recently finished postgraduate training at the University of Virginia’s allergy centre, and she mentioned the death to her former supervisor, Dr Thomas Platts-Mills.

    Tami carries an array of tablets that can beat back an allergy attack, and an auto-injecting EpiPen that can jolt her system out of anaphylactic shock

    The bad responses to the drug looked like allergic reactions, and they were common enough – and far enough from the manufacturer’s expectations – to be an intriguing research opportunity.

    Platts-Mills pulled together a team, looping in Hatley and several current research fellows as well. Fairly quickly, they discovered the source of the problem. People were reacting to the drug because they had a pre-existing sensitivity, indicated by a high level of antibodies (called immunoglobulin E, or IgE for short) to a sugar that is present in the muscles of most mammals, though not in humans or other primates. The name of the sugar was galactose-alpha-1,3-galactose, known for short as alpha-gal.

    Alpha-gal is familiar to many scientists because it is responsible for an enduring disappointment: its ability to trigger intense immune reactions is the reason that organs taken from animals have never successfully been transplanted into people. The puzzle was why the drug recipients were reacting to it. To have an allergic reaction, someone needs to have been primed with a prior exposure to a substance – but the trial recipients who reacted badly were all on their first dose of cetuximab.

    Team members scrutinised the patients and their families for anything that could explain the problem. The reactions appeared regional – patients in Arkansas and North Carolina and Tennessee experienced the hypersensitivity, but ones in Boston and northern California did not. They investigated parasites, moulds and diseases that occur only in pockets of the USA.

    Then Dr Christine Chung, a Nashville researcher recruited to the team, stumbled on an intriguing clue. Almost one in five of the patients enrolled at a cancer clinic at her hospital had high levels of IgE to alpha-gal. But when she checked those patients’ near neighbours, treating them as a control group – that is, people who lived their lives in the same way, but did not have cancer and had no reason to have received the drug – almost one in five had antibodies to alpha-gal as well.

    Almost a decade later, that correlation still makes Platts-Mills chuckle. The alpha-gal reaction “had nothing to do with cancer,” he says. “It had everything to do with rural Tennessee.”

    The question then became: what in rural Tennessee could trigger a reaction like this? The answer arose from a second coincidence. Dr Jacob Hosen, a researcher in Platts-Mills’s lab, stumbled across a map drawn by the Centers for Disease Control and Prevention (CDC) showing the prevalence of an infection called Rocky Mountain spotted fever. It exactly overlapped the hot spots where the cetuximab reactions had occurred.

    Rocky Mountain spotted fever is transmitted by the bite of a tick: Amblyomma americanum, one of the most common ticks in south-eastern USA. It’s known as the lone star tick for a blotch of white on the back of the female’s body.

    The researchers wondered – if the mystery reactions shared a footprint with a disease, and ticks caused the disease, could ticks be linked to the reactions too?

    It was an intriguing hypothesis, and was reinforced by a new set of patients who came trickling into Platts-Mills’s clinic at about the same time. They were all adults, and that was odd to start with, because allergies tend to show up in childhood. They had never had an allergic reaction before, but now they were experiencing allergy symptoms: swelling, hives and in the worst cases anaphylactic shock. They too had high levels of IgE antibodies to alpha-gal.

    None of them, though, were cancer patients. They told the physicians that they had no proof of what was causing their reactions – but more than a few of them sensed it had something to do with eating meat.

    Dr Scott Commins, another postgraduate fellow in Platts-Mills’s group, took it upon himself to phone every new patient to ask whether they’d ever suffered a tick bite. “I think 94.6 per cent of them answered affirmatively,” he says. “And the other few per cent would say, ‘You know, I’m outdoors all the time. I can’t remember an actual tick that was attached, but I know I’d get bites.’”

    Meat from mammals inevitably contains alpha-gal – so in already sensitised individuals, eating meat might constitute a second exposure, in the same way infusing cetuximab had been.

    If tick bites had sensitised them, then the alpha-gal reaction might be a food allergy as well as a drug reaction. But the connection was speculative, and cementing cause and effect would take one final, extraordinary coincidence.

    As it happens, Platts-Mills likes to hike. One weekend he took off across the central Virginia hills, tramping through grassy underbrush. He came home five hours later, peeled off his boots and socks, and discovered his legs and feet were speckled with tiny dots. They looked like ground pepper, but they were dug into his skin – he had to use a dull knife to scrape them off – and they itched something fierce. He saved a few, and sent them to an entomologist. They were the larval form of lone star ticks.

    This, he realised, was an opportunity. As soon as the work week started, he had his lab team draw his blood and check his IgE levels. They were low to start with, and then week by week began to climb. Platts-Mills is English – his father was a Member of Parliament – and in the midst of having his IgE tracked, he went to an event at the Royal Society of Medicine in London. “And at that point,” he says cheerfully, “I ate two lamb chops and drank two glasses of wine.”

    In the middle of the night, he woke up covered in hives.

    The lone star tick doesn’t receive much attention in the USA. It’s the black-legged tick, Ixodes scapularis, that has the dubious honour of being the most well-known, as it’s the carrier of Lyme disease, which causes an estimated 300,000 cases of illness in the USA each year.

    The lone star tick doesn’t transmit Lyme disease, but is the vector for other serious illnesses, including Q fever, ehrlichiosis, Heartland virus, Bourbon virus and tularaemia, an infection so serious that the US government classifies the bacteria that cause it as a potential agent of bioterrorism.

    While Lyme clusters in the northeast and the northern Midwest, the diseases carried by Amblyomma stretch from the coast of Maine to the tip of Florida, the Atlantic to the middle of Texas, and the southern shores of the Great Lakes all the way to the Mexican border.

    And that range appears to be expanding. “The northern edge of where these ticks are abundant is moving,” says Dr Rick Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies, north of New York City. “It is now well-established further north, into Michigan, Pennsylvania, New York and well up into New England.

    “Climate change is likely playing a role in the northward expansion,” Ostfeld adds, but acknowledges that we don’t know what else could also be contributing.

    It’s a universal complaint among tick scientists that we don’t know as much about ticks as we should. Tick-transmitted illnesses are more common in the USA than mosquito-borne ones – according to the CDC’s most recent accounting, in 2017 tick-borne diseases were 2.6 times more common than when the agency began counting in 2004 – yet it’s mosquitoes that receive the most public health attention and funding, from national surveillance programmes to local mosquito-control campaigns. (In fact, the CDC was founded in 1942 because of mosquito-borne disease its original title was the Office of Malaria Control in War Areas.)

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    What is known about where ticks live, what they feed on, and how they are affected by changes in land use and climate has mostly been assembled out of the findings of scientists fighting for scarce research funding.

    It’s impossible to talk to physicians encountering alpha-gal cases without hearing that something has changed to make the tick that transmits it more common – even though they don’t know what that something might be.

    The lone star tick is a sturdy, stealthy predator. It isn’t picky about conditions – it tolerates the damp of Atlantic beaches, and its western expansion only stopped when it ran up against the Texas desert – and it’s content to feed from dozens of animals, from mice all the way up the tree of life.

    It loves birds, which might have helped it move north so rapidly, and it has a special lust for the white-tailed deer that have colonised American suburbs. And, unlike most ticks, it bites humans in all three stages of its lifecycle: as an adult, as a nymph and as the poppy seed-sized larvae that attacked Platt-Mills, which linger on grass stalks in clusters and spring off hundreds at a time.

    Ticks detect scent with organs embedded in their first pair of legs, and what they’re sniffing for is carbon dioxide, the exhaled breath of an animal full of warm oxygenated blood. When lone star ticks catch wind of it, they take off. “The Lyme disease tick is a slow tick,” says Dr William Nicholson, a microbiologist at the CDC. “Amblyomma will run to you.

    When Tami planned to spend an afternoon gardening, spreading fertiliser and planting flowers, she passed out on the grass and had to be revived with an EpiPen

    There has been so little research into alpha-gal allergy that scientists can’t agree on exactly what stage of the bite starts victims’ sensitisation. It is possible that a fragment of a previous blood meal, from a mouse, bird or deer, lingers in a tick’s guts and works its way up through its mouth and into its human victim. It’s also possible that some still-unidentified compound in tick saliva is chemically close enough to alpha-gal to produce the same effect.

    One aspect of its epidemiology is becoming clear, though. The allergy isn’t only caused by the lone star tick.

    In Australia, van Nunen (who is now a clinical associate professor at the University of Sydney School of Medicine) couldn’t understand how her patients’ tick bites solved the mystery of their meat allergy. But she could see something else. The beaches that fringe the coast north and south of Sydney are rife with ticks. If bites from them were putting people at risk of a profound allergy, she felt compelled to get the word out.

    In 2007, van Nunen wrote up a description of 25 meat-allergic patients whose reactions she had confirmed with a skin-prick test. All but two had had severe skin reactions to a tick bite more than half had suffered severe anaphylaxis. That abstract formed the basis of a talk she gave later that year to an Australian medical association, which was then indexed – but not published in full – in an Australian medical journal. It took until 2009 for the Virginia group to catch up to it, after they had already published their first alert.

