Abstract
Peanut allergy is a common problem and can be the cause of severe, life-threatening allergic reactions. It rarely resolves, with the majority of patients carrying the disease onto adulthood. Peanut allergy poses a significant burden on the quality of life of sufferers and their families, which results mainly from the fear of accidental peanut ingestion, but is also due to dietary and social restrictions. Current standard management involves avoidance, patient education and provision of emergency medication, for use in allergic reactions, when they occur. Efforts have been made to develop a vaccine for peanut allergy. Recent developments have also highlighted the use of immunotherapy, which has shown promise as an active form of treatment and may present a disease-modifying therapy for peanut allergy. So far, results, especially from oral immunotherapy studies, have shown good efficacy in achieving desensitization to peanut with a good safety profile. However, the capacity to induce long-term tolerance has not been demonstrated conclusively yet and larger, phase III studies are required to further investigate safety and efficacy of this intervention. Peanut immunotherapy is not currently recommended for routine clinical use or outside specialist allergy units.
Keywords
Introduction
Peanut allergy was once rare, but is now the leading cause of fatal food-allergic reactions [Bock et al. 2001]. The prevalence has doubled over the past two decades, mostly in the Western world, the disease currently affecting 1–2% of children [Pereira et al. 2005; Hourihane et al. 2007; Venter et al. 2010]. Strict peanut avoidance, emergency medication and education on how to promptly recognize and treat reactions, form the cornerstone of management for peanut allergy. Unfortunately, accidental reactions are common, as food labelling is often inadequate, peanuts can be hidden in a variety of foods or contaminate meals in restaurants [Schäppi et al. 2001; Vadas and Perelman, 2003; Turner et al. 2011]. Annual incidence rates for accidental reactions of 15–75% have been recorded in large studies. Ewan and Clark report a rate of 15% in a group of 567 patients with nut allergy referred to their allergy clinic and followed up annually [Ewan and Clark, 2001]. Sicherer and colleagues noted a rate of accidental reactions of 55% over 5 years in a cohort of 102 children with peanut allergy [Sicherer et al. 1998], whereas Bock and Atkins reported a much higher percentage of 75% over a period of 14 years [Bock and Atkins, 1989]. Individuals with peanut allergy experience low quality of life due to high levels of anxiety and increased awareness that their condition can be fatal; they also feel that they have less control over their disease compared with children with other chronic conditions, such as diabetes [Avery et al. 2003]. Parents of children with peanut allergy also present high levels of stress, stemming from their child’s perceived risk of death and constant dietary and social restrictions [Primeau et al. 2000].
Unlike other food allergies, which usually resolve in the majority of patients, only one in five children are expected to outgrow their peanut allergy, which is often a lifelong condition [Hourihane et al. 1998; Bock and Atkins, 1989; Skolnick et al. 2001; Ho et al. 2008]. A recent trial, aiming to prevent the development of peanut allergy in high-risk children, has shown benefit in introducing regular peanut consumption early in life, before the disease presents itself [Du Toit et al. 2015]. However, for children with established peanut allergy, there is a clear need for a disease-modifying treatment.
Studies on food immunotherapy for milk and egg have shown promise in desensitizing (raising the threshold of reactivity) children with allergy [Longo et al. 2008; Burks et al. 2012]. A recent systematic review on milk immunotherapy reported that oral immunotherapy (OIT), when compared with a milk elimination diet alone, increased the likelihood of achieving full tolerance (ability to consume milk despite prolonged periods of avoidance) to cow’s milk [Brożek et al. 2012]. However, both milk and egg allergies tend to self-resolve, so it can be difficult to assess the effect of immunotherapy versus natural allergy resolution.
Subcutaneous peanut immunotherapy was initially attempted, many years ago, in two separate studies that showed good efficacy [Oppenheimer et al. 1992; Nelson et al. 1997]. Unfortunately, the rate of systemic reactions was significantly high (13.3–39%), which made this form of treatment unacceptable for routine use in subjects with peanut allergy. Different routes of administration of peanut allergen were subsequently examined, in an effort to improve the safety profile of this intervention.
