Edwin H. Kim

Sublingual versus oral immunotherapy for peanut-allergic children: A retrospective comparison

To the Editor: There has been considerable recent interest in developing therapies for food allergy, an increasingly common and highly morbid disorder for which strict dietary elimination and ready access to epinephrine remain the standard of care.(1) While both oral immunotherapy (OIT)(2-4) and sublingual immunotherapy (SLIT)(5) have been shown to induce clinical desensitization to foods (reviewed in 6), no head-to-head comparative analysis of the two treatments has been published. We conducted a retrospective study of two previously published protocols for peanut allergy(2,3). This new analysis includes additional subjects, compares the 12-month oral food challenge outcomes, and extends analysis of immunologic parameters out to 24 months. Eligible peanut-allergic subjects were recruited into one of two concurrent clinical trials: OIT (maintenance dose of 4000 mg/day and cumulative double-blind, placebo-controlled challenge (DBPCFC) dose of 5000 mg); or SLIT, (2 mg/day, and 2500 mg, respectively) [all quantities refer to peanut protein]. Although the optimal immunotherapy dose remains unknown, the doses chosen in these trials were based on preliminary data from pilot studies. Of note, unique properties of the oral mucosal immune response are hypothesized to account for SLIT’s efficacy at log-fold lower doses (reviewed in 7). Both trials utilized randomized, double-blind, placebo-controlled designs. Mechanistic studies were performed longitudinally as previously described using blood drawn from subjects within 24 hours of their last immunotherapy dose.(2, 3) At 12 months, subjects underwent DBPCFC to assess clinical desensitization; OIT subjects received a maximal 5000 mg cumulative protein dose, and for safety reasons SLIT challenges were limited to 2500 mg (Online Repository Tables E1/E2). We compared laboratory data between OIT and SLIT at baseline, 12 months, and 24 months, as well as DBPCFC pass/fail outcomes, using the Wilcoxon signed rank test (STATA 12; College Station, TX) and Mann-Whitney U test (GraphPad Prism; La Jolla, CA). Twenty-three subjects on OIT and 27 subjects on SLIT were evaluated after receiving 2 years of treatment (Table 1). We did not undertake a formal comparison of safety parameters between the two studies, and upcoming interval reports of each study will include these data. However, there were no serious adverse events reported in either study. No SLIT and two OIT subjects (one active, one placebo) required four total doses of epinephrine for dose-related reactions. At baseline, the peanut-specific IgE was similar between OIT and SLIT subjects (Fig 1A). Twelve months of treatment led to higher median peanut-specific IgE levels in the OIT group compared to the SLIT group (204.5 kU/L versus 66.7 kU/L, p=0.0382); however, levels were not significantly different between the groups at 24 months (Fig 1A). While peanut-specific IgG4 increased over time in both groups (Fig 1B), the effect was greater with OIT at 12 (20.1 mg/L versus 3.1 mg/L) and 24 months (20.3 mg/L versus 7.9 mg/L, p<0.001). Although decreased in both groups, median peanut-specific IgE/IgG4 ratios were significantly lower at 12 and 24 months for subjects receiving OIT (Fig 1C). Thirty-four subjects (14 OIT, 20 SLIT) had basophil activation assessed by CD63 up-regulation at baseline and 12 months. After 12 months, a significantly lower percentage of CD63+ basophils