Up to 30% of patients with food allergies have clinical reactivity to more than one food allergen. Although there is currently no cure, oral immunotherapy (OIT) is under investigation. Pilot data have shown that omalizumab may hasten the ability to tolerate over 4 g of food allergen protein.
Objective
To evaluate the safety and dose tolerability of a Phase 1 Single Site OIT protocol using omalizumab to allow for a faster and safe desensitization to multiple foods simultaneously.
Methods
Participants with multiple food allergies received OIT for up to 5 allergens simultaneously with omalizumab (rush mOIT). Omalizumab was administered for 8 weeks prior to and 8 weeks following the initiation of a rush mOIT schedule. Home reactions were recorded with diaries.
Results
Twenty-five (25) participants were enrolled in the protocol (median age 7 years). For each included food, participants had failed an initial double-blind placebo-controlled food challenge at a protein dose of 100 mg or less. After pre-treatment with omalizumab, 19 participants tolerated all 6 steps of the initial escalation day (up to 1250 mg of combined food proteins), requiring minimal or no rescue therapy. The remaining 6 were started on their highest tolerated dose as their initial daily home doses. Participants reported 401 reactions per 7,530 home doses (5.3%) with a median of 3.2 reactions per 100 doses. Ninety-four percent (94%) of reactions were mild. There was one severe reaction. Participants reached their maintenance dose of 4,000 mg protein per allergen at a median of 18 weeks.
Conclusion
These phase 1 data demonstrate that rush OIT to multiple foods with 16 weeks of treatment with omalizumab could allow for a fast desensitization in subjects with multiple food allergies. Phase 2 randomized controlled trials are needed to better define safety and efficacy parameters of multi OIT experimental treatments with and without omalizumab.
Up to 8% of the pediatric population suffers from food allergy and of those 30% have clinical reactivity to more than one food allergen [1–3]. The estimated cost of food allergies in the U.S. every year is approximately 25 billion U.S. dollars, with most of the burden (~$20 billion) borne by families themselves due to time lost from work, changing careers and emergency room visits [4]. Compared to those with single food allergies, multi-sensitized subjects experience a greater decrease in quality of life [5], are more likely to suffer from dietary deficiencies [6] and are less prone to spontaneously outgrow their allergies [7].
Oral, sublingual, and epicutaneous allergen-specific immunotherapies have been proposed as possible methods of desensitization for foods. Several prior studies have shown some success in using these approaches for single specific food allergens such as milk [8–15], egg [13, 14, 16–18], peanut [19–24], and hazelnut [25]. These current types of experimental treatments need to be tested for optimization in safety, efficacy, and length of time [26–34]. Safety is of critical importance at all phases of any protocol (initial dose escalation day, dose escalation, and maintenance phases) and allergic reactions while on OIT remain an important feature in long-term follow-up studies and in determining the overall success of food allergen immunotherapy [35]. However, one major limitation to the clinical application of current protocols is their use in participants with more than one food allergy, which would require multiple sequential rounds of immunotherapy over many years. We have recently reported that up to 5 allergens can be desensitized simultaneously without an increase in reaction rate when compared to single allergen desensitization [36]. However this protocol remained time consuming with a median of 85 weeks to reach maintenance dose (range = 54–156).
The use of IgE immunomodulatory therapies, including monoclonal antibodies and small molecules, has been under investigation in food allergies and has been reviewed recently in the literature [37–45]. Specifically, omalizumab has been shown to increase the threshold for adverse reactions on food challenge by up to 80 fold [41]. After obtaining pharmacodynamic data using basophil assays and free IgE measurements in subjects with food allergies who received standard omalizumab dosing, we found that 8 weeks post standard omalizumab therapy is an optimal time to start oral immunotherapy [46, 47]. This concept of rush immunotherapy with omalizumab was previously used in immunotherapy studies involving pollens, milk and peanut with promising results [28, 30, 48–52]. Combined with food OIT, omalizumab is posited to increase dose tolerability, thus allowing for the possibility of a higher initial starting dose and faster treatment progression.
The objective of this trial was to study the safety and dose tolerability of a phase 1, open-label, rush OIT protocol, which included up to 5 foods simultaneously. The primary endpoint of our investigation was safety (i.e. the occurrence of allergic reactions throughout the course of the study). The secondary endpoints (i.e. tolerability) were i) the time to reach and maintain doses of 300 mg, 1000 mg and 4000 mg per food allergen protein as well as ii) a 10 fold increase from the baseline reactivity threshold to each of the food allergen proteins.
Methods
This open-label, phase 1 study was performed in a single center hospital setting, with Institutional Review Board (IRB) and Investigational New Drug (IND) approvals. This project was approved by the IRB committee at Stanford University.
