The new AAAAI podcast is about Palforzia–surprise surprise. It was recorded just three days after the introduction. Like all these podcasts the host is our friend Dr. David Stukus. Appropriately the interviewee is Dr. Andrew Bird from Dallas who contributed a piece to this website five years ago called Food Allergy Testing in the Coming Age of Prescription Immunotherapy. Dr. Bird wrote at the time, “The response from the medical community must be to ensure that patients are appropriately diagnosed and diagnostic methods are used intentionally in patients with a history supporting a role of immediate reactivity following food ingestion.” Five years later, that remains a key concern as this first-ever drug enters the market and is clearly explained, as are such issues as cost, dosing, maintenance, overall efficacy for certain patients, reactions, goals of treatment, and why patients choose to discontinue treatment. There’s also forthright discussion of the pros and cons of offering the treatment for allergists and shared decision making in choosing to start the treatment or not.
Food Allergy Corner
BRISBANE, Calif.–(BUSINESS WIRE)–Aimmune Therapeutics, Inc. (Nasdaq: AIMT), a biopharmaceutical company developing and commercializing treatments for potentially life-threatening food allergies, today announced that the U.S. Food and Drug Administration (FDA) approved PALFORZIA™ [Peanut (Arachis hypogaea) Allergen Powder-dnfp]. PALFORZIA is the first approved treatment for patients with peanut allergy. It is an oral immunotherapy indicated for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut. PALFORZIA is approved for use in patients with a confirmed diagnosis of peanut allergy. Initial dose escalation may be administered to patients aged 4 through 17 years. Up-dosing and maintenance may be continued in patients 4 years of age and older. PALFORZIA is to be used in conjunction with a peanut-avoidant diet. PALFORZIA is not indicated for the emergency treatment of allergic reactions, including anaphylaxis.
“This is a defining moment for the peanut allergy community and for Aimmune Therapeutics, and we are excited to bring the first FDA-approved treatment for peanut allergy to patients and their families,” said Jayson Dallas, M.D., President and CEO of Aimmune Therapeutics. “Our commercial field team is ready to begin engaging with allergists to help them prepare to safely incorporate PALFORZIA into their practices and, with approval in hand, our payer team can also immediately begin work to secure formulary access to PALFORZIA. We view this approval as just the beginning for Aimmune, and it underscores our continued commitment to bringing innovative treatments to people with potentially life-threatening food allergies.”
“Not only is PALFORZIA the first approved therapy for peanut allergy, but it is the first approved therapy for any food allergy,” said Daniel Adelman, M.D., Chief Medical Officer of Aimmune Therapeutics. “We truly appreciate the efforts of the peanut allergy community who contributed to the development of PALFORZIA – including the more than 1,200 patients and their families who participated in our clinical trials, the study investigators and their staff, the advocacy community, and our dedicated employees – all of whom have helped us develop and deliver this first-of-its kind therapy.”
Peanut allergy is one of the most common food allergies in the world, affecting more than 1.6 million children and teens in the United States alone.i,ii It can be a chronic and life-long condition, and reactions to peanut can range from mild to potentially life-threatening,iii with one in five peanut-allergic patients visiting emergency rooms each year due to accidental exposures.iv
“Peanut allergy is more common now than ever before and has become a serious public health concern. The food allergy community has been eagerly awaiting an FDA-approved treatment that can help mitigate allergic reactions to peanut and, as allergists, we want nothing more than to have a treatment option to offer our patients that has demonstrated both the safety and efficacy to truly impact the lives of patients who live with peanut allergy,” said Christina Ciaccio, M.D., Associate Professor of Pediatrics and Medicine and Chief of Allergy/Immunology and Pediatric Pulmonary Medicine at the University of Chicago Medical Center and Biological Sciences. “With today’s approval of PALFORZIA, we can – for the first time – offer children and teens with peanut allergy a proven medicine that employs an established therapeutic approach.”
PALFORZIA is a complex biologic drug used with a structured dosing approach that builds on a century of oral immunotherapy (OIT) research.v With OIT, the specific allergenic proteins are ingested initially in very small quantities, followed by incrementally increasing amounts, resulting in the ability to mitigate allergic reactions to the allergen over time. PALFORZIA is a rigorously developed, pharmaceutical-grade OIT for peanut allergy with a well-defined allergen profile to assure that every dose, whether 0.5 mg (equivalent to 1/600th of a peanut) or 300 mg, has been prepared and analyzed for consistency.
