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1.  World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics 
Background
Prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.
Objective
The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy.
Methods
We identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations.
Results
Currently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence.
Conclusions
WAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.
Electronic supplementary material
The online version of this article (doi:10.1186/s40413-015-0055-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s40413-015-0055-2
PMCID: PMC4307749  PMID: 25628773
Allergy; Prevention; Probiotics; Practice guidelines; GRADE
2.  Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy 
Background
History and severity of atopic dermatitis (AD) are risk factors for peanut allergy. Recent evidence suggests that children can become sensitized to food allergens through an impaired skin barrier. Household peanut consumption, which correlates strongly with peanut protein levels in household dust, is a risk factor for peanut allergy.
Objective
We sought to assess whether environmental peanut exposure (EPE) is a risk for peanut sensitization and allergy and whether markers of an impaired skin barrier modify this risk.
Methods
Peanut protein in household dust (in micrograms per gram) was assessed in highly atopic children (age, 3-15 months) recruited to the Consortium of Food Allergy Research Observational Study. History and severity of AD, peanut sensitization, and likely allergy (peanut-specific IgE, ≥5 kUA/mL) were assessed at recruitment into the Consortium of Food Allergy Research study.
Results
There was an exposure-response relationship between peanut protein levels in household dust and peanut skin prick test (SPT) sensitization and likely allergy. In the final multivariate model an increase in 4 log2 EPE units increased the odds of peanut SPT sensitization (1.71-fold; 95% CI, 1.13- to 2.59-fold; P = .01) and likely peanut allergy (PA; 2.10-fold; 95% CI, 1.20- to 3.67-fold; P < .01). The effect of EPE on peanut SPT sensitization was augmented in children with a history of AD (OR, 1.97; 95% CI, 1.26-3.09; P < .01) and augmented even further in children with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P < .01); the effect of EPE on PA was also augmented in children with a history of AD (OR, 2.34; 95% CI, 1.31-4.18; P < .01).
Conclusion
Exposure to peanut antigen in dust through an impaired skin barrier in atopically inflamed skin is a plausible route for peanut SPT sensitization and PA.
doi:10.1016/j.jaci.2014.10.007
PMCID: PMC4282723  PMID: 25457149
Atopic dermatitis; peanut sensitization; peanut allergy; environmental peanut exposure; dust; AD, Atopic dermatitis; CoFAR, Consortium of Food Allergy Research; EPE, Environmental peanut exposure; FLG, Filaggrin; IQR, Interquartile range; LLQ, Lower limit of quantitation; LR, Logistic regression; OR, Odds ratio; PA, Peanut allergy; sIgE, Specific IgE; SPT, Skin prick test
5.  Guidelines for the Diagnosis and Management of Food Allergy in the United States 
Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.
doi:10.1016/j.jaci.2010.10.007
PMCID: PMC4241964  PMID: 21134576
food; allergy; anaphylaxis; diagnosis; disease management; guidelines
6.  Sublingual versus oral immunotherapy for peanut-allergic children: A retrospective comparison 
doi:10.1016/j.jaci.2013.02.017
PMCID: PMC3732569  PMID: 23534975
peanut allergy; sublingual immunotherapy; oral immunotherapy; food hypersensitivity; desensitization
7.  A Phase 1 Study of Heat/Phenol Killed, E. coli-Encapsulated, Recombinant Modified Peanut Proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the Treatment of Peanut Allergy 
Allergy  2013;68(6):803-808.
Background
Immunotherapy for peanut allergy may be limited by the risk of adverse reactions.
Objective
To investigate the safety and immunologic effects of a vaccine containing modified peanut proteins.
Methods
This was a Phase 1 trial of EMP-123, a rectally administered suspension of recombinant Ara h 1, Ara h 2 and Ara h 3, modified by amino acid substitutions at major IgE binding epitopes, encapsulated in heat/phenol killed E. coli. Five healthy adults were treated with 4 weekly escalating doses after which 10 peanut allergic adults received weekly dose escalations over 10 weeks from 10mcg to 3063mcg, followed by 3 biweekly doses of 3063 mcg.