Participant selection
Participants were eligible for inclusion if they: (1) were older than or equal to 4 years old; had proven sensitivity to at least two food allergens documented by both (2) a skin prick test (with neat extracts from Greer Laboratories, Lenoir, NC) greater than 3 mm (wheal), and (3) food-specific IgE greater than 0.35 ku/L (ImmunoCAP); (4) had clinical reactivity to those food proven by positive allergic reaction in a double-blind placebo-controlled oral food challenge (DBPCFC) as described below; and (5) had signed informed consent. Specific food allergens that were eligible for inclusion in this trial included cow’s milk, egg, peanut, nuts, grains and sesame seed. Exclusion criteria included: (1) eosinophilic esophagitis; (2) autoimmune disease; (3) severe cardiac disease; chronic treatment with (4) beta-adrenergic antagonists or (5) steroids; (6) a history of severe anaphylaxis requiring admission to an intensive care unit; (7) frequent allergic or non-allergic urticaria; and (8) poorly controlled asthma (defined as FEV1 below 80 percent of predicted).
DBPCFCs were performed on different days and separated by 72 hours for each qualifying food allergen and for the placebo (oat, or rice flour if allergic to oat). All participants performed spirometry, as appropriate per age, and had continuous pulse-oximetry and vital sign monitoring, every 15 minutes prior to and following increasing doses of placebo or allergenic food protein. DBPCFC doses were increased over 3.5 hours up to a cumulative dose of 182 mg food protein until an objective reaction occurred. Clinical reactivity was based on Bock’s criteria (grade 1 or above) [53]. The DBPCFC procedure used was described in a previous publication [36].
DBPCFCs and dose escalations occurred in a hospital with immediate access to a trained physician and study personnel. Given that reactions are expected to occur with OIT, training for the use of and indication for auto-injectable epinephrine was given to all participants and families/guardians at screening, on the initial dose escalation day and every three months during OIT. Our method of epinephrine training was described in detail in a previously [36].
Study medications
Food flours/powders
This study used food flours/powders dispensed through a Food Flour/Powder GMP facility at Stanford (as per FDA guidelines (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070273.pdf). A Chemistry and Manufacturing Control (CMC) section for each food allergen powder/flour included assessments for stability, identity, relative sterility, and purity of each of the food powders/flours. The food flours/powders we used include milk powder (Organic Valley, WI), egg powder (Deb El, NJ), peanut flour (Byrd Mill, VA), walnut flour (Carriere Family Farms, CA), cashew flour (Digestive Wellness, NY), almond flour (Just Almonds, NV), pecan flour (Green Valley, AZ), hazelnut flour (Holmquish Hazelnut Orchards, WA), wheat flour (Gold Medal, MN), soy flour (Honeyville Grain, Inc., UT), and sesame seed flour (Dispasa USA, Inc., TX). Each dose was weighed out by a trained professional on a professional-grade balance. Flour/powder protein content was calculated according to nutritional information provided by manufacturers and confirmed through protein assays run at Stanford laboratories.
Omalizumab
Omalizumab (Genentech, CA) was prepared and administered according to the product insert. Doses were determined based on weight and total IgE levels as per Omalizumab Global Dosing schedule as outlined in the online supplement (Additional file 1: Table S1).
Study design
Pre-treatment with omalizumab
After enrollment, participants (n = 25) were pre-treated with omalizumab for 8 weeks according to the product insert dosing schedule to equilibrate with anti-IgE mAb (Additional file 1: Table S1). Omalizumab injections were administered at the hospital’s Clinical Translational Food Unit (CTFU) under medical supervision and patients were observed for at least one hour after injection.
Initial escalation
On the 9th week after the 1st injection of omalizumab, the participants underwent rapid oral desensitization to up to five offending food allergens (Figure 1). The OIT regimen was customized to what the participant was found to be allergic to in their baseline DBPCFCs. As many as 5 allergens (in 1:1:1:1:1 proportions) could be included in an OIT treatment plan, provided all selected allergens met the inclusion criteria.
Figure 1
Rush mOIT protocol timeline. Amount of maintenance dose depends on number of allergens dosed (4000 mg per allergen). *Double-blind, placebo-controlled food challenges (DBPCFCs).
All participants were admitted to the CTFU (clinical trial food unit) and vital signs (heart rate, respiratory rate, temperature, blood pressure and pulse oximetry) were monitored every 15 minutes. Trained clinical staff administered doses of food allergen. Antihistamines, inhaled beta-2 agonists, prednisolone, and injectable epinephrine were all readily available at the bedside.
