Satya D. Narisety

Open-label maintenance after milk oral immunotherapy for IgE-mediated cow's milk allergy.

Maria D. Rivas, PhD Javier Molina-Infante, MD Maria A. Gonzalez-Nuñez, MD Moises Perez-G, BSc Juan F. Masa, MD Juan F. Sanchez, MD Jose Zamorano, PhD From Unidad de Investigación, Servicio de Digestivo, Servicio de Anatomia Patologica, Servicio de Neumologia-Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CiberRes), and Servicio de Medicina Interna, Hospital San Pedro de Alcantara, Caceres, Spain. E-mail: jose.zamorano@ses.juntaextremadura.net. Supported by Fondo Europeo Desarrollo Regional (FEDER) Funds, Spanish public funds Fondo de Investigacion Sanitaria 06/1431, and Junta de Extremadura PRI06A035 and SCSS0744. M.D.R. was supported by Subdireccion General de Investigacion Sanitaria CA06/0110. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

Long-term follow-up of oral immunotherapy for cow's milk allergy

To the Editor: Oral immunotherapy (OIT) for food allergy is currently under active investigation, and its use in clinical practice is spreading despite important concerns(1, 2). Among the many reasons for caution is the paucity of data on long-term outcomes. One study in Italy found that although 18/21 (86%) subjects were initially partially or completely desensitized to cows milk (CM) with OIT, this dropped to 14/20 (70%) after 4 ½ years(3). Other studies have generally reported limited or no follow-up data. Here, we report follow-up of two studies of CM OIT after up to five years in order to evaluate ongoing CM consumption, symptoms, and potential predictors of long-term outcomes. Both previously published studies enrolled CM allergic children at Johns Hopkins and Duke Universities after a double-blind placebo-controlled oral food challenge (OFC) (4-6). The first study was a double-blind placebo-controlled trial in 20 children (4). Dose escalation to 0.5 grams CM protein lasted approximately eight weeks, followed by three month maintenance. All placebo treated children were offered active OIT after the final OFC. The second study was an open label randomized trial of OIT versus sublingual immunotherapy (SLIT) in 30 children (6). Dose escalation, lasting approximately 30 weeks, started with a short course of SLIT, followed by OIT to a goal dose of 1 or 2 grams. After three months of maintenance, an OFC was administered and the dose was potentially adjusted to a maximum of 4 grams. Maintenance totaled 15 months and was followed by another OFC. For subjects who passed that challenge, tolerance challenges were done at one and six weeks later. In both studies, individualized recommendations regarding milk consumption after study completion were provided based on OFC results. Follow-up data were collected by standardized questionnaire and/or clinical follow-up for all 32 subjects treated with active OIT at Johns Hopkins, and 26/32 participated in a follow-up visit including phlebotomy and skin testing. Subjects were asked about CM consumption and symptoms with CM ingestion in the past year. Symptoms were classified as frequent or predictable if they typically occurred with CM consumption or sporadic if there were no frequent or predictable symptoms but definite reactions occurred on at least one occasion. In order to assess predictors of outcome, subjects were split into two groups: those who consumed at least one serving of CM daily with no more than oral/pharyngeal symptoms, and those who either consumed less CM or reported symptoms. Differences were evaluated by Fischers exact test for dichotomous variables or Wilcoxan rank sums for continuous variables. Sixteen subjects were eligible from each study, including 5 subjects who did not complete the questionnaire but for whom clinical data were available (including three who withdrew during active treatment). Subjects were followed-up after a median of 4.5 years (range 1.3-5.3) and 3.2 years (range 2.6-3.4) from end of dose escalation, in study 1 and study 2, respectively. Because outcomes were similar between studies, and between OIT randomization groups in the second study, data were combined for further analysis. Table 1 shows current CM consumption status and symptoms with CM ingestion. Twenty-two percent reported limiting their consumption because of symptoms, 9% because of anxiety and 13% because of taste. In addition, 25% limited CM with exercise and 6% with illness. Most reactions were not attributed to cofactors, but 13% reported increased symptoms with exercise, 9% with illness and 6% after missing several days of CM. Notably, some subjects who initially did well, and passed interim OFCs, subsequently had increased symptoms and began to restrict CM. Disturbingly, some subjects had significant symptoms after study completion of which we were unaware, with one subject reporting using epinephrine at least twice per month for reactions to CM. (Supplemental Table 1 describes types of symptoms with CM consumption). Table 1 Characteristics by long-term outcome category Baseline and follow-up characteristics and their relationship to long-term outcomes are shown in Table 2. Of note, several characteristics were associated with long-term outcome, including baseline CM-IgE, gastrointestinal and lower respiratory symptoms with OIT, food challenge threshold at three months of maintenance, amount of CM recommended for daily intake and SPT wheal size in follow-up. No subject with baseline CM IgE over 75 kU/L (n=8), respiratory symptoms with more than 2% of doses (n=8), or who had a post-treatment food-challenge threshold of less than 4 grams (n=7) was consuming at least one serving of milk in follow-up without symptoms. In addition, 7 (88%) of those with baseline CM IgE over 75 kU/L either had anaphylaxis or consumed no more than trace or baked milk in follow-up. (Supplemental Tables 2-3 and Figures 1-3) However, collectively these predictors identified only 48% of subjects in the poorer outcome group, and given the relatively small sample size, we would be hesitant to suggest that these specific cut-offs would necessarily apply to other studies. Table 2 Milk consumption status and symptoms during follow-up. This report has several important limitations. First, we do not have follow-up serology or skin prick testing on most subjects with the worst outcome – those who were avoiding milk – which may underestimate the discriminative capacity of these parameters. Second, we do not have a control group that was not treated to compare long-term outcomes. Third, these subjects may represent an especially severe phenotype of CM allergy. Most importantly, our data do not answer the question of whether subjects who continue to have symptoms are actually better off than they were before treatment. However, while we hope that newer OIT protocols that include higher doses and/or longer periods of maintenance will lead to better results, it is clear from these preliminary data that long-term outcomes following CM immunotherapy are decidedly mixed, with some subjects losing desensitization over time, and no more than 31% of subjects tolerating at least full servings of CM with minimal or no symptoms. These findings are particularly concerning for the future of OIT because, unlike most other allergenic foods, CM is typically consumed in diverse forms several times a day. Even young children are generally very motivated to incorporate CM into their diets. For foods like peanut, where aversion among formerly allergic children is common(7), results may be far worse than we have found here. It is therefore clear that more research into the long-term outcomes of OIT for food allergy is necessary and, most importantly, that OIT for food allergy is far from ready for clinical practice.

