Crossing the threshold of more precise allergy care

"We use thresholds every day without even thinking about it. When we do a food challenge in our office, whether we know it or not, we're relying on the fact that there is a threshold for every patient. Some are going to be on the first dose, some are going to be at the last. And that's just part of what a threshold is." 

– Dr. Doug Mack

Food allergies aren’t one-size-fits-all, but we don’t talk enough about thresholds—the amount of an allergen it actually takes to trigger a reaction. Should every patient be following the same strict avoidance rules? Or should we be aiming for something more precise?

To help us make sense of thresholds, we welcome back Dr. Douglas Mack, pediatric allergist, clinical immunologist, and Vice President of CSACI. Dr. Mack is known for his work on food allergy treatment, including oral immunotherapy, epinephrine use, and—you guessed it—thresholds.

On this episode, Dr. Mack and Dr. Mariam Hanna dig into:

• What a threshold actually is and why it matters in clinical practice – How thresholds shape food challenges, oral immunotherapy, and allergen risk assessments, even when we don’t explicitly discuss them.
• How much allergen is too much? – Why two patients with the same allergy can have vastly different tolerance levels, and why strict avoidance isn’t always the best approach.
• Eliciting dose, cumulative dose, and the numbers that matter most – How clinical trials define reaction thresholds, and how allergists can use these data points to guide patient care.
• Real-world factors that affect thresholds – How co-factors like exercise, illness, sleep deprivation, and even hot showers can shift a patient’s threshold and increase reaction risk.
• Precautionary labels, airplane bans, and the science behind food allergy risk in everyday life – What research tells us about trace exposures, why precautionary labeling varies worldwide, and how allergists can help patients navigate the gray areas of food safety.

Thresholds aren’t just theoretical—they impact how we advise patients, assess risk, and tailor treatments. Dr. Mack walks us through the science behind these numbers and how allergists can apply them in daily practice.

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The Allergist is produced for CSACI by PodCraft Productions

Transcript

Dr. Mariam Hanna: Hello, I'm Dr. Mariam Hanna, and this is The Allergist, a show that separates myth from medicine, deciphering allergies and understanding the immune system. In the diagnosis and treatment of food allergies, we don't discuss thresholds enough. I mean, the patient with a sesame allergy that has trace cross-contamination and has a reaction is quite different phenotypically from the sesame allergy patient that can have sesame seeds on a bun and perhaps the occasional mouth itch.

I'm questioning more and more these days my impression and plan statement where I say, "This patient has an allergy to food X. Strict avoidance is advised." Really? Strict? For everyone? Is this fear-based medicine and an appeal to their own or my own risk aversion? Or should we be aiming for something higher—precision medicine?

Are we giving patients the right advice? We're bringing back a dear colleague to discuss this paradox. Dr. Douglas  Mack is a pediatric allergist and clinical immunologist and an assistant clinical professor in the Department of Pediatrics at McMaster. He is the Vice President of the CSACI and co-author of guidelines on the prevention of allergy, epinephrine use and anaphylaxis, oral immunotherapy, and—he speaks internationally about the treatment of food allergies and, you guessed it, thresholds.

I'm also using free artistic license in adding a bit of a disclaimer to today's episode. The following presentation contains discussions of food allergy thresholds, the science behind reactions, and the occasional scientific rant. Listener discretion is advised. This episode may contain traces of controversy, unexpected food science, and deep dives into allergen thresholds.

Side effects may include questioning everything you thought you knew about food allergy severity, rethinking your approach to allergen exposure, and developing a newfound appreciation for EDO5 discussions. No allergists were harmed in the making of this podcast, though some may experience mild frustration when explaining thresholds to the risk-taking teenager.

And now, sit back, relax, and prepare to enter the wild world of food allergy thresholds. Dr. Mack, the stage is now set. Welcome back to the podcast, and thank you for agreeing to do this.

Dr. Douglas Mack: Thanks for having me. Looking forward to it.

Dr. Mariam Hanna: Okay, we start with the basics—and yet not. What are thresholds in food allergy?

Dr. Douglas Mack: I think the concept of threshold—the way I think of a threshold is that every patient has an amount of food that they need to have to induce a reaction, and that may shift based on the patient and what the food is.