Results
There were no significant adverse effects in the healthy volunteers. Of the 10 peanut allergic subjects [4 with intermittent asthma, median peanut-IgE 33.3kUA/L (7.2–120.2), median peanutskin prick test wheal 11.3mm (6.5–18)], 4 experienced no symptoms, one had mild rectal symptoms, and the remaining 5 experienced adverse reactions preventing completion of dosing. Two were categorized as mild but the remaining three were more severe, including one moderate reaction and two anaphylactic reactions. Baseline peanut IgE was significantly higher in the 5 reactive subjects (median 82.4 versus 17.2kUA/L, p=0.032), as was baseline anti-Ara h 2 IgE (43.3 versus 8.3, p=0.036). Peanut skin test titration and basophil activation (at a single dilution) were significantly reduced after treatment but no significant changes were detected for total IgE, peanut IgE, or peanut IgG4.
Conclusions
Rectal administration of EMP-123 resulted in frequent adverse reactions, including severe allergic reactions in 20%.
doi:10.1111/all.12158
PMCID: PMC3663889  PMID: 23621498
8.  Type B CpG oligodeoxynucleotides induce Th1 responses to peanut antigens: modulation of sensitization and utility in a truncated immunotherapy regimen in mice 
Molecular nutrition & food research  2013;57(5):10.1002/mnfr.201200410.
Scope
Peanut allergy stems from a Th2-biased immune response to peanut allergens leading to IgE production and allergic reactions upon ingestion.
Methods and Results
A model of peanut allergy in C3H/HeJ mice was used to assess whether Type A, B, or C CpG oligodeoxynucleotide (ODN) molecules would be effective in: (1) a prophylactic approach to prevent peanut allergy when administered simultaneously with a Th2-skewing adjuvant, and (2) a therapeutic model to allow for shortened immunotherapy. Type B ODNs were extremely effective in inhibiting anaphylaxis in the sensitization protocol as evidenced by differences in symptom scores, body temperature, and MMCP-1 release compared to sham treatment. In the therapeutic model, co-administration of Type B ODN plus peanut proteins was highly effective in reducing anaphylactic reactions in mice with established peanut allergy. The therapeutic effect was accompanied by an increase in IFN-γ and peanut-IgG2a, without a significant decrease in peanut-IgE or IL-4 responses.
Conclusions
CpG ODNs, especially Type B, were highly effective in inducing Th1-responses in mice undergoing induction of peanut allergy, as well as in mice undergoing therapy for established peanut allergy. Interestingly, the IgE response was not significantly altered, suggesting that IgG antibodies may be enough to prevent peanut-induced anaphylaxis.
doi:10.1002/mnfr.201200410
PMCID: PMC3810026  PMID: 23386314
food allergy; peanut allergy; TLR9; CpG; mouse model
10.  The natural history of milk allergy in an observational cohort 
Objective
There are few studies on the natural history of milk allergy. Most are single-site and not longitudinal, and these have not identified a means for early prediction of outcomes.
Methods
Children aged 3 to 15 months were enrolled in an observational study with either (1) a convincing history of egg allergy, milk allergy, or both with a positive skin prick test (SPT) response to the trigger food and/or (2) moderate-to-severe atopic dermatitis (AD) and a positive SPT response to milk or egg. Children enrolled with a clinical history of milk allergy were followed longitudinally, and resolution was established by means of successful ingestion.