    That was unfortunate, because the crucial detail in van Nunen’s research wasn’t just that her cases were earlier than the first round of American ones. It was that they were caused by bites from a different tick: Ixodes holocyclus, called the paralysis tick. Alpha-gal allergy was not just an odd occurrence in one part of the USA. It had occurred in the opposite hemisphere, making it literally a global problem.

    And so it has proved. Alpha-gal reactions linked to tick bites have now been found in the UK, France, Spain, Germany, Italy, Switzerland, Japan, South Korea, Sweden, Norway, Panama, Brazil, Cote d’Ivoire and South Africa. These cases trace back to at least six additional tick species. (An online map on which patients list themselves includes over a dozen more countries.)

    Wherever ticks bite people – everywhere other than the Arctic and Antarctic – alpha-gal allergy has been recorded. In Belgium, patients reacted badly to a drug produced in rabbit cells. In the Italian Alps, men who went hunting in the forests were more at risk than women who stayed in their village. In Germany, the most reactive food was a traditional delicacy, pork kidneys. In Sweden, it was moose.

    Van Nunen herself has now seen more than 1,200 patients. “The next busiest clinic, about 350,” she says. Those cases have all occurred in two decades, less than the span of a single human generation. As in America, the surge leaves van Nunen mystified as to what the cause might be. She reasons that the rise cannot be due to something in her patients neither genetic nor epigenetic change could occur so quickly.

    “It has to be environmental,” she says.

    It’s a sunny early morning at the University of North Carolina Medical Center in Chapel Hill. Commins, who moved here in 2016 to become an associate professor, has 11 patients to see before the end of the day. Seven of them have alpha-gal allergy.

    Laura Stirling, 51, is fretting over a list of questions. She does not live nearby she flew down from Maryland, drawn by Commins’s reputation. In 2016, she found a fat lone star tick attached to her, and afterwards had fierce indigestion whenever she ate or smelt pork – a challenge, because her husband likes to tinker with a smoker on weekends. In 2017, she was bitten again, and her symptoms worsened to midnight hives and lightheadedness that sent her to her doctor’s office. She immediately cut all meat and dairy from her diet. A year later, she wants to know if she can add anything back.

    “Can I eat dairy?” she asks. “Can I cook dairy? Can I eat it if it doesn’t have animal rennet in it?” She pauses. “I’ve been symptom-free, because I don’t take risks.”

    Commins walks her through a protocol he’s developed, a method for adding back mammal products one dose at a time. He has a hypothesis that alpha-gal reactions are linked to the fat content of food that might explain why they take so many hours to occur, because the body processes fat via a slower metabolic pathway than protein or carbs.

    He recommends that patients start with a spoonful of grated dry cheese, because its fat content is low, and graduate by slow steps up to full-fat yogurt and milk and then to ice cream. If those foods don’t provoke reactions, he suggests tiny doses of lean meat, starting with deli ham.

    Stirling lights up at that. “I dream of charcuterie,” she sighs.

    Because Commins was part of Platt-Mills’s earliest research, he has been seeing alpha-gal patients for more than a decade now. He estimates he has treated more than 900 men and women five new patients arrive every week. He has coached a significant number of them back to eating some mammal products and managing their exposures to the things they can’t handle, so their worst experience is hunting for an emergency Benadryl, not being rushed to the ER.

    Not every patient can do this. Julie LeSueur, who is 45 and lives in Richmond, Virginia, has been monitored by Platts-Mills for four years. (He is one of several doctors she has seen for the condition, after years of severe stomach issues escalated to repeated attacks of anaphylaxis that put her in hospital. One physician, frustrated she wasn’t getting better, told her: “This is all in your head.”)

    What started as an allergy to meat expanded into reactions to anything with an animal connection, including gelatine in medications and animal products in cosmetics, and then to sensitising her immune system to an array of other irritants, from nuts to mould. She buys vegan soap and shampoo, has prescriptions formulated by a compounding pharmacy, and mostly works from home to avoid unintended exposures. Reluctantly, she cut back a hobby that meant the world to her: fostering animals that have been rescued from abuse.

    “I’m at home all the time now,” she tells me by phone. “I’m lucky to get off the couch.”

    Commins and Platts-Mills named alpha-gal allergy a decade ago, and van Nunen saw her first patient 20 years before that. A lab test for the allergy, the one that Tami McGraw received, has been on the market since 2010. (Platts-Mills and Tina Hatley, now Merritt, share the patent.) That makes it hard to understand why patients still struggle to be diagnosed and understand the limits of what they can eat or allow themselves to be exposed to. But alpha-gal allergy defies some of the bedrock tenets of immunology.

    Food allergies are overwhelmingly caused by proteins, tend to surface in childhood and usually trigger symptoms quickly after a food is consumed. Alpha-gal is a sugar alpha-gal patients tolerate meat for years before their reactions begin and alpha-gal reactions take hours to occur. Plus, the range of reactions is far beyond what’s normal: not only skin reactions in mild cases and anaphylaxis in the most serious, but piercing stomach pain, abdominal cramps and diarrhoea as well.

    But alpha-gal reactions are definitely an allergy, given patients’ results on the same skin and IgE tests that immunologists use to determine allergies to other foods. That leads both van Nunen and Commins to wonder whether the syndrome will help to reshape allergy science, broadening the understanding of what constitutes an allergy response and leading to new concepts of how allergies are triggered.

    Merritt, who estimates she has seen more than 500 patients with alpha-gal allergy, has it herself she has had bad reactions to meat all her life, since being bitten by seed ticks at Girl Scout camp, and was re-sensitised by a lone star tick bite last year. She is sensitive enough to react not only to meat, but to other products derived from mammal tissues – and as she has discovered, they are threaded throughout modern life.

    The unrecognised dangers aren’t only sweaters and soaps and face creams. Medical products with an animal origin include the clotting drug heparin, derived from pork intestines and cow lung pancreatic enzymes and thyroid supplements medicines that include magnesium stearate as an inert filler vaccines grown in certain cell lines and other vaccines, and intravenous fluids, that contain gelatine.

    “We have enormous difficulty advising people about this,” van Nunen says. “Sometimes you have to sit down for seven hours, write seven emails and have four telephone conversations to be able to say to a 23-year-old woman who’s about to travel: ‘Yes, you may have this brand of Japanese encephalitis vaccine because they do not use bovine material. The vaccine is made in [cells from] the African green monkey and I have looked up that monkey and it does not contain alpha-gal.’”

    Some replacement heart values are grown in pigs they may cause alpha-gal sensitisation that could trigger an allergy attack later. And cardiac patients who have alpha-gal allergy seem to use up replacement heart valves more quickly than normal, putting them at risk of heart failure until they can get a replacement.

    There’s also a growing sense that alpha-gal may be an occupational hazard. Last year, researchers in Spain treated three farm workers who developed hives and swelling and had difficulty breathing after being splashed with amniotic fluid while they were helping calves to be born. All three of them – a 36-year-old woman, a 56-year-old woman and a 53-year-old man – already knew they had alpha-gal sensitivity, but had never imagined that skin contact would be risky.

    Commins has treated hunters who developed reactions after being splashed with blood after field dressing deer those cases raise the possibility that meat-processing workers could be at risk. In the two main Facebook groups where patients gather, it’s common to hear school cafeteria workers fret about reactions from breathing the fumes of meat cooking.

    Last summer, researchers working with Commins reported that people with alpha-gal allergy may have greater allergic reactions to the stings of bees and wasps, potentially endangering landscapers and other outdoor workers.

    There’s also a growing sense that alpha-gal may be an occupational hazard

    It’s hard to know how many people may be sensitised to alpha-gal without knowing it. A project at the National Institutes of Health (NIH) that studies unexplained occurrences of anaphylaxis found last year that 9 per cent of the cases weren’t unexplained after all: they were alpha-gal patients whose sensitivity had never been diagnosed.

    Platts-Mills points out that the prevalence of high levels of alpha-gal IgE in his earliest studies was up to 20 per cent in some communities, “but that was absolutely not the prevalence of allergic reactions to meat,” he says. “So there are clearly plenty of people out there who’ve got the antibody but don’t have this syndrome.”

    What this all means is that there are almost certainly people for whom a meat-containing meal or medical intervention could trigger an alpha-gal reaction of unknown severity.

    There may be further peril awaiting them. In June, Platts-Mills and other researchers revealed that more than a quarter of patients who came to the University of Virginia’s medical centre for cardiac catheterisation, to clear out life-threatening blood-vessel blockages, were sensitised to alpha-gal without knowing it.

    The patients with the undetected allergy had more arterial plaque than the ones without, and, most worrisome to the researchers, their plaques were of a type that is more likely to break away from the arterial wall and cause heart attacks and strokes. Though the research is early – done in one group of 118 patients, in a known hotspot for alpha-gal – Platts-Mills worries it presages a risk for heart disease that is larger than anyone expects.

    When a new disease surfaces in the USA, it’s usually the CDC that investigates, pouring epidemiologists and data scientists into the field to track down connections and bring back samples for lab analysis. But investigation of alpha-gal is caught in a bureaucratic quirk of federal science. The CDC is responsible for infections spread by insects and arthropods – but alpha-gal syndrome is not an infection. That makes it the responsibility of NIH – which has abundant lab scientists, but no shoe-leather disease detectives.

