Funding better "biomarkers" for food allergies

Update 5/1/15: Congratulations on surpassing the $50,000 funding goal before the April 30th deadline! Here are two wonderful summaries of the effort: Caroline Moassessi of Grateful Foodie and Henry Ehrlich at Asthma Allergies Children weigh in.

When our food allergy journey started out, one of the most challenging things to wrap my head around was allergy testing. I distinctly remember looking incredulously at our allergist and thinking, “You mean to tell me that a “positive” blood test or that giant hive from a skin prick test doesn’t necessarily mean our son has a REAL food allergy? What good is that?!”

Two common allergy tests rely on the IgE antibody as a "biomarker." The tips of the IgE antibody recognize specific food proteins, such as those found in a peanut. Blood tests measure the amount of IgE for a specific food that is found in the blood and skin prick tests look for the result of a food protein binding to IgE attached to a mast cell in the skin. The release of histamine (among other chemicals) causes the wheal or hive in a skin prick test. Image source: Atlas of Allergic Diseases

What I have learned over the course of several years is that there really are no great tests for food allergies – i.e. “biomarkers” –aside from actually consuming the food (oral food challenge supervised by a clinician). The two common current methods of testing - blood tests measuring food-specific blood IgE levels and skin prick tests that scratch the allergen into the skin surface are not a great tests because they frequently give “false positive” results. A “false positive” means that a person may test “positive,” but truly isn’t positive should they actually consume the suspected food. Frustrating. On top of this, most current testing methods that rely on IgE as a “biomarker” cannot predict how severe the allergy is. The only sure way to test for a suspected food allergy is to go to your allergist’s office and perform the supervised oral food challenge – you know, the test where you actually eat the suspected allergen and wait for a response. Having done this with my son several times now, I can’t stress enough just how stressful this stressful test is. There has to be a better “biomarker” – a test without the stress and risk of a reaction that can better predict an allergy and its severity. 

Image source: Selena Bluntzer from Amazing and Atopic

To help solve this problem, Dr. Xiu-Min Li, Professor of Pediatric Allergy and Immunology at the Icahn School of Medicine at Mount Sinai, and board-certified allergists Dr. Paul Ehrlich and Dr. Purvi Parikh designed a collaborative, practice-based study whose primary objective is to figure out better biomarkers of allergy (details of the study and how you can directly fund the study).

What makes the current peanut allergy prevention study so much better than past studies?

Update (2/27/15): Because of the concern among parents who have children with peanut allergies, the Kids with Food Allergies Foundation has issued the following statement. Please take a read. New Peanut Allergy Study Does Not Say Parents Are to Blame

Every now and again, a study comes along that changes things, and I truly believe that the Learning Early about Peanut Allergy (LEAP) study by Du Toit, et al.¹ will usher in an era of solid evidence-based guidance in terms of infant dietary recommendations and a much needed "benchmark" for designing future studies addressing allergy prevention. This study is only the first step for re-writing the guidelines that have yet to make it into medical practice. Contrary to headlines, actions to “feed your infant peanuts” should not be changed overnight without working with a healthcare provider first.

Before I get into why I feel this study truly changes things, I want to convey my initial emotions surrounding this study because I know that I am not alone. Even though I am scientist, I am also a mom to two young boys. One has multiple life-threatening food allergies and the other is at high risk of developing life-threatening food allergies. My oldest guy with allergies, “JR,” who is a first grader this year, is the inspiration behind this blog. You could say that because of JR’s many life-threatening food allergies, fear has been my constant companion, both for JR who could violently react to traces of allergen and his younger brother, “Luke,” who is at risk for developing life-threatening food allergies himself.

As a parent, I want nothing more than to do everything in my power to prevent food allergies for Luke. The fact is, the current advice has always been a “best guess” with very little hard data backing it up or scientific understanding of how our immune system learns to tolerate harmless foods in the first place. Within the last month, Luke gleefully blew out the three birthday candles lighting his dinosaur cake. To me, those three candles represent more than just a third birthday. To me, they symbolize a tinge of regret in light of new evidence from the LEAP study. In spite of a few food allergy scares while introducing solid foods, Luke currently tolerates all foods he has tried.  Conspicuously missing from his palate are peanuts and tree nuts. Based on “best guess” medical advice from our allergist, we decided to wait until three years old to introduce peanuts and tree nuts. We did everything “right,” and yet…

For the “emotional” part of me, the results of this study feel like a double whammy of fear and regret. Rationally, I know we’re – and by we’re, I mean parents, caregivers, clinicians, scientists, etc. - just doing our best, following the best advice/evidence, hopefully preventing fears from manifesting into reality. There’s fear and regret that perhaps I haven’t done enough to prevent a second child from developing allergies.  Then there’s fear of even having those allergenic substances in the house for an already-allergic child who could react with just a tiny trace of peanut or tree nut. Could I live with the regret of causing a life-threatening reaction because I failed to adequately clean up after a messy toddler in the name of prevention in my own home?! Damned if I do, and damned if I don’t, I guess.

