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Beyond Brushing Can Toothpaste Cure Your Child’s Peanut Allergy?
Beyond Brushing Can Toothpaste Cure Your Child’s Peanut Allergy?
Michael J. Heiss, D.D.S.; Benjamin Solomowitz, D.M.D.
ABSTRACT
Peanut allergies pose significant health risks globally, with an increasing prevalence observed over the past two decades. Accidental exposures to peanuts can lead to severe allergic reactions, including anaphylaxis, prompting the exploration of innovative therapeutic approaches to mitigate these risks. This literature review examines the potential use of peanut proteins embedded within toothpaste formulations as a novel avenue for inducing tolerance in individuals with peanut allergies. It includes recent studies and clinical trials in oral immunotherapy, focusing on mechanisms of action, safety profiles and long-term outcomes associated with controlled allergen exposure. Key findings suggest that oral mucosal therapy, particularly sublingual immunotherapy, may offer a safer alternative to traditional oral ingestion methods, with promising results in desensitization and sustained tolerance induction. Furthermore, the review highlights the broader implications of peanut allergy desensitization, including improved quality of life and the potential application of similar approaches for other allergens. While further research is needed to optimize this therapeutic modality, toothpaste-based immunotherapy presents a promising avenue for enhancing patient safety and promoting lasting tolerance in individuals with peanut allergies.
Peanut allergies represent a significant health concern worldwide, affecting millions and posing severe threats, ranging from mild allergic reactions to life-threatening anaphylactic shock. It is estimated that 1.4% to 3.8% of the U.S. population has a peanut allergy, and this number has tripled in the past 20 years.[1] This drastic increase in prevalence in peanut allergies may be attributed to increased reporting of allergies as health care improves over time, or to increased cleanliness and sanitation, a trend over recent decades, which also may contribute to the rise in peanut allergies. The “hygiene hypothesis” suggests that reduced exposure to infections and microbes in early childhood can lead the immune system to overreact to harmless substances, like peanuts, since it lacks the necessary training to distinguish between harmful and harmless triggers. Regardless of the cause, it is suspected that each year, 7% to 14% of those affected will experience an accidental exposure, which could lead to many negative outcomes, chief of which is anaphylaxis and death.[1]
In recent years, new research has explored innovative approaches to mitigate the impact of peanut allergies, aiming for the development of tolerance in affected individuals. Among these approaches a novel avenue has emerged—utilizing peanut proteins in toothpaste to induce tolerance.
This literature review will outline research in oral immunotherapy investigating the use of peanut proteins embedded within toothpaste formulations to provoke controlled exposure and tolerance in individuals allergic to peanuts. The premise underlying this approach lies in the principle of controlled allergen exposure as a means to gradually desensitize and potentially produce immune tolerance.
This review aims to critically analyze recent studies, clinical trials, mechanistic investigations, safety assessments and long-term outcome evaluations related to this innovative approach. By examining the collective findings and insights from these studies, this review seeks to offer a complete understanding of the efficacy and safety of using peanut proteins in toothpaste to foster tolerance in individuals with peanut allergies, and aims to extrapolate these findings to encourage, or discourage, future research that can use the same toothpaste approach for the treatment of other allergies.
Methodology
The selection of articles aimed to identify studies performed over the last 10 years in the field of oral immunotherapy, with those focused on desensitization and those pertinent to toothpaste-infused therapies favored. Preference was then given to peer-reviewed studies or meta-analyses. Articles were found across PubMed, Google Scholar
and other relevant immunology journals. Ultimately, articles were chosen based on their ability to drive conversation about toothpaste-based exposure to peanut proteins, including the mechanism of action, safety, side effects, efficacy and long- term impact of this novel immunotherapy.