    Recommended

    NIH does seem to be taking an interest. In June 2018, it hosted an invitation-only one-day IgE-mediated Meat Allergy Workshop in the past, such meetings have indicated the giant agency is considering launching a research programme. But just reading the workshop’s programme provides a hint of how new alpha-gal research is participants called the problem by multiple different names, displaying that there isn’t even yet any agreed nomenclature for it. Similarly, the US-run universal search engine for journal articles, PubMed, indexes papers on alpha-gal under “allergy to galactose-alpha-1,3-galactose”, “mammalian meat allergy”, “delayed red meat allergy”, “galactose-α-1,3-galactose syndrome” and more.

    Platts-Mills was one of the workshop’s invited speakers and gave the opening statement. Commins was there as well, along with researchers from New York, Germany, South Africa and Sweden.

    Dr Marshall Plaut, who convened the meeting and is now chief of the Food Allergy, Atopic Dermatitis, and Allergic Mechanisms Section at NIH’s National Institute of Allergy and Infectious Diseases, describes it as the earliest step in possibly committing to a research programme. (Platts-Mills and Commins have already received some NIH funding.) “It signals that NIH has some interest in understanding more about the disease,” he says. “There are a lot of things that need to be understood.”

    In August, Commins gave a talk on alpha-gal allergy at the International Conference on Emerging Infectious Diseases, a conference held every two or so years and sponsored by the CDC that often surfaces the earliest signals of illnesses that are destined to become big problems.

    The CDC’s director of foodborne illness was in the audience so was its director of vector-borne diseases, the department that deals with ticks. Afterwards, they both zoomed up to ask him questions. “I kind of had the impression this was just a weird, small thing,” Dr Lyle Petersen, the vector-borne director, told him. “But this seems like kind of a big deal.”

    With NIH and the CDC paying attention, research into alpha-gal might be reaching a threshold, a moment at which isolated investigations might coalesce into answers. For the patients, who feel isolated too, that can’t come soon enough.

    This article was first published by Wellcome on Mosaic and is republished here under a Creative Commons licence. Sign up to the newsletter at https://mosaicscience.com/#newsletter


    Are ticks causing a “red meat” allergy? Scientists are trying to understand unexplained anaphylaxis incidents

    Most allergies hit a person immediately after exposure: Symptoms are bound to develop immediately, from itchy hives to swelling, and even anaphylactic shock. The reactions can be dangerous and potentially fatal, but most of these can be identified and treated immediately.

    However, some people experience allergic reactions that seem to come out of nowhere. Recurring episodes of anaphylaxis (a serious allergic reaction which causes constriction of airways and a dangerous drop in blood pressure) for which the triggers are never identified have left both sufferers and doctors puzzled until recently.

    A study published by researchers at the National Institutes of Health have found that some patients’ inexplicable allergic reactions were triggered by a molecule found in red meat. They continue by saying that this type of allergy, which can be difficult to identify, has an unlikely culprit — a tick.

    Allergic reactions caused by a bite from the Lone Star tick can be delayed. Unlike other types of allergies, reactions can occur from three to 12 hours after eating red meat. This puts sufferers at a disadvantage, as identifying the trigger at the onset may prove to be difficult. The study also adds that this delayed reaction has caused physicians to mistakenly diagnose patients with this allergy as having unexplained anaphylaxis.

    “This unusually long time gap between a meal and an allergic reaction is probably a big reason that alpha-gal allergies are often initially misdiagnosed,” says Dr. Dean Metcalfe, chief of the Mast Cell Biology Section in the Laboratory of Allergic Diseases at the National Institute of Allergy and Infectious Diseases. “If you start to have trouble breathing in the middle of the night, you probably are not going to blame the hamburger you had for dinner.”

    The reasons for the delay are unknown, with some episodes starting during sleep, and they usually hit hard: aside from an anaphylactic reaction, common symptoms also include shortness of breath and a breakout of hives.

    Dr. Ronald Saff of the Florida State University College of Medicine puts it bluntly: “They’re sleeping, and they have no idea what they could be allergic to because the symptoms occurred so many hours after going to bed.”

    In the study, six of the 70 study participants that were evaluated were positive for an allergy to galactose-?-1,3-galactose, or alpha-gal, a sugar molecule that is naturally present in red meat. After the allergen was identified, participants were subjected to a diet without red meat in a span covering 18 months to three years. It was noted that none of them experienced anaphylaxis during those times. (Related: Eating Meat Kills More People Than Previously Thought.)

    Still, there are many things that we do not know about the allergic reaction to alpha-gal (also known as the “alpha-gal syndrome”) — one of which is its prevalence across the country. So far, the Lone Star tick is common in the Southeast however, cases of the alpha-gal syndrome have already been noted in areas like Minnesota, New Hampshire, and even Long Island.

    While experts know that a bite from the Lone Star tick causes changes in a person’s sensitivity to a sugar compound, it is still unclear how this change affects a person — with the degree of sensitivity varying from person to person. There have been reports of people becoming severely allergic that they are unable to consume animal products like dairy milk.

    Additionally, the duration that a person stays allergic to red meat after being exposed to the bite is also uncertain.


    What is behind the spread of a mysterious allergy to meat?

    Thousands of people are developing life-threatening reactions to animal products – and a single tiny creature is to blame.

    Last modified on Thu 20 Dec 2018 17.10 GMT

    I t was early morning in early summer, and I was tracing my way through the woods of central North Carolina, steering cautiously around S-curves and braking hard when what looked like a small rise turned into a narrow bridge. I was on my way to meet Tami McGraw, who lives with her husband and the youngest of their kids in a sprawling development of old trees and wide lawns just south of Chapel Hill. Before I reached her, McGraw emailed. She wanted to feed me when I got there.

    “Would you like to try emu?” she asked. “Or perhaps some duck?”

    These are not normal breakfast offerings. But for years, nothing about McGraw’s life has been normal. She cannot eat beef or pork, or drink milk or eat cheese or snack on a gelatine-containing dessert without feeling her throat close and her blood pressure drop. Wearing a wool sweater raises hives on her skin inhaling the fumes of bacon sizzling on a stove will knock her to the ground. Everywhere she goes, she carries an array of tablets that can beat back an allergy attack, and an auto-injecting EpiPen that can jolt her system out of anaphylactic shock.

    McGraw is allergic to the meat of mammals and everything else that comes from them: dairy products, wool and fibre, gelatine from their hooves, char from their bones. This syndrome affects thousands of people in the US and an uncertain but likely larger number worldwide, and after a decade of research, scientists have begun to understand what causes it. It is created by the bite of a tick, picked up on a hike or brushed against in a garden, or hitchhiking on the fur of a pet that was roaming outside.

    The illness, which generally goes by the name “alpha-gal allergy” after the component of meat that triggers it, is a trial that McGraw and her family are still learning to cope with. In much the same way, medicine is grappling with it, too. Allergies occur when our immune systems perceive something that ought to be familiar as foreign. For scientists, alpha-gal is forcing a remapping of basic tenets of immunology: how allergies occur, how they are triggered, whom they put in danger and when.

    For those affected, alpha-gal is transforming the landscapes they live in, turning the reliable comforts of home – the plants in their gardens, the food on their plates – into an uncertain terrain of risk.

    I n 1987, Dr Sheryl van Nunen was confronted with a puzzle. She was the head of the allergy department at a regional hospital in the suburbs of Sydney, Australia, and had a reputation among her colleagues for sorting out mysterious episodes of anaphylaxis. This time, a man had been sent to see her who kept waking up, in the middle of the night, in the grip of some profound reaction.

    Van Nunen knew at once that this was out of the ordinary, since most allergic reactions happen soon after exposure, rather than hours later. She also knew that only a few allergens affect people after they have gone to bed. (Latex, for instance – someone sensitive to it who has sex using a latex condom might fall asleep and wake up in the midst of an allergy attack.) She checked the man for the obvious irritants and, when those tests came up negative, took a thorough look at his medical history and did a skin test for everything he had eaten and touched in the hours before bedtime. The only potential allergen that returned a positive result was meat.

    This was weird (and dismaying, in barbecue-loving Australia). But it was the only such case Van Nunen had ever seen. She coached the patient on how to avoid the meals that seemed to be triggering his reactions, put it down to the unpredictability of the human immune system, and moved on.

    Then a few more such patients came her way. There were six others during the 1990s by 2003, she had seen at least 70, all with the same problem, all apparently affected by meat they had eaten a few hours before. Groping for an explanation, she lengthened the list of questions she asked, quizzing the patients about whether they or their families had ever reacted to anything else: detergents, fabrics, plants in their gardens, insects on the plants.

    “And invariably, these people would say to me: ‘I haven’t been bitten by a bee or a wasp, but I’ve had lots of tick bites,’” Van Nunen recalls.