Results
The cohort consists of 293 children, of whom 244 were given a diagnosis of milk allergy at baseline. Milk allergy has resolved in 154 (52.6%) subjects at a median age of 63 months and a median age at last follow-up of 66 months. Baseline characteristics that were most predictive of resolution included milk-specific IgE level, milk SPT wheal size, and AD severity (all P < .001). Baseline milk-specific IgG4 level and milk IgE/IgG4 ratio were not predictive of resolution and neither was expression of cytokine-inducible SH2-containing protein, forkhead box protein 3, GATA3, IL-10, IL-4, IFN-γ, or T-bet by using real-time PCR in CD25-selected, casein-stimulated mononuclear cells. A calculator to estimate resolution probabilities using baseline milk IgE level, SPT response, and AD severity was devised for use in the clinical setting. Conclusions: In this cohort of infants with milk allergy, approximately one half had resolved over 66 months of follow-up. Baseline milk-specific IgE level, SPT wheal size, and AD severity were all important predictors of the likelihood of resolution.
doi:10.1016/j.jaci.2012.10.060
PMCID: PMC3691063  PMID: 23273958
Milk allergy; natural history; food allergy; IgE
11.  Oral and sublingual immunotherapy for food allergy: current progress and future directions 
Current opinion in immunology  2013;25(6):781-787.
Food allergies are increasing in prevalence and present an emerging epidemic for westernized countries. Strict dietary avoidance is the only approved management for food allergy, but accidental exposures regularly occur, leading to significant patient anxiety and decreased quality of life. Over the past decade, oral and sublingual immunotherapies have emerged as potential treatments for food allergy. While several small clinical trials have demonstrated that immunotherapy can desensitize food-allergic individuals, strategies for further enhancing safety and definitively establishing long-term efficacy are needed. This review presents an overview of recent oral and sublingual immunotherapy trials, and provides a glimpse into what the next generation of food immunotherapy may entail.
doi:10.1016/j.coi.2013.07.011
PMCID: PMC3935613  PMID: 23972904
12.  Food Allergy Education for School Nurses: A Needs Assessment Survey by the Consortium of Food Allergy Research 
Food allergy is increasing in school-age children. School nurses are a primary health care resource for children with food allergy and must be prepared to manage allergen avoidance and respond in the event of an allergic reaction. An anonymous survey was administered to school nurses attending their association meetings to determine their educational needs regarding children with food allergy. With 199 school nurses responding, their self-reported proficiency for critical areas of food allergy knowledge and management varied, with weaknesses identified particularly for emergency plan development, staff education, delegation, developing guidelines for banning foods and planning school trips. Nurses reported a high interest in obtaining educational materials in these areas and prefer video and Internet resources that could be promoted through professional organizations.
doi:10.1177/1059840510369482
PMCID: PMC3888215  PMID: 20404357
school nurses; food allergy; education; emergency plan
13.  Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens 
Background
Peanut-allergic subjects have highly stable pathologic antibody repertoires to the immunodominant B cell epitopes of the major peanut allergens Ara h 1-3.
Objective
We used a peptide microarray technique to analyze the effect of treatment with peanut oral immunotherapy (OIT) on such repertoires.
Methods
Measurements of total peanut-specific IgE (psIgE) and psIgG4 were made with CAP-FEIA. We analyzed sera from 22 OIT subjects and 6 controls and measured serum specific IgE and IgG4 binding to epitopes of Ara h 1-3 using a high-throughput peptide microarray technique. Antibody affinity was measured using a competitive peptide microarray as previously described.
Results
At baseline, psIgE and psIgG4 diversity were similar between subjects and controls, and there was broad variation in epitope recognition. After a median 41 months of OIT, polyclonal psIgG4 increased from a median 0.3 mcg/mL (IQR 0.1-0.43) at baseline to 10.5 mcg/mL (3.95-45.48) (p<0.0001) and included de novo specificities. PsIgE was reduced from a median baseline of 85.45 kUA/L (23.05-101.0) to 7.75 kUA/L (2.58-30.55) (p<0.0001). Affinity was unaffected. Although the psIgE repertoire contracted in most OIT-treated subjects, several subjects generated new IgE specificities even as the total psIgE decreased. Global epitope-specific shifts from IgE to IgG4 binding occurred, including at an informative epitope of Ara h 2.
