"P.O.K.W.A.S.P.A." = Parents Of Kids With A Severe Peanut Allergy Group

"P.O.K.W.A.S.P.A." = Parents Of Kids With A Severe Peanut Allergy Group
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Sunday, January 25, 2015

Overseen, by Caryn Tatelli: Latest installment of "Eating Peanut"

Another post from one of the best mom-writers on the internet.

Mother-author Caryn Tatelli eloquently captures the complex emotional roller coaster surrounding how best to raise a child with a lethal food allergy. Her writing offers a window into the mind of a parent struggling to reach out toward newer, uncharted territories in order to best protect her daughter from a life of risks associated with anaphylaxis, all the while knowing that nothing at this stage can be confidently called "a sure bet," yet for curing food allergies.

Tatelli's blog, Eating Peanut, is an often poetic account of told in a series of impressionistic, fleeting moments she experienced while watching her daughter make the terrifying journey into a very new branch of treatment for food allergies involving what is known as "the OIT process." Her writing has provided an invaluable, often quite objective, window into a world many of us are afraid to journey ourselves, yet. She and her daughter are both brave and generous to share their journeys with us.


Here's her latest post:
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Overseen, by Caryn Tatelli

It has been nearly two years since we learned that Ann & Robert H. Lurie Children's Hospital would be a site for the PRROTECT clinical trial (Oral Immunotherapy for Peanut Allergy supported by Xolair).

It has been nearly eighteen months since I resigned from my job in anticipation of the clinical trial (knowing, but absolutely truly NOT -- even remotely -- understanding what was on the horizon).

It has been more than a year since we scheduled Susan's intake and screening appointments for the PRROTECT clinical trial at Ann & Robert H. Lurie Children's Hospital -- and I still remember how excited I was that day. (It wasn't until later that the reality of the failed food challenge for peanut required to be enrolled in the clinical trial set in...)

I have more indelible images in my mind from the last year than my whole lifetime.
Really.
Truly.

-- Brave, in my mind, will always be the image of Susan (hours after her failed peanut challenge required for enrollment in the clinical trial), self-injecting her EpiPen not once, but twice..the blood running down her leg...the scared and uncertain look on her face...terribly terrifying images for which I am thankful and grateful and...sad. (NO ONE would pick this for a child, any child...of that, I am certain...and yet, I am also grateful beyond words for the knowledge Susan now has that she has successfully self-administered her EpiPen.)


-- Stoic, in my mind, will always bring to mind the image of Susan, shaky and pale after vomiting a 45 mg dose of peanut just two hours earlier -- bound and determined to compete the program she had prepared to skate. (While it wasn't Susan's best-ever skate, it might well be the one I am most proud of, as she went after what she wanted, showing her grit and determination every second of the way.)


-- Determined, in my mind, will always bring to mind the image of my shy, quiet, humble Susan standing in front of nearly 500 guests at FARE's Spring Luncheon sharing her food allergy story, openly talking about how her food allergies have limited her life, and how terrible anaphylaxis is -- terrifying in and of itself and even scarier not knowing for certain that her medication will work.


Over the last year, I have accumulated memories no parent wants to have. I still remember how small...and insignificant...and vulnerable Susan looked as she lay sleeping after anaphylaxis during her failed rapid desensitization to peanut. I remember watching the machines that monitored her vitals, feeling both thankful to have them and sososo scared that we needed them. I will never forget the intense cold that enveloped me as I sat there, shaking as I kept watch on the machines that monitored my dear Susan, before climbing in next to her to hold her tight -- to keep her safe, I hoped.


The last year is comprised of the countless nights I laid awake watching Susan breathe, listening carefully for even the slightest change...and the mornings I allowed her to go off to school after taking her peanut dose, trusting those there to care for her as if she were their own.


I have changed in immeasurable ways in the past year.
As difficult as the last year has been, I would not change it -- not one bit, for the hardest, scariest moments are the very reason these clinical trials are so important...not just for us, but for everyone who is desperately seeking options.

I have learned how rapidly anaphylaxis can take a child, shattering families, schools and communities and terrifying those of us who are charged with keeping our children safe. I have vowed to not ever have to live with the regret of having waited to administer epinephrine.

I have lost friends who do not -- simply cannot or will not -- ever understand or accept our decision to pursue treatment for Susan through a clinical trial ...and I have gained a community of people who -- like me -- are searching for a safer passage for their children. (I have come to understand the value of true friends, and am beyond thankful for those in our circle who have supported us even if they may not fully understand or agree with our decision...)

As I look back on our year, and think forward to Susan's upcoming food challenge (4000 mg of peanut), I find myself remembering a silence that I half-wish I had poked at a bit (social worker hat on). As part of the clinical trial, we have been asked to complete questionnaires at various points. Our first questionnaire was administered during our intake visit. Mine was entitled "Food Allergy Quality of Life -- Parental Burden Questionnaire."