Mechanism of Action
Peanut allergies are an IgE antibody-mediated hypersensitivity in which certain peanut proteins are identified as threats by the host immune system on initial exposure. This initial exposure is deemed the “sensitization phase,” as there is only asymptomatic contact. Subsequent encounters with these same proteins, however, may trigger an immediate hypersensitivity reaction. The mechanism of action is as follows:
1. Antigen-presenting cells bind to peanut allergens and introduce them to T-cells.[2]
2. T-cells signal B-cells to produce IgE antibodies, which bind to Fc proteins on basophils and mast cells and induce degranulation.[2]
3. Release of inflammatory mediators (histamine, proteolytic enzymes, cytokines, prostaglandins, leukotrienes, platelet-activating factors, macrophage inflammatory proteins, tryptase, etc.), which can lead to a wide range of symptoms.[2]
4. Symptoms may include vascular permeability, peripheral vasodilation and smooth muscle contraction, which can manifest to increased mucous secretions, bronchospasm, abdominal cramping, rhinitis and, potentially, hypovolemia or hypoxia. Pulmonary edema or general edema can also occur due to fluid shifting into the interstitial space. Individuals can experience pruritus and local response of asthma or a systemic response of anaphylaxis.[2]
Oral immunotherapy treatments focus on desensitization, a process by which continued exposure to small quantities of the offending allergen result in recalibration of the immune response just described. This shift in response occurs through a change in the population of immune cells and cytokines activated upon allergen exposure. There are four major processes by which this occurs.[3]
1. Decreases in mast cell and basophil activity, which reduces degranulation and reduces the chances of systemic anaphylaxis.[3]
2. Generation of allergen-specific regulatory T and B cells, coupled with suppression of allergen-specific effector T-cell subsets.[3]
3. Regulation of antibodies, with specific IgE levels muted and their role replaced with a less locally aggressive, specific IgG4 antibody instead.[3]
4. Over several months of desensitization, decreases in mast cell, basophil and eosinophil activity occur and as a result, a decrease in the release of their inflammatory mediators causes a decrease in Type I skin test reactivity, a test often used by allergists and immunologists to observe a patient’s predilection towards anaphylaxis.[3] These four strategies take advantage of the immune system’s plasticity and aim to induce lasting changes in immune response over time.
One study focused on brushing with INT301, a specialized, fully functional toothpaste whose ingredients include peanut allergens at therapeutic doses. This method of exposure is different from a pill or peanut M&M daily as it removes the onus of daily dosing and, thus, avoids “medication fatigue,” which has proven to be an obstacle to longterm maintenance.[4] This marks new ground for patients with peanut allergies, offering the potential to mitigate dangerous symptoms and also rewire the immune response towards lasting tolerance.
In this study, researchers assigned patients to receive escalating doses of INT301, up to 80mg/dose, 120mg/dose or placebo for eight weeks. Half of the patients underwent maintenance dosing for 48 weeks to assess efficacy. Notably, patients in the assigned groups used their toothpaste for 97% of the days in the trial, indicating much higher patient compliance with this methodology when compared with other dosing methods.[4]
Another study (PACE) that did not involve toothpaste centered specifically on sublingual immunotherapy, and follows the same immunologic mechanism as INT301 with a transmucosal approach. In this study, 37 subjects completed three to five years of peanut sublingual therapy, with 67% (32) successfully consuming 750 mg or more during doubleblind, placebo-controlled food challenges (DBPCFC’s), the gold standard for allergy testing.[5] Furthermore, 25% (12) passed the 5000-mg DBPCFC without clinical symptoms. Peanut skin test wheals, peanut-specific IgE levels, and basophil activation decreased significantly, and peanut-specific IgG4 levels increased significantly after peanut SLIT.[5]
Safety and Side Effects
The safety of peanut protein-infused toothpaste is a critical aspect of its application as a therapeutic agent in patients with peanut allergies. The goal of this oral immunologic therapy is controlled exposure to induce and modulate a particular immune response. However, concerns surrounding adverse reactions or induction of a severe allergic response necessitate an in-depth safety analysis. Some studies have found that desensitization is more harmful than beneficial, due to production of internal allergic reactions during ingestion of allergens in 43% of doses.[4] However, this assessment focuses specifically on oral allergens that are ingested, rather than absorbed through mucosal tissues. Oral mucosal therapy, on the other hand, avoids the gastric tract almost entirely, and was found to cause far fewer adverse systemic reactions, while still effectively modulating the immune system.[4]
One study that honed in more closely on sublingual immunotherapy found that over 2,554 doses, the probability of any reaction was 4.7%.[5] These reactions were all classified as mild and presented without systemic symptoms, wheezing or cardiac involvement. The localized reactions were most likely to be oropharyngeal itching (2.6%), isolated hives (0.5%), skin itching (0.3%) and sneezing (0.2%).[5] It is noteworthy that incidences of these reactions were statistically independent of dosing in this study.[5] These findings coincide with those of the PACE study, in which all patients assigned INT301 were able to tolerate the treatment at the highest dose, with no moderate or severe systemic reactions. All nonsystemic reactions were mild and transient, with only five requiring treatment with oral Benadryl due to localized swelling/abdominal cramping and no one requiring epinephrine.[4]