Conclusion
OIT differentially alters Ara h 1-3 binding patterns. These changes are variable between subjects, not observed in controls, and include a progressive polyclonal increase in IgG4, with concurrent reduction in IgE amount and diversity.
doi:10.1016/j.jaci.2012.10.048
PMCID: PMC3529994  PMID: 23199605
peanut allergy; oral immunotherapy; IgE; IgG4; peptide microarray; epitope; B cell; antibody affinity
14.  Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial 
Background
There are presently no available therapeutic options for peanut-allergic patients.
Objective
To investigate the safety, efficacy, and immunologic effects of peanut sublingual immunotherapy (SLIT).
Methods
After a baseline oral food challenge (OFC) of up to 2g of peanut powder (~50% protein) (median successfully consumed dose [SCD] 46mg), 40 subjects, aged 12–37 (median 15) years, were randomized 1:1 across 5 sites to daily peanut or placebo SLIT. A 5g OFC was performed after 44 weeks followed by unblinding; placebo subjects then crossed over to higher dose peanut SLIT, followed by a subsequent crossover Week 44 5g OFC. Week 44 OFCs from both groups were compared to baseline OFCs; subjects successfully consuming 5g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders.
Results
After 44 weeks of SLIT, 14/20 (70%) subjects receiving peanut SLIT were responders compared to 3/20 (15%) subjects receiving placebo (p<0.001). In peanut-SLIT responders, median SCD increased from 3.5mg to 496mg. After 68 weeks of SLIT, median SCD significantly increased to 996mg (compared to week 44, p=0.05). The median SCD at the Week 44 crossover OFC was significantly higher than baseline (603mg vs 71mg; p=0.02). 7/16 (44%) crossover subjects were responders; median SCD increased from 21mg to 496mg among responders. Of 10,855 peanut doses through Week 44 OFCs, 63.1% were symptom-free; excluding oral/pharyngeal symptoms, 95.2% were symptom-free.
Conclusions
Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared to placebo. Longer duration of therapy showed statistically significant increases in the SCD.
doi:10.1016/j.jaci.2012.11.011
PMCID: PMC3550002  PMID: 23265698
peanut allergy; sublingual immunotherapy; desensitization; food allergy
15.  Pepsinized cashew proteins are hypoallergenic and immunogenic and provide effective immunotherapy in mice with cashew allergy 
The Journal of allergy and clinical immunology  2012;130(3):10.1016/j.jaci.2012.05.044.
Background
IgE-mediated allergic reactions to cashews and other nuts can trigger life-threatening anaphylaxis. Proactive therapies to decrease reaction severity do not exist.
Objectives
We aimed to determine the efficacy of pepsin-digested cashew proteins used as immunotherapy in a murine model of cashew allergy.
Methods
Mice were sensitized to cashew and then underwent challenges with digested or native cashew allergens to assess the allergenicity of the protein preparations. Using native or pepsinized cashew proteins, mice underwent oral or intraperitoneal sensitization protocols to determine the immunogenic properties of the protein preparations. Finally, cashew-sensitized mice underwent an immunotherapy protocol with native or pepsinized cashew proteins and subsequent provocation challenges.
Results
Pepsinized cashew proteins elicited weaker allergic reactions than native cashew proteins but importantly retained the ability to stimulate cellular proliferation and cytokine production. Mice sensitized with pepsinized proteins reacted on challenge with native allergens, demonstrating that pepsinized allergens retain immunogenicity in vivo. Immunotherapy with pepsinized cashew allergens significantly decreased allergic symptoms and body temperature decrease relative to placebo after challenge with native and pepsinized proteins.
Immunologic changes were comparable after immunotherapy with native or pepsinized allergens: TH2-type cytokine secretion from splenocytes was decreased, whereas specific IgG1 and IgG2a levels were increased.