I don't know exactly what Susan's questionnaire was entitled, but I still remember the effort it took for me NOT to put on my social work hat and probe at her answers that day. Her private answers.

I know the effort it took (takes, if I am perfectly honest) not to take advantage of the fact that I have easy access to my husband's answers in a scanned copy of the questionnaire in my e-mail...that I have not, and will not ever -- despite my curiosity -- open.

One thing that has NOT changed about me this year is my sense of what is right and wrong. (For better or for worse.)
My questionnaire is mine.
Susan's questionnaire is hers.
My husband's questionnaire is his.
Curious as I am, I would never go there. I just don't think it is right -- not even to poke and prod at it with that social worker hat of mine on...

I am sure at one point I knew that we would see the intake questionnaire (or some variation of it) again during the clinical trial...but, I had lost track of it, and so I was a bit surprised to be presented with it during Susan's Week 18 updose appointment.

There were questionnaires to be done.
And...because there was no school that day, I had Susan's younger brother and sister along with me.

I completed my questionnaire.
Susan completed hers.
I did NOT look.
I swear it.

Even to this day, I remember -- yet another indelible image -- the moment realization washed over me...

For despite my very best intentions, despite my certainty that Susan's answers needed to be her own...and only for her eyes (well, at least not for my eyes, for surely others have seen and reviewed them...)...I saw a part of her questionnaire. It happened so fast -- as I turned away from the sink, after washing my hands...

It wasn't much, really...just a part of the first page and even that was more a sense than anything...but, in that split second where I was seeing what was not for me to see when I was torn between once having seen wanting to see more and knowing that it was simply not right for me to allow myself to look beyond what I had accidentally seen.

I tore my eyes away.
And my heart sank.

For what I had seen was more than enough.

The answers are scaled, from 0-6, with 0 being "Not limited" or "Not troubled" and 6 being "Extremely limited" or "Extremely Troubled." While my questionnaire was skewed toward the middle, with answers of "Moderately limited" or "Moderately troubled" and "Quite a bit limited" or "Quite a bit troubled," which are scores of 3 and 4, Susan's answers were skewed toward the 5's and 6s, with most of her answers being "Very limited" or "Very troubled" or "Extremely limited" or "Extremely troubled."

And, as much as I wished I did not know, the questions Susan had answered were about eating out, and about being different from her peers...about social functions and gatherings.

I felt heartsick.
I still do.
Every time I allow myself to think about it.

My strong, kind, compassionate and brave Susan is saddened and [very] troubled every time she is different, left out...restricted...limited. And because she is the kind of person she is, she hides it.

I always wondered if Susan was as determined to see the clinical trial through -- even when things were so difficult last summer -- as she was because of how difficult it is to live with food allergies.

And now I know.

Friday, January 23, 2015

“What a Civilized Society Will Tolerate”: Van Halen Wins Appeal in Fight Over Safety at School for Allergic Daughter (Second post in Allergy Law Project)

“What a Civilized Society Will Tolerate”: Van Halen Wins Appeal in Fight Over Safety at School for Allergic Daughter


Kelly Van Halen (née Carter), interior designer and ex-wife of the drummer Alex Van Halen of the famous band of the same name, knows exactly how it feels to face a school that refuses to do what is necessary to protect an allergic child. Van Halen recently won an appeal reinstating her lawsuit against her daughter’s former private school for failing to put in place a safety net for her allergic child.

The Initial Suit

caseinpoint1Kelly Van Halen and Baron Rogers enrolled their daughter, Stella, in an LA preschool called Berkeley Hall at a cost of $13,000. Two years after Stella began school at Berkeley Hall, she developed a nut allergy. The suit alleges that Van Halen told the headmaster about Stella’s allergy and asked the school to restrict nuts in her classroom. Van Halen charged later that the headmaster assured her that he had implemented an allergy policy, that he committed to send a letter to the other parents asking them not to bring nut products into the classroom, and that he would make sure the staff was trained and willing to administer epinephrine.
Despite these assurances, Van Halen’s initial complaint alleges that Stella’s teacher later revealed that there was not a nut restriction in the classroom. Even worse, the teacher told her that the staff would never administer an epinephrine auto-injector because the school followed the doctrine of the Christian Science Church. Adherents do not believe in the use of medicines to treat or cure illness – instead members are taught to use their faith to heal themselves. Van Halen alleges that the school hid its basis in Christian Science and that as a result, she did not know that it was a Christian Science preschool. The headmaster (who allegedly made promises to Van Halen about the allergy policies) was subsequently forced to leave the school “shortly after adopting the policy banning nut products.” The complaint alleges that the school failed to implement the allergy policy he had promised. Fearing for the safety of her daughter, Van Halen pulled her out of the school, but Berkeley Hall allegedly refused to refund her tuition.
Van Halen filed suit in state court in California alleging, among other things, breach of contract, fraud, negligent misrepresentation, and intentional infliction of emotional distress. Van Halen alleged that the school lied about creating a nut-free environment and about their willingness to administer epinephrine. She also claimed that she was misled insofar as the school failed to inform parents up front that it was a Christian Science school.