If you think about it, I almost think of it like a cup. If you had a cup with a line measure on it and you put water into that cup, and it's below that line, you're not gonna react. But once you exceed that line, that's when you end up having your allergic reaction. Some patients' lines are a little bit lower, and some patients' lines are a little bit higher. And I think that is what, fundamentally, a threshold is. And I think we see a large spectrum of these thresholds across the population.

If you can imagine that, you know, if we had 30 peanuts, just about every peanut-allergic patient is going to react to that. But if I have a piece about one millimeter, two millimeters in size, probably only about one percent of the population is going to react to that.

And so there's significant variability here. And I think the challenge is defining what that threshold looks like for our patients. It’s something that we are trying to do more and more, both in clinical studies but also in clinical practice.

Dr. Mariam Hanna: I really like that analogy, and that kind of helps to visualize it for patients and explain it. But how is it important in clinical practice and daily life to discuss this?

Dr. Douglas Mack: So, I'm going to say that we use thresholds every day without even thinking about it. I think we use thresholds when we look at “may contain” products and product labeling. We look at this in the context of a nut-free school—is it truly nut-free, or are we just looking at thresholds here?

How about when we do a food challenge in our office? Whether we know it or not, we're relying on the fact that there is a threshold for every patient. Some are going to be on the first dose, some are going to be at the last. And that's just part of what a threshold is.

Oral immunotherapy—when we treat patients who have food allergy, we gradually increase their threshold. Even ladders rely on the concept of thresholds as well. So I think these are concepts that we use every single day in our practice without even thinking about why we’re doing these stepwise. It’s because of the threshold.

Dr. Mariam Hanna: Interesting. Okay, so I'm going to take you a step back, and we're going to just clarify some terminology. We've been using the word "threshold" a lot, but in clinical trials, we also talk about the eliciting dose and the total cumulative dose in addition to this discussion of thresholds.

Can we go through the differences or similarities of what these terms actually mean?

Dr. Douglas Mack: Yeah, so an eliciting dose is basically the actual dose that it takes to cause a reaction. So, say, for example, I have a patient who has a one-milligram dose, and they're fine. Then they get a three-milligram dose, and they're fine. Then they go to a ten-milligram dose, and they're fine.

So they've had fourteen milligrams, but that last dose was ten milligrams. And if they were to react at that ten-milligram dose, then that would be considered their eliciting dose. Okay, so their eliciting dose is ten milligrams. Their cumulative dose, however, is actually fourteen milligrams.

And so there is a difference, and I think this is one of the challenges that we look at—how do we interpret, yes, they've had only 10 milligrams in their last dose, but they already had four before that? And I think this is one of the challenges.

As long as we are standard in our approach to interpreting this, I think that's where we—what we do in clinical trials. And I think it's important that we look at this objectively and consistently. I think we can argue about what is more important—the cumulative dose or the eliciting dose—but what I think is most important is that if we are using consistent nomenclature and a consistent approach to grading, dosing, et cetera, then we should be able to compare results across studies and within the same study.

And I think this is important as we look at how we translate this into therapeutic effect. And I don't know if you want to talk about this, but to me, determining that therapeutic effect is important.

So, say, for example, once I go back to that patient again, who tolerated one milligram but then reacted at three milligrams—if we can increase their threshold during immunotherapy, we can reduce risk significantly. And I think that's where the importance of understanding these thresholds is, at least especially from a therapeutic perspective.

Because if I can figure out what that patient's threshold is, I can determine exactly what their—or pretty exactly what their—risk in the environment is. And then, if I can determine what their actual current threshold is after having the treatment, then I can say, "Your risk of reaction in this scenario is extremely low, and it’s been reduced by a certain percentage."

So that, to me, I think is super important.

Dr. Mariam Hanna: Okay, so two questions on that. First, are you using the term "threshold" here interchangeably to mean eliciting dose or total cumulative dose?

Dr. Douglas Mack: We'll say eliciting dose in this scenario. Yeah. Yeah.

Dr. Mariam Hanna: I worry that sometimes when we discuss thresholds, it gets interpreted as reaction severity.

Dr. Douglas Mack: Hmm.