Conclusions
Pepsinized cashew proteins are effective in treating cashew allergy in mice and appear to work through the same mechanisms as native protein immunotherapy.
doi:10.1016/j.jaci.2012.05.044
PMCID: PMC3810066  PMID: 22795369
Food allergy; tree nut allergy; cashew; immunotherapy; pepsin; murine model
16.  Future therapies for food allergy 
Human Vaccines & Immunotherapeutics  2012;8(10):1479-1484.
Food allergy affects 3.9% of US children and is increasing in prevalence. The current standard of care involves avoidance of the triggering food and treatment for accidental ingestions. While there is no current curative treatment, there are a number of therapeutic strategies under investigation. Allergen specific therapies include oral and sublingual immunotherapy with native food protein as well as recombinant food proteins. Allergen non-specific therapies include a Chinese herbal formula (FAHF-2) and the use of anti-IgE monoclonal antibody therapy. Although none of these treatments are ready for clinical use, these therapeutic strategies present promising options for the future of food allergy.
doi:10.4161/hv.20868
PMCID: PMC3660769  PMID: 22894951
anaphylaxis; desensitization; food allergy; oral immunotherapy; subcutaneous immunotherapy; sublingual immunotherapy; tolerance
17.  Evidence of pathway-specific basophil anergy induced by peanut oral immunotherapy in peanut-allergic children 
Background
In Westernized countries, over 1% of the population is allergic to peanuts or tree nuts, which carries a risk of severe allergic reactions. Several studies support the efficacy of peanut oral immunotherapy (OIT) for reducing the clinical sensitivity of affected individuals; however, the mechanisms of this effect are still being characterized. One mechanism that may contribute is the suppression of effector cells, such as basophils. Basophil anergy has been characterized in vitro as a pathway-specific hyporesponsiveness; however, this has not been demonstrated to occur in vivo.
Objective
To evaluate the hypothesis that basophil anergy occurs in vivo due to chronic allergen exposure in the setting of a clinical oral immunotherapy trial.
Methods
Samples of peripheral blood were obtained from subjects during a placebo-controlled clinical trial of peanut OIT. Basophil reactivity to in vitro stimulation with peanut allergen and controls was assessed by the upregulation of activation markers, CD63 and CD203c, measured by flow cytometry.
Results
The upregulation of CD63 following stimulation of the IgE receptor, either specifically with peanut allergen or non-specifically with anti-IgE antibody, was strongly suppressed by active OIT. However, OIT did not significantly suppress this response in basophils stimulated by the distinct fMLP receptor pathway. In the subset of subjects with egg sensitization, active peanut OIT also suppressed CD63 upregulation in response to stimulation with egg allergen. Allergen OIT also suppressed the upregulation of CD203c including in response to stimulation with IL-3 alone.
Conclusion
Peanut OIT induces a hyporesponsive state in basophils that is consistent with pathway-specific anergy previously described in vitro. This suggests the hypothesis that effector cell anergy could contribute to clinical desensitization.
doi:10.1111/j.1365-2222.2012.04028.x
PMCID: PMC3779434  PMID: 22805467
human basophils; desensitization; basophil anergy; CD63; CD203c; oral immunotherapy; peanut allergy
19.  A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy 
Background
Orally administered, food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals.
Objective
We sought to determine whether milk oral immunotherapy (OIT) is safe and efficacious in desensitizing children with cow’s milk allergy.
Methods
Twenty children were randomized to milk or placebo OIT (2:1 ratio). Dosing included 3 phases: the build-up day (initial dose, 0.4 mg of milk protein; final dose, 50 mg), daily doses with 8 weekly in-office dose increases to a maximum of 500 mg, and continued daily maintenance doses for 3 to 4 months. Double-blind, placebo-controlled food challenges; end-point titration skin prick tests; and milk protein serologic studies were performed before and after OIT.