Lately, there has been a lot of interest in sublingual, epicutaneous, but mostly peanut OIT studies, as a novel form of active treatment for peanut allergy, with many researchers around the world leading phase I and II trials. A comprehensive review of this research is presented in this paper. Efforts to develop a peanut vaccine are also described below. (Table 1: summary of key studies on peanut immunotherapy).
Key studies of peanut immunotherapy.
Key studies on peanut immunotherapy are described, including the study reference (authors, journal and date of publication), the study design, the route of immunotherapy used and the top dose tolerated orally after immunotherapy treatment, the study protocol (rush, build up or maintenance), the relevant population (age range in brackets, shown in years), the duration of each study (in days, weeks or months) and the main results (success rate of desensitization and rate of systemic reactions).
IgE, immunoglobulin E; OIT, oral immunotherapy.
Development of a peanut vaccine
Wood and colleagues investigated the safety and immunological effects of a vaccine containing modified Ara h1, Ara h2 and Ara h3 (heat/phenol-killed, Escherichia coli-encapsulated, recombinant modified peanut proteins) in 5 healthy volunteers and 10 adults with peanut allergy. The proteins were designed with site-directed mutagenesis in order to reduce immunoglobulin E (IgE) binding, but retain T-cell receptor binding. The vaccine was administered rectally, following the hypothesis that the rich immunological environment of the lower colon would promote the development of tolerance. All healthy volunteers received 4-weekly escalating doses without suffering any adverse events. Subjects with peanut allergy received weekly dose escalations (from 10 to 3063 μg) followed by three bi-weekly doses of 3063 μg. Unfortunately, the administration of the vaccine in the subjects with peanut allergy resulted in frequent allergic reactions, with 20% experiencing anaphylaxis. The vaccine failed to induce tolerance to the dominant peanut proteins and 50% of participants were unable to complete the dosing regimen. No significant changes were detected in peanut-specific IgE and IgG4. Overall, the use of vaccine did not prove safe or efficacious for peanut allergy [Wood et al. 2013].
Sublingual immunotherapy
A double-blind placebo-controlled study of sublingual peanut immunotherapy enrolled 18 participants who underwent a 6-month period of dose escalation, followed by a 6-month period of maintenance therapy. Side effects mostly consisted of oropharyngeal symptoms and only 0.3% of doses required antihistamine treatment. Following a year of treatment, a double-blind placebo-controlled food challenge (DBPCFC) was used to assess the final outcome; this showed the treatment group safely ingesting 20 times more peanut protein than the placebo group (1710 mg versus 85 mg) [Kim et al. 2011].
A subsequent multicentre, randomized controlled trial (RCT) of peanut sublingual immunotherapy (SLIT) demonstrated a modest effect in desensitization to peanut. After 44 weeks of treatment, clinical desensitization was observed in 70% of the active versus 15% of the placebo subjects. For the active group, the median successfully consumed dose increased form 3.5 mg at baseline to 496 mg peanut flour (approximately 50% peanut protein) after a year of therapy. Unfortunately, none of the participants were able to pass a 5 g peanut challenge (the study’s primary outcome). The safety profile was very good with 59.9% of doses in the active group being symptom free, and once oropharyngeal symptoms were excluded, the percentage rose to 94.7% of symptom-free doses [Fleischer et al. 2014].
Although SLIT appears to have a favourable safety profile, the effect of desensitization is modest compared with other routes of administration (especially OIT). The allergen doses used in SLIT are much lower, due to practical limitations and this limits its efficacy. In order to determine whether this is a clinically useful intervention for peanut allergic patients, more research is required.