Dr. Mariam Hanna: Do thresholds correlate with reaction severity?

Dr. Douglas Mack: The concept of severity is multifold. And I think I interpret severity as a patient who is potentially more at risk of a more significant reaction because of inherent characteristics like uncontrolled asthma or other factors such as this. And so I think, yes, the dose can play a role in this, but I would say that in reality, it doesn't necessarily translate into the severity of a reaction.

Dr. Douglas Mack: Once again, if a patient has that, the risk of a reaction being anaphylaxis—even amongst a patient who is having an objective allergic reaction—the risk of anaphylaxis is less than 5%. So I think these are challenging concepts for us, but I think when we look at it objectively, it does instruct us on how we move forward a little bit.

Dr. Mariam Hanna: How is threshold actually determined? We talked a little bit about it in oral food challenges. Is that the only way that we can determine thresholds?

Dr. Douglas Mack: The reality is that's probably the only objective way that we can do this. We have lots of data looking at this, and as we do clinical trials—I think probably clinical trials have given us the most information about that—because those are very controlled oral challenges where we have absolutely known doses, whether it's one milligram, three milligrams, 10 milligrams, 30 milligrams, et cetera, et cetera.

So we know exactly what that patient is getting, and we have an objective grading scheme to determine what their actual threshold is. And I think that's where we have extracted most of this data for determining what the average amount is that is required to induce a reaction, but also what the reaction characteristics are at those levels.

Because we can once again go back over thousands of patients enrolled in clinical trials and say, "Okay, what do we see at this level? What was the reaction, and what was the reaction severity?" And then we can extrapolate that to the population. But this is the most controlled way of sorting this out.

So yes, an oral challenge—ideally in a clinical trial or one that uses standardized guidelines outside of a clinical trial—is a very reasonable way to do that. We can all do this in our office. We can all measure out the amount at one milligram, three milligrams, 10 milligrams, et cetera, and we can then determine what that patient's threshold is.

Now, are all of us going to do that? Probably not. I think it is labor-intensive. And I think this is something that, yes, it's nice to have the exactness to this, but in a practical sense, you and I see this all the time in our offices—that the patient gets to 10 peanuts down the road, and you're like, "Well, listen, it's hard to say that you should be outright avoiding this."

Perhaps we talk about something like immunotherapy in this scenario, where we're giving this on a more regular basis. So I think there are nuances to this. And yes, strictly speaking, a controlled food challenge is probably the best way—but we do this all the time.

Dr. Mariam Hanna: And, just repeating—to date, a skin test doesn't associate with the threshold that a patient has, and blood work doesn't associate with the threshold.

Dr. Douglas Mack: That's a really good question. In fact, we looked at some of our data that we presented at some conferences recently, looking at the patch data—the epicutaneous immunotherapy for peanut patch data.

There was some indication that the IgE level was associated with threshold potentially, and not necessarily with severity, but the higher the levels of antibodies, the lower the threshold was. It wasn't exact, and I think this is something that we're still looking at, but there may be a trend toward that. And I think that story is just not—I don’t think it’s finished yet.

Dr. Mariam Hanna: I always worry a little bit to say that a lot of our threshold knowledge comes from food allergy trials, but food allergy trials are not like cardiology trials, and we’re making population-based recommendations based off of that. What do you think about that? Is this enough data to talk about thresholds?

Dr. Douglas Mack: I think it does. I think it gives us the most objective information that we can. These are patients that are under ideal circumstances, however, and I think that’s where maybe the challenge exists. I think that sometimes we know that thresholds can vary to some degree.

However, what’s really cool about this—at least in the short term—is that 71% of patients have reproducibility of this reaction threshold. And you’ve probably heard that, “I heard that my next allergic reaction is going to be worse,” and that’s the kind of myth that I hear all the time.

Well, we can say that most patients are going to have a very similar threshold. What’s also cool about that is that no patients, when you look at a case where they do one food challenge and then repeat it a year or two later—no patients who had previously tolerated a dose had anaphylaxis.

What that means is that if they had no reaction the first time and reacted the second time, none of those were anaphylaxis.