The Biologics License Application (BLA) for PALFORZIA included efficacy and safety data from seven clinical studies, including the pivotal Phase 3 PALISADE and RAMSES clinical trials. In addition, data from the Phase 2 ARC001 study and the ARC002 open-label follow-on study were included, as well as data from ARC004, ARC008 and ARC011, which are ongoing studies.
PALFORZIA is available only through a Risk Evaluation and Mitigation Strategy (REMS). Requirements of the REMS include: the prescribing physician and patient must be enrolled in the REMS prior to initiation of treatment; the initial dose escalation and the first dose of each up-dosing level must be administered in a certified healthcare setting; epinephrine must always be immediately available to patients; and pharmacies/distributors must be certified with the REMS and dispense PALFORZIA only to certified healthcare settings or to patients who are enrolled in the REMS. Consistent with approved immunotherapies indicated to treat allergic conditions, the Prescribing Information for PALFORZIA contains a boxed warning.
Aimmune will provide resources to patients and families who, upon consultation with their physician, wish to seek treatment with PALFORZIA. These resources will include educational materials, a dedicated call center, a co-pay program for eligible patients, and a Patient Assistance Program to provide PALFORZIA at no cost to eligible patients.
“Peanut allergy carries an overwhelming psychosocial burden that impacts patients and their families daily – peanuts are everywhere, and the threat of a severe reaction related to an accidental peanut exposure dominates families’ daily lives,” said Lisa Gable, Chief Executive Officer, Food Allergy Research and Education (FARE). “The risk of accidental exposure is real, and we, as a community, have long awaited an option beyond avoiding peanuts alone. As one of the organizations that originally highlighted the need for an FDA-approved oral treatment approach to food allergy back in 2011, we are thrilled with today’s FDA approval of PALFORZIA as it fills a long-standing need in the treatment of peanut allergy.”
Aimmune Therapeutics was founded directly in response to a united call to action by leading stakeholders in food allergy. At an advocacy-sponsored research retreat in 2011 aimed at reaching consensus on the direction of food allergy treatment research, a group of parents of children with severe food allergies, patient advocacy organizations, leading clinical and academic physicians, representatives from government, and members of the pharmaceutical industry recognized the need for a structured approach to OIT and approved treatments. This meeting eventually led to the formation of Aimmune Therapeutics to specifically address that need.
As reported in the Journal of Allergy and Clinical Immunology, team of UK researchers administered an estimated threshold dose of peanut in a blind challenge. Then participants with a confirmed allergy “underwent 3 open peanut challenges in random order: with exercise after each dose, with sleep deprivation preceding challenge, and with no intervention.” They concluded: Exercise and sleep deprivation each significantly reduce the threshold of reactivity in patients with peanut allergy, putting them at greater risk of a reaction. Adjusting reference doses using these data will improve allergen risk management and labeling to optimize protection of consumers with peanut allergy.
By Dr. Paul Ehrlich
With the age of prescription therapy for food allergies rapidly approaching, it’s not too early to start figuring out what patients will prefer among the options presented. Allergists and their patients have confronted similar dilemmas before, although simple preference doesn’t solve the problem. For example, we have been offering shots for a hundred years, and no one is terribly fond of them. To many, sublingual immunotherapy (SLIT) sounds like a dream, but experience teaches us that in the real world patients don’t like them in nearly equal measure. Taking a medicine every day is burdensome, and many patients don’t like the way the medicine feels and tastes in their mouths.
Thus, it was fascinating to read about Dr. Matthew Greenhawt’s presentation to the ACAAI meeting in Houston about patient and caregiver feelings concerning two modes of therapy that are rapidly nearing availability—Palforzia oral immunotherapy (OIT) and the Viaskin “peanut patch,” also called epicutaneous immunotherapy or EPIT. A total of 200 children aged 7-11 and 206 caregivers were surveyed with questionnaires replete with emoticons to express their feelings in addition to straight answers. Compliments to Matt and his team for their imagination in assaying patient emotions as part of the package.
Unsurprisingly their greatest concerns were over the prospect of medical emergency, but they were also deeply disturbed by things like touching, tasting, and smelling peanuts. Questioned about the prospective treatments, many rejected the oral approach. Many more were drawn to the idea of the patch.