Results
Nineteen patients, 6 to 17 years of age, completed treatment: 12 in the active group and 7 in the placebo group. One dropped out because of persistent eczema during dose escalation. Baseline median milk IgE levels in the active (n = 13) versus placebo (n = 7) groups were 34.8 kUa/L (range, 4.86–314 kUa/L) versus 14.6 kUa/L (range, 0.93–133.4 kUa/L). The median milk threshold dose in both groups was 40 mg at the baseline challenge. After OIT, the median cumulative dose inducing a reaction in the active treatment group was 5140 mg (range 2540-8140 mg), whereas all patients in the placebo group reacted at 40 mg (P = .0003). Among 2437 active OIT doses versus 1193 placebo doses, there were 1107 (45.4%) versus 134 (11.2%) total reactions, with local symptoms being most common. Milk-specific IgE levels did not change significantly in either group. Milk IgG levels increased significantly in the active treatment group, with a predominant milk IgG4 level increase.
Conclusions
Milk OIT appears to be efficacious in the treatment of cow’s milk allergy. The side-effect profile appears acceptable but requires further study.
doi:10.1016/j.jaci.2008.09.030
PMCID: PMC3764488  PMID: 18951617
Cow’s milk; food allergy; IgE; prognosis; desensitization; tolerance; oral immunotherapy
20.  Increased peanut-specific IgA in saliva correlates with food challenge outcomes following 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.
doi:10.1016/j.jaci.2011.11.045
PMCID: PMC3763925  PMID: 22236732
Food allergy; peanut allergy; sublingual immunotherapy; saliva; IgA; secretory IgA
21.  The future of food allergy therapeutics 
Seminars in immunopathology  2012;34(5):703-714.
Food allergy is increasing in prevalence in westernized countries, leading to significant morbidity including nutritional deficiencies and growth delay as well as psychosocial burdens and the potential for fatal anaphylaxis. There is currently no effective form of therapy, and the mainstay of treatment remains strict avoidance. However, there are a number of promising therapeutic strategies currently being investigated for the treatment of food allergies. Allergen-specific approaches, such as various forms of immunotherapy, have been a major focus of investigation and appear to be promising methods of desensitization. More recently, the addition of anti-IgE monoclonal antibodies (mAbs) to immunotherapy regimens has been studied. Early work with antigen-fixed leukocytes in a murine model has shown promise in inducing tolerance, as have vaccines containing modified recombinant food proteins coadministered with heat-killed Escherichia coli. Nonspecific approaches include a Chinese herbal formulation, anti-IgE mAbs, and Trichuris suis ova therapy. The array of treatment modalities currently being investigated increases the likelihood of finding one or more effective therapies for the treatment of food allergy.
doi:10.1007/s00281-012-0319-7
PMCID: PMC3464915  PMID: 22735939
Food allergy; Oral immunotherapy (OIT); Double-blind, placebo-controlled food challenge (DBPCFC); Anti-IgE antibody/omalizumab; Desensitization
22.  Allergic Reactions to Foods in Preschool-Aged Children in a Prospective Observational Food Allergy Study 
Pediatrics  2012;130(1):e25-e32.
OBJECTIVE:
To examine circumstances of allergic reactions to foods in a cohort of preschool-aged children.
METHODS:
We conducted a prospective, 5-site observational study of 512 infants aged 3 to 15 months with documented or likely allergy to milk or egg, and collected data prospectively examining allergic reactions.
RESULTS:
Over a median follow-up of 36 months (range: 0–48.4), the annualized reaction rate was 0.81 per year (367/512 subjects reporting 1171 reactions [95% confidence interval: 0.76–0.85]). Overall, 269/512 (52.5%) reported >1 reaction. The majority of reactions (71.2%) were triggered by milk (495 [42.3%]), egg (246 [21.0%]), and peanut (93 [7.9%]), with accidental exposures attributed to unintentional ingestion, label-reading errors, and cross-contact. Foods were provided by persons other than parents in 50.6% of reactions. Of 834 reactions to milk, egg, or peanut, 93 (11.2%) were attributed to purposeful exposures to these avoided foods. A higher number of food allergies (P < .0001) and higher food-specific immunoglobulin E (P < .0001) were associated with reactions. Of the 11.4% of reactions (n = 134) that were severe, 29.9% were treated with epinephrine. Factors resulting in undertreatment included lack of recognition of severity, epinephrine being unavailable, and fears about epinephrine administration.