What was even cooler—and this is really important—is that 75% of patients who had initial anaphylaxis had no anaphylaxis on the subsequent reaction. And I think that’s what’s really cool. You've heard this myth before: “I heard the next reaction is going to be worse.” And that, to me, is a complete myth.

Now, we’re talking about ideal circumstances here, right? Because they come into the office, they’re healthy, et cetera. But I think what you’re getting at is that in the real world, we do have variability in what contributes to reaction severity and perhaps can lower the threshold.

So there are co-factors, and we consider co-factors things like exercise. You and I know that during oral immunotherapy, if a patient exercises after a previously tolerated dose, they can react. We know that this happens all the time.

If they’re sleep-deprived, if they’re jet-lagged—we have objective data to suggest that can reduce thresholds in some patients.

Other co-factors might include infection, hot tubs, hot baths or showers, potentially alcohol. So I think one of the challenges with applying it to the real world is that there are co-factors in there.

Now, if you look at some of the data in the real world, they don't appear to have a great effect from a population perspective, but on the individual perspective, it may change things to some degree. And it becomes challenging.

Dr. Mariam Hanna: How much—do we know, like, the delta of how much it would change the threshold? So I really like the fact that you use the water-in-a-cup analogy, because to date, I keep telling them it’s like a shifting line in the sand, and the water can just move it right back and forth. So how much does it shift?

Dr. Douglas Mack: Probably around 50%. You know, I think this is one of the challenges, at least from some of the objective data—perhaps around 50% when it comes to exercise or sleep deprivation. So once again, we're talking about thresholds here.

That’s why when we are doing OIT—once again, practical application here—we often will either reduce or hold the dose at times of exercise, illness, et cetera, or we’ll reduce the dose to try to account for that shift in threshold. So this is something that we do on a practical basis all the time.

Dr. Mariam Hanna: So, flipping from immunotherapy—what about with food challenges? Like, the practice parameters don’t tell people to go run up and down the stairs during your food challenge just to make sure that threshold really doesn’t exist.

Dr. Douglas Mack: So—

Dr. Mariam Hanna: Should we be doing that?

Dr. Douglas Mack: It's a—it's a great question. I don’t think so.

During a food challenge, because we go to such a high level, the reality is that we probably don’t need to do that. And I think that this is—if I get a patient to eat 20 peanuts, could they still be allergic? Highly unlikely. And exercise is likely not going to make a big difference there.

But there are people who will incorporate an exercise challenge in the setting of oral immunotherapy. And that is something that we see—people will challenge them after, so give them the food and then have them exercise shortly afterwards and ascertain whether or not they’re reactive or not.

Now, this is also somewhat variable because, as you know, we have some patients who will react sometimes with exercise and not other times with exercise. So there are differences here, and I don’t think that they can be widely transferred.

But at the same time, they are a start, and they increase our knowledge. So I’m certainly in favor of that.

Dr. Mariam Hanna: What is a meaningful change in threshold? Does one to three actually matter if there's a 50% change if co-factors are in play and both of those numbers are ridiculously low?

Dr. Douglas Mack: Yeah. Okay. Can I give you an example? Okay. Because we can—I—this is going to get a little bit weedy here. Okay? And so you're—whoever's listening in, stick with me here for a second.

So we can figure out how much exposure may occur in a typical product. So we've done clinicals, we've done research on this, where you basically take muffins from a bakery, and you figure out how much—what is the range of peanut protein found in those muffins.

And they can range quite a bit, actually. But then you do that, and you look across other studies that have done that, and we can figure out what is the typical amount of contamination that's been reported for peanut, for example, in the literature. And we have quite a bit of data on this.

Then we can figure out—so we say, I have this amount of protein that could be in here, and then you figure out what is the average amount of that product that's consumed, or the range of the product that's consumed.

So we can actually figure out what is the probable dose range that might be found in a product and then ingested by a patient. Okay? So that helps us to determine risk a little bit.

Okay, so say, for example, I have a cookie, and I can estimate that it has a certain amount of protein in it. If a patient has a threshold of three milligrams, in a typical cookie, they actually have about a 31% chance of having a reaction to that food.

Okay? Because their threshold is three milligrams, we know that the amount in that cookie could be in this range, so they actually have about a 31% chance of having a reaction to that cookie.