Suppression of the immunologic response to peanut during immunotherapy is often transient

BACKGROUND Studies suggest that oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) for food allergy hold promise; however, the immunologic mechanisms underlying these therapies are not well understood. OBJECTIVE We sought to generate insights into the mechanisms and duration of suppression of immune responses to peanut during immunotherapy. METHODS Blood was obtained from subjects at baseline and at multiple time points during a placebo-controlled trial of peanut OIT and SLIT. Immunologic outcomes included measurement of spontaneous and stimulated basophil activity by using automated fluorometry (histamine) and flow cytometry (activation markers and IL-4), measurement of allergen-induced cytokine expression in dendritic cell (DC)-T-cell cocultures by using multiplexing technology, and measurement of MHC II and costimulatory molecule expression on DCs by using flow cytometry. RESULTS Spontaneous and allergen-induced basophil reactivity (histamine release, CD63 expression, and IL-4 production) were suppressed during dose escalation and after 6 months of maintenance dosing. Peanut- and dust mite-induced expression of TH2 cytokines was reduced in DC-T-cell cocultures during immunotherapy. This was associated with decreased levels of CD40, HLA-DR, and CD86 expression on DCs and increased expression of CD80. These effects were most striking in myeloid DC-T-cell cocultures from subjects receiving OIT. Many markers of immunologic suppression reversed after withdrawal from immunotherapy and in some cases during ongoing maintenance therapy. CONCLUSION OIT and SLIT for peanut allergy induce rapid suppression of basophil effector functions, DC activation, and TH2 cytokine responses during the initial phases of immunotherapy in an antigen-nonspecific manner. Although there was some interindividual variation, in many patients suppression appeared to be temporary.