Beyond emotion.

As human beings, we tend to interpret information with our "hearts" first and let "reason" come later. And many people never even get beyond that initial "heart” interpretation.  I acknowledge it’s ok to have these feelings (and I hope that other allergy parents/caregivers out there do, too!), but I hope to illuminate those dark places where fear and regret lurk. This study was aimed at preventing peanut allergy in infants at high risk of developing food allergies. If you are already dealing with a food allergy, this study does not apply to your situation. Even though this new research can’t help my family or maybe even your family, I am overjoyed that we have the beginning of how to prevent allergies for other children! Refrain from reading any and all article commentary from non-experts to avoid the “I told you so” and “stupid, fearful parents for not feeding your kid our nation’s best, right-to-eat it anywhere, delicious, nutritious snack.” These comments are examples of ignorant people wrongfully interpreting scientific findings through a way too generalized media filter to support what they already “believe” to be true.  Science is not about what we “believe” to be true, but what we “know” to be true. And what we “know” to be true for an entire population of human infants is not determined by this one study. Far from it.

What makes this study so special?

Prospective, randomized controlled trial. Say what?! In terms of study designs, this type provides possible causal relationships. The researchers recruited a large, VERY defined population before the study began, and then they randomly assigned the participants to either the “avoid peanut” group or the “consume peanut” group. You can imagine it to be like putting 600 little pieces of paper with names into a hat, shaking all the pieces of paper, and then the first 300 chosen are assigned to the “avoid peanut group” and the remaining 300 individuals go to the “consume peanut” group.

Even though the study participants were highly defined upfront, it is possible that when you look across all participants included in the study, there may be other “factors” that could influence or “confound” the results. By doing this randomization process upfront, "treating" to an exact and defined protocol, and following those individuals over time, the hope is that these other potentially "confounding factors” will not be factors. Rather, a prospective, randomized trial aims to evenly distribute or shake out potentially confounding variables (i.e., sex, age, etc) between avoidance group and peanut consumption group so they are testing what they want to test – does introducing peanuts early or avoiding peanuts prevent peanut allergies from developing. Nothing more. Nothing less. This has NOTHING to do with reversing an already established food allergy. And the beauty of this study design is that they can ask all of their study participants for potential confounding information to later confirm that those potential “confounding” variables did in fact shake out evenly between the groups during the randomization process! How awesome is that?!

Many of the studies in the past rely on a different, less robust study design – observational and retrospective (looking back on what has already happened, i.e., peanut allergy vs. no peanut allergy correlated to when peanuts are typically introduced into the diet across a large population). This involves recruiting individuals who were “out in the wild” already consuming or avoiding peanut in who knows what kinds of quantities for one reason or another. While meaningful information may be gleaned, confounding variables are difficult to control. Observational and retrospective studies are a great starting point and often provide evidence to pursue those answers more definitively with a much better (much more expensive, I might add), prospective, randomized controlled trial. In fact, it was this same research group a few years back who did a study of this type showing that the prevalence of peanut allergy was much lower in Jewish children from Israel, where peanuts are introduced very early in infancy, compared to Jewish children in the United Kingdom, where peanut products, at the time, were not recommended for infants before a year old.²

What this does NOT mean

Because the study participants were a VERY defined population – they were between 4-11 months at the start of the study, and they were at risk of developing a peanut allergy (severe eczema, established egg allergy, or both severe egg allergy and eczema), we cannot safely extrapolate the findings beyond either the study population or the specific study parameters. The accompanying editorial published in the New England Journal of Medicine by Gruchalla and Sampson put it best:

"Given the results of this prospective, randomized
trial, which clearly indicates that the early
introduction of peanut dramatically decreases the
risk of development of peanut allergy (approximately
70 to 80%), should the guidelines be
changed? Should we recommend introducing
peanuts to all infants before they reach 11
months of age? Unfortunately, the answer is not
that simple, and many questions remain unanswered:
Do infants need to ingest 2 g of peanut
protein (approximately eight peanuts) three times
a week on a regular basis for 5 years, or will it
suffice to consume lesser amounts on a more
intermittent basis for a shorter period of time?
If regular peanut consumption is discontinued
for a prolonged period, will tolerance persist?
Can the findings of the LEAP study be applied to
other foods, such as milk, eggs, and tree nuts?"³

While many questions do remain, the same editorial goes on to say:

"…we believe that because the results of this trial are
so compelling, and the problem of the increasing
prevalence of peanut allergy so alarming, new
guidelines should be forthcoming very soon."³

They go on with suggestions for health care providers to follow for introduction of peanuts while we patiently wait for those new guidelines.

Where to go from here

In the words of pediatric allergist Dr. Dave Stukus, “This study may be called LEAP, but it’s still only one step.” This study provides a “benchmark” for many future studies. Being a basic scientist myself, I want nothing more than to take this information and understand how and why. What features of early immune system development impart tolerance when foods are introduced early? What changes happen to the immune system after you cross that critical period or window of opportunity? Along those same lines, how does prevention by early introduction differ from a child or adult who clearly tolerated a food for some time period, but went on to develop allergies much later on? We need to understand at a very fundamental level how we define immune tolerance at a cellular level, what establishes it, how it is maintained, and how it is lost.

Population studies such as the beautifully executed LEAP study give us guidance, but my hope is that by honing in on the how’s and why’s, we will move toward tailoring prevention and treatment strategies to the individual.

PS - Wish us luck as we trudge forward with introducing peanuts and tree nuts to Luke!

References

1. Du Toit G, Roberts G, Sayre PH, et al. Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy. N Engl J Med. 2015;372(9):150223141105002. doi:10.1056/NEJMoa1414850.

2. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984-991. doi:10.1016/j.jaci.2008.08.039.

3. Gruchalla RS, Sampson HA. Preventing Peanut Allergy through Early Consumption - Ready for Prime Time? N Engl J Med. 2015;372(9):875-877. doi:10.1056/NEJMe1500186.

Headline hyperbole - probiotics cure peanut allergy?

Note about study discussed below – please do not try oral immunotherapy (OIT) or OIT with probiotic supplements on your own! This is an experimental food allergy treatment to be performed under strict medical supervision.

In the latest edition of medical headline hyperbole, many of us learned last week that “Fatal peanut allergies could be cured by probiotic bacteria, say Australian doctors” and “This Breakthrough Treatment Helped Over 80 Percent of Allergic Kids Tolerate Peanuts.”

Sigh… We all want a cure, and many scientists/clinicians are working tirelessly toward that goal (including the research group that performed the original peer-reviewed study(1)), but please, oh please media, stop overselling the scientific findings! I’m quite literally tired of having to explain the same thing over and over again! Unfortunately, there is a reason why one of my blog labels is now “Misleading Science Headlines.” I don’t necessarily want to go into the details of why this is so detrimental to both the science and food allergy communities, but rather I’d like to take the rest of this two part post to explain why the headlines got it wrong, what can actually be concluded from the study, and where the science may go from here. Lianne Mandelbaum, who founded No Nut Traveler, authored an excellent piece at the Huff Post Blog explaining why misleading headlines are such a problem when it comes to food allergies. I encourage you to take a read.

Brief summary of the study:

Mimi Tang, et al., from the Royal Children’s Hospital in Melbourne, Australia tested if the combination of oral immunotherapy (OIT) and a probiotic supplement could lead to “sustained unresponsiveness” in peanut allergic children compared to a placebo group  (peanut allergic children who did not receive peanut OIT or probiotic). They found that after stopping treatment (ranging from 2-5 weeks) over 80% of children who received OIT + probiotic maintained a “sustained unresponsiveness” to peanut compared to only 3.6% of the placebo group (1).

Study design: Randomized, double-blind, placebo-controlled

My "hot" new asthma piece at Asthma Allergies Children!

I'm no stranger to my enthusiasm for Asthma Allergies Children as a source of great information and thought-provoking original pieces on allergic disorders. 

I'm delighted to share my new piece  - Allergic Asthma: When Organ Systems Communicate, We Might Not Always Like What They Have to Say.

You'll just have to go read the piece to find out why it's so "hot!"