Okay, so that's if their threshold is three milligrams. If it's 10 milligrams, their risk is about 16% or so.

If I can bring that threshold from three milligrams up to 300 milligrams—the risk baseline, once again, is about 31%—but if I get them to 300 milligrams, then their risk of having a reaction is 0.012%.

Okay? That's a tiny amount. And that's a 99.9% risk reduction of having an accidental reaction.

So, to me, that's a very, very big difference. And I think, to patients, this is huge.

We don't have to get them eating 20 peanuts to reduce their risk of accidental reaction. All we have to do is raise it to a level that's above what is found in most products accidentally.

And that—if we can raise their threshold above that level—then, for the most part, most of our patients are going to be actually very well protected.

Dr. Mariam Hanna: And it's important to say that while they're on treatment, their threshold may not immediately change.

Dr. Douglas Mack: Yeah. And I do that in my office all the time. I say, "Okay, listen, your child is at this level for immunotherapy, this is your risk." And then they can see it drop down as they go on.

It’s—it’s pretty amazing to do. I love pulling up those tables and charts in my office.

For those of you listening, Joe Baumert—B-A-U-M-E-R-T—has a great article published in JACI in 2018 that kind of outlines this. You have to read through it. There are some great tables in there, but they are—they’re very useful.

Dr. Mariam Hanna: Okay. Now, not to be super peanut-centric—can we talk about allergen thresholds for other common allergens that we see in the clinic?

We do a lot of this extrapolation from peanut, but is EDO5 the same for other allergens like milk or wheat or others?

Dr. Douglas Mack: Yeah, it isn’t. It—but it’s—we consider peanut the reference, and there are a number of many articles that look like that.

The reality is that it is similar for most foods. Okay, so things like almond, milk, egg, sesame, peanuts—they’re all relatively similar.

Wheat is a little bit different, a little bit higher for a threshold.

Shrimp and other crustacea? Way off the charts. It’s not even comparable.

But the other foods are actually pretty similar. And so, because of that, we are—there—there are—we can start to look at how to apply this from a population perspective, for precautionary allergen labels.

So we can use that reference of two milligrams total protein, which is—which is visible.

By the way, these are visible amounts. I think that's really important. A lot of people come into my office, and they think that the invisible amount of peanut on the surface of a food is going to cause a reaction.

I mean, even for the most sensitive 1%, it’s still a visible amount of protein that is required to induce a reaction. And I think that’s—and once again, a reaction—less than 5% of those are going to be anaphylaxis.

And once again, we can—we can extrapolate that less than 1 in 60,000 are going to be severe, refractory anaphylaxis.

So this is—that’s—I think that is critical. So this is why we look at that.

Dr. Mariam Hanna: Yeah, I think it's actually a very reassuring statement to tell people that this is a visible quantity—not like the ether that was touching it.

Okay. So, precautionary labeling is—is a hot topic. It differs worldwide. And as we are globally becoming more interconnected, we are getting products from other parts of the world where some of my patients are like, "Oh, you can't trust that because it's different there."

Why is it different worldwide?

Dr. Douglas Mack: There are so many reasons why precautionary allergen labeling is different.

It's economics. It's practical, it's cultural, it's recognition, it's the presence of allergy in different parts of the world—higher and lower amounts.

I think in Canada, we take an approach where if we put it in there, you have to label it. If we are unsure, then you can put a “may contain” on that, or if—if a company wants to just put it on there, they can put it. t's a voluntary label—"may contain."

Other parts of the world have taken a bit of a different approach, and the WHO and the Food and Agricultural Organization of the United Nations has endorsed what's called the VITAL process. And I think what the VITAL process does is—it uses these thresholds.

So, it’s amazing—what it does is determine, once again, that it may be acceptable for some foods to have up to a small amount of protein in it. Okay, that has peanut in it, and that accounts for the fact that that very, very small amount—which, again, that's that EDO5, that's the amount that less than 5% of the population could react to—the probability of anaphylaxis is, once again, less than 5% of those who have objective symptoms.

And that’s, I think, really important because, once again, the risk of severe anaphylaxis is between less than one in 60,000 and one in 100,000 person-years. So this is, I think, critical. They’ve taken these same principles and said we can reassuringly have companies determine that if it's less than 5% threshold, then, for the most part, this is a very safe amount for most patients to be eating.