    A s she remembers it, Tami McGraw’s symptoms began after 2010. That was the year she and her husband, Tom, a retired surgeon, spied a housing bargain in North Carolina, a development next to a nature reserve whose builder had priced the big houses to sell. The leafy spread of streams and woodland pockets was everything she wanted in a home. She didn’t realise that it offered everything that deer and birds and rodents – the main hosts of ticks – want as well.

    She remembers one tick that attached to her scalp, raising such a welt that the spot was red for months afterwards, and a swarm of baby ticks that climbed her legs and had to be scrubbed off in a hot bath laced with bleach. Unpredictably, at odd intervals, she began to feel dizzy and sick.

    A white-tailed deer in Wisconsin, US.
    Photograph: Michael Tatman/Alamy

    “I’d have unexplained allergic reactions, and I’d break out in hives and my blood pressure would go crazy,” she told me. The necklines of all her T-shirts were stretched, because she tugged at them to relieve the feeling that she couldn’t take a deep breath. She trekked to an array of doctors who diagnosed her with asthma or early menopause or a tumour on her pituitary gland. They prescribed antibiotics and inhalers and steroids. They sent her for MRI scans, pulmonary function tests, echocardiograms of her heart. Nothing yielded a result.

    Looking back, she realises she missed clues as to the source of her problem. She always seemed to need to use an asthma inhaler on Wednesdays – the day she spent hours in her car, delivering steaming-hot dinners for meals on wheels. She would feel short of breath, and need to visit an urgent-care clinic, on Saturdays – which always started, in her household, with a big breakfast of eggs and sausages.

    Then a close friend had a scary episode: after going for a run, she arrived home and passed out on the hot concrete of her driveway. Once the friend had recovered, McGraw quizzed her. Her friend said: “They thought I got stung by a bee while I was running. But now they think maybe I have a red-meat allergy.”

    McGraw remembers her first reaction: that’s crazy. But her second was: maybe I have that too. She did some searching online, and then asked her doctor to order a little-known blood test that would show if her immune system was reacting to a component of mammal meat. The test result was so strongly positive that her doctor called her at home to tell her to step away from the stove.

    The test launched her on an odyssey of discovering just how much mammal material is present in everyday life. One time, she took capsules of liquid painkiller and woke up in the middle of the night, itching and covered in hives provoked by the drug’s gelatine covering.

    When she bought an unfamiliar lip balm, the lanolin in it made her mouth peel and blister. She planned to spend an afternoon gardening, spreading fertiliser and planting flowers, but passed out on the grass and had to be revived with an EpiPen. She had reacted to manure and bone meal that had been added as enrichments to the bagged compost she had bought.

    She struggled with the attacks’ unpredictability, and even more with the impact on her family. “I think I’m getting better, and then I realise I’m not,” she says. “It’s just that I’m more knowledgable about what I can and can’t do.”

    T he discovery of new diseases often follows a pattern. Scattered patients realise they are experiencing strange symptoms. They find each other, face to face in a neighbourhood or across the world on the internet. They bring their experience to medicine, and medicine is sceptical. And then, after a period of pain and recalcitrance, medicine admits that, in fact, the patients were right.

    That is the story of the discovery of CFS/ME and Lyme disease, among others. But it is not the story of alpha-gal allergy. An odd set of coincidences brought this bizarre illness to the attention of researchers almost as soon as it occurred.

    The story begins with a cancer drug called cetuximab, which came on to the market in 2004. Cetuximab is a protein grown in cells taken from mice. For any new drug, there are likely to be a few people that react badly to it, and that was true for cetuximab. In its earliest trials, one or two of every 100 cancer patients who had it infused into their veins had a hypersensitive reaction: their blood pressure dropped and they had difficulty breathing.

    That 1-2% stayed consistent as cetuximab was given to larger and larger groups. And then there was an aberration. In clinics in North Carolina and Tennessee, 25 of 88 recipients proved hypersensitive to the drug, with some so sick that they needed emergency shots of adrenaline. At about the same time, a patient who was receiving a first dose of cetuximab in a cancer clinic in Bentonville, Arkansas collapsed and died.

    The manufacturers, ImClone and Bristol-Myers Squibb, checked every obvious thing about the trial: the drug’s ingredients, the cleanliness of the manufacturing plants, even the practices at the medical centres where cetuximab had been administered. Nothing stood out. The most that researchers could guess at the time was that the recipients might have some kind of mouse allergy.

    Then the first coincidence occurred: a nurse whose husband worked at the Bentonville clinic mentioned the death to Dr Tina Hatley, an immunologist in private practice in Bentonville. Hatley had recently finished postgraduate training at the University of Virginia’s allergy centre, and she mentioned the death to her former supervisor, Dr Thomas Platts-Mills.

    The bad responses to the drug looked like allergic reactions, and they were common enough – and far enough from the manufacturer’s expectations – to be an intriguing research opportunity.

    Platts-Mills pulled together a team, looping in Hatley and several current research fellows as well. Fairly quickly, they discovered the source of the problem. People were reacting to the drug because they had a pre-existing sensitivity, indicated by a high level of antibodies (called immunoglobulin E, or IgE for short), to a sugar that is present in the muscles of most mammals, though not in humans or other primates. The name of the sugar was galactose-alpha-1,3-galactose, known for short as alpha-gal.

    Alpha-gal is familiar to many scientists because it is responsible for an enduring disappointment: its tendency to trigger intense immune reactions is the reason that organs taken from animals have never successfully been transplanted into people. The puzzle was why the drug recipients were reacting to it. To have an allergic reaction, someone needs to have been primed with a prior exposure to a substance – but the trial recipients who reacted badly were all on their first dose of cetuximab.

    Team members scrutinised the patients and their families for anything that could explain the problem. The reactions appeared regional – patients in Arkansas and North Carolina and Tennessee experienced the hypersensitivity, but ones in Boston and northern California did not. They investigated parasites, moulds and diseases that occur only in pockets of the US such as rural Tennessee.

    The question then became: what in rural Tennessee could trigger a reaction like this? The answer arose from a second coincidence. Dr Jacob Hosen, a researcher in Platts-Mills’s lab, stumbled across a map drawn by the Centers for Disease Control and Prevention (CDC) showing the prevalence of an infection called Rocky Mountain spotted fever. It exactly overlapped the hot spots where the cetuximab reactions had occurred.

    Rocky Mountain spotted fever is transmitted by the bite of a tick: Amblyomma americanum, one of the most common ticks in the south-eastern US. It’s known as the lone star tick because of the blotch of white that appears on the back of the female’s body.

    The researchers wondered – if the mystery reactions shared a footprint with a disease, and ticks caused the disease, could ticks be linked to the reactions, too?

    A lone star tick (Amblyomma americanum). Photograph: incamerastock/Alamy

    It was an intriguing hypothesis, and was reinforced by a new set of patients who came trickling into Platts-Mills’s clinic at about the same time. They were all adults, and that was odd to start with, because allergies tend to show up in childhood. They had never had an allergic reaction before, but now they were experiencing allergy symptoms: swelling, hives and, in the worst cases, anaphylactic shock. They too had high levels of IgE antibodies to alpha-gal.

    Dr Scott Commins, another postgraduate fellow in Platts-Mills’s group, took it upon himself to phone every new patient to ask whether they’d ever suffered a tick bite. “I think 94.6% of them answered affirmatively,” he says. “And the other few would say, ‘You know, I’m outdoors all the time. I can’t remember an actual tick that was attached, but I know I’d get bites.’”

    Meat from mammals inevitably contains alpha-gal – so in already sensitised individuals, eating meat may constitute a second exposure, in the same way infusing cetuximab had been.

    If tick bites had sensitised them, then the alpha-gal reaction might be a food allergy as well as a drug reaction. But the connection was speculative, and cementing cause and effect would take one final, extraordinary coincidence.

    As it happens, Platts-Mills likes to hike. One weekend he took off across the central Virginia hills, tramping through grassy underbrush. He came home five hours later, peeled off his boots and socks, and found that his legs and feet were speckled with tiny dots. They looked like ground pepper, but were dug into his skin – he had to use a dull knife to scrape them off – and they itched fiercely. He saved a few, and sent them to an entomologist. They were the larval form of lone star ticks.

    This, he realised, was an opportunity. When he returned to the lab, he had his team draw his blood and check his IgE levels. They were low to start with, and then week by week began to climb. Platts-Mills is British – his father was an MP – and in the midst of having his IgE tracked, he went to an event at the Royal Society of Medicine in London. “And at that point,” he says cheerfully, “I ate two lamb chops and drank two glasses of wine.”

    In the middle of the night, he woke up covered in hives.

    T he lone star tick doesn’t receive much attention in the US. It’s the black-legged tick, Ixodes scapularis, that has the dubious honour of being the most well-known, as it’s the carrier of Lyme disease, which causes an estimated 300,000 cases of illness in the US each year. The lone star tick doesn’t transmit Lyme disease, but is the vector for other serious illnesses, including Q fever, ehrlichiosis, Heartland virus, Bourbon virus and tularaemia, an infection so serious that the US government classifies the bacteria that cause it as a potential agent of bioterrorism.