On Appeal

quote9A lower court dismissed the majority of Van Halen’s claims, but an appeals court in December 2014 sided with Van Halen and reinstated her suit.
In an unpublished decision (which means that it decides the issues before it but does not set a precedent for other cases), the court held that Van Halen had alleged sufficient facts to justify her claims for breach of contract and emotional distress. Notably, the court said, “[a]llegations that a school lied to parents about its plans and intentions to eliminate a life-threatening hazard and concealed the continuing existence of a condition that could threaten a child’s life do approach the limits of what a civilized society will tolerate” and are consistent with a claim for emotional distress. The court likewise found that “the school placed Stella in a dangerous environment that could have killed her, falsely stated it was addressing the problem and making the environment safer, and then failed to take appropriate steps and commit the resources to be able to respond to a medical emergency in Stella’s case if one arose.”
The court also found that Berkeley Hall may have engaged in negligent behavior, by concealing “that it was in fact continuing to expose Stella to nuts and doing nothing to prepare for an allergenic emergency.” In so holding, the court noted that the school owes a special duty of protection to its students.

The Road Ahead

quote10Van Halen’s win in the appeals court does not end the case. Ultimately, the finder of fact (be it jury or judge) will decide whether Berkeley Hall is liable to Van Halen. But for parents and advocates, the court’s acknowledgement that a school’s failure to put in place a safety net to protect an allergic child could cause serious emotional distress is a promising development. That a court found such conduct to be “beyond what a civilized society will tolerate” signals progress about issues that relate to the rights of allergic families and reaffirms the special duty of care owed to a student by a school.
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Thursday, January 22, 2015

Oral and sublingual immunotherapy for food allergy, from World Allergy Journal, 12/8/2014

Oral and sublingual immunotherapy for food allergy

Uyenphuong H Le and A Wesley Burks*
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill NC 260 MacNider Hall, CB 7220, Chapel Hill, NC 27599-7220, USA
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World Allergy Organization Journal 2014, 7:35  doi:10.1186/1939-4551-7-35
The electronic version of this article is the complete one and can be found online at: http://www.waojournal.org/content/7/1/35

Received:17 April 2014
Accepted:31 October 2014
Published:8 December 2014
© 2014 Le and Burks; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Abstract

IgE-mediated food allergy is a potentially life-threatening allergic disease with an increase in prevalence in developed countries over the past 15 years. Currently, there are no approved forms of therapy and the standard of care is dietary restriction and ready access to emergency medications, such as self-injectable epinephrine and antihistamines. Allergen-specific modalities of treatment currently being studied include oral immunotherapy (OIT) and sublingual immunotherapy (SLIT). Both forms demonstrate the ability to desensitize patients to a variety of specific food allergens and show great promise. However, more research is needed to evaluate the safety and efficacy of OIT and SLIT prior to routine use in clinical practice.
Keywords: 
Food allergy; Oral immunotherapy; Sublingual immunotherapy; Desensitization; Tolerance

Introduction

Food allergy is a major public health concern that affects approximately 8% of US children [1]. The most common food allergens that elicit IgE-mediated reactions include milk, egg, peanut, tree nuts, wheat, soy, fish and shellfish [2]. Of these, peanut allergy is the most common cause of anaphylaxis in children presenting to the emergency department, as well as the most common cause of fatal food anaphylaxis [3,4]. The prevalence of peanut allergy has tripled from 0.4% to 1.4% from 1997 to 2008 [5,6]. Approximately 85% of children allergic to foods such as cow’s milk, egg, wheat and soy will outgrow their allergy, whereas 80-85% of children allergic to peanut, tree nuts, fish and shellfish will not [7].
There is currently no approved treatment or disease-modifying therapy for the routine management of patients with food allergies. The present standard of care is strict dietary avoidance of appropriately-diagnosed food allergens and ready access to emergency medications, such as self-injectable epinephrine and antihistamines [2]. Despite parent and patient vigilance with food allergen avoidance, accidental exposures resulting in clinical symptoms do occur [8]. As a result, patients and their families experience significant psychosocial burden and diminished health-related quality of life [9,10]. Recent efforts have focused on developing safe and effective therapies for patients with food allergies, with the most active research involving oral and sublingual immunotherapy (OIT and SLIT).

Mechanism for the development of food allergy

Oral tolerance is the process by which previously encountered proteins exposed to the gastrointestinal tract are tolerated through the suppression of cellular or humoral immune responses [11]. This suppression occurs through a number of mechanisms including the production of regulatory T cells (Tregs), the deletion of antigen-specific T cells, or the induction of anergy in antigen-specific T cells [11,12]. Food hypersensitivity is thought to result from either the failure to establish or the breakdown of existing oral tolerance [12]. Essentially, food allergy starts with an initial sensitization event to the food protein; however, the route and timing by which sensitization occurs remains unclear. Patients with a predisposition for food allergy develop a T helper (Th)2-predominant immune response. Th2 cells secrete cytokines including interleukin (IL)-4, IL-5 and IL-13, which stimulate B cells to produce allergen-specific IgE. These IgE antibodies bind to the surface of mast cells and basophils by high affinity receptors and cross-link upon re-exposure to the protein allergen, releasing mediators such as histamine, leukotrienes, cytokines and prostaglandins. These mediators lead to symptoms of allergic reactions [13].