On the initial escalation day, dosing began at 5 mg total food allergen protein divided equally between each of the offending food allergens (i.e. 1 mg protein of each allergen if 5 were given) and doses were slowly increased until the participant reached a final dose of 1250 mg protein (i.e. up to 250 mg protein of each offending food allergen if the participant’s regimen included 5 allergens). Food allergens were given over a period of 2.5 hours as outlined in Table 1. Participants were monitored for vital signs and physical assessments throughout the dosing process and were observed for an additional 2 hours after receiving the final dose. The highest tolerated dose (i.e. with no clinical reactivity) determined the participant’s starting daily home dose (up to a total dose of 1250 mg protein, divided evenly into each of the separate offending food allergens).
Table 1
Rush mOIT initial escalation day schedule
Dose in mg of protein
Dosing interval in minutes
5
30
50
30
150
30
300
30
625
30
1250
120
Home dosing
Individual doses were provided containing all of the participant’s allergens. Participants were instructed to ingest their dose after a full meal at approximately the same time each day. Each food allergen was given simultaneously in applesauce or pudding (or another medium the participant had shown tolerance to during placebo challenge). They were instructed not to miss their daily dose. Participants and their families were given instructions on how to monitor for reactions at home and record any symptoms in their dosing diary. Research staff kept in close contact with participants and families to investigate and document any adverse events. All families and participants had 24-hour contact information for study personnel in case of an allergic reaction and/or questions at any point during the study. All participants were provided with injectable epinephrine devices, oral antihistamines, and a treatment plan for possible allergic reactions. They were trained on the use of self-injectable epinephrine. Participants were instructed to avoid physical exertion 1 hour before and 2 hours after dosing and to contact the on-call service in the event of infection or environmental allergies. The goal of the OIT was to achieve a daily maintenance dose of 4000 mg protein of each allergen (up to 20,000 mg protein cumulative dose for participants taking 5 allergens in their OIT).
Dose escalation
The participants returned to the CTFU every two weeks for a dose escalation visit with daily home diaries, which detailed any symptoms that occurred and treatments given during the daily home dosing for the prior 2 weeks. Staff reviewed the dose diaries with the participants and their families at each visit. If home daily protein flour/powder doses had been well tolerated, the dose was increased in the hospital setting according to a predetermined scale as outlined in Table 2. Trained clinicians in the CTFU monitored participants for at least one hour following their new dose. If the new dose was tolerated, it subsequently became their daily dose for the following two weeks; otherwise they continued on their previous dose. Importantly, OIT protocols did not advance according to a fixed calendar, but, rather were individualized according to participants’ allergic reactions and safety outcomes.
Table 2
Rush mOIT dose escalation schedule
Dose of protein (mg)
Interval in weeks
% of increase from previous
2350 mg
2
88%
4000 mg
2
70%
5800 mg
2
45%
7600 mg
2
50%
9400 mg
2
30%
11200 mg
2
20%
14000 mg
2
25%
17500 mg
2
25%
20000 mg
2
14%
Omalizumab discontinuation
Omalizumab treatment was discontinued 8 weeks after the initial escalation day of food allergens, totaling 16 weeks total of omalizumab treatment.
Allergy testing
Peanut was the most frequent food allergen determined in the 25 participants (Additional file 1: Tables S2). Specific skin prick test (peanut extract from Greer Laboratories, Lenoir, NC) and serologies were compared at baseline and after a year of therapy. Sera were analyzed for peanut-specific IgE and IgG4 levels at John Hopkins Allergy and Clinical Immunology Reference Laboratory by immunoCAP FEIA (Thermofisher Scientific/Phadia, Kalmazoo, MI). IgE antibody levels < 0.1 kUA/L and IgG4 antibody levels <0.01 kUA/L were considered undetectable.
Statistical analysis
Dose progression was measured as the time to reach: 1) a 10-fold increase from initial cumulative dose eliciting a reaction on DBPCFC to each food allergen; as well as doses of 2) 300 mg; 3) 1000 mg; and 4) 4000 mg protein per food allergen. Food allergy testing results before and after therapy were compared with the Wilcoxon paired T test. All analyses were performed using GraphPad PRISM software version 6.0b (GraphPad, LaJolla, CA).
Results
Overall
Of a total of 53 participants screened, 25 met inclusion criteria and were enrolled in the phase 1 protocol. Detailed food allergen diagnoses are available in the online supplement (Additional file 1: Tables S3). Initial baseline clinical characteristics and number of allergens are presented in Table 3.