Epicutaneous immunotherapy
The epicutaneous route of immunotherapy is currently under investigation in an effort to optimize allergen administration for food immunotherapy and, at the same time, minimize the frequency and severity of immunotherapy-induced side effects. Epicutaneous administration of the allergen has the advantage of avoiding highly vascularized sites, which are associated with systemic side effects. However, it is able to target professional allergen-presenting cells (such as Langerhans cells of the epidermis) that are necessary for optimal allergen presentation [Senti et al. 2014]. A pilot study testing clinical efficacy and safety of epicutaneous immunotherapy in children with cow’s milk allergy showed a tendency towards a higher threshold dose after a 3-month treatment period. Although the results were not statistically significant, the intervention was well tolerated with no observed systemic reactions [Dupont et al. 2010]. Phase I and II epicutaneous immunotherapy trials are currently underway for peanut allergy [Senti et al. 2014].
Oral immunotherapy
Phase I trials of peanut OIT tentatively investigated the feasibility and acceptability of this novel intervention for peanut allergy, showing some promising initial results [Jones et al. 2009; Blumchen et al. 2010; Anagnostou et al. 2011]. These small studies paved the way for further, phase II, randomized trials of peanut OIT.
A RCT of peanut OIT was undertaken in the USA, including 19 children who completed a year of OIT (initial escalation phase, home dosing, build up visits and maintenance phase) and 9 placebo subjects. Participants were aged between 1 and 16 years. The investigators reported that 84% of the active subjects passed a final challenge of 20 peanuts, successfully ingesting 5 g of peanut protein compared with only one peanut or 280 mg of peanut protein (median value) ingested by the placebo subjects. The authors concluded that the degree of protection following successful immunotherapy was likely to prevent accidental peanut anaphylaxis. The study regimen was well tolerated with clinically relevant symptoms seen after only 1.2% of build up doses and no peanut OIT subject requiring adrenaline administration [Varshney et al. 2011].
The largest phase II, randomized, controlled, crossover trial of peanut OIT was published in The Lancet, investigating the role of peanut OIT in desensitizing 99 children, aged 7–16 years, inclusive of all severities of peanut allergy. There was an initial gradual up dosing phase with 2-weekly increments up to a top dose of 800 mg/day, followed by a maintenance period of daily doses for a total of 26 weeks of OIT. Following completion of the intervention, in the active group, 84% were desensitized to 800 mg (approximately five peanuts), whereas 24 of 39 (62%) OIT participants were successfully desensitized to 1400 mg of peanut protein (approximately 10 peanuts). Subjects who successfully completed the study protocol had a significant 25-fold increase of their peanut threshold, the treatment therefore allowing them to eat large quantities of peanuts, well above the levels present in contaminated snacks and meals. Quality of life was measured with a validated quality of life questionnaire. Both participants who were successfully desensitized, and their caregivers, had a significant improvement in quality of life. Adverse effects, seen in most participants, were mild and easily treatable. Oral itching was the most common side effect, occurring after 6.3% of all doses. Adrenaline was administered to one subject with prompt resolution of symptoms. Factors associated with successful desensitization included lower levels of peanut-specific IgE at baseline, younger age and absence of a family history of peanut allergy [Anagnostou et al. 2014].
Overall, it is clear from the above studies that peanut OIT presents an interesting and promising novel form of intervention for children with peanut allergy, resulting in good efficacy for desensitization. The safety profile is also good with most subjects experiencing mild or moderate reactions during treatment.
Some concerns have been raised regarding the onset of eosinophilic eosophagitis (EoE) after OIT. A recent meta-analysis has shown that up to 2.7% of patients with IgE-mediated food allergies undergoing food OIT could develop this complication, with EoE often resolving following discontinuation of OIT treatment. However, the available data are limited, often of low quality and a causal relationship between food OIT and EoE remains controversial [Lucendo et al. 2014].
OIT with multiple allergens/nuts
Approximately 30–40% of patients with peanut allergy are also allergic to other foods, such as tree nuts. Unfortunately, OIT to more than one food allergen can be time consuming and expensive, if the allergens are to be administered one at a time.
