Food allergy is increasing in prevalence; as a result, there is intense focus on developing safe and effective therapies. Current methods of specific immunotherapy include oral, sublingual, and epicutaneous, while nonspecific methods that have been investigated include: Chinese herbal medicine, probiotics, and anti-IgE antibodies. Although some studies have demonstrated efficacy in inducing desensitization, questions regarding safety and the potential for achieving immune tolerance remain. Although some of these therapies demonstrate promise, further investigation is required before their incorporation into routine clinical practice.
Key points
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The standard of care for the management of food allergies is education, avoidance of trigger foods, and treatment of allergic reactions due to accidental ingestion.
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Oral, sublingual, and epicutaneous immunotherapy are all investigational treatment modalities primarily performed in research settings.
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Evidence from clinical trials suggests that oral immunotherapy and possibly sublingual immunotherapy can effectively desensitize many subjects to trigger foods. A subset of desensitized subjects may achieve sustained unresponsiveness after withdrawal of therapy.
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Nonspecific immunotherapy and other emerging therapies using modified food antigens may also be options for treatment, but they are currently limited to early clinical or preclinical trials.
Introduction
The increase in food allergy in the United States and throughout the world is a growing public health concern. From 1997 to 2007, the prevalence of food allergy in children increased by 18%. An estimated 15 million Americans have a food allergy, accounting for approximately 8% of children and 5% of adults. Although most reactions from accidental ingestions are typically mild and self-limited, severe cases of anaphylaxis are associated with peanut, tree nuts, and shellfish and have resulted in fatalities. Appropriately, there has been an increase in research for food allergy treatments. Current guidelines for food allergy management include education, strict avoidance, nutritional monitoring, appropriate treatment of anaphylaxis with injectable epinephrine, and regular follow-up with an allergy specialist. In this review, the authors seek to update the previous article on food allergy therapy from this series, highlighting key clinical trials and emerging approaches for the treatment of food allergies.
Introduction
The increase in food allergy in the United States and throughout the world is a growing public health concern. From 1997 to 2007, the prevalence of food allergy in children increased by 18%. An estimated 15 million Americans have a food allergy, accounting for approximately 8% of children and 5% of adults. Although most reactions from accidental ingestions are typically mild and self-limited, severe cases of anaphylaxis are associated with peanut, tree nuts, and shellfish and have resulted in fatalities. Appropriately, there has been an increase in research for food allergy treatments. Current guidelines for food allergy management include education, strict avoidance, nutritional monitoring, appropriate treatment of anaphylaxis with injectable epinephrine, and regular follow-up with an allergy specialist. In this review, the authors seek to update the previous article on food allergy therapy from this series, highlighting key clinical trials and emerging approaches for the treatment of food allergies.
Standard of care
At present, there is no cure for food allergy. Diagnosis and management are focused on identification of triggers and targeted dietary elimination. Patients are encouraged to read ingredient labels, avoid cross-contamination, and consult with a nutritionist to ensure adequate growth. They are taught to recognize anaphylaxis and administer injectable epinephrine. In principle, strict dietary elimination should protect an individual from immunoglobulin (Ig) E–mediated reactions; however, in practice, patients with food allergies experience multiple exposures following diagnosis from both accidental and nonaccidental ingestions. Constant vigilance and perpetual risk produce significant anxiety. Quality-of-life surveys among children with food allergies and their parents suggest this anxiety leads to restriction of daily activities. Avoidance measures can also result in nutritional deficits and growth impairment.
Immunotherapy background
Oral immunotherapy (OIT) is not conceptually new, as instructions for treatment of egg sensitivity with egg white are recorded in the Babylonian Talmud. There are reports of physicians attempting food desensitization published as early as 1905 with varied success ( Table 1 ). Investigators demonstrated that patients were able to tolerate foods after a period of gradual incremental exposure, usually occurring over a period of months to years. Clinical texts through the mid-twentieth century reference hyposensitization to foods as a treatment for food allergy, although its effectiveness remained in question. In the 1980s, European investigators renewed interest in OIT after publishing positive results from small case series. These early reports and studies paved the way for more systematic investigation of immunotherapy as an active treatment for food allergy. An understanding of the pathogenesis of IgE-mediated disease and mechanisms of desensitization has elucidated pathways for targeted approach. Interestingly, many questions raised by early investigators continue to elude researchers today ( Box 1 ).