Table 3
Subjects baseline characteristics
Number of subjects
25
Median age in yrs (range)
7.4 (4.5-15.4)
Male
19 (76%)
Clinical reaction
Respiratory
5 (20%)
Gastro-intestinal
13 (52%)
Epinephrine
1 (4%)
Number of foods dosed
2
7 (28%)
3
4 (16%)
4
7 (28%)
5
7 (28%)
Peanut baseline allergy test (if included in mix) (median and range)
SPT in mm
13 (3.5-26)
Specific IgE in kUa/L
31 (1–192)
Lowest amount triggering reaction in DBPCFC in mg protein
15.5 (1.6-100)
Highest baseline allergy test (median and range)
SPT in mm
17 (6–29.5)
Specific IgE in kUa/L
66 (2–256)
Lowest amount triggering reaction in DBPCFC in mg protein
6 (0.1-100)
Total IgE in kuA/L (median and range)
645 (67–1829)
Over the study period, there were 3 withdrawals because of non-compliance with study medication. Overall, a total of 227 hospital-based dose escalation doses and 7,530 home doses were given (Table 4). Throughout the study, no participant missed more than 3 doses consecutively as recorded per their dose diaries.
Table 4
Reaction rates with rush mOIT
Initial escalation day
Escalations performed
25
Reactions
13 (52%)
Mild (Grade 1)
13 (52%)
Moderate (Grade 2)
0
Severe (Grade 3)
0
Epinephrine use
0
Dose escalations
Doses administered
227
Reactions
13 (5.7%)
Mild (Grade 1)
13 (5.7%)
Moderate (Grade 2)
0
Severe (Grade 3)
0
Median reaction rate [range]
0% [0–25]
Epinephrine use
0
Home dosing
Doses administered
7530
Reactions
401 (5.3%)
Mild (Grade 1)
385 (5.1%)
Moderate (Grade 2)
15 (0.2%)
Severe (Grade 3)
1 (0.01%)
Median reaction rate [range]
3.2% [0.1-18.5]
Epinephrine use
1 (0.01%)
Safety
Rates and nature of dose reactions are depicted in Figure 2 for initial dose escalation day, dose escalations, and home dosing. Most (94%) allergic reactions were mild and included mainly abdominal pain, pruritus, and local ENT symptoms. Although 13 participants (52%) experienced some symptom on their initial dose escalation day, 19 (76%) were able to reach the full 1250 mg of food protein total. With home dosing, 401 of the 7530 doses (5.3%) triggered reactions with a median reaction rate of 3.2 per 100 doses [0.1-18.5]. Most home reactions occurred in the first months of therapy, with reaction rates dropping by 70% after 6 months of therapy, from 11 to 3 reactions per 100 doses (p < 0.0001) (Figure 3).
Figure 2
Symptom occurrence during rush mOIT with (A) initial escalation day, (B) dose escalations and (C) home dosing.
Figure 3
Time distribution of home dosing reactions for the first year of rush mOIT.
Throughout the trial, there were no serious adverse events. One severe reaction occurred shortly after reaching maintenance phase (16,000 mg) in a participant desensitized to peanut, almond, milk and egg. He presented with wheezing, abdominal pain and throat tightness 30 minutes after his dose, which resolved 5 minutes after the self-injection of epinephrine. The family did not report any obvious triggers such as exercise or viral infection.
Dose progression
As up-dosing was dependent on tolerance to the current dose, dose progression was treated as a marker of tolerability. Kaplan-Meier curves showing time to reach and maintain a 10-fold increase in threshold dose of index food allergen protein, as well as time to reach a dose of 300 mg, 1000 mg, and 4000 mg per food allergen protein are presented in Figure 4. The median time to reach maintenance dose (4000 mg per allergen) was 18 weeks [7–36 weeks] with all participants able to reach this dose by 9 months. All participants had reached a dose equivalent to a 10-fold increase of all their allergens by 2 months of therapy.
Figure 4
Kaplan-Meier curves showing (A) time to reach the dose corresponding to a 10 fold increase from the threshold at which the patient reacted to index foods on initial DBPCFC (each food reported as a separate event) as well as (B) time to dose of 300 mg, 1000 mg, and 4000 mg protein per each allergen.
Allergy testing
After 52 weeks of therapy, peanut-specific IgE (PN-IgE) did not change significantly (Figure 5). However, peanut-specific IgG4 (PN-IgG4) levels showed median increases of 8.23 mgA/L (p < 0.0001) while peanut SPT decreased by a median of 8 mm (p < 0.0001).
Figure 5
Peanut specific (A) IgE, (B) IgG4, (C) IgE/IgG4 ratio and (D) skin prick test results at baseline and after a year of therapy for participants with proven peanut allergy (* indicates p < 0.0001).
Discussion
In this phase 1 safety study, we have shown that participants allergic to multiple foods were safely and rapidly desensitized to up to five food allergens simultaneously, using a rush OIT protocol with concomitant treatment with omalizumab. To the best of our knowledge, this is the first study to use omalizumab with OIT to multiple allergens simultaneously. These findings are particularly relevant considering the already high (~30%) and likely growing number of food allergic participants who are sensitized to more than one food allergen [3, 53–56].