Sublingual vs oral immunotherapy for food allergy: Identifying the right approach

The incidence of food allergy in developed countries has increased in recent years, escalating the need to find a suitable form of treatment as an alternative to current management, which includes strict avoidance and ready availability of injectable epinephrine (adrenaline). Allergen immunotherapy is currently being studied for use in the treatment of IgE-mediated food allergy to the most common foods, including peanut, tree nut, milk and egg. Two modalities, oral immunotherapy (OIT) and sublingual immunotherapy (SLIT), have shown great promise. Both OIT and SLIT have been able to desensitize subjects to varying degrees, but the two treatment methods differ in doses that can be achieved, duration of treatment, safety profile and ease of use outside the research setting, among other aspects. More research is needed to conclude which mode of treatment is more effective in inducing long-term tolerance with the least amount of serious adverse reactions. However, OIT and SLIT show great promise, and a widespread treatment for food allergy may be within reach.

Forecast for food allergen immunotherapy: partly desensitized or a chance of cure?

IgE-mediated food allergy is a common disorder that has been growing in prevalence in recent years. Currently, the standard of care is strict avoidance of the culprit food with ready access to injectable epinephrine. However, given that accidental reactions are common and often severe, there is great interest in the development of new therapeutic approaches for food allergy. While subcutaneous immunotherapy is currently used for the treatment of IgE-mediated respiratory disease and insect sting allergy, the use of subcutaneous immunotherapy in food allergy has been complicated by high rates of systemic reactions and cannot be recommended for general use [1,2]. However, newer strategies, including alternative routes of delivery as well as modification of the allergens to reduce IgE-mediated reactivity, are now being studied with encouraging results. Recently, oral immunotherapy (OIT) has been studied for milk, egg and peanut allergies [3–13]. These studies have shown that many individuals with severe allergy to these foods can be successfully desensitized and, in some cases, can even introduce the food into their diets. A few studies have attempted to address the question of whether these OIT protocols confer long-term tolerance along with short-term desensitization. It appears that between a third and a half of children treated with OIT for milk or egg allergy are truly tolerant, in that they are able to eat the food after all exposure was stopped [3,12]. Another approach to immunotherapy involves the sublingual route (sublingual immunotherapy [SLIT]), which has been used with success for hazelnut allergy [14] and is currently being studied for milk and peanut allergy. Most OIT and SLIT protocols involve rush or modified-rush desensitization followed by a longer period of gradual escalation and maintenance. These studies have varied with regard to participant age, dosing regimen, length of treatment, placebo control, and the use of baseline and follow-up food challenges. Side effects have been inconsistently reported but appear to be very common, ranging from local reactions to more severe systemic reactions, including anaphylaxis. SLIT has generated interest as it may be effective at lower doses, thereby potentially reducing the number and severity of side effects that have been seen with other forms of immunotherapy. It is also theorized that there are a plethora of cells that are part of the innate immune system in the oral mucosa that jump start the mechanism of desensitization and possibly augment the development of long-term tolerance. Among the published food immunotherapy trials, adverse reactions have been common in all phases of the treatment regimen. Reactions most often have included hives, pruritis, and/or eczema flares of the skin, the upper and lower respiratory tract, and the GI tract with oropharyngeal pruritis and/or edema, nausea, vomiting Satya D Narisety, MD Post-Doctorate Fellow, Division of Pediatric Immunology & Allergy, The Johns Hopkins Hospital, School of Medicine/CMSC 1102, 600 North Wolfe Street, Baltimore, MD 21287-3923, USA Tel.: +1 410 955 5883 Fax: +1 410 955 0229 snarise1@jhmi.edu