    While Lyme clusters in the north-east and the northern midwest US, diseases carried by Amblyomma stretch from the coast of Maine to the tip of Florida, the Atlantic to the middle of Texas, and the southern shores of the Great Lakes all the way to the Mexican border. And that range appears to be expanding. “The northern edge of where these ticks are abundant is moving,” says Dr Richard Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies, north of New York City. “It is now well-established further north, into Michigan, Pennsylvania, New York and well up into New England.

    “Climate change is likely playing a role in the northward expansion,” Ostfeld adds, but acknowledges that we don’t know what else could also be contributing.

    The lone star tick is a sturdy, stealthy predator. It isn’t picky about conditions – it tolerates the damp of Atlantic beaches, and its western expansion only stopped when it ran up against the Texas desert – and is content to feed from dozens of animals, from mice all the way up. It loves birds, which may have helped it move north so rapidly, and it has a special lust for the white-tailed deer that have colonised many American suburbs. And, unlike most ticks, it bites humans in all three stages of its lifecycle: as an adult, as a nymph and as the poppy seed-sized larvae that attacked Platt-Mills, which linger on grass stalks in clusters and spring off hundreds at a time.

    Ticks detect scent with organs embedded in their first pair of legs, and what they’re sniffing for is carbon dioxide, the exhaled breath of an animal full of warm, oxygenated blood. When lone star ticks catch wind of it, they take off. “The Lyme disease tick is a slow tick,” says Dr William Nicholson, a microbiologist at the CDC. “Amblyomma will run to you.”

    There has been so little research into alpha-gal allergy that scientists can’t agree on exactly what stage of the bite starts victims’ sensitisation. One aspect of its epidemiology is becoming clear, though: the allergy isn’t only caused by the lone star tick.

    In Australia, Van Nunen (who is now a clinical associate professor at the University of Sydney School of Medicine) couldn’t understand how her patients’ tick bites solved the mystery of their meat allergy. But she could see something else. The beaches that fringe the coast north and south of Sydney are rife with ticks. If bites from them were putting people at risk of a profound allergy, she felt compelled to get the word out.

    In 2007, Van Nunen wrote up a description of 25 meat-allergic patients whose reactions she had confirmed with a skin-prick test. All but two had had severe skin reactions to a tick bite more than half had suffered severe anaphylaxis. The crucial detail in Van Nunen’s research was that her cases were caused by bites from Ixodes holocyclus, called the paralysis tick. Alpha-gal allergy was not just an odd occurrence in one part of the US. It had occurred in the opposite hemisphere, making it literally a global problem.

    And so it has proved. Wherever ticks bite people – everywhere other than the Arctic and Antarctic – alpha-gal allergy has been recorded.

    I t was a sunny early morning at the University of North Carolina Medical Center in Chapel Hill. Scott Commins, who moved here in 2016 to become an associate professor, had 11 patients to see before the end of the day. Seven of them had alpha-gal allergy.

    Laura Stirling, 51, was fretting over a list of questions. In 2016, she found a fat lone star tick attached to her, and afterwards had fierce indigestion whenever she ate or smelled pork – a challenge, because her husband likes to tinker with a smoker on weekends. In 2017, she was bitten again, and her symptoms worsened to midnight hives and lightheadedness that sent her to her doctor’s office. She immediately cut all meat and dairy from her diet. A year later, she wanted to know if she could add anything back.

    “Can I eat dairy?” she asked. “Can I cook dairy? Can I eat it if it doesn’t have animal rennet in it?” She paused. “I’ve been symptom-free, because I don’t take risks.”

    Commins walked her through a protocol he has developed, a method for adding back mammal products one dose at a time. He has a hypothesis that alpha-gal reactions are linked to the fat content of food that might explain why they take so many hours to occur, because the body processes fat via a slower metabolic pathway than protein or carbs.

    He recommends that patients start with a spoonful of grated dry cheese, because its fat content is low, and graduate by slow steps up to full-fat yoghurt and milk and then to ice-cream. If those foods don’t provoke reactions, he suggests tiny doses of lean meat, starting with deli ham. Stirling lit up at that. “I dream of charcuterie,” she sighed.

    Because Commins was part of Platt-Mills’s earliest research, he has been seeing alpha-gal patients for more than a decade now. He estimates he has treated more than 900 men and women five new patients arrive every week. He has coached a significant number of them back to eating some mammal products and managing their exposures to the things they can’t handle, so their worst experience is hunting for an emergency antihistamine tablet, not being rushed to hospital.

    Commins and Platts-Mills named alpha-gal allergy a decade ago, and Van Nunen saw her first patient 20 years before that. A lab test for the allergy, the one that Tami McGraw received, has been on the market since 2010. (Platts-Mills and Tina Hatley, now Merritt, share the patent.) That makes it hard to understand why patients still struggle to be diagnosed and understand the limits of what they can eat or allow themselves to be exposed to. But alpha-gal allergy defies some of the bedrock tenets of immunology.

    Food allergies are overwhelmingly caused by proteins, tend to surface in childhood and usually trigger symptoms quickly after a food is consumed. Alpha-gal is a sugar alpha-gal patients tolerate meat for years before their reactions begin and alpha-gal reactions take hours to occur. Plus, the range of reactions is far beyond what’s normal: not only skin reactions in mild cases and anaphylaxis in the most serious, but piercing stomach pain, abdominal cramps and diarrhoea as well.

    But alpha-gal reactions are definitely an allergy, given patients’ results on the same skin and IgE tests that immunologists use to determine allergies to other foods. That leads both Van Nunen and Commins to wonder whether the syndrome will help to reshape allergy science, broadening the understanding of what constitutes an allergy response and leading to new concepts of how allergies are triggered.

    Merritt, who estimates she has seen more than 500 patients with alpha-gal allergy, has it herself she has had bad reactions to meat all her life, since being bitten by seed ticks at girl scout camp, and was re-sensitised by a lone star tick bite last year. She is sensitive enough to react not only to meat, but to other products derived from mammal tissues – and as she has discovered, they are threaded throughout modern life.

    The unrecognised dangers aren’t only sweaters and soaps and face creams. Medical products with an animal origin include the clotting drug heparin, derived from pork intestines and cow lung pancreatic enzymes and thyroid supplements medicines that include magnesium stearate as an inert filler vaccines grown in certain cell lines and other vaccines, and intravenous fluids, that contain gelatine.

    “We have enormous difficulty advising people about this,” Van Nunen says. “Sometimes you have to sit down for seven hours, write seven emails and have four telephone conversations to be able to say to a 23-year-old woman who’s about to travel: ‘Yes, you may have this brand of Japanese encephalitis vaccine because they do not use bovine material. The vaccine is made in [cells from] the African green monkey and I have looked up that monkey and it does not contain alpha-gal.’”

    Some replacement heart valves are grown in pigs they may cause alpha-gal sensitisation that could trigger an allergy attack later. And cardiac patients who have alpha-gal allergy seem to use up replacement heart valves more quickly than normal, putting them at risk of heart failure until they can get a replacement.

    There’s also a growing sense that alpha-gal may be an occupational hazard. Last year, researchers in Spain treated three farm workers who developed hives and swelling and had difficulty breathing after being splashed with amniotic fluid while they were helping calves to be born. All three of them – a 36-year-old woman, a 56-year-old woman and a 53-year-old man – already knew they had alpha-gal sensitivity, but had never imagined that skin contact would be risky. In the two main Facebook groups where patients gather, it’s common to hear school cafeteria workers fret about reactions from breathing the fumes of meat cooking.


    Why are so many people getting a tick-borne meat allergy?

    It is early morning in early summer, and I am tracing my way through the woods of central North Carolina, steering cautiously around S-curves and braking hard when what looks like a small rise turns into a narrow bridge. I am on my way to meet Tami McGraw, who lives with her husband and the youngest of their kids in a sprawling development of old trees and wide lawns just south of Chapel Hill. Before I reach her, McGraw emails. She wants to feed me when I get there:

    "Would you like to try emu?" she asks. "Or perhaps some duck?"

    These are not normal breakfast offerings. But for years, nothing about McGraw's life has been normal. She cannot eat beef or pork, or drink milk or eat cheese or snack on a gelatine-containing dessert without feeling her throat close and her blood pressure drop. Wearing a wool sweater raises hives on her skin inhaling the fumes of bacon sizzling on a stove will knock her to the ground. Everywhere she goes, she carries an array of tablets that can beat back an allergy attack, and an auto-injecting EpiPen that can jolt her system out of anaphylactic shock.

    McGraw is allergic to the meat of mammals and everything else that comes from them: dairy products, wool and fibre, gelatine from their hooves, char from their bones. This syndrome affects some thousands of people in the USA and an uncertain but likely larger number worldwide, and after a decade of research, scientists have begun to understand what causes it. It is created by the bite of a tick, picked up on a hike or brushed against in a garden, or hitchhiking on the fur of a pet that was roaming outside.

    The illness, which generally goes by the name 'alpha-gal allergy' after the component of meat that triggers it, is a trial that McGraw and her family are still learning to cope with. In much the same way, medicine is grappling with it too. Allergies occur when our immune systems perceive something that ought to be familiar as foreign. For scientists, alpha-gal is forcing a remapping of basic tenets of immunology: how allergies occur, how they are triggered, whom they put in danger and when.

