Diagnosis and management of food allergies: new and emerging options: a systematic review

Figures & data

Figure 1 Results of the database search for literature about food allergy diagnosis and management.

Table 1 Diagnosis of food allergy

Modality	Allergen	Type of study	Authors, publication year	Reference	Findings	Comments
SPT	Milk	Retrospective cohort	Bellini et al, 2011	^Citation12	Used end-point prick test to help predict results of OFC in milk-allergic children. Wheal diameter >4.5 mm in SPT with a 1/10,000 dilution of fresh milk was best able to discriminate milk-allergic patients from tolerant ones.	End-point titration is an accessible and safe test and should be considered in the diagnosis of milk allergy. This study used a cohort of patients with known milk allergy, so results may not be generalizable.
SPT and specific IgE	Peanut	Prospective cohort	Johannsen et al, 2011	^Citation14	Study of 49 preschoolers with peanut sensitization but unknown reactivity. Half of the children reacted to challenge. SPT wheal diameter of >7 mm predicted positive challenge with 83% sensitivity and 84% NPV. Specific IgE >2 kUA/L showed sensitivity of 79% and 80% NPV. Using a combination of SPT and specific IgE, results increased sensitivity to 96% and NPV to 95%.	Half of peanut-sensitized preschoolers will pass OFC. If SPT wheal diameter is <7 mm and specific IgE <2 kUA/L, there is a 5% chance of reaction to the OFC.
SPT	Egg	Cross-sectional	Tripodi et al, 2009	^Citation13	1:256 dilution of egg extract used for SPT with wheal size >3 mm was 95% specific and 100% sensitive in distinguishing a positive from a negative OFC.	As extracts are not standardized, these study results may not be reproducible.
SPT and specific IgE	Milk and egg	Retrospective cohort	Mehl et al, 2012	^Citation17	23% of children with milk allergy had discordant SPT and specific IgE results, as did 10% with egg allergy. For milk-allergic children with a positive OFC, 84% had a positive SPT response (wheal >3 mm) and 87% had specific IgE >0.35 kUA/L. For egg-allergic children, 93% with a positive SPT response had a positive OFC, and 96% with positive challenge had specific IgE >0.35 kUA/L.	SPT and specific IgE should not be used interchangeably. Low thresholds were used to qualify a positive SPT or specific IgE in this study.
Specific IgE, component testing	Peanut	Cross-sectional	Chiang et al, 2010	^Citation22	89.5% of Asian children with peanut allergy had detectable Ara h 1 or Ara h 2.	Milk and egg SPT and sIgE levels associated with a positive OFC were similar in Asian children with peanut allergy and Western counterparts. This study did not confirm peanut allergy with oral challenge.
Specific IgE	Peanut	Cross-sectional	van Nieuwaal et al, 2010	^Citation18	90% failed peanut challenge at specific IgE 24.8 kUA/L, and95% failed at 43.8 kUA/L.	This study reported higher specific IgE cutoff levels than others, perhaps due to examining a different population.
Specific IgE, component testing	Peanut	Experimental technique	Lin et al, 2012	^Citation23	Specific peptides Ara h 2_10, Ara h 2_18, Ara h 1_16, and Ara h 3_140 had 90% sensitivity and 95% specificity.	This study used a novel approach to the diagnosis of peanut allergy but is not yet ready for clinical application.
Specific IgE, component testing	Peanut	Cross-sectional	Asarnoj et al, 2012	^Citation21	89.5% of children who were Ara h 8 reactive could safely consume peanut.	Most children who were Ara h 8-positive and reacted had mild reactions, though some had systemic reactions.
Specific IgE, component testing	Peanut	Cross-sectional	Eller and Bindslev-Jensen, 2013	^Citation20	Best correlation between IgE and clinical thresholds was with using Ara h 2 levels >1.63 kUA/L which had a specificity of 100% and sensitivity of 70%.	Ara h 2 may be helpful in distinguishing between peanut allergy and sensitization.
Specific IgE, component testing	Peanut	Cross-sectional	Lieberman et al, 2013	^Citation19	IgE to peanut (>0.35 kUA/L) was the most sensitive test (93%) for predicting results of OFC. Ara h 2 was most specific (92%) and had the best PPV (94%).	This study used patients from three sites, some of whom were on oral immunotherapy for peanut.
Salivary specific IgA	Peanut	Prospective cohort	Kulis et al, 2012	^Citation24	Salivary peanut-specific IgA increased in patients receiving SLIT compared to controls, but did not change significantly over a 12-month period of treatment.	Increased levels of salivary peanut-specific IgA are induced by the SLIT intervention although it is not clear if it might serve to predict effectiveness of SLIT.
Specific IgE, component testing	Egg	Retrospective cohort	Montesinos et al, 2010	^Citation25	Egg white-specific IgE of 1.52, 1.35, and 2.59 kUA/L predicted reactivity in patients aged 2–3, 3–4, and 4–5 years, respectively.	Retrospective study finding that children who outgrow egg allergy had significantly lower specific IgE to egg white, OVA, and OVM.
Specific IgE, component testing	Egg	Cross-sectional	Alessandri et al, 2012	^Citation27	94% of Gal d 1-negative patients tolerated boiled egg and95% of Gal d 1-positive patients reacted to raw egg.	Gal d 1 IgE reactivity is a good predictor of clinical egg allergy. This study does not discuss baked egg versus boiled egg.
Specific IgE, component testing	Egg	Cross-sectional	Caubet et al, 2012	^Citation26	In children who were allergic to both raw and baked egg there were higher ratios of specific IgE/IgG for OVA and OVM antigens compared to children who could tolerate baked egg. IgG4 levels themselves did not differ significantly between the two groups.	IgE/IgG4 ratio may be useful in diagnosis of baked egg-tolerant children.
Specific IgE, SPT	Sesame	Cross-sectional	Permaul et al, 2009	^Citation28	Specific IgE >7 kUA/L was >90% specific. SPT wheal diameter of >6 mm was >90% specific.	This study offers SPT and specific IgE values to help predict the likelihood of positive reaction in OFC to sesame.
Specific IgE	Wheat and soy	Cross-sectional	Komata et al, 2009	^Citation29	Median specific IgE in wheat-allergic children was 4.31 kUA/L, and in soybean-allergic children 3.89 kUA/L.	Increasing levels of specific IgE are associated with increased risk of failed OFC in wheat- and soybean-allergic patients. In wheat allergy, age influences this relationship, with younger children being more likely to react when specific IgE levels were low.
OFC	Milk	Cross-sectional	Correa et al, 2010	^Citation111	OFC in Brazilian children on a milk-free diet to assess for immediate and delayed reactions (up to 30 days). 23.1% of patients had a positive challenge.	This study did not assess IgE-mediated illness. Those with a history of anaphylaxis were excluded from the study.