Allergen immunotherapy

Allergen immunotherapy is a form of treatment that involves administering gradually increasing doses of allergen over time to induce immunologic changes. There are two possible immune states that can be achieved through food allergen immunotherapy: desensitization and tolerance. Desensitization occurs when daily allergen exposure increases the threshold of clinical reactivity to the food. Patients are therefore able to tolerate more food protein during an oral food challenge while on treatment. When dosing is stopped or interrupted, the protection is lost or reduced. However, the ultimate goal of allergen immunotherapy is tolerance, which is the ability to ingest the food without allergic symptoms after discontinuation of the therapy. Immunologic changes during immunotherapy show a shift away from a Th2 profile with decrease reactivity of mast cells and basophils, increase Treg production, increase food-specific IgG4 antibodies and eventual decrease in food-specific IgE antibodies [7].
Current protocols in food immunotherapy involving OIT and SLIT typically comprise of 3 phases: (1) an initial modified dose escalation or modified rush desensitization that takes place over 1-2 days with 6-8 doses of the allergen given, (2) a build-up phase that consists of weekly to biweekly dose escalations performed over 6-12 months and (3) a maintenance phase with daily home dosing that occurs over months to years. Oral food challenges (OFC) are used to test clinical reactivity while on treatment (desensitization) and while off therapy but still on diet restriction (tolerance) [7,14]. The initial desensitization and dose escalations, as well as OFCs, are performed in a supervised clinical setting while maintenance dosing is carried out at home.

OIT

OIT involves the daily administration of food allergen (milligrams to grams) mixed with a food vehicle in gradually increasing doses over months to years. OIT has been studied in several uncontrolled clinical studies for more than a decade involving mainly milk, egg and peanut allergies. Recent trials have provided invaluable efficacy and safety data as well as compelling evidence that OIT frequently induces desensitization, and possibly even tolerance, in patients with food allergies (Table 1).
Table 1. Summary of selected studies reviewed
In 2012, Burks et al. published the first multicenter, randomized, double-blind, placebo-controlled trial of egg OIT [15]. The study was designed to evaluate the clinical effect of egg OIT on desensitization and “sustained unresponsiveness,” the ability to consume 10 g of egg-white powder after 22 months of OIT and subsequent avoidance of egg for 4 to 6 weeks. Fifty-five children were enrolled with 40 subjects receiving egg OIT and 15 placebos. Subjects underwent a 1-day dose escalation, and a build-up phase to a goal maintenance dose of 2000 mg. After 10 months, subjects underwent the first 5 g OFC where 22 (55%) active subjects passed (desensitized) versus none in the placebo group. The study was unblinded at this point and the active treatment group was continued on maintenance OIT until a 22-month 10 g OFC, during which 30 (75%) of the active group passed (desensitized) compared to 0 (0%) of the placebo group. Active subjects who passed the 22-month OFC were taken off OIT for 4 weeks and returned for another 10 g OFC to determine sustained unresponsiveness (tolerance). Eleven (28%) active subjects passed and continued to incorporate egg into their diet without symptoms. Symptoms occurred with 25% of the total doses taken by the actively treated subjects compared to 3.9% of placebo doses. No serious therapy-related adverse reactions were reported. Egg white-specific IgG4 was higher for subjects who passed OFCs at 10, 22 and 24 months than for those who did not. Higher IgG4 levels at 10 months also suggested ability to pass OFCs at all 3 time points. Egg white-specific IgE and basophil activation levels were lower at 10 months for subjects who passed the 22-month OFC compared to those who failed.
In 2011, Varshney et al. published the first randomized, double-blind, placebo-controlled study to date, which conclusively demonstrated that peanut OIT induces desensitization and immune modulation [16]. Twenty-eight children were enrolled. However, 3 subjects withdrew early leaving 16 subjects in the active treatment group and 9 in the placebo group. The study protocol included 1-day initial escalation, 44-week build-up and 4-week maintenance phases (goal maintenance dose 4000 mg peanut protein) followed by a 5 g OFC at about 1 year. All 16 (100%) subjects receiving OIT passed the 5 g OFC compared to the median cumulative dose tolerated by the placebo group of 280 mg. The peanut OIT was well tolerated with subjects experiencing symptoms after only 1.2% of build-up doses. No active subjects required epinephrine with dose escalation visits or home doses. Peanut OIT subjects showed decrease IL-5 and IL-13, increase in peanut-specific IgG4 and peanut-specific FoxP3 Tregs, but no significant change in peanut-specific IgE at the time of OFC.
Subsequently, the first study to demonstrate clinical tolerance, or sustain unresponsiveness, after peanut OIT was recently published by Vickery et al. [17], who reported end-of-study results from an initial pilot trial of peanut OIT that was published in 2009 [18]. Twenty-four of 39 subjects originally enrolled in the pilot trial at 2 US centers were recruited to continue this OIT protocol. The maximum daily maintenance dose was 4000 mg. Subjects were treated for either a maximum duration of 5 years or once specific criteria were met, such as peanut IgE less than 2 kU/L or less than 15 kU/L with peanut skin prick test response less than 5 mm and no peanut-related reactions in the previous 6 months. Subjects then underwent two 5 g DBPCFC. The first was a desensitization OFC performed to assess clinical reactivity while receiving treatment and the second was to evaluate for sustained unresponsiveness after stopping OIT for 4 weeks. Twelve (50%) of the 24 subjects consumed 5 g of peanut protein and passed the open oral feeding of peanut butter without symptoms. These subjects were considered to have achieved sustained unresponsiveness and classified as treatment successes. Immunologically, they had smaller skin test results as well as lower peanut-specific IgE, Ara h 1, Ara h 2 levels and peanut-specific IgE/total IgE ratios. However, there were no between-group differences in peanut IgG4 levels or Treg cell numbers. Although this study lacked randomization and a placebo control group, it describes for the first time that immune tolerance, or sustained unresponsiveness, among children with peanut allergy treated with OIT is possible.