    For those affected, alpha-gal is transforming the landscapes they live in, turning the reliable comforts of home – the plants in their gardens, the food on their plates – into an uncertain terrain of risk.

    In 1987, Dr. Sheryl van Nunen was confronted with a puzzle. She was the head of the allergy department at a regional hospital in the suburbs of Sydney, Australia, and had a reputation among her colleagues for sorting out mysterious episodes of anaphylaxis. This time, a man had been sent to see her who kept waking up, in the middle of the night, in the grip of some profound reaction.

    Van Nunen knew at once that this was out of the ordinary, since most allergic reactions happen quickly after exposure instead of hours later. She also knew that only a few allergens affect people after they have gone to bed. (Latex, for instance – someone sensitive to it who has sex using a latex condom might fall asleep and wake up in the midst of an allergy attack.) She checked the man for the obvious irritants and, when those tests came up negative, took a thorough look at his medical history and did a skin test for everything he had eaten and touched in the hours before bedtime. The only potential allergen that returned a positive result was meat.

    This was weird (and dismaying, in barbecue-loving Australia). But it was the only such case Van Nunen had ever seen. She coached the patient on how to avoid the meals that seemed to be triggering his reactions, put it down mentally to the unpredictability of the human immune system, and moved on.

    Then a few more such patients came her way. There were six additional ones across the 1990s by 2003, she had seen at least 70, all with the same problem, all apparently affected by meat they had eaten a few hours before. Groping for an explanation, she lengthened the list of questions she asked, quizzing the patients about whether they or their families had ever reacted to anything else: detergents, fabrics, plants in their gardens, insects on the plants.

    "And invariably, these people would say to me: 'I haven't been bitten by a bee or a wasp, but I've had lots of tick bites," Van Nunen recalls.

    In her memory, Tami McGraw's symptoms began after 2010. That was the year she and her husband Tom, a retired surgeon, spied a housing bargain in North Carolina, a development next to a nature reserve whose builder had priced the big houses to sell. The leafy spread of streams and woodland pockets was everything she wanted in a home. She didn't realise that it offered everything that deer and birds and rodents, the main hosts of ticks, want as well.

    She remembers one tick that attached to her scalp, raising such a welt the spot was red for months afterwards, and a swarm of baby ticks that climbed her legs and had to be scrubbed off in a hot bath laced with bleach. Unpredictably, at odd intervals, she began to get dizzy and sick.

    "I'd have unexplained allergic reactions, and I'd break out in hives and my blood pressure would go crazy," she told me. The necklines of all her T-shirts were stretched, because she tugged at them to relieve the feeling she couldn't take a deep breath. She trekked to an array of doctors who diagnosed her with asthma or early menopause or a tumour on her pituitary gland. They prescribed antibiotics and inhalers and steroids. They sent her for MRI scans, pulmonary function tests, echocardiograms of her heart. Nothing yielded a result.

    Looking back, she realises she missed clues as to the source of her problem. She always seemed to need to use an asthma inhaler on Wednesdays – the day she spent hours in her car, delivering steaming-hot dinners for Meals on Wheels. She would feel short of breath, and need to visit an urgent-care clinic, on Saturdays – which always started, in her household, with a big breakfast of eggs and sausages.

    Then a close friend had a scary episode, going for a run, arriving home and passing out on the hot concrete of her driveway. Once she was recovered, McGraw quizzed her. Her friend said: "They thought I got stung by a bee while I was running. But now they think maybe I have a red-meat allergy."

    McGraw remembers her first reaction was: That's crazy. Her second was: Maybe I have that too.

    She Googled, and then she asked her doctor to order a little-known blood test that would show if her immune system was reacting to a component of mammal meat. The test result was so strongly positive, her doctor called her at home to tell her to step away from the stove.

    That should have been the end of her problems. Instead it launched her on an odyssey of discovering just how much mammal material is present in everyday life. One time, she took capsules of liquid painkiller and woke up in the middle of the night, itching and covered in hives provoked by the drug's gelatine covering.

    When she bought an unfamiliar lip balm, the lanolin in it made her mouth peel and blister. She planned to spend an afternoon gardening, spreading fertiliser and planting flowers, but passed out on the grass and had to be revived with an EpiPen. She had reacted to manure and bone meal that were enrichments in bagged compost she had bought.

    She struggled with the attacks' unpredictability, and even more with the impact on her family. "I think I'm getting better, and then I realise I'm not," she says. "I'm more knowledgeable about what I can and can't do."

    The discovery of new diseases often follows a pattern. Scattered patients realise they are experiencing strange symptoms. They find each other, face to face in a neighbourhood or across the world on the internet. They bring their experience to medicine, and medicine is sceptical. And then, after some period of pain and recalcitrance, medicine admits that, in fact, the patients were right.

    That is the story of the discovery of CFS/ME and Lyme disease, among others. But it is not the story of alpha-gal allergy. An odd set of coincidences brought the bizarre illness to the attention of researchers almost as soon as it occurred.

    The story begins with a cancer drug called cetuximab, which came onto the market in 2004. Cetuximab is a protein grown in cells taken from mice. For any new drug, there are likely to be a few people that react badly to it, and that was true for cetuximab. In its earliest trials, one or two of every 100 cancer patients who got it infused into their veins had a hypersensitivity reaction: their blood pressure dropped and they had difficulty breathing.

    That 1–2 per cent stayed consistent as cetuximab was given to larger and larger groups. And then there was an aberration. In clinics in North Carolina and Tennessee, 25 of 88 recipients were hypersensitive to the drug, with some so sick they needed emergency shots of epinephrine and hospitalisation. At about the same time, a patient who was receiving a first dose of cetuximab in a cancer clinic in Bentonville, Arkansas, collapsed and died.

    The manufacturers, ImClone and Bristol-Myers Squibb, checked every obvious thing about the trial: the drug's ingredients, the cleanliness of the manufacturing plants, even the practices at the medical centres where cetuximab had been administered. Nothing stood out. The most that researchers could guess at the time was that the unlucky recipients might have some kind of mouse allergy.

    Then the first coincidence occurred: a nurse whose husband worked at the Bentonville clinic mentioned the death to Dr. Tina Hatley, an immunologist in private practice in Bentonville. Hatley had recently finished postgraduate training at the University of Virginia's allergy centre, and she mentioned the death to her former supervisor, Dr. Thomas Platts-Mills.

    The bad responses to the drug looked like allergic reactions, and they were common enough – and far enough from the manufacturer's expectations – to be an intriguing research opportunity.

    Platts-Mills pulled together a team, looping in Hatley and several current research fellows as well. Fairly quickly, they discovered the source of the problem. People were reacting to the drug because they had a pre-existing sensitivity, indicated by a high level of antibodies (called immunoglobulin E, or IgE for short) to a sugar that is present in the muscles of most mammals, though not in humans or other primates. The name of the sugar was galactose-alpha-1,3-galactose, known for short as alpha-gal.

    Alpha-gal is familiar to many scientists because it is responsible for an enduring disappointment: its ability to trigger intense immune reactions is the reason that organs taken from animals have never successfully been transplanted into people. The puzzle was why the drug recipients were reacting to it. To have an allergic reaction, someone needs to have been primed with a prior exposure to a substance – but the trial recipients who reacted badly were all on their first dose of cetuximab.

    Team members scrutinised the patients and their families for anything that could explain the problem. The reactions appeared regional – patients in Arkansas and North Carolina and Tennessee experienced the hypersensitivity, but ones in Boston and northern California did not. They investigated parasites, moulds and diseases that occur only in pockets of the USA.

    Then Dr. Christine Chung, a Nashville researcher recruited to the team, stumbled on an intriguing clue. Almost one in five of the patients enrolled at a cancer clinic at her hospital had high levels of IgE to alpha-gal. But when she checked those patients' near neighbours, treating them as a control group – that is, people who lived their lives in the same way, but did not have cancer and had no reason to have received the drug – almost one in five had antibodies to alpha-gal as well.

    Almost a decade later, that correlation still makes Platts-Mills chuckle. The alpha-gal reaction "had nothing to do with cancer," he says. "It had everything to do with rural Tennessee."

    The question then became: what in rural Tennessee could trigger a reaction like this? The answer arose from a second coincidence. Dr. Jacob Hosen, a researcher in Platts-Mills's lab, stumbled across a map drawn by the Centers for Disease Control and Prevention (CDC) showing the prevalence of an infection called Rocky Mountain spotted fever. It exactly overlapped the hot spots where the cetuximab reactions had occurred.

    Rocky Mountain spotted fever is transmitted by the bite of a tick: Amblyomma americanum, one of the most common ticks in south-eastern USA. It's known as the lone star tick for a blotch of white on the back of the female's body.

    The researchers wondered – if the mystery reactions shared a footprint with a disease, and ticks caused the disease, could ticks be linked to the reactions too?

    It was an intriguing hypothesis, and was reinforced by a new set of patients who came trickling into Platts-Mills's clinic at about the same time. They were all adults, and that was odd to start with, because allergies tend to show up in childhood. They had never had an allergic reaction before, but now they were experiencing allergy symptoms: swelling, hives and in the worst cases anaphylactic shock. They too had high levels of IgE antibodies to alpha-gal.