This study was designed as a proof of concept, open-label phase 1 study, with safety measurements as the primary endpoint. The rate of reactions observed in the rush mOIT group was similar to a group with the same eligibility and demographics undergoing mOIT in a previous study without omalizumab, despite the more rapid desensitization schedule [36]. The goal of adding omalizumab in this phase 1 study was primarily to enable rapid desensitization rather than to suppress allergic symptoms during OIT.
As the half-life of omalizumab is 24 days, we further hypothesized that any protective safety effect might wane over time. Participants were observed closely for the development of symptoms, including hives, worsening of eczema, or wheezing after omalizumab discontinuation (at 8 weeks after initial dose escalation), and were instructed to keep a diary of food allergy symptoms throughout the study. Our data show that the home reaction rate actually went down after 24 weeks of therapy from 11 to 3 per 100 doses (p < 0.0001) (Figure 4). This increase in safety could relate to the fact that participants were not up-dosing anymore at that point. However, the only use of epinephrine occurred shortly after the participant had reached the maintenance phase, thus vigilance should not be relaxed at any point. Rescue epinephrine was also required during the maintenance phase of previous rush studies using omalizumab (2 of 2 and 1 of 4 in peanut and milk rush OIT respectively) [28, 52].
In addition to the safety data, this phase 1 study of rush mOIT provides initial preliminary evidence of increased dose tolerability. The median time at which participants on rush mOIT reached their maintenance dose (4000 mg per allergen) was 67 weeks earlier than that reported in a previous report on mOIT without omalizumab [36]. This represents a difference of about 34 dose escalations and about 67 additional weeks of enrollment. This might be relevant from a pharmaco-economic perspective. Considering a cost per visit in 2013 of approximately $160 [approximate cost of an office open food challenge per MediCare or public health insurance in Canada (RAMQ)], those 34 extra visits represent a minimal additional cost of approximately $5,440 in 2013 [57]. This could possibly offset the cost of omalizumab at the current time, which varies between $2,164 and $10,824 for 16 weeks, depending on the patient’s weight and total IgE levels. Furthermore, these calculations do not take into account the additional cost and impact of absenteeism from school and work for the participant and his/her parents during these approximate 34 additional visits [4]. However, one should be cautious when comparing these two phase 1 trials as the dose progression schedules were different. A phase 2 study comparing omalizumab to placebo in participants with a similar dosing schedule is needed to truly assess the efficacy gained from the addition of omalizumab to mOIT.
There are limitations to this study. Oral immunotherapy regimens were customized to the participant’s food allergies. This has led to some diversity when comparing the composition of specific food allergies between subjects. However, no one food allergen was found to be associated with greater dose tolerability or safety. This is consistent with one of the key long term goals of the study which was to begin to develop customized, patient-based, regimens for oral immunotherapy that could be tested for safety, and dose tolerability.
Importantly, our study showed desensitization but not tolerance. Clinical tolerance is proven by demonstrating sustained unresponsiveness to the food after stopping the maintenance dose for a prolonged period of time. Future phase 2 trials on the use of omalizumab combined with OIT will be useful to see if omalizumab affects this outcome.
Our cohort did not include subjects with high total serum IgE levels as this is sometimes the case for children with multiple food allergies. Three subjects had total serum IgE slightly greater than 1500 kUa/L and received the maximum dose of Omalizumab (600 mg every 2 weeks). The optimal dosing for subjects with higher levels would require further study.
Serological analyses were performed for peanut to allow for consistent comparisons between participants, as this was the most frequent allergen. The serologic changes after 52 weeks of therapy were identical to those previously reported in subjects undergoing non-rush OIT (without omalizumab) [36, 58].
In conclusion, the data from a single site, phase 1 study demonstrate that a rush OIT protocol to multiple food allergens using adjunct omalizumab can be performed safely in a hospital setting. At this time, rush mOIT is an experimental treatment and should be conducted by trained research personnel with immediate access to emergency equipment. Phase 2, blinded, multicenter trials are needed to continue to determine safety and efficacy parameters of rush mOIT in larger numbers of multi-sensitized participants.
Abbreviations
CTFU:
Clinical trial food unit
DBPCFC:
Double-blind placebo-controlled food challenge
EMEA:
European Medicines Agency
FDA:
Food and drug administration
GMP:
Good manufacturing practice
IND:
Investigational new drug
IRB:
Institutional review board
mOIT:
Multiple allergen oral immunotherapy
PN-IgE:
Peanut specific Immunoglobulin E
PN-IgG4:
Peanut specific immunoglobulin G4
SPT:
Skin prick test.
Declarations
Acknowledgement
The authors would like to acknowledge Bruce Barnett, PhD and Jelena Berglund, PhD for their review of good manufacturing practices. Funding for this study was provided by the Fund for Food Allergy Research at Stanford. We would like to thank members of the DSMB for their review of the safety data. Philippe Bégin MD, FRCPC was supported by AllerGen NCE Inc. (the Allergy, Gene and Environment Network), a member of the Networks of Centre of Excellence Canada program. We thank the FDA for their review and feedback on the clinical trial. We thank Dr. Sharon Chinthrajah for the reading and editing of the manuscript.