Looking at the numbers, I began to think about my own experience over many years. The two key senses—taste and smell—have figured heavily in the lives of many patients whom I first met as children, and treated on into adulthood, and in many cases treated their own children. While there was no such thing as active treatment all those years, some of them did manage to outgrow their allergies, including to peanut. I would test them for IgE and do skin prick testing and urge them to try their allergens or do an office food challenge. But for some, the chance to eat the allergen just wasn’t enough to overcome that sensory aversion, although some do arrive at some remarkable strategies over time. The key is to associate food with the pleasure it is meant to give rather than regard it as medicine.
It’s early days for food immunotherapy, but it’s not so early that we can’t start figuring in the dimension of time. Longitudinal data for some of the earliest studies show that many subjects drop out. Medication fatigue is a real thing with all chronic disease management. It’s likely to factor heavily as OIT, the patch, and other non-curative treatments hit your allergist’s office. Those early aversions and fears at the front end have their analogues on the back end.
But maybe that’s not a bad thing. In a recent talk, one of the pioneers of private practice OIT observed that patients he had treated as little kids would come to him as they reached adolescence and inform him they were quitting. He was okay with that. He had helped them deal with their allergies long enough to come of age and could make their own decisions. They could negotiate the risks for themselves. I liked hearing this.
With a range of treatment options on the horizon, the allergist’s responsibility remains the same. To understand patient and caregiver needs and fears, to provide treatment when appropriate while explaining all the risks and offering lots of encouragement, and be just as considerate and well-reasoned when rejecting a treatment. One thing is sure: all those fears and aversions covered in Matt’s study are going to be a constant. We may have seen it all before, but it’s always new to the patient.
By Henry Ehrlich
Congratulations to Gwen Smith and the team from Allergic Living for the “Food Allergy Anxiety Guide.” This 90-page e-magazine will surely be the definitive guide to all aspects of the subject for years to come. As Gwen writes in her introduction, “The purpose of this e-magazine is to discuss the fears and the ‘what ifs’ with honesty, without sugar-coating, and to begin to understand this phenomenon as its own anxiety disorder.” Mission accomplished. It is an authoritative and polished product, complete with podcast, and should be on the desktops of patients, parents, and practitioners.
I wrote to Gwen and asked her a couple of questions:
AAC: What was the impetus for starting the project and how long did it take?
Gwen: I have a long interest in the anxiety issues surrounding food allergies. But the impetus for this full-on ‘Food Allergy Anxiety Guide’ stems directly from our decision earlier this year to transition to a digital publication. Doing so related to the future direction of publishing, but it also provided me an opportunity to stand back and assess: What could a digital Allergic Living be that was truly useful to the community? Coming from a current affairs (radio) and news magazine background, I’m always interested in taking apart and packaging big topics.
This led to my idea of a “big topic” special edition guide, and I had a sense from our community that a natural such subject/need was food allergy anxiety. We tested the idea on our social media channels by asking: “If you are stuck in food allergy stress, tell us your story.” (The Consulting Editor on this issue is Gina Clowes; she asked the same on Allergy Moms.) The outpouring in emails and posts was incredible, and people’s stories were so affecting. The need here, just as quality-of-life surveys have shown, is clear.
The edited-down reader quotes (preview publicly available here) are what led me to go slightly overboard and create a 90-page interactive publication. I felt compelled to do something exceptional on this topic. It’s almost more a book than a magazine. I honestly think this is the best work we’ve done in a dozen years of publishing. The reason is the importance of the topic and the fact that our writers and podcast moderator were able to get top food allergy therapists to give actionable strategies to show that you don’t have to stay locked in stress and fears.
We pulled it together four months. We burned lot of midnight oil. But we got there.
AAC: Wow. Tight timeframe. Were there any particular challenges?
Gwen: Even with Allergic Living’s big audience, getting enough people to know about the Guide and to understand it’s a significant and unique piece of work on the food allergy anxiety topic is taking a great deal of work. It’s also a bit of a challenge to communicate that while the Guide discusses anxiety, the real focus is on the steps toward stress control and better quality of life.
There were some hiccups at the beginning, but fortunately we got those sorted out quickly. Transitions always seem to come with learning curves.