    None of them, though, were cancer patients. They told the physicians that they had no proof of what was causing their reactions – but more than a few of them sensed it had something to do with eating meat.

    Dr. Scott Commins, another postgraduate fellow in Platts-Mills's group, took it upon himself to phone every new patient to ask whether they'd ever suffered a tick bite. "I think 94.6 per cent of them answered affirmatively," he says. "And the other few per cent would say, 'You know, I'm outdoors all the time. I can't remember an actual tick that was attached, but I know I'd get bites.'"

    Meat from mammals inevitably contains alpha-gal – so in already sensitised individuals, eating meat might constitute a second exposure, in the same way infusing cetuximab had been.

    If tick bites had sensitised them, then the alpha-gal reaction might be a food allergy as well as a drug reaction. But the connection was speculative, and cementing cause and effect would take one final, extraordinary coincidence.

    As it happens, Platts-Mills likes to hike. One weekend he took off across the central Virginia hills, tramping through grassy underbrush. He came home five hours later, peeled off his boots and socks, and discovered his legs and feet were speckled with tiny dots. They looked like ground pepper, but they were dug into his skin – he had to use a dull knife to scrape them off – and they itched something fierce. He saved a few, and sent them to an entomologist. They were the larval form of lone star ticks.

    This, he realised, was an opportunity. As soon as the work week started, he had his lab team draw his blood and check his IgE levels. They were low to start with, and then week by week began to climb. Platts-Mills is English – his father was a Member of Parliament – and in the midst of having his IgE tracked, he went to an event at the Royal Society of Medicine in London. "And at that point," he says cheerfully, "I ate two lamb chops and drank two glasses of wine."

    In the middle of the night, he woke up covered in hives.

    The lone star tick doesn't receive much attention in the USA. It's the black-legged tick, Ixodes scapularis, that has the dubious honour of being the most well-known, as it's the carrier of Lyme disease, which causes an estimated 300,000 cases of illness in the USA each year.

    The lone star tick doesn't transmit Lyme disease, but is the vector for other serious illnesses, including Q fever, ehrlichiosis, Heartland virus, Bourbon virus and tularaemia, an infection so serious that the US government classifies the bacteria that cause it as a potential agent of bioterrorism.

    While Lyme clusters in the north-east and the northern Midwest, the diseases carried by Amblyomma stretch from the coast of Maine to the tip of Florida, the Atlantic to the middle of Texas, and the southern shores of the Great Lakes all the way to the Mexican border.

    And that range appears to be expanding. "The northern edge of where these ticks are abundant is moving," says Dr. Rick Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies, north of New York City. "It is now well-established further north, into Michigan, Pennsylvania, New York and well up into New England.

    "Climate change is likely playing a role in the northward expansion," Ostfeld adds, but acknowledges that we don't know what else could also be contributing.

    It's a universal complaint among tick scientists that we don't know as much about ticks as we should. Tick-transmitted illnesses are more common in the USA than mosquito-borne ones – according to the CDC's most recent accounting, in 2017 tickborne diseases were 2.6 times more common than when the agency began counting in 2004 – yet it's mosquitoes that receive the most public health attention and funding, from national surveillance programmes to local mosquito-control campaigns. (In fact, the CDC was founded in 1942 because of mosquito-borne disease its original title was the Office of Malaria Control in War Areas.)

    What is known about where ticks live, what they feed on, and how they are affected by changes in land use and climate has mostly been assembled out of the findings of scientists fighting for scarce research funding.

    It's impossible to talk to physicians encountering alpha-gal cases without hearing that something has changed to make the tick that transmits it more common – even though they don't know what that something might be.

    The lone star tick is a sturdy, stealthy predator. It isn't picky about conditions – it tolerates the damp of Atlantic beaches, and its western expansion only stopped when it ran up against the Texas desert – and it's content to feed from dozens of animals, from mice all the way up the tree of life.

    It loves birds, which might have helped it move north so rapidly, and it has a special lust for the white-tailed deer that have colonised American suburbs. And, unlike most ticks, it bites humans in all three stages of its lifecycle: as an adult, as a nymph and as the poppy seed-sized larvae that attacked Platt-Mills, which linger on grass stalks in clusters and spring off hundreds at a time.

    Ticks detect scent with organs embedded in their first pair of legs, and what they're sniffing for is carbon dioxide, the exhaled breath of an animal full of warm oxygenated blood. When lone star ticks catch wind of it, they take off. "The Lyme disease tick is a slow tick," says Dr. William Nicholson, a microbiologist at the CDC. "Amblyomma will run to you."

    There has been so little research into alpha-gal allergy that scientists can't agree on exactly what stage of the bite starts victims' sensitisation. It is possible that a fragment of a previous blood meal, from a mouse, bird or deer, lingers in a tick's guts and works its way up through its mouth and into its human victim. It's also possible that some still-unidentified compound in tick saliva is chemically close enough to alpha-gal to produce the same effect.

    One aspect of its epidemiology is becoming clear, though. The allergy isn't only caused by the lone star tick.

    In Australia, Van Nunen (who is now a clinical associate professor at the University of Sydney School of Medicine) couldn't understand how her patients' tick bites solved the mystery of their meat allergy. But she could see something else. The beaches that fringe the coast north and south of Sydney are rife with ticks. If bites from them were putting people at risk of a profound allergy, she felt compelled to get the word out.

    In 2007, Van Nunen wrote up a description of 25 meat-allergic patients whose reactions she had confirmed with a skin-prick test. All but two had had severe skin reactions to a tick bite more than half had suffered severe anaphylaxis. That abstract formed the basis of a talk she gave later that year to an Australian medical association, which was then indexed – but not published in full – in an Australian medical journal. It took until 2009 for the Virginia group to catch up to it, after they had already published their first alert.

    That was unfortunate, because the crucial detail in Van Nunen's research wasn't just that her cases were earlier than the first round of American ones. It was that they were caused by bites from a different tick: Ixodes holocyclus, called the paralysis tick. Alpha-gal allergy was not just an odd occurrence in one part of the USA. It had occurred in the opposite hemisphere, making it literally a global problem.

    And so it has proved. Alpha-gal reactions linked to tick bites have now been found in the UK, France, Spain, Germany, Italy, Switzerland, Japan, South Korea, Sweden, Norway, Panama, Brazil, Côte d'Ivoire and South Africa. These cases trace back to at least six additional tick species. (An online map on which patients list themselves includes over a dozen more countries.)

    Wherever ticks bite people – everywhere other than the Arctic and Antarctic – alpha-gal allergy has been recorded. In Belgium, patients reacted badly to a drug produced in rabbit cells. In the Italian Alps, men who went hunting in the forests were more at risk than women who stayed in their village. In Germany, the most reactive food was a traditional delicacy, pork kidneys. In Sweden, it was moose.

    Van Nunen herself has now seen more than 1,200 patients. "The next busiest clinic, about 350," she says. Those cases have all occurred in two decades, less than the span of a single human generation. As in America, the surge leaves Van Nunen mystified as to what the cause might be. She reasons that the rise cannot be due to something in her patients neither genetic nor epigenetic change could occur so quickly.

    "It has to be environmental," she says.

    It's a sunny early morning at the University of North Carolina Medical Center in Chapel Hill. Commins, who moved here in 2016 to become an associate professor, has 11 patients to see before the end of the day. Seven of them have alpha-gal allergy.

    Laura Stirling, 51, is fretting over a list of questions. She does not live nearby she flew down from Maryland, drawn by Commins's reputation. In 2016, she found a fat lone star tick attached to her, and afterwards had fierce indigestion whenever she ate or smelled pork – a challenge, because her husband likes to tinker with a smoker on weekends. In 2017, she was bitten again, and her symptoms worsened to midnight hives and lightheadedness that sent her to her doctor's office. She immediately cut all meat and dairy from her diet. A year later, she wants to know if she can add anything back.

    "Can I eat dairy?" she asks. "Can I cook dairy? Can I eat it if it doesn't have animal rennet in it?" She pauses. "I've been symptom-free, because I don't take risks."

    Commins walks her through a protocol he's developed, a method for adding back mammal products one dose at a time. He has a hypothesis that alpha-gal reactions are linked to the fat content of food that might explain why they take so many hours to occur, because the body processes fat via a slower metabolic pathway than protein or carbs.

    He recommends that patients start with a spoonful of grated dry cheese, because its fat content is low, and graduate by slow steps up to full-fat yogurt and milk and then to ice cream. If those foods don't provoke reactions, he suggests tiny doses of lean meat, starting with deli ham.

    Stirling lights up at that. "I dream of charcuterie," she sighs.

    Because Commins was part of Platt-Mills's earliest research, he has been seeing alpha-gal patients for more than a decade now. He estimates he has treated more than 900 men and women five new patients arrive every week. He has coached a significant number of them back to eating some mammal products and managing their exposures to the things they can't handle, so their worst experience is hunting for an emergency Benadryl, not being rushed to the ER.