Funding
Funding for this study was provided by philanthropy and by the Fund for Food Allergy Research at Stanford.
Authors’ Affiliations
(1)
Allergy, Immunology, and Rheumatology Division, Stanford University
(2)
Dermatology, Allergy and Clinical Immunology Reference Laboratory, Johns Hopkins University School of Medicine
References
McGowan EC, Keet CA: Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007–2010. J Allergy Clin Immunol. 2013, 132 (5): 1216-9. 10.1016/j.jaci.2013.07.018.PubMedGoogle Scholar
Soller L, Ben-Shoshan M, Harrington DW, Fragapane J, Joseph L, St Pierre Y: Overall prevalence of self-reported food allergy in Canada. J Allergy Clin Immunol. 2012, 130 (4): 986-988. 10.1016/j.jaci.2012.06.029.PubMedGoogle Scholar
Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J: The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011, 128 (1): e9-e17. 10.1542/peds.2011-0204.PubMedGoogle Scholar
Gupta R, Holdford D, Bilaver L, Dyer A, Holl JL, Meltzer D: The economic impact of childhood food allergy in the United States. JAMA Pediatr. 2013, 137 (11):Google Scholar
Sicherer SH, Noone SA, Munoz-Furlong A: The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol. 2001, 87 (6): 461-464. 10.1016/S1081-1206(10)62258-2.PubMedGoogle Scholar
Christie L, Hine RJ, Parker JG, Burks W: Food allergies in children affect nutrient intake and growth. J Am Diet Assoc. 2002, 102 (11): 1648-1651. 10.1016/S0002-8223(02)90351-2.PubMedGoogle Scholar
Savage JH, Matsui EC, Skripak JM, Wood RA: The natural history of egg allergy. J Allergy Clin Immunol. 2007, 120 (6): 1413-1417. 10.1016/j.jaci.2007.09.040.PubMedGoogle Scholar
Skripak JM, Nash SD, Rowley H, Brereton NH, Oh S, Hamilton RG: A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy. J Allergy Clin Immunol. 2008, 122 (6): 1154-1160. 10.1016/j.jaci.2008.09.030.PubMed CentralPubMedGoogle Scholar
Pajno GB, Caminiti L, Ruggeri P, De Luca R, Vita D, La Rosa M: Oral immunotherapy for cow’s milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study. Ann Allergy Asthma Immunol. 2010, 105 (5): 376-381. 10.1016/j.anai.2010.03.015.PubMedGoogle Scholar
de Boissieu D, Dupont C: Sublingual immunotherapy for cow’s milk protein allergy: a preliminary report. Allergy. 2006, 61 (10): 1238-1239. 10.1111/j.1398-9995.2006.01196.x.PubMedGoogle Scholar
Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L: Specific oral tolerance induction in children with very severe cow’s milk-induced reactions. J Allergy Clin Immunol. 2008, 121 (2): 343-347. 10.1016/j.jaci.2007.10.029.PubMedGoogle Scholar
Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG: A protocol for oral desensitization in children with IgE-mediated cow’s milk allergy. Allergy. 2004, 59 (9): 980-987. 10.1111/j.1398-9995.2004.00542.x.PubMedGoogle Scholar
Fisher HR, du Toit G, Lack G: Specific oral tolerance induction in food allergic children: is oral desensitisation more effective than allergen avoidance?: a meta-analysis of published RCTs. Arch Dis Child. 2011, 96 (3): 259-264. 10.1136/adc.2009.172460.PubMedGoogle Scholar
Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K: Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy. 2007, 62 (11): 1261-1269. 10.1111/j.1398-9995.2007.01501.x.PubMedGoogle Scholar
Dupont C, Kalach N, Soulaines P, Legoue-Morillon S, Piloquet H, Benhamou PH: Cow’s milk epicutaneous immunotherapy in children: a pilot trial of safety, acceptability, and impact on allergic reactivity. J Allergy Clin Immunol. 2010, 125 (5): 1165-1167. 10.1016/j.jaci.2010.02.029.PubMedGoogle Scholar
Dello Iacono I, Tripodi S, Calvani M, Panetta V, Verga MC, Miceli SS: Specific oral tolerance induction with raw hen’s egg in children with very severe egg allergy: a randomized controlled trial. Pediatr Allergy Immunol. 2013, 24 (1): 66-74. 10.1111/j.1399-3038.2012.01349.x.PubMedGoogle Scholar
Burks AW, Jones SM, Wood RA, Fleischer DM, Sicherer SH, Lindblad RW: Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012, 367 (3): 233-243. 10.1056/NEJMoa1200435.PubMed CentralPubMedGoogle Scholar