SLIT

SLIT involves the administration of small drops of allergen extract (micrograms to milligrams) under the tongue, which is then eventually spit or swallowed. Doses are approximately 1000-times less than OIT doses, but SLIT protocols include similar escalation and maintenance dosing [14,19]. The mechanism of action involves allergen interaction with protolerogenic Langerhans cells in the oral mucosa, resulting in suppression of the allergic response [20]. SLIT has been shown to be effective for other atopic diseases such as asthma and allergic rhinoconjunctivitis [21,22]. A number of studies involving SLIT and a variety of food allergens, including kiwi [23], hazelnut [24,25], milk [26], peach [27] and peanut allergies have been promising. Thus far, available evidence suggests that SLIT is less effective than OIT of inducing desensitization, but has a better safety profile given the low dose of peanut allergen required for treatment [28,29].
Fleischer et al. recently published results from a randomized, double-blind, placebo-controlled multicenter trial of peanut SLIT with a crossover design in which 40 subjects, adolescents and young adults, were enrolled after baseline OFC of up to 2 g of peanut powder [30]. Subjects were randomized 1:1 across 5 sites to receive either daily peanut or placebo SLIT. At 44 weeks, a 5 g OFC was performed, followed by unblinding of the protocol. Placebo-treated subjects were then crossed over to receive higher dose peanut SLIT, followed by a subsequent 5 g OFC after 44 weeks on SLIT. OFCs on 44 weeks of SLIT were compared to baseline OFCs from both groups and subjects were considered responders if they successfully consumed 5 g or at least 10-fold more peanut powder than at baseline. Fourteen (70%) active subjects were considered responders compared to 3 (15%) placebo subjects. In peanut SLIT responders, the median successfully consumed dose increased from 3.5 to 496 mg after 44 weeks on therapy. When challenged again after 68 weeks of SLIT, the median dose consumed again significantly increased to 996 mg. This study clearly showed that peanut SLIT can safely induce a desensitized state in a majority of subjects compared with placebo and that the length of therapy can significantly affect the amount of allergen consumed.

Combined SLIT/OIT

In the first study to compare SLIT with OIT, Keet el al. published the results of a randomized clinical trial of cow’s milk allergy in 30 children [29]. After entry DBPCFC, all subjects were treated with SLIT for 4 weeks. They were then randomized equally into 3 groups: (1) continued SLIT escalation to 7 mg daily, (2) cross over with OIT to 1000 mg (OITB), or (3) cross over with OIT to 2000 mg (OITA). Subjects were challenged with 8 g milk protein after 12 and 60 weeks of therapy. If they passed the 60-week challenge, therapy was stopped and challenges were repeated 1 and 6 weeks later to assess for tolerance.
After therapy, 1 (10%) in the SLIT group, 6 (60%) in the SLIT/OITB group and 8 (80%) in the SLIT/OITA group passed the 8 g OFC. However, the food challenge threshold increased in all subjects who completed the full maintenance period: 40-fold for SLIT/SLIT, 159-fold for SLIT/OITB and 54-fold for SLIT/OITA groups. After 1 week of avoidance, 2 subjects in the SLIT/OITB group reacted during challenge. After 6 weeks off therapy, an additional subject in the SLIT/OITB group and 3 subjects in the SLIT/OITA group failed the OFC. Therefore, this left 1 in the SLIT/SLIT and 8 in the combined SLIT/OIT groups who were considered tolerant.
Adverse reactions occurred more frequently with SLIT (29%) than OIT (23%) doses; however, while SLIT caused more mild symptoms such as oral pruritus, OIT doses caused more multisystem, gastrointestinal, upper and lower respiratory tract symptoms, as well as increased need for β-agonist and antihistamine treatment. Mechanistic studies revealed increased cow’s milk-specific IgG4 in all groups, but decreased specific-IgE and basophil histamine release only in the combined OIT subjects when compared to baseline. The study showed that OIT was more effective than SLIT alone in inducing desensitization to cow's milk, but not without more systemic side effects. While a handful of subjects achieved clinical tolerance after 1 and 6 weeks of avoidance, it is still unclear how long the clinical effects of immunotherapy lasts once exposure is stopped.