Now, for some patients, they won’t feel comfortable with this, and we can understand that. Perhaps for those patients, we might be doing more threshold challenges in the office to say, "Listen, is your threshold above this?"  Great. You can eat these products, even if it doesn't say "does not contain," et cetera. 

So, I think these are—I think important initiatives that are based on science, and I would love to see how this translates. It is being—it is being taken up. Certainly has been taken with—with gusto in Australia, New Zealand, but I think that it's moving its way around. And I'm hopeful that we continue to provide science-based guidance because it's really challenging for families to have a "may contain" label when they don’t—when it probably doesn’t have it in there to begin with. And I think this is why having standardization actually may reduce anxiety for many of our families.

Dr. Mariam Hanna: Okay, so—um, and then the last one that I'm going to pick your brain about is a little bit to do with the airplane debate. It’s kind of similar to me, or along the same lines as precautionary labeling and interpreting that. Given what is known and founded about thresholds, do allergen announcements and/or bans on airplanes make sense?

Dr. Douglas Mack: We didn't find that—that they were particularly helpful from a school perspective in our systematic review. The data for airplanes is relatively similar. I'm really not trying to say that—that we shouldn’t have preparedness in this scenario and that we shouldn’t have epinephrine available and that we shouldn’t take precautions. I think—absolutely, patients on a plane should take precautions. But the reality is that a patient—how do you put this?

I think from a personal perspective, they should not be taking risks on an airplane. I think eating foods that may contain, for example, or whatever, might be somewhat risky. I think this is all about risk stratification. I think it’s all about—would I be willing to take a risk when I’m in a city? That’s one thing—near a hospital. Am I willing to take a risk when I’m 30,000 feet up? I think this is more challenging. And I think—so from an individual level, I think not taking individual risks is really important.

Not just eating anything off the plane—going to the food court before you get on a plane and then eating whatever you find. To me, that’s risky, and I think that's something that most of my patients would be advised to bring their own food, for example, or eat foods that you know have an extremely low risk of having enough to cause a reaction.

I think having a ban on a plane is almost a different discussion. I think that this is—that is a systems issue. That is a societal concern. And I think probably the most important thing for a patient is to, A, have their epinephrine, and not take unnecessary risks when they’re getting on that plane or on the plane.

Dr. Mariam Hanna: A nice answer, and this episode has flown by. Ha ha.

Alright, time to wrap up and ask today’s allergist, Dr. Douglas Mack, for his top three key messages to impart to patients and physicians on today’s topic: thresholds. Dr. Mack, over to you.

Dr. Douglas Mack: I think that the first thing is that thresholds, to me, are critical in us determining—how do our treatments work, and how do they reduce risk? I think that this is inherent, but us understanding that, I think, is key for how we counsel families.

I think it’s also really important to understand that the vast majority of patients will not have extremely low thresholds. Once again—many families believe that that's the case, that their child is extremely sensitive, and yes, they might be. But the reality is, on a population level, we see—I see—10, 20 patients in a day. Not every one of those patients is going to be in that top 1%. It’s just the law of statistics. And so, there is a variability here, and every patient will fit in a different level.

I think the final thing is—I think risk-taking is something that is really nuanced. I think there are high-risk foods. There are foods that are risky—baked goods, chocolates, ice cream. These are riskier foods. But then there are also foods that are extremely low risk. And I think—we do still need to stratify risk a bit, and we will do that based on, whether we know it or not, the concept of thresholds.

And I think this is—this will inform us as we’re moving forward, and it’s something that I use to counsel families every single day.

Dr. Mariam Hanna: Thank you, Dr. Mack, for joining us on today's episode of The Allergist.

Dr. Douglas Mack: I really appreciate your time. Thanks so much.

Dr. Mariam Hanna: This podcast is produced by the Canadian Society of Allergy and Clinical Immunology. The Allergist is produced for CSACI by PodCraft Productions. The views expressed by our guests are theirs alone and do not necessarily reflect the views of the Canadian Society. This podcast is not intended to provide any individual medical advice to our listeners.

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