| Year | Summary of Key Findings |
|---|---|
| 1905 | Finkelstein conceptualizes OIT. He successfully desensitizes nurslings with “milk idiosyncrasy” by gradually administering increasing drops of milk. |
| 1908 | Schofield treats a 13-year-old patient with egg allergy over an 8-mo period by incrementally increasing small amounts of raw egg disguised in pill form. |
| 1912 | Schloss describes a patient with allergies to egg, oat, and almond, which he orally desensitizes to egg. Sensitivity to almond and oat also decreases during this treatment. He uses skin testing to guide up-dosing during therapy. |
| 1920 | Schloss reports 5 patients with egg allergy treated with subcutaneous injection of ovomucoid. He also describes 12 children with food allergies successfully desensitized using OIT. |
| 1920 | Park describes oral desensitization of a child with hypersensitiveness to cow’s milk. Pallor and drowsiness were noted during build-up phase. |
| 1926 | Stuart and Farnham advise treatment of food allergies by the oral method at an early age. In cases of milk or egg sensitization, their recommendation is enthusiastic because treatments are “simple and regularly successful.” |
| 1930 | Freeman performs rush inoculation over 8 d with cod fish juices in a 7-y-old boy with fish sensitivity. The patient is subsequently started on a fish diet and prescribed an ounce of cod-liver oil daily. A concurrent egg allergy resolves with this therapy. |
| 1935 | Keston, Waters, and Hopkins report effectively desensitizing 50 cases of food allergy to milk, wheat, egg, orange, tomato, or cocoa and publish oral desensitization protocols to each of these foods. |
| 1940 | Edwards describes successful oral desensitization of 11 of 12 patients with milk allergy using protocols published by Keston et al. |
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Can true immune tolerance be achieved through food desensitization?
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What is the preferred route for antigen administration?
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Do clinical outcomes improve if immunotherapy is started earlier in life?
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How long must therapy continue in order to achieve a permanent effect?
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What differences exist between children who naturally outgrow food sensitivity and those who are desensitized?
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Does immunotherapy hasten the development of immunologic tolerance in children who will ultimately outgrow a food allergy?
In an effort to answer these questions, researchers are now performing clinical trials in humans, predominantly with OIT, sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT). It is important to note that these 3 most commonly considered methods of immunotherapy are allergen-specific, meaning that the therapy is only effective for the particular food given. Nonspecific therapies such as monoclonal antibodies to IgE have also been used to alter host immune responses. Second-generation OIT trials are beginning to use specific and nonspecific approaches in tandem to increase safety and efficacy.
Immunotherapy mechanisms
Immunotherapy is based on the principle that incremental exposure to a given antigen can render an individual temporarily less reactive to that antigen (eg, desensitization) and eventually result in longer-lasting changes. Although the exact mechanisms are unknown, some of the immunologic changes that occur have been elucidated ( Fig. 1 ). Early on, repeated administration of increasing immunotherapy doses suppressed basophil and mast cell reactivity. Interleukin-10 is produced, presumably by lymphocytes, which is thought to suppress allergic responses and drive production of IgG4 antibody. Initially, immunotherapy increased the production of antigen-specific IgA, IgG1, IgG4, and IgE, although IgE tends eventually to decline to below baseline values in response to therapy (around 12–18 months). Ultimately, these changes result in a decrease in tissue mast cells and eosinophils, accounting for clinical hyporesponsiveness to antigen exposure and diminished skin prick test reactivity.
Desensitization versus tolerance
Interpretation of food allergy literature requires understanding of an important distinction between the concepts of clinical desensitization and tolerance. Desensitization refers to a reversible state induced by short-term exposure to an allergen. Once administration of the allergen is discontinued, the previous level of clinical reactivity returns. An analogy would be the brief desensitization protocols widely used to manage patients with certain drug allergies. On the other hand, therapeutic tolerance would suggest that the immunotherapy treatment has induced disease-modifying changes that will persist even after the treatment is discontinued. Importantly, some individuals, regardless of treatment, will spontaneously develop immune tolerance and naturally outgrow their food sensitivity. Although eventual tolerance to milk and egg are relatively common, peanut, tree nut, and seafood allergies tend to persist over time.