Food immunotherapy in clinical practice

Recent studies, including those mentioned above, show promising data for the use of immunotherapy in food allergic patients. However, therapies such as OIT and SLIT are not recommended for routine clinical practice and the current standard of care in the treatment of food allergies is allergen avoidance and ready access to self-injectable epinephrine [31]. Despite these recommendations, a recent article summarizes the results of a retrospective chart review of patients treated with peanut OIT in 5 different practices: 4 office-based practices in the United States and 1 hospital-based practice in Israel [32]. The authors report a total of 352 treated patients who received 240,351 doses of peanut, peanut butter, or peanut flour, and experienced 95 reactions that required epinephrine administration. The study cites a success rate of 85% based on the number of patients who achieved goal maintenance dose and a reaction rate of 0.7 per 1000 doses during escalation and 0.2 of 1000 doses during maintenance. It should be noted that the OIT methods used at each site were locally developed and had considerable variability, including maintenance doses ranging from 415 to 8000 mg, differences in selection criteria for enrolling patients, definition for mild reactions and criteria for administering epinephrine. Despite these differences, the authors conclude that peanut OIT may be a suitable therapy when managed by qualified allergists/immunologists.
However, several recent systematic reviews and meta-analyses do not support this notion and conclude that “there is insufficient evidence in terms of long-term effectiveness, safety, and cost-effectiveness of peanut OIT to recommend its routine use in clinical practice [33,34].” At this time, variations in immunotherapy protocols, such as study product used, starting and ending doses, study schedule, blinding, use of placebo, selection of study subjects and reporting of adverse reactions, make direct comparisons and evaluation of true efficacy and safety of OIT and SLIT difficult [35,36]. Experts in the field strongly recommend that these experimental therapies continue to be administered under the oversight of institutional review boards and the US Food and Drug Administration as food OIT remains in a state of equipoise [37].

Conclusions

Food allergy is an increasingly prevalent disorder in the United States and other Westernized countries with no definitive cure or approved treatment. Patients living with food allergies are at risk of accidental ingestions daily that can result in potentially life-threatening reactions. Over the past decade, there has been resurgence in interest and an increase number of clinical trials to evaluate immunotherapy options for food allergy, particularly OIT and SLIT. Several studies have demonstrated the ability of OIT and SLIT to induce desensitization, in which patients are able to tolerate the ingestion of more food allergen while on treatment, and immunologic changes with ongoing therapy. However, concerns and questions still remain regarding the allergic side effects and the development of immune tolerance with these therapies, the ultimate goal of allergen immunotherapy in which patients tolerate the ingestion of food off treatment. Further research is needed to address the safety and efficacy of OIT and SLIT for long-term use.

Abbreviations

IgE: Immunoglobulin E; OIT: Oral immunotherapy; SLIT: Sublingual immunotherapy; Tregs: Regulatory T cells; Th: T helper; IL: Interleukin; OFC: Oral food challenge; DBPCFC: Double-blind, placebo-controlled food challenge.

Competing interests

A. W. Burks has received research support from the NIH, the Wallace Research Foundation, and Hycor Biomedical; has board memberships with the Academy of Allergy, Asthma & Immunology, the Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section of the NIH, the Food and Drug Administration Food Advisory committee, the Food Allergy & Anaphylaxis Network Research Advisory Board, and the Merck US Allergy Immunotherapy Allergist Advisory Board; has consultant arrangements with Dow AgroSciences, McNeill Nutritionals, Merck, Novartis Pharma AG, Sanofi Aventis US, Schering Plough, Unilever, ExploraMed Development, GLG Research, and Regeneron Pharmaceuticals; is employed by UNC Children’s Hospital; has a pending grant from Food Allergy Research and Education; has received payment for lectures from Abbott Laboratories, Mylan Specialty, and the American College of Allergy, Asthma & Immunology; has various US patents related to peanut allergens and methods; has received payment for development of educational presentations 3 from CurrentViews 2012; and is a minority stockholder in Allertein and Mastcell Pharmaceuticals.

Authors’ contributions

UHL and AWB equally contributed to writing the manuscript. Both authors read and approved the final manuscript.

Acknowledgements

Support for the dissemination of the WAO Immunotherapy and Biologics Online Monograph is provided by the following sponsors: Circassia, Boehringer-Ingleheim, and ORA Inc.