    Not every patient can do this. Julie LeSueur, who is 45 and lives in Richmond, Virginia, has been monitored by Platts-Mills for four years. (He is one of several doctors she has seen for the condition, after years of severe stomach issues escalated to repeated attacks of anaphylaxis that put her in hospital. One physician, frustrated she wasn't getting better, told her: "This is all in your head.")

    What started as an allergy to meat expanded into reactions to anything with an animal connection, including gelatine in medications and animal products in cosmetics, and then to sensitising her immune system to an array of other irritants, from nuts to mould. She buys vegan soap and shampoo, has prescriptions formulated by a compounding pharmacy, and mostly works from home to avoid unintended exposures. Reluctantly, she cut back a hobby that meant the world to her: fostering animals that have been rescued from abuse.

    "I'm at home all the time now," she tells me by phone. "I'm lucky to get off the couch."

    Commins and Platts-Mills named alpha-gal allergy a decade ago, and Van Nunen saw her first patient 20 years before that. A lab test for the allergy, the one that Tami McGraw received, has been on the market since 2010. (Platts-Mills and Tina Hatley, now Merritt, share the patent.) That makes it hard to understand why patients still struggle to be diagnosed and understand the limits of what they can eat or allow themselves to be exposed to. But alpha-gal allergy defies some of the bedrock tenets of immunology.

    Food allergies are overwhelmingly caused by proteins, tend to surface in childhood and usually trigger symptoms quickly after a food is consumed. Alpha-gal is a sugar alpha-gal patients tolerate meat for years before their reactions begin and alpha-gal reactions take hours to occur. Plus, the range of reactions is far beyond what's normal: not only skin reactions in mild cases and anaphylaxis in the most serious, but piercing stomach pain, abdominal cramps and diarrhoea as well.

    But alpha-gal reactions are definitely an allergy, given patients' results on the same skin and IgE tests that immunologists use to determine allergies to other foods. That leads both Van Nunen and Commins to wonder whether the syndrome will help to reshape allergy science, broadening the understanding of what constitutes an allergy response and leading to new concepts of how allergies are triggered.

    Merritt, who estimates she has seen more than 500 patients with alpha-gal allergy, has it herself she has had bad reactions to meat all her life, since being bitten by seed ticks at Girl Scout camp, and was re-sensitised by a lone star tick bite last year. She is sensitive enough to react not only to meat, but to other products derived from mammal tissues – and as she has discovered, they are threaded throughout modern life.

    The unrecognised dangers aren't only sweaters and soaps and face creams. Medical products with an animal origin include the clotting drug heparin, derived from pork intestines and cow lung pancreatic enzymes and thyroid supplements medicines that include magnesium stearate as an inert filler vaccines grown in certain cell lines and other vaccines, and intravenous fluids, that contain gelatine.

    "We have enormous difficulty advising people about this," Van Nunen says. "Sometimes you have to sit down for seven hours, write seven emails and have four telephone conversations to be able to say to a 23-year-old woman who's about to travel: 'Yes, you may have this brand of Japanese encephalitis vaccine because they do not use bovine material. The vaccine is made in [cells from] the African green monkey and I have looked up that monkey and it does not contain alpha-gal.'"

    Some replacement heart values are grown in pigs they may cause alpha-gal sensitisation that could trigger an allergy attack later. And cardiac patients who have alpha-gal allergy seem to use up replacement heart valves more quickly than normal, putting them at risk of heart failure until they can get a replacement.

    There's also a growing sense that alpha-gal may be an occupational hazard. Last year, researchers in Spain treated three farm workers who developed hives and swelling and had difficulty breathing after being splashed with amniotic fluid while they were helping calves to be born. All three of them – a 36-year-old woman, a 56-year-old woman and a 53-year-old man – already knew they had alpha-gal sensitivity, but had never imagined that skin contact would be risky.

    Commins has treated hunters who developed reactions after being splashed with blood after field dressing deer those cases raise the possibility that meat-processing workers could be at risk. In the two main Facebook groups where patients gather, it's common to hear school cafeteria workers fret about reactions from breathing the fumes of meat cooking.

    It's hard to know how many people may be sensitised to alpha-gal without knowing it. A project at the National Institutes of Health (NIH) that studies unexplained occurrences of anaphylaxis found last year that 9 per cent of the cases weren't unexplained after all: they were alpha-gal patients whose sensitivity had never been diagnosed.

    Platts-Mills points out that the prevalence of high levels of alpha-gal IgE in his earliest studies was up to 20 per cent in some communities, "but that was absolutely not the prevalence of allergic reactions to meat," he says. "So there are clearly plenty of people out there who've got the antibody but don't have this syndrome."

    What this all means is that there are almost certainly people for whom a meat-containing meal or medical intervention could trigger an alpha-gal reaction of unknown severity.

    There may be further peril awaiting them. In June, Platts-Mills and other researchers revealed that more than a quarter of patients who came to the University of Virginia's medical centre for cardiac catheterisation, to clear out life-threatening blood-vessel blockages, were sensitised to alpha-gal without knowing it.

    The patients with the undetected allergy had more arterial plaque than the ones without, and, most worrisome to the researchers, their plaques were of a type that is more likely to break away from the arterial wall and cause heart attacks and strokes. Though the research is early – done in one group of 118 patients, in a known hotspot for alpha-gal – Platts-Mills worries it presages a risk for heart disease that is larger than anyone expects.

    When a new disease surfaces in the USA, it's usually the CDC that investigates, pouring epidemiologists and data scientists into the field to track down connections and bring back samples for lab analysis. But investigation of alpha-gal is caught in a bureaucratic quirk of federal science. The CDC is responsible for infections spread by insects and arthropods – but alpha-gal syndrome is not an infection. That makes it the responsibility of NIH – which has abundant lab scientists, but no shoe-leather disease detectives.

    NIH does seem to be taking an interest. In June 2018, it hosted an invitation-only one-day IgE-mediated Meat Allergy Workshop in the past, such meetings have indicated the giant agency is considering launching a research programme. But just reading the workshop's programme provides a hint of how new alpha-gal research is participants called the problem by multiple different names, displaying that there isn't even yet any agreed nomenclature for it. Similarly, the US-run universal search engine for journal articles, PubMed, indexes papers on alpha-gal under "allergy to galactose-alpha-1,3-galactose", "mammalian meat allergy", "delayed red meat allergy", "galactose-α-1,3-galactose syndrome" and more.

    Platts-Mills was one of the workshop's invited speakers and gave the opening statement. Commins was there as well, along with researchers from New York, Germany, South Africa and Sweden.

    Dr. Marshall Plaut, who convened the meeting and is now chief of the Food Allergy, Atopic Dermatitis, and Allergic Mechanisms Section at NIH's National Institute of Allergy and Infectious Diseases, describes it as the earliest step in possibly committing to a research programme. (Platts-Mills and Commins have already received some NIH funding.) "It signals that NIH has some interest in understanding more about the disease," he says. "There are a lot of things that need to be understood."

    In August, Commins gave a talk on alpha-gal allergy at the International Conference on Emerging Infectious Diseases, a conference held every two or so years and sponsored by the CDC that often surfaces the earliest signals of illnesses that are destined to become big problems.

    The CDC's director of foodborne illness was in the audience so was its director of vector-borne diseases, the department that deals with ticks. Afterwards, they both zoomed up to ask him questions. "I kind of had the impression this was just a weird, small thing," Dr. Lyle Petersen, the vector-borne director, told him. "But this seems like kind of a big deal."

    With NIH and the CDC paying attention, research into alpha-gal might be reaching a threshold, a moment at which isolated investigations might coalesce into answers. For the patients, who feel isolated too, that can't come soon enough.

    This article first appeared on Mosaic and is republished here under a Creative Commons licence.


    The galactose-α-1,3-galactose (α-Gal) syndrome has many novel features that are relevant to diagnosis and management. In most cases, the diagnosis can be made on a history of delayed allergic reactions to mammalian meat and the blood test for IgE to the oligosaccharide α-Gal. In general, the diagnosis also dictates the primary treatment, that is, avoiding mammalian meat and also dairy in some cases. In the United States, the lone star tick is the primary cause of this disease, but different ticks are responsible in other countries. Blood levels of IgE to α-Gal often drop in patients who avoid recurrent tick bites, but the rate of decline is variable. Similarly, the delay before reactions is variable and the severity of the allergic reactions is not predicted by the delay or the titer of specific IgE. Some mammalian-derived products such as heart valves, gelatin-based plasma expanders, and pancreatic enzymes are relevant to only select patient groups. A minority of cases may benefit from avoiding a wide range of products that are prepared with mammalian-derived constituents, such as gelatin. This review focuses on the nature of the syndrome, common challenges in diagnosis and management, and also gaps in our current knowledge that would benefit from additional investigation.

    This work was supported by the National Institutes of Health (grant no. R37-AI-20565 to T.A.E.P.-M.).

    Conflicts of interest: T. A. E. Platts-Mills has a patent on an IgE assay to α-Gal and has received assay support from Thermo-Fisher/Phadia . J. M. Wilson has received research support from Thermo-Fisher/Phadia . The rest of the authors declare that they have no relevant conflicts of interest.