What was NOT a challenge – finding people to speak on this topic. There are many wanting to talk, wanting to find a way through.
The finished product is worth the cost: $7.95. It’s not a one-time thing. Readers should go back again and again for the advice, for the inspiration, and for the exposure to multiple points of view. Print out pieces of it and show them to your uncomprehending friends and relatives. Get a grip. You are not alone.
Long-time readers of this website will remember an article by Dr. Eva Untersmayr linking use of antacids to adult onset of an allergy to Beluga caviar in an individual patient. He had eaten the delicacy at a party with no ill effects, but several months later had a severe reaction after eating more. The Dr. Untersmayr and her colleagues learned that he had been taking antacids during the first ingestion, reducing the crucial acid environment of his stomach. Poorly digested larger protein components found their way into the intestines and the blood, where the immune system went on alert and cranked out allergic antibodies in case it ever happened again. The same pattern was observed for patients with dyspeptic disorders treated using anti-ulcer medication. When Dr. Untersmayr popped up again recently as a co-author of an article in the journal Nature Communications entitled “Country-wide medical records infer increased allergy risk of gastric acid inhibition” which elaborates on the connection between anti-ulcer drugs and allergy, not just to food but to all kinds. She has generously agreed to answer some questions about the new article. – Henry Ehrlich
AAC: Eva, welcome back and thanks for volunteering your time. First, your methodology in this study was fascinating. You were able to access the medical records of 97% of the population of Austria between 2009 and 2013 because the country has near-universal health insurance. As an American I marvel at that all by itself. Simply put, you compared prescriptions of anti-allergy medicine to patients who had previously been taking H2 agonists—antacids–and proton pump inhibitors, or PPIs. How did you arrive that this approach? Also, I know it’s not as easy as it sounds. How did you construct the study? And what protections are there for patient privacy?
Eva: Henry, thank you very much for the invitation and your questions. You are right, our approach sounds straightforward, but it was made only possible within a network of excellent collaborations. The reason why we designed the study that way was to evaluate the impact of this medication on the entire Austrian population. We are very lucky to have compulsory health insurance ensuring nearly complete health care coverage, even paying for most of the medication Austrians are prescribed by medical doctors. In the health insurance databases, in- and outpatient data on medical services covered by the health insurance is available. And of course the study was performed in strict agreement with data protection and patient privacy law. Therefore, a pseudonymized data set was used and only after approval by our ethics committee of course. And in the end the analysis means a lot of statistical calculations and comparisons, which were done by the expert in our team.
AAC: The idea that digestion is impaired by these drugs so that allergenic protein components sneak through is familiar enough. But your study shows that they also activate Th2 mechanisms, which are more generally allergic, as indicated by patients needing medicines that don’t work on food allergies. How do these medicines affect the larger immune system? Could you particularly highlight their effects on the gut and oral microbiome?
Eva: I am not so sure that the concept of digestion impairment and higher risk for allergy development is familiar to everyone working in the field of allergy or gastroenterology. I still get a lot of questions from the audience when I present even our older data at scientific meetings. But you are right, our current data shows that the effect goes beyond food allergy, as we investigated use of anti-allergy medication, which is most frequently used for respiratory allergies and far less frequently in case of food allergies. One mechanism, which we also highlight in our paper, could be the direct effect on the immune response as immune cells have H2 receptors, PPIs can induce mast cell activation and the aluminum-containing Sucralfate might act as an adjuvant. Moreover, anti-ulcer drugs have an enormous effect on microbiota, which is even more prominent than the effect of antibiotics when considering the entire population due to longtime intake of this medication. So there are different layers of mechanisms that might explain our results.
AAC: These changes take place very quickly, don’t they? You mention as few as six days.
Eva: The change in the gastric milieu takes place very quickly. You are right that approximately 5-6 days of PPI intake elevates the gastric pH to around 5. But long-term use of anti-ulcer drugs seems to especially increase the risk for need of anti-allergy medication, which we could also prove in our current study.
AAC: I was particularly struck by how many young boys are on these drugs. Why? Is it because they eat a lot of junk? If so, why are their doctors prescribing these things and not focusing on improving their diets?
Eva: There is not really a difference between anti-ulcer drug prescription between boys and girls in childhood. Around puberty girls are more likely to get prescription for this medication and the female gender dominates until very old age.