A recent phase I study investigated the simultaneous administration of multiple food allergens (peanut + tree nuts/milk/egg/sesame) compared with administration of a single allergen (peanut) in the form of OIT. Forty participants (4–46 years) were enrolled in the study, 15 were monoallergic to peanut, whereas 25 had additional food allergies. The OIT protocol for both groups consisted of an initial escalation phase, a biweekly dose-escalation phase and a maintenance phase (top dose 4 g of protein for each allergen). The primary aim was to achieve a 10-fold increase from the initial challenge threshold. This goal was achieved by the majority of study participants. Most reactions to multiple food OIT were mild, with abdominal pain most frequently reported. There was no statistical difference in adverse event rate or severity when comparing single with multi-OIT regimens. Two severe reactions requiring epinephrine occurred in each group. The researchers concluded that participants allergic to multiple foods can be safely desensitized to up to five foods simultaneously. This approach has the potential to minimize the number of hospital patient visits and the overall cost of treatment [Bégin et al. 2014b].
Use of immune modulators in peanut OIT
The use of a bacterial adjuvant in combination with OIT was recently suggested as a potential treatment for peanut allergy. Tang and colleagues performed a double-blind, placebo-controlled randomized trial of the probiotic Lactobacillus rhamnosus and peanut OIT in 62 children with peanut allergy. This combination of treatment was effective in inducing desensitization in the majority (89.7%) of the active subjects and possible sustained unresponsiveness was also seen in 82.1% of the same group. The authors concluded that the coadministration of a probiotic and peanut OIT may offer a novel approach to induce possible sustained unresponsiveness in children with peanut allergy [Tang et al. 2015].
A recent pilot study examined the use of anti-IgE (omalizumab) as an adjuvant in peanut OIT, with the aim of reducing the number of adverse reactions and minimizing in-hospital time and number of visits for participants. Thirteen children with peanut allergy with high peanut-specific IgE (median 229 kUA/liter) were pretreated with omalizumab, all of whom tolerated the initial rush desensitization phase (first day) with minimal or no rescue therapy. As soon as the maximum maintenance dose was reached (2 g peanut protein, successfully reached by 12/13 subjects) omalizumab was discontinued, but participants continued receiving peanut OIT for a further 12 weeks. A DBPCFC at the end of the 12 weeks showed all subjects tolerating 4 g of peanut protein (8 g peanut flour). During the study, six subjects experienced mild or no allergic reactions, five subjects had moderate reactions and two subjects had severe reactions. It appears that omalizumab may facilitate rapid oral desensitization in patients with peanut allergy and high peanut-specific IgE levels at baseline, but reactions recur once it is discontinued [Schneider et al. 2013].
Omalizumab was also evaluated in oral OIT with multiple food allergens. Twenty-five participants (median age 7 years) were enrolled in a phase I trial, following positive inital DBPCFCs to a maximum number of five foods (including peanut). Omalizumab was administered for 8 weeks prior to and 8 weeks following the initiation of the study’s rush OIT schedule. After pretreatment with omalizumab, 19/25 participants tolerated the escalation day with minimal or no rescue therapy. The majority of reactions experienced by subjects were mild. Only one severe reaction was reported, which was treated successfully with adrenaline. Interestingly, participants were able to reach the top maintenance dose (4 g) for each allergen at a median time of just 18 weeks. In a previous study, without administration of omalizumab, participants required a median of 85 weeks to reach the same top dose, for up to five foods administered simultaneously with oral OIT [Bégin et al. 2014a].
The use of anti-IgE has limitations in clinical practice, as it can be expensive as a form of long-term treatment. Currently, it is not known for how long anti-IgE needs to be administered in order to obtain a long-lasting effect of desensitization to peanut.
Although promising, these initial findings will require further study in order to ascertain the role of anti-IgE and probiotics in combination with peanut immunotherapy.
Long-term tolerance versus transient desensitization
The acquisition of long-term tolerance (where participants are able to consume peanut ad lib, without any need for ongoing therapy) versus transient desensitization (an increase in the threshold of reactivity to peanut that requires regular consumption in order to be maintained) following the administration of OIT, is still unknown and under investigation. This is clearly an issue of great importance to patients with peanut allergy and their families and a few studies have been published so far addressing this question.