Hofmann AM, Scurlock AM, Jones SM, Palmer KP, Lokhnygina Y, Steele PH: Safety of a peanut oral immunotherapy protocol in children with peanut allergy. J Allergy Clin Immunol. 2009, 124 (2): 286-291. 10.1016/j.jaci.2009.03.045. e1-6PubMed CentralPubMedGoogle Scholar
Blumchen K, Ulbricht H, Staden U, Dobberstein K, Beschorner J, de Oliveira LC: Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy Clin Immunol. 2010, 126 (1): 83-91. 10.1016/j.jaci.2010.04.030. e1PubMedGoogle Scholar
Clark AT, Islam S, King Y, Deighton J, Anagnostou K, Ewan PW: Successful oral tolerance induction in severe peanut allergy. Allergy. 2009, 64 (8): 1218-1220. 10.1111/j.1398-9995.2009.01982.x.PubMedGoogle Scholar
Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M: Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009, 124 (2): 292-300. 10.1016/j.jaci.2009.05.022. e1-97PubMed CentralPubMedGoogle Scholar
Yu GP, Weldon B, Neale-May S, Nadeau KC: The safety of peanut oral immunotherapy in peanut-allergic subjects in a single-center trial. Int Arch Allergy Immunol. 2012, 159 (2): 179-182. 10.1159/000336391.PubMed CentralPubMedGoogle Scholar
Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R: Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005, 116 (5): 1073-1079. 10.1016/j.jaci.2005.08.027.PubMedGoogle Scholar
Gomez E, Mayorga C, Gomez F, Blazquez AB, Diaz-Perales A, Blanca M: Food allergy: management, diagnosis and treatment strategies. Immunotherapy. 2013, 5 (7): 755-768. 10.2217/imt.13.63.PubMedGoogle Scholar
Sabato V, Faber M, Van Gasse A, Hagendorens MM, Leysen J, Bridts CH: State of the art and perspectives in food allergy (part II): therapy. Curr Pharm Des. 2013, EPub May 17 2013Google Scholar
Nadeau KC, Kohli A, Iyengar S, DeKruyff RH, Umetsu DT: Oral immunotherapy and anti-IgE antibody-adjunctive treatment for food allergy. Immunol Allergy Clin North Am. 2012, 32 (1): 111-133. 10.1016/j.iac.2011.11.004.PubMedGoogle Scholar
Yang YH, Chiang BL: Novel approaches to food allergy. Clin Rev Allergy Immunol. 2013, EPub Jan 18 2013Google Scholar
Khoriaty E, Umetsu DT: Oral immunotherapy for food allergy: towards a new horizon. Allergy Asthma Immunol Res. 2013, 5 (1): 3-15. 10.4168/aair.2013.5.1.3.PubMed CentralPubMedGoogle Scholar
Kim EH, Burks W: Managing food allergy in childhood. Curr Opin Pediatr. 2012, 24 (5): 615-620. 10.1097/MOP.0b013e32835741e3.PubMedGoogle Scholar
Virkud YV, Vickery BP: Advances in immunotherapy for food allergy. Discov Med. 2012, 14 (76): 159-165.PubMedGoogle Scholar
Nurmatov U, Venderbosch I, Devereux G, Simons FE, Sheikh A: Allergen-specific oral immunotherapy for peanut allergy. Cochrane Database Syst Rev. 2012, 9: CD009014Google Scholar
Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, Schroeder JT, Hamilton RG, Boden S: The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol. 2012, 129 (2): 448-455. 10.1016/j.jaci.2011.10.023. e1-5PubMed CentralPubMedGoogle Scholar
Bégin P, Wintheroth L, Dominguez T, Wilson SP, Bacal L, Mehrotra A: Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. Allergy Asthma Clin Immunol. 2014, 10 (1): 1-10.1186/1710-1492-10-1.PubMed CentralPubMedGoogle Scholar
Leung DY, Sampson HA, Yunginger JW, Burks AW, Schneider LC, Wortel CH: Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med. 2003, 348 (11): 986-993. 10.1056/NEJMoa022613.PubMedGoogle Scholar
Sampson HA, Leung DY, Burks AW, Lack G, Bahna SL, Jones SM: A phase II, randomized, doubleblind, parallelgroup, placebocontrolled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J Allergy Clin Immunol. 2011, 127 (5): 1309-1310. 10.1016/j.jaci.2011.01.051. e1PubMedGoogle Scholar
Iyengar SR, Hoyte EG, Loza A, Bonaccorso S, Chiang D, Umetsu DT: Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial. Int Arch Allergy Immunol. 2013, 162: 89-93. 10.1159/000350486.PubMed CentralPubMedGoogle Scholar