"Large Cayenne" by André Karwath aka Aka - Own work. Licensed under Creative Commons Attribution-Share Alike 2.5 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Large_Cayenne.jpg#mediaviewer/File:Large_Cayenne.jpg

Eosinophilic Esophagitis - Scientific Excitement - Part 1 of 2

The allergy world was abuzz this past week that a major research breakthrough for Eosinophilic Esophagitis (EoE) was published in Nature Genetics (1), spear-headed by Dr. Marc Rothenberg’s lab at Cincinnati Children’s Hospital (follow the lab on FaceBook). For anyone dealing with this devastating allergic disorder, the news was welcome, but what does it all mean? And what could the future hold for people dealing with EoE or allergic disorders more generally?

My hope is to distill some pretty intense science in this two part series – the paper is scientifically very cool, yet very dense! Tackling this paper is not for the faint of heart (myself included)!

Pets are people, too? Allergy edition.

Most of us are familiar with allergies to dogs and cats. But what about our dogs and cats who suffer from allergies?  Here is a question I have about the allergy epidemic - if environmental factors contribute to the allergy epidemic in people, wouldn't we expect our fellow mammalian pets who share our same environment (dogs, cats, etc!) to be increasingly allergic? This little thought was inspired by discovering that a new animal clinic specializing in allergy and ears recently opened in my neck of the woods. Who would've thunk - a specialty clinic for allergies in our pets?! Basic economics dictates that supply and demand strive to be in equilibrium. Clearly there must be a great enough demand...

I honestly do not know the answer, but I hope to explore this idea further. Thoughts? Any vets out there willing to weigh in with knowledge/observations/peer-reviewed evidence? Feel free to comment below or send me a direct email (see contact) Stay tuned...

Genetic glitch at the root of food allergies?

I see a lot of different research articles on a weekly basis, and there is certainly a lot to be excited about in the realm of basic science research when it comes to understanding the immune system and allergic disorders.  I have to admit, though, a recent study published in Science Translational Medicine has my head spinning (in a good way!), and I hope this post accurately communicates why.

Summer morning thoughts digging their way out

I find myself digging out from under a pile of the previous Spring term which ended last week.  Remnants of everything important - from tiny hand prints artfully crafted on special Mother's Day paper awaiting a more permanent framed display, to the last edition of Allergic Living, to stacks (and I mean STACKS!) of fascinating allergy/immunology papers awaiting meticulous consideration.

Crouching down on one knee with a small grin, I pump my fist and quietly exclaim, "Yes!  I made it.  I made it to summer."  It was a busy term, but worth it in every sense.  I have an appreciation of the microbial world that I did not have before, and suddenly pieces of complicated immunology literature that reference "bacterial things" like LPS and teichoic acid and how it relates to our immune system make perfect sense (at least more than it did). 

Our immune system is fine-tuned to recognize components of bacterial cell membranes/cell walls that we don't have in our cells (e.g. teichoic acid and lipopolysaccharide - LPS).  Source:  http://en.wikipedia.org/wiki/Lipoteichoic_acid

Getting Schooled

In my continuing blog series, (Mis)adventures in Microbiology, I want to share the next leg of my journey into understanding the critters living on and within us.  I promise, this is related to allergy, so bear with me while I convince you that yes, there is a definite reason behind this microbiology madness.  You are reading an allergy blog, after all!

As the title implies, I'm getting schooled!  For the Spring term, I signed up for a course in Microbiology, which means I'm sharing a classroom with some of the very students I could have taught anatomy and physiology to in previous terms! 

Vitamin D - A Tale of Two Studies

I'm throwing this out there today because this is confusing and definitely demands further attention.  Just in case you only noticed one of these studies making the rounds through the social networks, I wanted to make you aware of the other study showing a seemingly opposite finding.  Let me make this clear at the beginning, I do not have an answer today.  I merely just want you to be aware of the "controversy," which I will highlight in future posts.  The take-home message I want to stress today is that you should not change any current habits based solely on either of these studies!  In fact, it is never a good idea to change any habits based on evidence from any one study you see in the news.  A tenet of science is that results MUST BE REPRODUCIBLE, and the Vitamin D story appears to be, shall we say, a bit... umm (throat clear, nervous pulling at collar)... complicated.