Blumchen and colleagues enrolled 23 children with confirmed peanut allergy to undergo a rush protocol of OIT for 7 days. The participants subsequently continued with a long-term build up protocol and once this was achieved, they took a daily maintenance dose of peanut protein for 2 months, before finally stopping OIT completely for 2 weeks. The peanut challenge was repeated at the end of this 2-week avoidance period and it was shown that 57% of subjects maintained their clinical tolerance, despite having avoided the allergen for 14 days [Blumchen et al. 2010].
A two-centre US study included 24 children who received peanut OIT for a total of 5 years, and subsequently discontinued OIT for 1 month. Following these 4 weeks of complete avoidance, participants were challenged to 5 g of peanut protein. Half of the subjects (50%) were able to pass this high-dose challenge to peanut without reactions. For those who failed the challenge, the eliciting symptom dose (median: 3750 mg) was noted to be much higher than their baseline threshold to peanut (median: 50 mg) [Vickery et al. 2014].
Syed and colleagues studied 23 participants who underwent peanut OIT for 24 months. Discontinuation of treatment for 3 months resulted in 13 subjects losing their clinical tolerance to peanut. After a further 3 months off therapy, a further four participants regained their sensitivity to peanut [Syed et al. 2014].
Until now, studies have demonstrated successful long-term tolerance to peanut after completion of OIT, in a variable proportion of subjects. The effect is much smaller compared with successful desensitization (which is usually achieved by the majority). Research trials have used different protocols and different periods of peanut OIT discontinuation. However, it is important that this issue is systematically addressed with well designed and much larger studies.
Suggested mechanisms of OIT
The mechanisms underlying successful immunotherapy and induction of long-term tolerance are still under investigation. Allergen-specific immunotherapy has been associated with a decrease in the number of mast cells and basophils (early desensitization effect) as well as a decrease in degranulation and mediator release from the above cells. It also induces a major change in allergen-specific T cells with a decrease in the proportion of interleukin-4 (IL-4)-secreting T helper 2 (Th2) cells and a concomitant increase in IL-10-producing T-regulatory cells [Cavkaytar et al. 2014].
Peanut OIT studies have shown downregulation of the allergen-specific Th2 response, upregulation of the Th1 response and induction of regulatory T cells, following use of immunotherapy. In particular, successful peanut immunotherapy has resulted in a peanut-specific IgE decrease, peanut skin prick test decrease, peanut IgG and IgG4 increase, as well as decreased IL-4, IL-5 and IL-13 and increased IL-10 and transforming growth factor β cytokine production [Jones et al. 2009; Varshney et al. 2009; Blumchen et al. 2010; Kim et al. 2011]. Microarray data have demonstrated downregulation of genes in several apoptosis pathways in patient T cells, although it is not clear whether these changes included apoptosis of antigen-specific cells as well as total peripheral blood T cells [Jones et al. 2009]. Clinical immune tolerance has been associated with demethylation of forkhead box protein 3 (FOXP3) CpG sites in antigen-induced regulatory T cells [Syed et al. 2014].
A recent study has shown that spontaneous and allergen-induced basophil reactivity was suppressed during dose escalation and after 6 months of maintenance dosing in children undergoing OIT. Dendritic cell-driven Th2 cytokine responses to peanut were also suppressed. However, in many patients, immunological suppression reversed after withdrawal from immunotherapy and in some cases even during maintenance treatment, suggesting that these changes are transient [Gorelik et al. 2014].
Generally, most of these immunological changes are similar to those seen in patients receiving immunotherapy for environmental allergens, however more research is needed in the area of food immunotherapy to clearly identify the underlying mechanisms of desensitization and long-term tolerance.
Is peanut OIT ready for clinical practice?