AAC: Finally, the paragraph on “imprinting the next generation for allergy” was very troubling. I know that reflux is a big problem during pregnancy. I kind of hate to ask because mothers of food allergic kids are constantly worrying about what they did wrong, but I have to. How does antacid use “imprint” the next generation? Is this an epigenetic change or something else?
Eva: We and other groups have demonstrated this link in previous studies, both in experimental models and in human data. When the mother takes anti-ulcer medication during pregnancy, the child is more prone to become allergic due to skewing the immune response. Moreover, as mentioned above, anti-ulcer drugs affect the microbiota composition and we know how important our microbes are for immune health and how much the mother’s microbiota influences the colonization of the child. But I think much more research is needed until we fully understand all the mechanisms involved here. As an advice for pregnant mothers-to-be suffering from reflux (like I did with my second child): Lifestyle changes are also a good option and can prevent the need for medication. Do not eat too late and try to sleep with your upper body slightly elevated.
AAC: In your previous article, you wrote, “There is evidence that patients and doctors are trading long-term health for short-term comfort. In Europe, and I suspect elsewhere, the sales figures of acid-suppressive drugs are continuously on the rise and they are being used for long periods of time.” Do you have the feeling that patients and their doctors are taking better care of their digestion? Are they eating better? Are they using alkaline water instead of antacids and PPIs? Or is it business as usual?
Eva: Unfortunately I do not see a big difference in caring for a functional gastrointestinal digestion. Nevertheless, it is very important to raise awareness, to constantly inform medical doctors and patients. We once launched an awareness campaigns together with one of our health insurance companies here in Austria and we could really see an impact of this campaign on anti-ulcer drug prescription habits. Making important information available is very helpful!
AAC: Your biography says that you are a trained acupuncturist. The only doctors I know who address digestion as part of treatment for food allergies are also trained in Asian medicine—one in Chinese medicine and one in Ayurvedic medicine. Do you think that Western doctors have something to learn from these disciplines?
Eva: I am personally very keen on a broad approach in medicine. There are so many fields to learn from. Asian traditional medicine is one example, but we also should not forget traditional medical knowledge from our cultures, where much more attention was given to how, when and what to eat.
AAC: Thank you for your time.
Eva: Thank you Henry for your interesting questions and for highlighting our research!
Eva Untersmayr, MD, PhD, is Associate Professor and head of the Gastrointestinal immunology research group at Institute of Pathophysiology and Allergy Research at the Medical University of Vienna. She is a Clinical Immunologist especially interested in the connection between digestion, food allergy and the immune system of the gastrointestinal tract. Her work was continuously funded by several grants of the Austrian Science Fund, the Austria National bank, the EC Horizon 2020 and other funding agencies. Following her medical studies, Dr. Untersmayr also trained as an acupuncturist in Austria.
Fotocredits, © MedUni Wien, Felicitas Matern”
When IgE was discovered more than half a century ago, allergists had hopes that it would be the key to better diagnosis and treatment of allergies, but it has remained a riddle wrapped in an enigma, although there has been exciting research along the way. A new paper entitled “High-affinity allergen-specific human antibodies from single IgE B cell transcriptomes” by Stanford researchers Derek Croote, Spyros Darmanis, Kari R. Nadeau, and Stephen R. Quake has provided an exciting new glimpse of IgE’s nature that may lead to breakthroughs. We reached out to lead author Derek Croote of the Department of Bioengineering, who had recently followed us on Twitter. (Confession: another article by Hannah J. Gould and Faruk Ramadani was published in the same issue and as Derek suggested I used it as a cheat sheet for understanding the basic science.) – Henry Ehrlich
AAC: Thanks very much for taking time with our readers. Before we discuss the science in your paper, I’d like to ask you a few “process” questions. Can you tell us how you came to do this work? I’ve found that personal experience is the impetus for some researchers, either their own or a family member. Do you have a personal interest in food allergies or was it pure scientific curiosity?
Derek: This work began roughly three years ago actually. Professor Stephen Quake has always pursued clinically-relevant projects and at the time, techniques for studying single cells were maturing in the lab. These two factors, combined with Dr. Kari Nadeau’s clinical expertise and my interest in food allergies paved the way for our idea to study the rare B cells that produce IgE antibodies responsible for food allergies. I think my personal motivation also likely played a part–I have a severe milk allergy myself.