Bedoret D, Singh AK, Shaw V, Hoyte EG, Hamilton R, DeKruyff RH: Changes in antigen-specific T-cell number and function during oral desensitization in cow’s milk allergy enabled with omalizumab. Mucosal Immunol. 2012, 5 (3): 267-276. 10.1038/mi.2012.5.PubMed CentralPubMedGoogle Scholar
Savage JH, Courneya JP, Sterba PM, Macglashan DW, Saini SS, Wood RA: Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy. J Allergy Clin Immunol. 2012, 130 (5): 1123-1129. 10.1016/j.jaci.2012.05.039. e2PubMed CentralPubMedGoogle Scholar
MacGlashan DW, Savage JH, Wood RA, Saini SS: Suppression of the basophil response to allergen during treatment with omalizumab is dependent on 2 competing factors. J Allergy Clin Immunol. 2012, 130 (5): 1130-1135. 10.1016/j.jaci.2012.05.038. e5PubMed CentralPubMedGoogle Scholar
Lieberman JA, Chehade M: Use of omalizumab in the treatment of food allergy and anaphylaxis. Curr Allergy Asthma Rep. 2013, 13 (1): 78-84. 10.1007/s11882-012-0316-x.PubMedGoogle Scholar
Patil SP, Wang J, Song Y, Noone S, Yang N, Wallenstein S: Clinical safety of food allergy herbal formula-2 (FAHF-2) and inhibitory effect on basophils from patients with Food allergy: extended phase I study. J Allergy Clin Immunol. 2011, 128 (6): 1259-1265. 10.1016/j.jaci.2011.06.015. e2PubMed CentralPubMedGoogle Scholar
Gernez Y, Tirouvanziam R, Yu G, Ghosn EE, Reshamwala N, Nguyen T: Basophil CD203c levels are increased at baseline and can be used to monitor omalizumab treatment in subjects with nut allergy. Int Arch Allergy Immunol. 2011, 154 (4): 318-327. 10.1159/000321824.PubMed CentralPubMedGoogle Scholar
Yu GP, Tuano KS, Hamilton RG, Nadeau KC: Omalizumab in peanut-allergic patients reduces free IgE anti-peanut and skin prick test to peanut. J Allergy Clin Immunol. 2010, 125 (2 Supp 1): AB22-Google Scholar
Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT: Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy. J Allergy Clin Immunol. 2011, 127 (6): 1622-1624. 10.1016/j.jaci.2011.04.009.PubMed CentralPubMedGoogle Scholar
Klunker S, Saggar LR, Seyfert-Margolis V, Asare AL, Casale TB, Durham SR: Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: Inhibition of IgE-facilitated allergen binding. J Allergy Clin Immunol. 2007, 120 (3): 688-695. 10.1016/j.jaci.2007.05.034.PubMedGoogle Scholar
Parks KW, Casale TB: Anti-immunoglobulin E monoclonal antibody administered with immunotherapy. Allergy Asthma Proc. 2006, 27 (2 Suppl 1): S33-S36.PubMedGoogle Scholar
Schneider LC, Rachid R, Lebovidge J, Blood E, Mittal M, Umetsu DT: A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients. J Allergy Clin Immunol. 2013, 132 (6): 1368-1374. 10.1016/j.jaci.2013.09.046.PubMed CentralPubMedGoogle Scholar
Bock SA, Sampson HA, Atkins FM, Zeiger RS, Lehrer S, Sachs M: Double-blind, placebo-controlled food challenge (DBPCFC) as an office procedure: a manual. J Allergy Clin Immunol. 1988, 82 (6): 986-997. 10.1016/0091-6749(88)90135-2.PubMedGoogle Scholar
Wang J, Visness CM, Sampson HA: Food allergen sensitization in inner-city children with asthma. J Allergy Clin Immunol. 2005, 115 (5): 1076-1080. 10.1016/j.jaci.2005.02.014.PubMedGoogle Scholar
Wang J: Management of the patient with multiple food allergies. Curr Allergy Asthma Rep. 2010, 10 (4): 271-277. 10.1007/s11882-010-0116-0.PubMed CentralPubMedGoogle Scholar
Park JH, Ahn SS, Sicherer SH: Prevalence of allergy to multiple versus single foods in a pediatric food allergy referral practice. J Allergy Clin Immunol. 2010, 125: AB216-10.1016/j.jaci.2009.07.002.Google Scholar
Food Allergy in Children and Young People: Diagnosis and Assessment of Food Allergy in Children and Young People in Primary Care and Community Settings. 2011, London: National Institute for Health and Clinical Excellence: GuidanceGoogle Scholar
Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P: A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011, 127 (3): 654-660. 10.1016/j.jaci.2010.12.1111.PubMed CentralPubMedGoogle Scholar
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