Incomplete understanding of the immunologic changes induced by immunotherapy, and whether these changes truly reflect immune tolerance, has led to the emergence of the term sustained unresponsiveness (SU). SU refers to the ability to successfully consume the treated allergen during an oral food challenge (OFC) performed typically 1 to 4 weeks after stopping active treatment. Importantly, many of the studies addressed in this review have only measured desensitization as a primary outcome. Only a few trials have addressed whether OIT results in SU, and none have done so in a rigorous, placebo-controlled fashion.
Oral immunotherapy
Milk, egg, and peanut are the most studied foods in OIT trials. Most modern studies have been single-food OIT trials; as a result, these 3 major foods will be discussed separately. Overall, OIT trials have a dropout rate of 15% to 20%. Moreover, several studies have observed spontaneous resolution of food allergy among subjects receiving placebo. This finding is consistent with observational studies of the natural history of peanut allergy, for example, which have found spontaneous resolution in about 20% of individuals.
General conclusions regarding efficacy are difficult to draw from the current literature because success rates for OIT have been defined differently. Ideally, subjects completing a course of immunotherapy should be able to incorporate culprit foods into their diets, consuming them ad libitum without symptoms. However, most studies only approximate the inclusion of the culprit food ad libitum in subjects’ diets. Studies often define success in terms of reaching a target maintenance dose or passing an endpoint challenge; therefore, it is important to interpret results in the context of the selected outcome measures. Overall safety of immunotherapy is also somewhat variable among studies, with adverse events not always being categorized in the same way (eg, many exclude oral itching). The lack of natural history or control groups as comparisons in many studies has also limited the determination of safety. Safety and efficacy are discussed further with regards to specific studies.
In addition to significant heterogeneity and varied primary endpoints, published trials have other scientific shortcomings. Most clinical protocols incorporate a crossover design that allows subjects in the placebo group to be reassigned to the treatment arm after a desensitization challenge. Although this may facilitate subject recruitment and retention and satisfy ethical concerns associated with repeatedly challenging subjects treated with placebo, it does not allow for comparisons between subjects who successfully complete immunotherapy and those who might have developed natural tolerance. Table 2 provides a general overview of study design for OIT.
| Phase | Length | Description |
|---|---|---|
| Modified rush | 1 d | Minute quantities given and dose is escalated over a period of several hours (6–8 doses) |
| Build-up period | 6–9 mo | Daily doses taken at home with gradual increases performed under clinical observation every 1–2 wk |
| Maintenance | Months to years | Target dose of allergen consumed daily at home |
Despite the paucity of data supporting tolerance induction, some argue that OIT protects against accidental ingestions and improves quality of life, thus justifying its incorporation into clinical practice. It is clear from multiple studies that OIT increases reaction thresholds, but there are no good data to prove this protects from reactions due to accidental ingestions. OIT has also not been thoroughly studied in subjects who are the most sensitive. A history of severe anaphylaxis is often a criterion for exclusion, while these patients might benefit the most from food immunotherapy.
Milk
Cow’s milk (CM) is the most common food allergy in early childhood. It is also one of the most important foods to reintroduce into the diets of children with food allergies, because children who must avoid milk are at an increased risk for significantly decreased weight, height, and body mass index–for-age percentiles. A recent systematic review and meta-analysis examined 6 randomized, controlled trials conducted between 2007 and 2012. Pooled data demonstrated a 10-fold increased likelihood of achieving desensitization to CM in children undergoing CM OIT than in non-OIT-treated patients. Subjects with CM allergy who underwent milk OIT tended to tolerate more milk protein, although these data did not reach statistical significance. A wide range of children received treatment with epinephrine during OIT trials (6.7%–30.8% of children); however, most reactions were mild.
Maintenance of desensitization after CM OIT has been evaluated in 2 recent studies. A study published in 2013 evaluated 2 different CM maintenance regimens. Thirty-two children with milk allergy were randomized after successfully completing CM OIT and achieving desensitization, defined as consumption of 200 mL of CM. For 1 year, 16 patients continued daily maintenance ingestion of 150 to 200 mL of CM (group A), while the other 16 ingested the same amount twice weekly (group B). Both groups were also allowed to consume CM ad libitum. The primary outcome was maintenance of desensitization without symptoms on CM ingestion. Three subjects were lost to follow-up (1 in group A and 2 in group B). Adverse events were similar between groups, and none discontinued therapy due to adverse events or noncompliance. The authors concluded that twice-weekly ingestion of a maintenance dose seems to be equally effective at safely maintaining desensitization as the daily regimen, with 9 of 15 subjects in group A and 9 of 15 subjects in group B consuming CM without symptoms. It is important to note the absence of a placebo group or a group exclusively consuming CM ad libitum. Moreover, differences in the quantity of CM consumed ad libitum between groups were not assessed.