References

  1. Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, Holl JL: The prevalence, severity, and distribution of childhood food allergy in the United States. 
    Pediatrics 2011,  128:e9-e17.  PubMed Abstract | Publisher Full Text OpenURL
  2. Boyce JA, Assa'ad A, Burks AW, Jones SM, Sampson HA, Wood RA, Plaut M, Cooper SF, Fenton MJ, Arshad SH, Bahna SL, Beck LA, Byrd-Bredbenner C, Camargo CA Jr, Eichenfield L, Furuta GT, Hanifin JM, Jones C, Kraft M, Levy BD, Lieberman P, Luccioli S, McCall KM, Schneider LC, Simon RA, Simons FE, Teach SJ, Yawn BP, Schwaninger JM: Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report. 
    J Allergy Clin Immunol 2010,  126:1105-1118.  PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
  3. Bock SA, Munoz-Furlong A, Sampson HA: Fatalities due to anaphylactic reactions to foods. 
    J Allergy Clin Immunol 2001,  107:191-193.  PubMed Abstract | Publisher Full Text OpenURL
  4. Bock SA, Munoz-Furlong A, Sampson HA: Further fatalities caused by anaphylactic reactions to food, 2001-2006. 
    J Allergy Clin Immunol 2007,  119:1016-1018.  PubMed Abstract | Publisher Full Text OpenURL
  5. Branum AM, Lukacs SL: Food allergy among children in the United States. 
    Pediatrics 2009,  124:1549-1555.  PubMed Abstract | Publisher Full Text OpenURL
  6. Sicherer SH, Munoz-Furlong A, Godbold JH, Sampson HA: US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. 
    J Allergy Clin Immunol 2010,  125:1322-1326.  PubMed Abstract | Publisher Full Text OpenURL
  7. Nowak-Wegrzyn A, Sampson HA: Future therapies for food allergies. 
    J Allergy Clin Immunol 2011,  127:558-573. 
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  8. Yu JW, Kagan R, Verreault N, Nicolas N, Joseph L, St Pierre Y, Clarke A: Accidental ingestions in children with peanut allergy. 
    J Allergy Clin Immunol 2006,  118:466-472.  PubMed Abstract | Publisher Full Text OpenURL
  9. Akeson N, Worth A, Sheikh A: The psychosocial impact of anaphylaxis on young people and their parents. 
    Clin Exp Allergy 2007,  37:1213-1220.  PubMed Abstract | Publisher Full Text OpenURL
  10. Sicherer SH, Noone SA, Munoz-Furlong A: The impact of childhood food allergy on quality of life. 
    Ann Allergy Asthma Immunol 2001,  87:461-464.  PubMed Abstract | Publisher Full Text OpenURL
  11. Chehade M, Mayer L: Oral tolerance and its relation to food hypersensitivities. 
    J Allergy Clin Immunol 2005,  115:3-12. 
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  12. Burks AW, Laubach S, Jones SM: Oral tolerance, food allergy, and immunotherapy: implications for future treatment. 
    J Allergy Clin Immunol 2008,  121:1344-1350.  PubMed Abstract | Publisher Full Text OpenURL
  13. Burks AW: Peanut allergy. 
    Lancet 2008,  371:1538-1546.  PubMed Abstract | Publisher Full Text OpenURL
  14. Jones SM, Burks AW, Dupont C: State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous. 
    J Allergy Clin Immunol 2014,  133:318-323.  PubMed Abstract | Publisher Full Text OpenURL
  15. Burks AW, Jones SM, Wood RA, Fleischer DM, Sicherer SH, Lindblad RW, Stablein D, Henning AK, Vickery BP, Liu AH, Scurlock AM, Shreffler WG, Plaut M, Sampson HA, Consortium of Food Allergy R: Oral immunotherapy for treatment of egg allergy in children. 
    N Engl J Med 2012,  367:233-243.  PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
  16. Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, Hiegel A, Kamilaris J, Carlisle S, Yue X, Kulis M, Pons L, Vickery B, Burks AW: A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. 
    J Allergy Clin Immunol 2011,  127:654-660.  PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
  17. Vickery BP, Scurlock AM, Kulis M, Steele PH, Kamilaris J, Berglund JP, Burk C, Hiegel A, Carlisle S, Christie L, Perry TT, Pesek RD, Sheikh S, Virkud Y, Smith PB, Shamji MH, Durham SR, Jones SM, Burks AW: Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. 
    J Allergy Clin Immunol 2014,  133:468-475. 
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  18. Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, Shreffler WG, Steele P, Henry KA, Adair M, Francis JM, Durham S, Vickery BP, Zhong X, Burks AW: Clinical efficacy and immune regulation with peanut oral immunotherapy. 
    J Allergy Clin Immunol 2009,  124:292-300. 
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  19. Sheikh SZ, Burks AW: Recent advances in the diagnosis and therapy of peanut allergy. 
    Expert Rev Clin Immunol 2013,  9:551-560.  PubMed Abstract | Publisher Full Text OpenURL