CONCLUSIONS:
There was a high frequency of reactions caused by accidental and nonaccidental exposures. Undertreatment of severe reactions with epinephrine was a substantial problem. Areas for improved education include the need for constant vigilance, accurate label reading, avoidance of nonaccidental exposure, prevention of cross-contamination, appropriate epinephrine administration, and education of all caretakers.
doi:10.1542/peds.2011-1762
PMCID: PMC3382915  PMID: 22732173
food allergy; IgE-mediated allergic reaction; epinephrine
23.  The 2S albumin allergens of Arachis hypogaea, Ara h 2 and Ara h 6, are the major elicitors of anaphylaxis and can effectively desensitize peanut-allergic mice 
Clinical and Experimental Allergy  2012;42(2):326-336.
Background
Ara h 2 and Ara h 6, co-purified together in a 13-25 kD fraction (Ara h 2/6; 20 kD fraction) on gel filtration chromatography, account for the majority of effector activity in a crude peanut extract (CPE) when assayed with RBL SX-38 cells sensitized with IgE from human peanut allergic sera.
Objectives
To determine if Ara h 2/6 are the primary peanut allergens responsible for allergic reactions in vivo and to determine if Ara h 2/6 would be sufficient to prevent allergic reactions to a complete CPE.
Methods
An oral sensitization mouse model of peanut allergy was used to assess the activity of Ara h 2/6 (20 kD) and CPE without the 20 kD fraction (CPE w/o 20 kD) for allergic provocation challenge and immunotherapy. The activity of these preparations was also tested in an assay of histamine release from human basophils in whole blood.
Results
Compared to mice challenged with control CPE, mice challenged with CPE w/o 20 kD experienced reduced symptoms (p<0.05) and a smaller decrease in body temperature (p<0.01). Results with the basophil histamine release assay corroborated these findings (p<0.01). The mouse model was also used to administer Ara h 2/6 (20 kD) in an immunotherapy protocol, in which peanut-allergic mice treated with the 20 kD fraction experienced significantly reduced symptoms, changes in body temperature, and mast cell protease (MMCP-1) release compared to placebo (p<0.01 for all parameters). Importantly, immunotherapy with the 20 kD fraction was just as effective as treatment with CPE, whereas CPE w/o 20 kD was significantly less effective for higher dose peanut challenges.
Conclusions and Clinical Relevance
Ara h 2/6 are the most potent peanut allergens in vivo and can be used to desensitize peanut-allergic mice. These results have potential implications for clinical research in the areas of diagnosis and immunotherapy for peanut allergy.
doi:10.1111/j.1365-2222.2011.03934.x
PMCID: PMC3270336  PMID: 22288514
Food allergy; peanut allergy; Ara h 2; Ara h 6; desensitization; immunotherapy; human basophil assay; mouse model
24.  The safety and efficacy of sublingual and oral immunotherapy for milk allergy 
Background
Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of response remain unknown.
Objective
We sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow’s milk (CM) allergy.
Methods
We randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG4 levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels.
Results
Thirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge (P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG4 levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group.
Conclusion
OIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.
doi:10.1016/j.jaci.2011.10.023
PMCID: PMC3437605  PMID: 22130425
Food allergy; immunotherapy; milk allergy; basophil; spontaneous histamine release
25.  Oral Immunotherapy for Treatment of Egg Allergy in Children 
The New England journal of medicine  2012;367(3):233-243.
BACKGROUND
For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy.
METHODS
In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months.
RESULTS
After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months.
CONCLUSIONS
These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.)
doi:10.1056/NEJMoa1200435
PMCID: PMC3424505  PMID: 22808958

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