In contrast, a retrospective study examined 32 patients who had successfully completed CM OIT under 2 different protocols (16 from each), with follow-up ranging from 1.3 to 5.3 years. Twenty-two percent of subjects limited their consumption of CM due to symptoms, and only 31% of subjects tolerated full servings of CM with minimal or no symptoms. One subject required multiple doses of epinephrine for ongoing symptoms. Both studies provide important data that must be considered before starting OIT. Strict adherence to daily maintenance dosing may be difficult for children and families for a variety of reasons (eg, illness, travel, strenuous exercise, menses, food aversion). The same may be true for regular incorporation of trigger foods after OIT. It is also clear from these data that satisfactory long-term outcomes after CM immunotherapy appear to be dependent on ongoing exposure, which is difficult for some individuals. Importantly, some subjects who had been classified as protocol-defined successes in the trial seemed to have relapsed completely.
Egg
In 2012, a multicenter study by the Consortium for Food Allergy Research (CoFAR) randomized 55 subjects with egg allergy (placebo 15, treatment 40). After 22 months of OIT using a daily maintenance dose of 2 g of egg white powder, 30 subjects (75%) passed a desensitization challenge (10 g of egg powder). After 6 to 8 weeks off treatment, just 11 of 29 subjects tolerated this same amount of egg. Using intention-to-treat analysis, 28% had developed SU. This study revealed differences in rates of desensitization after OIT for 10 months (55% passed a 5-g challenge) and 22 months (75% passed a 10-g challenge), suggesting that continued allergen administration over a prolonged period might improve efficacy. None of the subjects in the placebo arm passed the challenge at 10 months. In a more recent, smaller open trial of egg OIT, Meglio and colleagues achieved desensitization rates of 80% (8/10, active treatment) versus 20% (2/10, placebo) after 6 to 9 months of OIT.
A 2014 Cochrane Review analyzed 4 randomized, controlled trials of egg OIT. Only the CoFAR trial mentioned earlier included a placebo arm, whereas the other 3 compared subjects on OIT versus standard avoidance diet. Of the 100 patients receiving OIT in the 4 studies, 69% experienced adverse events, with 5% requiring epinephrine. Overall, 44% could tolerate a partial serving of egg, while 39% could tolerate a whole egg. However, because of the small sample size, low quality of evidence, and methodological differences, the only conclusion that could be drawn was that desensitization seems to be possible in a large number of egg-allergic patients, but adverse events remain a significant concern.
Peanut
Although less common than milk and egg allergy, peanut allergy is less likely to resolve spontaneously; as a result, it may be easier to study the effects of treatment in peanut-allergic subjects. The only double-blind, placebo-controlled (DBPC) trial of OIT for peanut allergy was conducted in 2011 and assessed desensitization. Twenty-eight subjects (ages 1–16) were randomized to receive peanut OIT (n = 19) or placebo (n = 9). Three subjects (16%) in the OIT group discontinued treatment because of side effects, but all remaining participants tolerated a maintenance dose of 4000 mg of peanut protein and completed 12 months of therapy. Each of the treatment subjects passed an OFC with 5000 mg of peanut protein after 1 year of therapy, compared with 280 mg in the placebo group (range, 0–1900 mg; P <.001).
The first study to investigate SU to peanut was published in 2014. In this open, non-placebo-controlled trial of peanut OIT, 24 of 39 (61.5%) subjects completed therapy for up to 5 years. Of these 24, 12 (50% per protocol, and 31% by intention to treat) were able to consume 5000 mg of peanut protein and 8000 to 10,000 mg of peanut butter after stopping OIT for 4 weeks. Thus, 12 patients were considered to achieve SU. These patients were subsequently instructed to incorporate peanut into their diet ad libitum at least several days per week. Questionnaire follow-up completed by 87.5% of the SU patients revealed that none experienced any allergic reactions due to peanut exposure, with a median follow-up time of 40 months.
