By Jessica Martin, PhD
Welcome back contributor Jessica Martin who has written about the TrpV1 receptor for us before. She responds to Dr. Pete Smith’s ideas on anaphylactic risks from her special dual perspective as neuroscientist and food allergy mom.
Over the course of several years, I’ve come to appreciate how incredibly complex the science of allergy and specifically anaphylaxis is. On top of this, anaphylaxis is a very challenging problem to study. Good science aims to control as many confounding factors as possible and make relevant comparisons that get at true causative effects versus what only end up being factors that are just along for the ride (correlation). The first problem with studying anaphylaxis in humans is that you can’t perform the “perfect study.” In one example from the interview with Dr. Pete Smith, he mentioned that spicy food could be a contributing factor in severe food allergic reactions. To test this idea with a “perfect study,” you would need to set out from the beginning with the intent to cause an anaphylactic reaction in all participants where you compare one anaphylactic group who ate the offending allergen in the presence of chili peppers, while the other anaphylactic group receives the same treatment minus the chili peppers (of course this assumes we already put these patients through the double blind, placebo, controlled food challenge to show they do in fact have a food allergy). It’s not ethical, and I can tell you that as a mother to a food allergic child, I would never willingly put my son into such a study for the sake of science. Thus, we rely on less powerful studies and observational methods secondary to the question we truly want to answer, which is “what factors actually contribute to severe reactions?”
Even if you could design the “perfect” study, we’re still left with a beast of a phenomenon – anaphylaxis – which is highly unpredictable from person-to-person and even within the same person over time. If we go down the path of our “perfect study,” in order to answer this one question definitively, we would need each participant to – on different days over an extended period of time – be a part of both the spicy group and the non-spicy group. Oh, and it would be immensely helpful if we could repeat that process a few of time in each person because there’s so much variability even within the same person over time. Again, not going to fly. The problem with anaphylaxis is that it’s so highly variable that for the “perfect study,” you need a LOT of trials to pin down what’s actually going on and you’re still ultimately left with the question of what other factors are playing into the severity of an allergic response.
I was recently reminded of this variability when my son experienced anaphylaxis to the sublingual immunotherapy tablets for grass allergy (Grasstek). He had been taking the same dose at roughly the same time daily for two weeks, when one evening, it just happened to progress rapidly to anaphylaxis. Up to that day, he only experienced an itchy mouth and throat, which are normal, common side effects of this treatment. What was different? Most of us living with the threat of anaphylaxis understand this variability and wants answers, but how do we get answers?
The 2015 review article by Smith, Hourihane, and Lieberman raises many interesting factors that all may pile on top of each other to contribute to a reaction’s severity. In other words, “the stars align” in a cursed way. The article raises many possibilities derived from combining observations in patients and the molecular stew of signals known to be involved in an allergic immune response, but only tested on a singular basis in imperfect models. For example, one molecular receptor mentioned, TrpV1, has been studied extensively in cells that are grown in a culture dish. It’s best known to be found in nervous system cells that help us sense our environment and alert us to danger, but it’s found elsewhere, too, including cells of the immune system. We know that this one receptor is promiscuous in that it is activated by many things – hot temperatures, the chemical capsaicin (the spicy ingredient in chili peppers), acid, immune chemicals involved in inflammation, just to name a few. This promiscuity explains why this one receptor may hide the sensation of immune mediators released early in an allergic reaction if spicy food is consumed at the same time. An allergic person perceives the “heat” and assume it’s the spicy food while continuing to eat more of the food, when in reality there’s much more going on in that molecular stew. Our nervous system doesn’t know any better.
The problem is that many of these ideas – which are quite likely true – remain in the realm of hypothetical and quite likely will stay there for a long time due to how incredibly difficult it is to study anaphylaxis in humans. Advice is rightly given based on these good educated guesses, but I’m skeptical we will gain definitive answers from what we currently view as the gold standard of “perfect studies.”
So what does it mean? Is it hopeless? Will these remain questions unanswered while continuing to fuel the mainstream myths surrounding risk of anaphylaxis? I’m looking at you, “but it’s only a mild peanut allergy so I don’t need to carry epinephrine!” Until we know more, can we just acknowledge how wildly unpredictable allergies are and just be prepared for responding to severe reactions already? As a society, can we lose the fear of using autoinjectors until it’s too late?
Here are a few ideas to go forward. Can we somehow glean data from patients currently doing various forms of immunotherapy? The good thing about this is that at least one factor is controlled – a regular dose of an allergen in known amounts instead of unknown amounts during an exposure “out in the wild.” On top of this, my hope is that we can start taking advantage of powerful mathematical models to combine the molecular pieces that we do know in the singular and make combinations of those factorin silico. If predictions of many combined factors in a model start to mimic a bigger data set of observations from patients, perhaps we can get somewhere. Let’s see if we can string together the pieces of observations from all of us unfortunate enough to have suffered or watched someone suffer from these terrifying reactions. It’s not the perfect experiment but having more imperfect data may get around some of the issues making anaphylaxis such a hard problem to study.
P.S. – As a quick follow-up: my son was ok after his reaction. We used his epinephrine autoinjector very quickly after he said his throat felt like it was closing, and the reaction began reversing just as quickly. He was chatting it up with the fire fighters and EMT’s by the time we left in an ambulance as a precaution. It had been years since we experienced a reaction of that magnitude and my son (and us!) learned that the injection “didn’t even hurt” and it worked fast. I can’t stress this enough – the injection is no big deal. It’s the reaction to fear.
Jessica Martin earned a Ph.D. in Neuroscience from Oregon Health and Science University in 2011. She is the mother to two young boys, one of whom has multiple life-threatening food allergies. She lives in the Portland, Oregon area with her family where she teaches undergraduate biology and anatomy and physiology at Portland Community College. Jessica has a passion for education and sharing understandable, scientifically accurate information that encourages open, honest discussion. She is the author of the blog, The Food Allergy Sleuth.
Diagram from Wikimedia commons