There has been a lot of discussion among allergists on whether peanut OIT is ready for clinical practice [Allen and O’Hehir, 2011; Sampson, 2013; Wood and Sampson, 2014]. The reality of life for children with peanut allergy is that there is not much difference is school and social settings between those patients who are at high risk of anaphylaxis and those who have had previous minimal reactions. This reflects a lack of competency in making accurate risk assessments, and as a consequence all children with peanut allergy are subject to the same restrictions and isolation. Peanut OIT is already been offered as a clinical treatment in some parts of the world.
Wasserman and colleagues describe their experience of treating over 300 patients with peanut OIT, in both the private and hospital sector. Although there was a wide variation in the protocols used, it is reported that 85% of patients managed to reach the target maintenance dose. Adverse reactions occurred in 11.9% of patients but only one-fifth of these required adrenaline administration. The investigators reported 0.7 of 1000 doses during dose escalation and 0.2 of 1000 doses during maintenance, needing treatment with adrenaline [Wasserman et al. 2014].
Greenhawt and colleagues recently published the results of an online survey of members of the American Academy of Allergy Asthma and Immunology aiming to understand the current practices of allergists who perform OIT. A total of 442 clinicians responded to the survey, with a minority (13.8%) providing OIT as a service or studying OIT under a research protocol. Some important differences in the practice of OIT between academic and nonacademic providers were highlighted, with academics obtaining institutional review board and Investigational New Drug approval more often than nonacademic clinicians. For those allergists who were not offering OIT, there was a strong desire for US Food and Drug Administration approval, a standardized product for use in OIT and additional data on safety and long-term tolerance induction, prior to undertaking OIT [Greenhawt and Vickery, 2015].
There have been two meta-analyses published so far on peanut OIT. The first included six studies with just over 100 subjects with peanut allergy, treated with a variety of OIT regimes. The rate of adverse reactions was 2–25% and side effects were mostly mild. The authors concluded that although OIT for peanut allergy appeared effective for desensitization, long-term effects required further study. They recommended that peanut OIT should be limited to clinical trial settings [Jones et al. 2009]. A Cochrane systematic review followed, which examined the effectiveness and safety of OIT in patients with IgE-mediated peanut allergy. The reviewers identified only a small RCT that fit their specified inclusion criteria. They concluded that peanut OIT represents a promising therapeutic approach for the management of peanut allergy. However, the evidence was not sufficient to draw conclusions regarding long-term effectiveness, safety and cost effectiveness of this intervention and it was not recommended for use in clinical practice [Nurmatov et al. 2012]. A more updated systematic review is awaited, since many more studies on peanut OIT have been published over the last 2–3 years.
Generally, translating research findings into clinical practice involves various challenges, including a cost/benefit assessment, for both patients and the National Health System. A close collaboration between academics and clinicians is essential in order to bring novel research from ‘the bench to the bedside’.
Conclusion
Overall, published studies on peanut OIT have reported good results regarding its efficacy in desensitizing patients with peanut allergy and an acceptable safety profile. The majority of subjects are able to achieve the top target dose and most reactions occurring during treatment are mild to moderate. Sublingual immunotherapy appears less effective, although its safety profile is excellent. There are not enough data available on epicutaneous immunotherapy yet.
Current protocols have used different dosing schedules and varying durations of treatment; patient selection also varied between studies. It is not yet known which would be the optimal escalation and maintenance dose and duration, nor how severity of the disease may affect individual patient results.
It is still unclear what the long-term effects of this intervention are and for how long the treatment should be continued. Cessation of maintenance dosing and its effect on previously treated patients, as well as long-term tolerance, constitute important issues that have not been fully addressed yet. In addition, OIT protocols are labour intensive, require dedicated personnel and there are risks involved. The question of whether peanut immunotherapy is better than peanut avoidance is still controversial and the health economics of this novel treatment are also largely unknown.
In summary, peanut immunotherapy presents an exciting, potentially disease-modifying treatment approach for peanut allergy, but is not yet recommended for routine clinical use.
Footnotes
Conflict of interest statement
The author declares no conflicts of interest in preparing this article.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.