was found in the OIT group compared with the SLIT group when stimulated with 100 (median 5.90% versus 21.50%) and 10−1 μg/mL (median 6.34% versus 30.75%) crude peanut extract (p<0.01). No between-group difference was seen after stimulation with weaker dilutions of 10−2 and 10−3 μg/mL crude peanut extract. Too few samples were obtained at 24 months to perform an analysis. FIG 1 A and B, Change in serum peanut-IgE and peanut-IgG4 (SLIT/OIT). C, IgE/IgG4 ratio to peanut (SLIT/OIT). D, Cumulative amount tolerated during DBPCFC (SLIT/OIT). E, Serum peanut-IgE (Pass/Fail). F, Fold change in serum peanut-IgG4 from baseline to 12 months ... Table 1 Baseline subject characteristics Eighteen subjects on OIT and 27 subjects on SLIT underwent 12 month desensitization DBPCFCs, results of which are shown in Figure 1D. Despite differences in DBPCFC protocols, SLIT subjects reacted at lower eliciting dose thresholds. A Fisher’s exact test was used to calculate the difference in proportions and relative risk for passing or failing the DBPCFC according to treatment group. The difference in proportions was statistically significant (p=0.002), with OIT-treated subjects 3 times more likely to pass the 12 month desensitization DBPCFC than SLIT-treated subjects (RR=3.00, 95% CI 1.64-5.49). In an attempt to identify candidate biomarkers, we combined all SLIT and OIT subjects and then categorized them by “pass” or “fail” based upon their ability to complete the DBPCFC without symptoms. Consistent with other studies, subjects passing the 12 month desensitization DBPCFC tended to have lower baseline peanut-specific IgE levels (34.6 kU/L versus 167 kU/L, p=0.0575) (Fig 1E). Peanut-specific IgG4 was increased by 27-fold in the “pass” group compared to a 6.5-fold increase in the “fail” group (p=0.01; Fig 1F). Interestingly, the percentage of CD63+ basophils was significantly lower at 12 months in the “pass” group compared with the “fail” group when stimulated with 100 (median 5.90% versus 21.50%) and 10−1 μg/mL (median 6.34% versus 34.75%) crude peanut extract (p<0.01). Again no differences were seen between groups after stimulation with weaker dilutions. Skin prick tests decreased over time in all subjects. Wheal size, serum peanut-specific IgA and peanut-specific IgG, and CD4+CD25+FoxP3+ T-regulatory cells were not significantly different between the OIT and SLIT groups or the “pass” and “fail” groups. In summary, our results suggest that after two years of treatment, OIT produces greater immunologic changes than SLIT in peanut-allergic children. Specifically, peanut OIT resulted in greater changes in peanut-specific IgE, IgG4, and IgE/IgG4 ratio as well as basophil activation. In addition, eliciting dose thresholds were lower and more variable during DBPCFC at 12 months in SLIT-treated subjects, compared to OIT-treated subjects. Subjects who passed the DBPCFC tended to have lower baseline peanut-IgE levels, in addition to a larger fold change in peanut-IgG4 and less basophil activation at 12 months. The major limitation of this study is that it was not a randomized prospective study designed to directly compare the two modalities with a uniform protocol and consecutive enrollment. It is important to also note that interim clinical endpoints measured after only 12 months of immunotherapy likely do not provide a full assessment of the efficacy of either method. Further research is needed to determine the optimal length of treatment, dose, and ideal immunotherapy candidate for each modality.

Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective

Background: Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. Objective: We sought to test the safety, effectiveness, and feasibility of early OIT (E‐OIT) in the treatment of peanut allergy. Methods: We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block‐randomized 1:1 to receive E‐OIT at goal maintenance doses of 300 or 3000 mg/d in a double‐blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4‐SU), was assessed by double‐blinded, placebo‐controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut‐specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard‐care controls. Results: Of 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent‐to‐treat analysis achieved 4‐SU (300‐mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P = .43) over a median of 29 months. Per‐protocol, the overall proportion achieving 4‐SU was 29 of 32 (91%). Peanut‐specific IgE levels significantly declined in E‐OIT‐treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard‐care controls, in whom peanut‐specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7‐43.7; P < .001). Allergic side effects during E‐OIT were common but all were mild to moderate. Conclusions: At both doses tested, E‐OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.

Increased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy

Capsule Summary Peanut-specific IgA in saliva correlates with DBPCFC outcomes following peanut SLIT, suggesting that peanut-specific salivary IgA may be a potential biomarker for SLIT used to treat peanut allergy.

Clinical Characteristics of Peanut-Allergic Children: Recent Changes

OBJECTIVE. The goal was to determine whether patients seen in a referral clinic are experiencing initial allergic reactions to peanuts earlier, compared with a similar population profiled at a different medical center 10 years ago, and to investigate other changes in clinical characteristics of the patients between the 2 groups. METHODS. We reviewed the medical charts of peanut-allergic patients seen in the Duke University pediatric allergy and immunology clinic between July 2000 and April 2006. RESULTS. The median ages of first peanut exposure and reaction were 14 and 18 months, respectively; the respective ages in a similar population profiled between 1995 and 1997 were 22 and 24 months. Within our patient group, those born before 2000 were first exposed to peanuts at a median age of 19 months and reacted at a median age of 21 months, compared with first exposure at 12 months and first reaction at 14 months for those born in or after 2000. Most patients (68%) demonstrated sensitization or clinical allergy to other foods (53% to eggs, 26% to cows milk, 20% to tree nuts, 11% to fish, 9% to shellfish, 7% to soy, 6% to wheat, and 6% to sesame seeds). CONCLUSIONS. In the past decade, the ages of first peanut exposure and reaction have declined among peanut-allergic children seen in a referral clinic. Egg allergy is very common in peanut-allergic patients, and sesame seeds should perhaps be considered one of the major food allergens. The decline in the age of first peanut reaction seems to be attributable to earlier exposure.

Letter to the editorIncreased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy

Capsule Summary Peanut-specific IgA in saliva correlates with DBPCFC outcomes following peanut SLIT, suggesting that peanut-specific salivary IgA may be a potential biomarker for SLIT used to treat peanut allergy.

Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial

BACKGROUND Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by regulatory agencies. OBJECTIVE We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product. METHODS A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms. RESULTS Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs. CONCLUSIONS In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults.

Managing food allergy in childhood

Purpose of review This study reviews the newest developments on experimental therapies for the treatment of food allergy. Recent findings Epitope studies and microarray technology promise to improve the accuracy of diagnostic testing and may allow the prediction of reaction severity and the likelihood of allergy resolution. The regular ingestion of small amounts of food in oral immunotherapy (OIT) has been shown to dramatically increase reaction thresholds. However, a subset of patients have developed significant gastrointestinal symptoms requiring discontinuation of the treatment. A similar treatment given sublingually has appeared safer than OIT, but has also shown a less robust effect. Ingestion of extensively heated foods seems to accelerate the natural resolution of milk and egg allergy. The injectable anti-IgE therapy omalizumab has been shown to benefit in conjunction with OIT and preliminary data has suggested that it may also be effective as monotherapy. The Chinese herbal formula FAHF-2 has been shown to suppress anaphylaxis from single and multiple food allergies in mice, and early human studies have shown that it is well tolerated. Summary Improved testing should allow more accurate diagnosis of food allergy. For these patients, treatments are on the horizon, but further studies are needed to determine long-term safety and efficacy.

Oral Desensitization for Food Hypersensitivity

Food allergy has become an increasingly prevalent international health problem. Allergic reactions can result in life-threatening anaphylaxis in a short period of time, so the current standard of care dictates strict avoidance of suspected trigger foods and accessibility to injectable epinephrine. Intervention at the time of exposure is considered a rescue therapy rather than a disease-modifying treatment. Investigators have been studying allergen immunotherapy to promote induction of oral tolerance. This article examines the mechanisms of oral tolerance and the breakdown that leads to food allergy, as well as the history and current state of oral and sublingual immunotherapy development.

Utility of component analyses in subjects undergoing sublingual immunotherapy for peanut allergy

Sublingual immunotherapy (SLIT) with peanut changes clinical and immune responses in most peanut‐allergic individuals, but the response is highly variable.

Immunological Basis of Food Allergy (IgE-Mediated, Non-IgE-Mediated, and Tolerance)

Food allergy includes a number of diseases that present with adverse immunological reactions to foods and can be IgE-mediated, non-IgE-mediated, or a combination of both mechanisms. IgE-mediated food allergy involves immediate hypersensitivity through the action of mast cells, whereas non-IgE-mediated food allergy is most commonly cell-mediated. These food allergies are thought to occur as a result of a breakdown in oral tolerance and, more specifically, from an aberrant regulatory T-cell response. Ongoing studies of experimental treatments for food allergy strive to induce oral tolerance and to teach us more about the pathogenesis of food allergy.