AAC: Would you give our readers some insight into how you think? What were the factors that led you to your hypothesis for this study? What previous research provided the building blocks?
Derek: From studies of humans and mice dating back decades, it has been known that B cells produce antibodies and that a specific class of antibodies, IgE, causes allergic reactions through interactions with other immune cells such as mast cells and basophils. However, studying the B cells that produce IgE antibodies has been a longstanding challenge due to their scarcity. By our estimates, B cells producing IgE antibodies can be as rare as one in ten million white blood cells! We thought that a new technique, called single cell RNA-sequencing, could allow us to capture these rare cells and study their antibodies.
AAC: This an extraordinarily rich paper—meaning there’s an awful lot I don’t understand—so I’m just going to focus on a few areas. B cells come in multiple subtypes including naïve and memory, which do not secrete antibodies, as well as plasmablasts and plasma cells, which do. As described in the Gould article, the IgE plasmablasts you discovered seem to learn their allergen specificity from other cells—on the job as it were, instead of at the factory. This gives them an advantage because they can go right to work pumping out new IgE when challenged. This is a good thing when there’s an infestation of helminths, which require a heavy-duty response. But it’s a problem when the target is a harmless allergen because it causes a reaction disproportionate to the threat. Am I correct in my description? Could you elaborate?
Derek: There are multiple interesting points there to unpack. In contrast to other antibody classes, such as IgM or IgG, most of the IgE B cells we found were plasmablasts, meaning- as you said- they were actively secreting IgE antibodies, many of them peanut-specific, into the blood when we isolated them. This is interesting because it suggests a bias in the fate of IgE B cells towards antibody-secreting plasmablasts. The question of where these IgE plasmablasts came from is more challenging to answer because we only have a single time point from each of the individuals in our study, but a large amount of research in mice and some in humans suggests that other antibody classes have a role in allergic “memory.” I think the method we developed using single cell RNA sequencing will help further answer these types of questions in humans going forward.
AAC: I think the most interesting thing about your paper is that it begins to explain how tendencies to specific allergens are inherited. You isolated identical gene sequences – converged sequences — from two unrelated patients with peanut allergens. I know that sickle-cell anemia started out as a defense against malaria, but it’s a disaster in those who have inherited the genes. Do food allergies have a parallel history? Does this mean that all these people (and millions more peanut-allergic patients) are somehow descended from some group that needed defenses against particular parasites, and that they are just waiting for a fight? Can we also infer that if you studied, say, milk allergies you would find a comparable set of convergent gene sequences?
Derek: We did find one instance of convergent evolution where two unrelated individuals produced antibodies derived from identical gene rearrangements, but unfortunately we cannot say more on the general importance of specific immunoglobulin genes in allergies because of the limited number of individuals in our study. Broader claims about genetics, inheritance, and the importance of specific genes will require further studies with more individuals and more allergen-specific antibodies.
AAC: You state that the different allergenic peanut proteins most associated with anaphylaxis—Ara h 1, 2, and 3—are very different from one another. Why do these generate a stronger immune response than other peanut proteins and how do they relate to the IgE antibodies you found?
Derek: How the immune system decides which proteins in foods are “harmful” is still poorly understood, but some proteins, such as Ara h 2, are clearly more allergenic than others. One surprising result of our work was that some IgE antibodies we found bind strongly to two distinct allergens- Ara h 2 and Ara h 3. When we dissected the features of these antibodies that gave them this ability to “cross-react,” we found that it was a result of affinity maturation, a process during which mutations to the antibody sequence give antibodies the ability to bind more strongly to a target. We think this molecular approach will prove useful going forward when studying other allergies, such as tree nut allergies, where individuals can be allergic to some tree nuts but not others.
AAC: This question of a particular food allergy being descended from an ancient defense mechanism does beg the question why don’t all people with that gene sequence become food allergic? Many more millions of people who have these sequences don’t present as allergic, so far at least. Here I’m going to draw on your co-author Dr. Kari Nadeau and her work on epigenetics—namely the science of how genes are expressed—which can be influenced by many environmental and societal factors. Could you tell us some of the latest thinking about the food allergy epidemic from the epigenetic standpoint? Is it just a matter of time and generations before more trends in diet, pollution, and behavior uncover the food allergies in us all?