In the sublingual immunologic study, 83% of participants demonstrated sustained unresponsiveness after two to four weeks.[5] Side effects were reported with 4.8% of doses (3,599/75,366 doses), with transient oropharyngeal itching reported most commonly as 75% of reported symptoms. This itching sensation decreased with continued dosing, with 89% of all episodes reported within the first two years of treatment. The majority of symptoms self-resolved, with only 0.21% (159) requiring antihistamine treatment, and no epinephrine was administered.[5] Three episodes of wheezing and cough were treated with albuterol in addition to antihistamines. No dosing reactions were treated with oral steroids. Local lip swelling was reported with 0.15% of doses. Gastrointestinal symptoms, including stomach pain, vomiting and diarrhea, were reported with 0.3% of doses.[5]
Each prospective new therapy must undergo a costbenefit analysis. Currently, without immune modulation, the number-one strategy for treating peanut allergies is avoidance.[6] While avoidance is extremely effective, it cannot always be relied upon, as there are many seemingly safe products on the market that contain peanuts. This avoidance strategy thus requires vigilance on the part of not only the parents, but also of the child with the peanut allergy. Avoidance can be challenging for a blossoming child, taxing both mentally and socially.[6]
Even with vigilance, exposures can, and do, occur, which often result in hospitalizations and adverse effects. Many accidental exposures lead to life-threatening reactions, including anaphylaxis and even death.[4] Oral immunotherapy can be coupled with current avoidance strategies, used as a safeguard to either dampen or entirely eliminate the adverse effects that may result from accidental exposure.
Ultimately, oral peanut immunotherapy with toothpaste application is a novel and promising treatment modality that can be used in conjunction with avoidance strategies to provide safety and peace of mind to children struggling with peanut allergies and their families.[7] There should be additional research performed to further ensure safety, with close monitoring during intervention and consideration of specific patients’ varying immune responses. This therapy has alternative applications as well that should be studied further, including for other types of allergies that have also become more prominent in the 21st century, and as firstline therapy of hypersensitivity reactions to medications in children undergoing treatment for leukemia.[7]
Long-Term Impact
Sustainability of Tolerance
Uncovering these immunological mechanisms can provide insight into ways by which we might take advantage of the immune system’s plasticity to create targeted results. The observed immune shift following toothpaste-based exposure hints at the plausibility of inducing a state of desensitization and potentially fostering lasting tolerance. By manipulating specific immune cell populations or cytokine cascades, there’s potential for tailored approaches aimed at amplifying and sustaining the induced tolerance.[7]
In one study, patients undergoing oral immunotherapy were found at six months after discontinuing therapy to have a 141-fold increase in the amount of peanut protein tolerated. This decreased to 122-fold by the 12-month interval.[8] For sublingual immunotherapy, the results were different, with a 22-fold increase in tolerance at both 6- and 12-month intervals. While this is a stark difference to oral immunotherapy, we must recall that a 22-fold increase is still quite significant, safer as outlined above, and coupled with an avoidance strategy would produce excellent results. The stability in a patient’s measured level of tolerance over the span of one year is also noteworthy, as this is a novel finding that was not seen in strictly ingestible oral immunotherapy studies. The benefit of sustained tolerance, coupled with an avoidance strategy, is that it could prevent those with peanut allergies from having life-threatening reactions, or reactions entirely, following an accidental exposure.[9]
Avoiding Allergy Recurrence
Dangers of allergy recurrence can result in numerous adverse effects to patients. Development of tolerance over time can cause patients to take their foot off the gas when it comes to their avoidance strategies and accidentally consume peanut products that they otherwise would not have. This can induce potentially life-threatening anaphylaxis in patients who have ceased therapy or have been inconsistent. It is crucial for researchers, doctors, parents and patients to know how long we can expect desensitization to persist following oral mucosal immunotherapy. It is also important to choose an application method that is not cumbersome for patients who must comply each and every day.
One of the benefits of the toothpaste method for oral immunotherapy is that patients have been socialized and accustomed to brushing their teeth twice a day throughout most of their lives. Current immunotherapies involve daily consumption of peanut M&M’s.[10] While this is a creative idea that makes medicine of M&M’s, patients who undergo lengthy therapy end up hating the taste of these candies. By offering the allergen hidden within the contents of their toothpaste, patients are able to absorb the allergen through their oral mucosal tissues multiple times daily, all while promoting great oral health and masking the taste with various flavors.