Another study in 2014 evaluated immunologic parameters and the possibility of SU to peanut after OIT or SLIT. Gorelik and colleagues found a greater effect for OIT than SLIT, but both demonstrated suppression of basophil activity and decreased Th2 responses to peanut. However, these changes were not preserved in some patients while on maintenance and waned in others after stopping immunotherapy. Despite the lack of a placebo group and its crossover design, the data strongly suggest that immunologic changes associated with SU may not be truly sustained in most patients.
The recent STOP II trial conducted in the United Kingdom was a 2-phase, randomized, controlled crossover trial of 99 children with peanut allergy (ages 7–16). During phase I, subjects were allocated to active treatment (n = 49) or elimination (n = 50). After an OFC at 6 months, placebo subjects were reallocated to the treatment arm for phase II. The primary outcome measure of the study was the proportion of subjects able to tolerate 1400 mg of peanut protein following 6 months of OIT with 800 mg of peanut protein daily. Despite the lower maximum daily dose than that used in other OIT trials, 62% (24/39) of the treatment group was able to tolerate 1400 mg of peanut protein (approximately 10 peanuts) and were considered to be desensitized, while none of the placebo group passed the OFC. By the end of phase II, however, 84% of the active group and 91% of the control group were able to tolerate the daily maintenance doses. The study did not have participants stop OIT and thus did not assess for SU. Adverse reactions were higher in the treatment group as expected, although they were mild, primarily consisting of oral pruritus and abdominal pain.
The findings described have led some clinicians to incorporate OIT into routine clinical practice. A retrospective chart review of peanut OIT used in clinical practice, not as research, following different protocols in multiple clinical sites was recently published. Results for 352 patients showed that 85% reached maintenance dosing, but actual dose and length of maintenance therapy differed by site. The authors argue that OIT is safe for use in clinical practice given the low rate of epinephrine administration (0.7 per 1000 escalation doses, 0.2 per 1000 maintenance doses). However, other adverse reactions were not reported, and there is no evidence that accidental exposures were reduced or any other benefits were achieved. In addition, other studies have reported significantly higher rates of allergic reactions among OIT participants compared with those avoiding the food. Quality-of-life changes with OIT have also not been significantly observed, despite the assumption of improved quality of life with OIT. The Food Allergy Quality of Life Questionnaire was used before and after egg OIT in 22 children and their parents. They found only minimal improvement in health-related quality of life as rated by the parents, whereas children reported a benefit in terms of dietary restriction, but a negative impact by allergic reactions due to OIT. More data conclusively demonstrating safety and efficacy are needed in order to justify routine clinical use of OIT outside of a research setting.
Extensively heated milk and egg as oral immunotherapy
Baking egg or milk proteins decreases their allergenicity, likely due to alteration of conformational epitopes. However, heating alone does not reduce the allergenicity of all proteins; in fact, with limited heat application, some foods can form neoepitopes, increasing their allergenicity. Baking food proteins with wheat may also confer a matrix effect in which the wheat-protein complex alters sequential IgE-binding epitopes that are unaffected by heat alone. This decreased allergenicity is sufficient for many patients to tolerate the trigger food on a regular basis. There is evidence to suggest that regular consumption of baked egg- and milk-containing products may help patients outgrow these allergies more quickly, although this evidence is weakened by the lack of an appropriate control group. Several studies have demonstrated that regular ingestion of baked egg or milk may hasten and increase rates of SU to nonbaked egg or milk when compared with strict avoidance. These studies have also shown that consumption of baked egg or milk decreases skin prick test size and increases IgG4. As seen in OIT, specific IgE increases initially and ultimately decreases with time. Although tolerance to baked goods may be associated with a milder clinical phenotype, these data suggest that introduction of baked allergens may actually alter the natural history of egg and milk allergies.
Introduction of baked egg or milk into the diets of allergic children should be performed cautiously. Although some studies suggest that some patients can perform these OFCs at home, passage rates range from 60% to 85%, and up to 20% of failures to baked egg require epinephrine. Ideally, patients should be evaluated by an allergist and undergo a medically supervised OFC before introducing baked allergens.
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