Derek: Food allergies are increasing in prevalence at a rate that cannot be purely explained by genetics, and indeed, Dr. Kari Nadeau here at Stanford and others around the world are finding that the types and timing of environmental exposures play a key role in determining if and when allergies develop. While some trends are certainly worrying, I would say that there are numerous recent advances that are encouraging. For example, it appears that early childhood exposure to food allergens can be protective. Going forward I think this will be a major focus of clinicians as they seek to develop interventions to reduce the incidence all types of allergic disease.
AAC: Finally, let’s talk about hope for the future. IgG4 is a class of antibody that greatly increases in individuals undergoing immunotherapy and is believed to act as a “shield” to prevent the immune system from reacting to an allergen. In one individual, you found a B cell producing a peanut-specific IgG4 antibody and a separate B cell producing a peanut-specific IgE antibody. Could you, for example, “selectively breed” cells to produce more IgG4 rather than IgE or administer peanut-specific IgG4 to accelerate immunotherapy? And if I’m way off base, could you please explain why? What should we be thinking about?
Derek: I first want to be fully transparent and say that our study was focused on our basic understanding of allergies and a potential therapeutic is still far in the distance. That being said, IgG4 is an exciting future direction for the exact reasons you mentioned. For our work in particular, a potential therapeutic could be based on re-engineering our antibodies to retain their ability to bind peanut allergens, but modify them such that they belonged to the IgG4 antibody class. If these were then reintroduced into someone and that person accidentally consumed an allergen, these antibodies would ideally bind the peanut allergens and prevent the immune system from reacting to them.
AAC: Thanks for your time and your provocative research.
Derek: It was a pleasure, thank you.
Derek Croote is pursuing a Ph.D. in Bioengineering in the laboratory of Professor Stephen Quake at Stanford University. Broadly, his research interests include allergy, B cells, antibodies, genomics, and bioinformatics. His most recent research focuses on a fundamental understanding of the human immune system for translational applications in allergic disease. He is excited by today’s unprecedented capacity for generating biological data and can be followed on Twitter: @DerekCroote.
Graphic by GeekyMedics.com
By Dr. Paul Ehrlich
The 2019 new year brought heartbreak to a South Brooklyn family as an 11-year old boy died after reacting to the smell of fish being cooked in his home. As described by the New York Daily News, the family hooked him up to a “medical device”, and when that didn’t help they called 911. While the medical device wasn’t identified, I suspected that it might have been a nebulizer pointing to a history of asthma. A later report in the New York Post confirmed that he did have asthma, and also a fish allergy.
This tragedy is a reminder of the dangers of poorly controlled asthma more than a food allergy story. When the small airways are inflamed, the space through which the air flows is reduced. When a new trigger further shrinks the diameter due to mucous and swelling, the volume plummets. When the airways belong to a child, there just isn’t that much room to constrict.
Years ago I was asked to consult with the health authorities of a Caribbean country on the rapid increase in the incidence of asthma. We concluded that it was because people had shifted away from cooling their homes using natural air exchange and the installation of air conditioners, which trapped the allergens. This problem of reduced access to fresh air is also a problem in cold weather. In the winter months with windows shut, environmental allergens such as dust mite and cockroach are trapped in the home. Lungs become “twitchy” as the English put it. As a kind of double jeopardy, this condition can be exacerbated by breathing cold winter air.
Thus, the airways are primed for exposure to airborne allergens, in this case fish.`The literature contains examples of incidents like this, usually when people wander through a food court where shrimp are being boiled, or in restaurants. Roasting peanuts are another known trigger if being roasted in commercial quantities.
Every death is a tragedy, but it is also a warning. Respiratory anaphylaxis can be thought of as an asthma attack triggered via the blood. Control your asthma. Know your triggers. And minimize your exposures. In addition you can’t control environments where the odors are secondary to what others might be doing, such as cooking obviously but also sanding or spray painting. These irritants can also trigger an attack. If your child is susceptible to these, asthma control is the first line of defense. If a patient is using albuterol frequently, the asthma is not controlled.