  20. Mousallem T, Burks AW: Immunology in the Clinic Review Series; focus on allergies: immunotherapy for food allergy. 
    Clin Exp Immunol 2012,  167:26-31.  PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
  21. Di Rienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati F, Sensi L, Canonica GW, Passalacqua G: Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. 
    Clin Exp Allergy 2003,  33:206-210.  PubMed Abstract | Publisher Full Text OpenURL
  22. Vourdas D, Syrigou E, Potamianou P, Carat F, Batard T, Andre C, Papageorgiou PS: Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization. 
    Allergy 1998,  53:662-672.  PubMed Abstract |  Publisher Full Text OpenURL
  23. Mempel M, Rakoski J, Ring J, Ollert M: Severe anaphylaxis to kiwi fruit: immunologic changes related to successful sublingual allergen immunotherapy. 
    J Allergy Clin Immunol 2003,  111:1406-1409.  PubMed Abstract | Publisher Full Text OpenURL
  24. Enrique E, Malek T, Pineda F, Palacios R, Bartra J, Tella R, Basagana M, Alonso R, Cistero-Bahima A: Sublingual immunotherapy for hazelnut food allergy: a follow-up study. 
    Ann Allergy Asthma Immunol 2008,  100:283-284.  OpenURL
  25. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R, Castello JV, Alonso R, de Mateo JA, Cerda-Trias T, San Miguel-Moncin Mdel M, Monzon S, Garcia M, Palacios R, Cistero-Bahima A: Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. 
    J Allergy Clin Immunol 2005,  116:1073-1079.  PubMed Abstract | Publisher Full Text OpenURL
  26. de Boissieu D, Dupont C: Sublingual immunotherapy for cow’s milk protein allergy: a preliminary report. 
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  27. Fernandez-Rivas M, Garrido Fernandez S, Nadal JA, de Durana MD D, Garcia BE, Gonzalez-Mancebo E, Martin S, Barber D, Rico P, Tabar AI: Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract. 
    Allergy 2009,  64:876-883.  PubMed Abstract | Publisher Full Text OpenURL
  28. Chin SJ, Vickery BP, Kulis MD, Kim EH, Varshney P, Steele P, Kamilaris J, Hiegel AM, Carlisle SK, Smith PB, Scurlock AM, Jones SM, Burks AW: Sublingual versus oral immunotherapy for peanut-allergic children: a retrospective comparison. 
    J Allergy Clin Immunol 2013,  132:476-478. 
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  29. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, Schroeder JT, Hamilton RG, Boden S, Steele P, Driggers S, Burks AW, Wood RA: The safety and efficacy of sublingual and oral immunotherapy for milk allergy. 
    J Allergy Clin Immunol 2012,  129:448-455. 
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  30. Fleischer DM, Burks AW, Vickery BP, Scurlock AM, Wood RA, Jones SM, Sicherer SH, Liu AH, Stablein D, Henning AK, Mayer L, Lindblad R, Plaut M, Sampson HA, Consortium of Food Allergy R: Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. 
    J Allergy Clin Immunol 2013,  131:119-127. 
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  31. Sampson HA: Peanut oral immunotherapy: is it ready for clinical practice? 
    J Allergy Clin Immunol Pract 2013,  1:15-21.  PubMed Abstract | Publisher Full Text OpenURL
  32. Wasserman RL, Factor JM, Baker JW, Mansfield LE, Katz Y, Hague AR, Paul MM, Sugerman RW, Lee JO, Lester MR, Mendelson LM, Nacshon L, Levy MB, Goldberg MR, Elizur A: Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions. 
    J Allergy Clin Immunol Pract 2014,  2:91-96. 
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  33. Nurmatov U, Venderbosch I, Devereux G, Simons FE, Sheikh A: Allergen-specific oral immunotherapy for peanut allergy. 
    Cochrane Database Syst Rev 2012,  9:Cd009014.  PubMed Abstract | Publisher Full Text OpenURL
  34. Sheikh A, Nurmatov U, Venderbosch I, Bischoff E: Oral immunotherapy for the treatment of peanut allergy: systematic review of six case series studies. 
    Prim Care Respir J 2012,  21:41-49.  PubMed Abstract | Publisher Full Text OpenURL
  35. Wang J, Sampson HA: Oral and sublingual immunotherapy for food allergy. 
    Asian Pac J Allergy Immunol 2013,  31:198-209.  PubMed Abstract | Publisher Full Text OpenURL
  36. Narisety SD, Keet CA: Sublingual vs oral immunotherapy for food allergy: identifying the right approach. 
    Drugs 2012,  72:1977-1989.  PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL
  37. Wood RA, Sampson HA: Oral immunotherapy for the treatment of peanut allergy: is it ready for prime time? 
    J Allergy Clin Immunol Pract 2014,  2:97-98.  PubMed Abstract | Publisher Full Text OpenURL