How does a tick bite cause a red meat allergy?

[MUSIC PLAYING] FLORA LICHTMAN: Hey, it’s Flora, and you’re listening to Science Friday. For two decades, a perplexing illness has been spreading. After a Lone Star tick bite, people find themselves having a severe allergic reaction to red meat. Gone are the days of burgers and steaks, some people are sensitive even to the smell of barbecue or cow-derived gelatin.

This tick-borne allergy is called alpha-gal syndrome. The CDC estimates up to 450,000 people in the US may be affected, and that’s up from just a few dozen documented cases in 2009.

Dr. Scott Commins started researching alpha-gal syndrome almost 20 years ago, before anyone really knew what it was. He was part of the team that tied this allergy to ticks. He’s an allergist and immunologist at the University of North Carolina’s Medical School. Scott, welcome to Science Friday, thanks for being here.

SCOTT COMMINS: Thanks for having me.

FLORA LICHTMAN: I think people think of alpha-gal syndrome as a red meat allergy, that’s the shorthand, but what are the symptoms?

SCOTT COMMINS: Well, they’re often the classic symptoms that bring people into an allergist’s office. So itching, swelling, hives. And then frequently, there’s accompanying gastrointestinal distress. So terrible abdominal cramping and pain, often nausea, vomiting, diarrhea. You can even have progression from there where people will feel short of breath or have difficulty maintaining their blood pressure, the things that we think about as anaphylaxis.

FLORA LICHTMAN: What are people exactly becoming allergic to?

SCOTT COMMINS: Well, they’re allergic to a sugar. So alpha-gal is a carbohydrate, and the allergic antibody recognizes alpha-gal, which is present in the meat and tissues of all non-human mammals.

FLORA LICHTMAN: So this is a sugar that we must encounter all the time throughout our lives. So what is in the Lone Star tick that is making people sensitive to the sugar?

SCOTT COMMINS: Well, the ticks, it turns out, seem to have the sugar. And so when they bite a human, their tick saliva and factors in the tick spit seem to cause the human immune system to create this allergic response. And in some ways, alpha-gal is just an innocent bystander, and if it weren’t in hot dogs, hamburgers, et cetera, we probably would never even about this allergy, but the distribution of alpha-gal in the foods that we eat and the medications that we take create that issue.

FLORA LICHTMAN: I mean, can we get into the nerdy details here, though? Why is my body suddenly recognizing this sugar as bad when it comes from a tick, but not when it comes from a hot dog I’ve had the day before?

SCOTT COMMINS: Yeah, it’s a great question, and there’s probably a nuanced answer, only some of which we really about. But one portion of that is the route of administration. So oral, like, you’re eating your hot dog or hamburger, that seems to be associated with tolerance. So very unlikely to develop an allergic response just by consuming the food, particularly when it’s been consumed for decades.

The skin, however, is a fantastic way to make an allergic response. So it probably really matters that the tick bite is happening to our skin. And we don’t really know the exact like factor and how it’s hooked to alpha-gal, but probably the tick saliva contains what we might call alarmins. So it turns the human immune system on and activates it, and basically it’s like a danger signal to our immune system, and then alpha-gal just becomes an innocent bystander that we make an allergic response to.

FLORA LICHTMAN: Is an alarmin a technical term?

SCOTT COMMINS: It can be, but it’s also a simple term.

FLORA LICHTMAN: You published a study recently that analyzed blood samples from people across 10 states, and you had this sort of amazing finding that one in four people had alpha-gal antibodies in their blood. What does this mean? Because not all those people have the syndrome, right?

SCOTT COMMINS: Correct, not at all. The numbers seem incredibly high– 20%, 30% of blood donors in some states, but that’s just what we call sensitization, meaning you have a positive blood test. Overwhelmingly, those people would eat red meat just fine.

We have a major issue in the field of allergy and immunology with our blood tests and our skin tests for that matter, too. They are not good screening tests. They should be used when we suspect someone has an allergy. So just taking a lot of samples and applying the test is not how that test should be used.

FLORA LICHTMAN: Does that mean that those people who were positive for these antibodies were bitten by a Lone Star tick?

SCOTT COMMINS: Basically we think that’s the truth. In some ways, it probably is a marker for Lone Star tick bites– and other bites, too, because alpha-gal syndrome is a global issue. So it happens beyond just Lone Star ticks, and you’re correct to think that the alpha-gal IgE that we detected in this recent publication, that probably serves as a marker for tick bites.