Regardless, be sure to have an epinephrine auto-injector like the Auvi-Q, Epi-Pen, or one of the generics readily available. Epinephrine is both a Beta 1 agonist and a Beta 2 agonist. That is, it treats the respiratory system the way albuterol does for an asthma exacerbation (Beta 2), as well as the heart (Beta 1)–crucial for correcting plummeting blood pressure from anaphylaxis. It was the go-to treatment for asthma exacerbations before albuterol was developed.
Illustrations from Asthma Allergies Children: a parent’s guide
By Henry Ehrlich
In October, we wrote about a new horse in the epinephrine race and wondered if it would be the tipping point, based on the idea that it takes several competitors in a niche to drive down monopoly prices. Here it is, early December, and we read about still another, this one from Sandoz, the company that brought us LSD, but that was long ago and far away.
This one will not be an auto-injector, but a prefilled syringe instead. Sold under the name Symjepi, the price will be $250 for two, without insurance. People are so accustomed to auto-injectors adjusting to the pre-filled syringes will take some doing. Auto-injectors were developed by the military to administer nerve gas antidote under battlefield conditions. Anxious parents and teachers no doubt feel the same level of duress when a child is having anaphylaxis. Introducing another step into the process of deliver a life-saving drug will require additional training and enough practice to so without panic, although the unit appears to be well designed with clear instructions. But once that familiarity threshold is reached, Mylan’s market dominance may suffer a real blow. Maybe the invisible hand will reach out to help patients instead of picking their pockets at the same time.
A salutary effect on pricing is by no means a given. Generic drug makers are described as a price-fixing cartel, with its own private language. As reported in the Washington Post, “The ‘sandbox,’ …was the market for generic prescription drugs, where everyone was expected to play nice.
“’ Fair share’ described dividing up the sales pie to ensure that each company reaped continued profits. ‘Trashing the market’ was used when a competitor ignored these unwritten rules and sold drugs for less than agreed-upon prices.”
The investigation began as an an antitrust lawsuit agains two drugs in 2016 and now encompasses at least 16 companies and 300 drugs.”
By Henry Ehrlich
The first commercial oral immunotherapy product for food allergies has come through a phase 3 clinical trial, clearing the way for commercial release, possibly in 2019. The drug (made from peanut flour) received one of the highest honors in the world of medical publishing: publication in the New England Journal of Medicine. The co-authors are a food allergy all-star team, including several who have contributed to this website.
Although for the time being it is peanut only, Daniel C. Adelman, M.D. the head researcher for Aimmune Therapeutics, the company that made it, and lead author told me last year that it was the company’s ambition to be the largest maker of food immunotherapy products in the world. Dr. Brian Vickery, MD, Director, Food Allergy Program, Children’s Healthcare of Atlanta who led the international trial, said, “This was the largest clinical trial ever conducted in food immunotherapy, and the results suggest that the treatment could potentially protect peanut-allergic children from severe reactions due to accidental exposures, which would be life-changing for families. We are excited to be able to conduct research that could one day lead to new treatment options that improve the lives of families dealing with peanut allergies.”
AR101 performed well in children and adolescents 4 to 17 years of age compared to placebo. “Overall, 67% of the participants 4 to 17 years of age in the active-drug group could tolerate a single dose of at least 600 mg of peanut protein, the equivalent of approximately two whole peanut kernels, during the exit food challenge.” All had showed reaction symptoms at a challenge dose of 100 mg or less at baseline… no more than 30 mg of peanut protein, the equivalent of 1/10th of a peanut kernel. “A total of 50% of the participants 4 to 17 years of age in the active-drug group were able to complete the entire double-blind, placebo-controlled exit food challenge, which was capped by a 1000-mg single dose (the equivalent of approximately three or four peanut kernels).”
The bad news was that in participants 18 to 55 years of age the therapeutic effect was not significant.
So, we now have one on the board, an OIT protocol that will surely be offered much more widely than the “OIT underground” that has been treating patients for years. They will have to make the choice to perform, or at least authorize, more food challenges. As Dr. Andrew Bird (one of the co-authors) wrote on this website, the age of prescription food allergy treatment demands more rigorous diagnosis. They also must impress on patients and families that this is not a cure, but will require long-term maintenance and vigilance. And while it raises the threshold for eliciting a reaction, it doesn’t remove it altogether.
Another therapy, the DVB peanut patch is on its way.
Photos courtesy of Aimmune Therapeutics