OFC	Milk	Prospective cohort	Mendonça et al, 2012	^Citation37	46 children with a clinical history of reaction to milk and a positive SPT response underwent challenge. Challenge was positive in 41.3%. Cutaneous symptoms were the most common (73.7%), followed by respiratory (57.9%) and gastrointestinal (36.8%). Reactions were classified as mild (57.9%), moderate (36.8%), or severe (5.3%). Epinephrine was not used in any of the patients.	OFC is safe and effective in establishing the diagnosis of milk allergy.
SPT, specific IgE, OFC	Milk(baked)	Retrospective chart review	Bartnikas et al, 2012	^Citation39	Among 35 baked milk challenges, 83% passed. Of the six who failed, 50% passed the initial challenge but developed symptoms at home with ongoing exposure. Children with an SPT wheal diameter of <12 mm were 90% likely to pass the baked milk challenge. No child with wheal diameter of <7 mm failed the baked milk challenge.	Most milk-allergic children tolerate baked milk. Some children who initially pass the baked milk challenge may develop symptoms with ongoing exposure at home.
OFC	Milk	Prospective cohort	Dambacher et al, 2013	^Citation38	116 participants underwent OFC for milk. In 66%, diagnosis of milk allergy was rejected. Of the remaining patients, 32% had an acute reaction, 39% had a late reaction, and 29% had both reactions. Infants had a higher minimum eliciting dose than older children.	OFC is important in establishing the diagnosis of milk allergy and helps to avoid unnecessary elimination diets.
OFC	Milk, egg, peanut	Retrospective chart review	Mudd et al, 2009	^Citation112	41% of patients who failed their initial OFC to milk, peanut, or egg passed a subsequent challenge to the same food. Severe reaction with the initial challenge was a predictor of failure of subsequent challenge with milk.	As a retrospective chart review, there may be several uncontrolled factors.
OFC	Milk, egg, cod, soy, wheat	Cross-Sectional	Winberg et al, 2013	^Citation44	Validation study of recipes used in DBPCFC for milk, egg, soy, cod, and wheat. 275 children aged 8–10 or 14–15 years could not detect any sensorial differences between the active culprit food and placebo for any of the challenge foods.	Provides a range of validated recipes for DBPCFC for several foods that are easy to prepare and use the same liquid test vehicle.
OFC	Egg	Prospective cohort	Escudero et al, 2013	^Citation43	Challenged egg-allergic patients to both dried egg white and raw egg white. 25% of patients reacted to both dried egg white and raw egg white. 75% did not react to either.	Dried egg white is suitable for use in OFC and has some advantages over raw egg.
OFC	Peanut	Prospective cohort	Glaumann et al, 2013	^Citation36	To evaluate the reproducibility of OFC, 27 peanut-allergic patients underwent a DBPCFC followed by a single-blind OFC. A novel test, basophil allergen threshold sensitivity (CD-sens), evaluating basophil allergen threshold sensitivity, was also used. 48% did not react to either challenge; 52% reacted at both. CD-sens testing was not reproducible.	OFCs are 100% reproducible for both negative and positive tests. Peanut allergen sensitivity threshold was not reproducible using the CD-sens test.
OFC		Retrospective chart review	Lieberman et al, 2011	^Citation34	701 OFCs performed in 521 patients. Reactions were elicited in 132 (18.8%) cases. 1.7% of the reactions required treatment with epinephrine.	OFC performed in an outpatient setting under appropriate supervision is safe. It is an important step in establishing the diagnosis of food allergy and avoiding unnecessary elimination diets.
OFC		Retrospective chart review	Fleischer et al, 2011	^Citation32	Following OFCs in children with elimination diets based on immunoassays, 84%–93% were able to reintroduce foods they had been avoiding.	This study examined a population of children referred to a specialized care centre. OFC is an essential element in the diagnosis of food allergy. Relying solely on immunoassays can result in unnecessary elimination diets.
OFC		Retrospective chart review	Calvani et al, 2012	^Citation35	Of 544 OFCs analyzed, 48.3% were positive, of which 65.7% were mild. 31.9% of those who reacted had multiorgan involvement, and 2.4% had anaphylaxis. Antihistamines were the most commonly used treatment during challenge.	OFCs are safe when performed by an allergist in the appropriate setting.
OFC		Review	Järvinen and Sicherer, 2012	^Citation33	Food-specific IgE tests are helpful biomarkers of allergy, but lack sensitivity and specificity. OFC remains the standard for diagnosis of reactivity. IgE testing does not assess for non-IgE-mediated reactions.	Review article providing an overview on technique and interpretation of OFCs.
OFC		Review	Asero et al, 2009	^Citation4	While DBPCFC is the gold standard for diagnosis of food allergy, it is clinically cumbersome and difficult to perform. Open challenges have fewer disadvantages.	Discretion is needed when deciding whether a patient needs a food challenge, and whether it should be DBPCFC or open.
OFC		Prospective cohort	van der Velde et al, 2012	^Citation41	Health-related QOL scores improved after DBPCFC, with greater improvement after negative challenge than positive challenge. There was longitudinal validity of the Food Allergy Quality of Life Questionnaire.	When indicated, OFC should be performed, as health-related QOL improves following this assessment.
OFC	Peanut, tree nuts	Prospective cohort	Knibb et al, 2012	^Citation42	40 patients and their mothers completed questionnaires before and 3–6 months after OFC. Both parent and child experienced improved food-related QOL after challenge. Patient anxiety levels were decreased after challenge, while parental anxiety remained the same. Improvement was independent of challenge outcome, despite coexisting food allergies in 50% of children.	OFC is associated with increased parental anxiety on the day of the challenge but leads to improved QOL and decreased patient anxiety following challenge.
OFC		Cross-sectional	Indinnimeo et al, 2013	^Citation40	Reported QOL was worse among those with a history of anaphylaxis and aged >3 years. Duration of exclusion diet had a significant impact on QOL for milk-allergic children but not children with other food allergies.	Elimination diets negatively impact QOL. They must only be employed when necessary and for the shortest duration possible.
Gut tryptase		Cross-sectional	Hagel et al, 2013	^Citation113	Patients with gastrointestinal symptoms of food allergy had elevated levels of tryptase in gut mucosa compared to controls.	Novel approach in investigation of food allergy, but clinical relevance and application may not warrant its use.
Specific IgG		Cross-sectional	Zeng et al, 2013	^Citation30	Food-specific IgG is variable in symptomatic and healthy Chinese adults.	Specific IgG is not a reliable means of diagnosing food allergy.