The two different studies, published in two different journals, only one month apart - 

1.  Higher Vitamin D levels linked to the development of food allergy in the first 2 years (24 months) of life.

Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study
Authors: Weisse, K, et al.
Journal: Alllergy, 2013, Vol. 68, Issue 2, pages 220-228 

2.  Insufficient (Lower) Vitamin D levels linked to food allergy in infants aged 12-18 months.

Vitamin D insufficiency is associated with challenge-proven food allergy in infants
Authors: Allen, KJ, et al.
Journal: Journal of Allergy and Clinical Immunology (JACI), 2013, Published online March 1.  

Is one of these studies "wrong?"  Is one of them "right?" Maybe they're both "right!"  It turns out that upon further analysis of past "controversies" in science, what seemingly appears to be conflicting results often reveals a very complicated process going on in the body - meaning, they both may be right!  Stay tuned!

Keys to thoroughly analyzing the Vitamin D controversy will be:

1.  What is Vitamin D and how does the body get it and use it?
2.  Are there known direct effects of Vitamin D on the cells of the immune system?  If so, what are those effects?  Would those effects seen on an individual cell level support the development of allergy or refute it?
3.  When and how did each of these studies measure vitamin D?
4.  When and how did each of these studies measure food allergy?
5.  Are there previous studies on this issue?  What do those studies show?
6.  What about previous studies on vitamin D and other allergic disorders (e.g. eczema, asthma, etc.)? 

Would you like to add any other suggestions to the list?  Please feel free to comment below!
 

Image source:  http://savingdinner.com/wp-content/uploads/vitaminD.jpg

Research from Scientific Meetings - Cautious Optimism

In light of the recent meeting of the American Academy of Allergy Asthma and Immunology (AAAAI), I wanted to take a little time to explain to the non-science folks out there:  1) what is a scientific meeting and 2) what can we conclude from meeting highlights that are press-released and thus have been shared like wildfire across various social media platforms like Facebook and Twitter.  By the way, those live tweets from various scientists/MDs, such as the Allergist Mommy, convinced my to join Twitter (FYI - you can find me at FdAllergySleuth, although I have NO idea what I am doing!).

1) What is a scientific meeting?

Poster session from a recent meeting for the Society for Neuroscience.  Image source:  http://www.flickr.com/photos/helloooo/4045778043/

The Immune System Defined - Part 1 of 5 - Overview

At the heart of food allergies is an underlying problem in the immune system.  It quickly became clear that JR’s food-induced reactions left him at the mercy of an immune system that is simply “out of whack” or not properly balanced.  After all, why would the immune system mount such a strong attack against a harmless, nutritious food like a pistachio?  It’s not bubonic plague or anything!

Ah… the immune system. If you happened to be in the same room as me, you would note a very long, drawn-out sigh. For a neuroscientist, there is perhaps no other bodily system that strikes more fear than the immune system. One exception may be the neuroscientists specializing in the autoimmune disorder, multiple sclerosis, but then again, I haven’t asked one! For years now, I have had the utmost admiration for scientists seeking to understand both the nervous and immune systems because they are each equally and insanely complex. My poor brain just hurt at the thought of tackling journal articles such as - Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes. CD8+ T cell? B cell? HLA class I?! And there is a virus, too?! What is all this stuff? No thank you, sirs and madams (no offense to the authors of this work; I’m sure it is great stuff, and I have the utmost respect)! But I digress…

For this momma and neuroscientist of a child with at least 20 different food allergies, some of them life-threatening (please see Our Story), I wanted answers, and if I wanted answers, it could only mean one thing – ready or not immune system, here I come!

But what exactly is the immune system and what does it do?  Most of us have an intuitive sense that it is our protector from all things disease-causing.  However, critical for any scientific discussion, and hopefully there will be many on this blog, are precise definitions.  So while an intuitive sense can take you pretty far (even in science!), precision is ultimately essential.

I hope this will serve as a reference if some of my future posts get a bit technical.  I promise to keep the jargon to a minimum, and if I do get too technical, feel free to leave scathing comments, and I'll try my darndest to clarify and improve any future posts.  I’m learning right along with you!  I welcome all feedback, especially if it helps improve my ability to communicate some pretty complicated stuff.

Key questions I seek to answer over the next four posts:

1. What does the body-wide immune system look like and what are the major organs?
2. Who are the key players (cells of the immune system)?
3. What are the known functions of the immune system? 
4. What is immune system balance (homeostasis, !EEK - jargon alert!) and what happens when the system is not balanced (Hint, hint... food allergy)?

Stick with me over the next four posts and we’re well on our way to a better understanding of the immune system!