Conclusion
Summary of Key Findings
Increasing the clinical threshold to 300 mg of peanut protein was estimated to provide a greater than 95% reduction in risk for allergic reactions to common foods, such as chips, cookies, snack cakes and ice cream. Achieving a clinical threshold of 1,000 mg/dose increased this risk reduction to nearly 99%. This data further supports a clinically meaningful level of desensitization for the majority of our subjects treated with peanut SLIT (sublingual immunotherapy).[4]
Implications and Future Directions
Implications for peanut allergy desensitization range widely from reducing anxiety/promoting social interaction in children to preventing life- threatening anaphylaxis in both children and adults. Toothpaste as a vessel for topical application of peanut allergens to oral mucosal tissues bypasses many of the traditional issues that can arise during desensitization. While peanut allergies are among the most common allergies in our population, this same desensitization methodology can be applied to other allergy-inducing agents as well. It can also be used as a method to prevent peanut allergies from arising at all.
In a recent study published by the journal NEJM Evidence, 500 participants were followed until age 12, and it was determined that 15.4% of children who had avoided peanuts in infancy to age 5 developed a peanut allergy, compared to only 4.4% of those children who had consumed peanuts from a young age.[11] This further contributes to the theory behind oral mucosal immunotherapy and gives weight to the argument that the rise in allergies in the American population is due to underexposure to potential allergens.[11]
Queries about this article can be sent to Dr. Heiss at mikeheiss96@gmail.com.
REFERENCES
1. Lieberman JA, Gupta R, Knibb RC, et al. The global burden of illness of peanut allergy: a comprehensive literature review. Allergy 2020;76(5). doi:https://doi.org/10.1111/all.14666.
2. Abbas M, Moussa M, Akel H. Type I hypersensitivity reaction. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024;54(3) Jan–. PMID: 32809396. https:// www.ncbi.nlm.nih.gov/books/NBK560561/#:~:text=reactions%3A%5B1%5D-3.
3. Simons E. Assessing the efficacy of oral immunotherapy for the desensitization of peanut allergy in children (STOP II): a Phase 2 randomized controlled trial. PEDIATRICS 2014;134(Supplement):S155-S156. doi:https://doi.org/10.1542/peds.2014-1817nn.
4. Chu DK, Wood RA, French S, et al. Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety. Lancet 2019;393(10187):2222-2232. doi:10.1016/s0140-6736(19)30420-9.
5. Kim EH. Safety of peanut sublingual immunotherapy (SLIT) in children with peanut allergy. Journal of Allergy and Clinical Immunology 2010;125(2):AB20. doi:https://doi.org/10.1016/j. jaci.2009.12.109.
6. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. Journal of Allergy and Clinical Immunology 2014;133(3):621-631. doi:https://doi.org/10.1016/j.jaci.2013.12.1088.
7. Esenboga S, Akarsu A, Ocak M, et al. Safety and efficacy of rapid drug desensitization in children. Pediatric Allergy and Immunology 2022;33(3). doi:https://doi.org/10.1111/pai.13759.
8. Calvani M, Bianchi A, Imondi C, Romeo E. Oral desensitization in IgE-mediated food allergy: effectiveness and safety. Pediatric Allergy and Immunology 2020;31(S24):49-50. doi:https:// doi.org/10.1111/pai.13171.
9. Dantzer JA, Mudd KE, Wood RA. Long-term follow-up of oral and sublingual immunotherapy for peanut allergy. Journal of Allergy and Clinical Immunology 2019;143(2):AB247. doi:https://doi.org/10.1016/j.jaci.2018.12.755.
10. Assa’ad AH, Lierl MB. Oral immunotherapy to peanuts in children with mild and moderate peanut allergy results in long-term tolerance. Journal of Allergy and Clinical Immunology 2019;143(2):AB248. doi:https://doi.org/10.1016/j.jaci.2018.12.758.
11. George Du Toit, Huffaker MF, Radulovic S, et al. Follow-up to adolescence after early peanut introduction for allergy prevention. NEJM Evidence 2024;3(6). doi:https://doi.org/10.1056/ evidoa2300311.
Michael J. Heiss, D.D.S., was a general practice resident at Jamaica Hospital Medical Center, Queens, NY. He now practices general dentistry at Pearly Whites Dental Studio, Oceanside, NY.
Benjamin Solomowitz, D.M.D., is director of the General Practice Residency Program and associate director, training, Department of Dental Medicine, Jamaica Hospital Medical Center, Queens, NY.