FLORA LICHTMAN: Will you define IgE for us?

SCOTT COMMINS: It’s just the allergic class of antibody. So if you’re allergic to cats or dogs, your allergists, immunologists might say you have IgE to cat or dog.

FLORA LICHTMAN: OK, so this is probably the million-dollar question, but why do some people develop the syndrome and some people don’t?

SCOTT COMMINS: That is the million-dollar question, and we’re not sure. So there’s clearly some risk that is attributable to the tick, and there are good studies that look at male ticks versus female ticks and what they’ve been fed on, and the scientists can detect different levels of alpha-gal in the tick saliva between various life stages, between males and females. So it probably really matters exactly which tick you were bitten by.

But then there’s certainly going to be host issues, too. As humans, we find often I will have a spouse or a partner in the exam room, and many times they’ll say, well, as long as I go out with Debbie, I don’t get any tick bites, they all go to her. And so there seems to be very clear risk things, risk factors that are happening at the host level.

The other example is blood type. It is becoming increasingly clear that if your blood type B or AB, your risk of developing alpha-gal syndrome is much lower than people who are A or O. So your question is right on, these are the things that we’re thinking about, too. I think there’s a tick risk and a host risk, and we’re still working on both of those.

FLORA LICHTMAN: What’s the profile of the tick that’s most dangerous? So I which ones to avoid.

SCOTT COMMINS: The female Lone Star tick is a bad actor, but I will tell you that increasingly we hear a lot about the larval life stage, which some people call seed ticks. They’re really difficult to see. They’re like the head of a pin, and you can be bitten by 100 at once because they often come out of an egg mass.

So there are thousands of these tiny little ticks that are laid in a very small space, and if you brush by the wrong leaf or blade of grass, you can literally end up with hundreds of bites, and that also seems to be a bad actor.

FLORA LICHTMAN: I remember this happened to me as a kid growing up in Missouri, and I just remember my leg being covered and brushing them off like it was– I’ll never forget. Anyway, side note, why is the allergic reaction delayed? If people with peanut allergies, you see it right away. They can swell up within minutes. This takes hours. Why?

SCOTT COMMINS: We think it has to do with the fat content of the meat or meal being the important part of delivering alpha-gal. So fat has alpha-gal on it, and it can exist in the science realm as what we call a glycolipid. So a fat molecule that has sugar on it.

It turns out that the absorption of fat takes much longer than proteins or carbohydrates on their own. That whole process takes several hours, and patients will often say that the fattier meals bother them more. If you were to give alpha-gal intravenously, as was occurring with the cancer medicine cetuximab, those reactions happen within minutes.

FLORA LICHTMAN: There’s been a lot of attention on alpha-gal in Martha’s Vineyard and Long Island. How widespread is it, and where is the highest exposure?

SCOTT COMMINS: Well, it is fairly widespread. So basically, the entire East Coast all the way west to around the Rockies because we’re starting to see a lot of cases in Oklahoma and Nebraska. There are cases around the Great Lakes areas as well. And I mentioned Maine. So we’ve extended now from the original Southeastern states up the East Coast.

And then there are these hotspots. Suffolk County, Long Island has a tremendous issue with AGS. So as you mentioned, Martha’s Vineyard seems to be a recent hotspot and is currently receiving a lot of attention because the rates have just gone up exponentially.

FLORA LICHTMAN: Mm. We have to take a quick break, but when we come back, we’ll talk about whether new treatments or interventions are on the horizon. Stay with us.

OK. Are there treatments? I know that Xolair’s an allergy medicine that seems to work, but is it an approved treatment? Is it an off-label use?

SCOTT COMMINS: No, Xolair is on-label because Xolair, as the FDA-approved, it is for any IgE-mediated food allergy. So there’s the IgE term again, but AGS falls in that, too, same as peanut, cow’s milk, egg, et cetera. So you can use Xolair broadly and it’s on-label for alpha-gal syndrome. We have a host of patients on it, probably nearly 100 at this point, and they do quite well.

FLORA LICHTMAN: Do they take it after a possible exposure or are you on it all the time?

SCOTT COMMINS: You’re on it all the time. So the way it works is it binds IgE, and over a period of months, generally, basically kind of renders you non-allergic. So a small exposure, cross-contamination, that kind of thing doesn’t cause a reaction.

FLORA LICHTMAN: Hm. I mean, for other allergens we’ve talked about early and often exposures. Is there a version of that that people are thinking about for alpha-gal syndrome?

SCOTT COMMINS: Well, we’d love to have that, something like what we call Oral Immunotherapy, or OIT for short, where you basically eat a tiny bit of the allergen every day to desensitize yourself. I think that’s possible in the long term with alpha-gal syndrome, but we really struggle at the moment with what that should be.

I don’t think we should– at least based on the dietary guidelines that we’re being told, the cardiovascular risk with red meat, I don’t know that we should be feeding our patients– or telling them every day, you have to eat a certain amount of beef. I worry that in the long run, the cardiologist is going to come back to me and say, you did what? But I think it’s doable, we’ve just got to figure out the form of alpha-gal for that daily consumption.

FLORA LICHTMAN: Mm. What about vaccines?

SCOTT COMMINS: Yeah, we are thinking about vaccines. We need to know what that factor or factors are in tick saliva that really could drive the immune response.

And I think once we know that, we can take an approach similar to what we do for, say, bee or wasp venom where you can’t prevent that first bad bee sting reaction, but then we put them on venom shots, and then future stings don’t cause that allergic response. So I think we could do that for the tick bite, we just have to what it is in the tick saliva that’s the real trigger.

FLORA LICHTMAN: You see, patients, I’m sure, across the allergy spectrum. What does this diagnosis like for people? Is it emotionally different from getting a different kind of food allergy diagnosis?

SCOTT COMMINS: It seems to be emotionally different, and I think part of that is most patients that I’m seeing these days, because I’m in the adult clinic, they’re either adolescents or adults, so they’ve safely eaten beef, pork, lamb, venison, et cetera for years. And then you take that away, for some people, it’s a big part of their diet.

And the other thing I tell folks is, when you’re an adult, we don’t get together for a play date, we get together for lunch or coffee or dinner. So there’s a social part of this, too, that really changes for people and we’re I think increasingly aware that there is a mental health aspect to these severe food allergies.

FLORA LICHTMAN: Working on this for 20 years, has it changed your feelings about ticks or your behaviors?

SCOTT COMMINS: Oh yeah, absolutely. Now if I’m going to be out there, I’m definitely using permethrin, and I’m not bashful about tucking my pants into my socks and using some double-sided tape where I need to. I think what we learned over time is that truly an ounce of prevention on the tick bite side can save you years of this severe allergic reaction.

FLORA LICHTMAN: I mean, this has been basically your career. What do you still want to know?

SCOTT COMMINS: We have Xolair. We’d love to have a more targeted treatment. And I think we can make some breakthroughs there. I’d love to have an on-demand treatment in some way because the allergy actually tends to go away over time. The immune response that the tick bites tend to trigger does not seem to be a permanent one.

So this thing can fade over time. The issue is additional tick bites basically boost that allergic response. So something that should go away in three to four years with no additional tick bites can take decades to go away or perhaps never resolve if someone has to work outside or gets additional tick bites.

So I would love to have a therapy that we could use very quickly in someone who already has the allergy, and we could deliver a therapy on-demand after a tick bite to try to intervene and prevent that rise or boost in the allergic response.

FLORA LICHTMAN: Are we anywhere near that? Is that the pie in the sky, or are you working on that?

SCOTT COMMINS: No, I think there are some candidate molecules that are available, and hopefully we can try to do some clinical trials where we’re really focused in that area. I think the other thing is, as we mentioned earlier, trying to understand the risk that the tick poses, but then also understand what the risk factors in the host side might be. And if any of those are potentially modifiable, then that would be something that would potentially offer a treatment or therapy as well.

FLORA LICHTMAN: It’s interesting to hear you say that because I think people who feel like they’re a magnet for insects will feel very validated by this.

SCOTT COMMINS: When you talk to patients, this theme comes up over and over again, that somehow, you’re in the woods with your friend or spouse or partner, and one of them is more of a tick magnet or bug magnet. It comes up all the time, and so I really think there is something to that.

FLORA LICHTMAN: There’s something real there. Thank you, Scott.

SCOTT COMMINS: Thank you.

FLORA LICHTMAN: Dr. Scott Commins, Associate Chief for Allergy and Immunology at UNC School of Medicine in Chapel Hill, North Carolina. This podcast was produced by Kathleen Davis. And if you’re itching for more from us, check out our newsletter, sciencefriday.com/newletters. Thanks for listening. I’m Flora Lichtman.

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