Abbreviations: DBPCFC, double-blind, placebo-controlled food challenge; IgA, immunoglobulin A; IgE, immunoglobulin E; IgG₄, immunoglobulin G, type 4; NPV, negative predictive value; OFC, open food challenge; OVA, ovalbumin; OVM, ovomucoid; PPV, positive predictive value; QOL, quality of life; SLIT, sublingual immunotherapy; SPT, skin prick test.

Table 2 Management of food allergy

Modality	Allergen	Type of study	Authors, publication year	Reference	Findings	Comments
Prevention in pregnancy	Peanut	Retrospective	Sicherer et al, 2010	^Citation46	In a cohort of infants with likely milk or egg allergy, frequent peanut consumption (OR 2.9), IgE levels to milk and egg, male sex, and non-white race were associated with peanut-sIgE >5 kUA/L.	Maternal peanut consumption during pregnancy may be associated with sensitization of infants, although allergy was not evaluated.
Prevention in pregnancy	Peanut	Retrospective	DesRoches et al, 2010	^Citation48	Mothers of peanut-allergic children reported higher consumption of peanut during pregnancy and breastfeeding (OR 4.22, 1.57–11.30 [95% CI]; 0.28, 1.31–3.97 [95% CI]).	Recall bias may have influenced the results of this study.
Prevention in pregnancy		RCT	West et al, 2012	^Citation51	Higher maternal vitamin C intake showed a trend toward a reduced association with wheeze, although it was not statistically significant (P=0.06). Increased maternal copper intake was associated with reduced risk of wheeze and eczema, but not food allergy.	Maternal antioxidant intake may influence the development of allergic disease in children. Particularly, increased dietary copper may reduce wheeze and eczema at 1 year. There was no significant effect on food allergy.
Prevention in pregnancy		RCT	Palmer et al, 2012	^Citation52	No significant difference at age 1 year between children of mothers who were supplemented with polyunsaturated fatty acids during pregnancy and controls.	Polyunsaturated fatty acid supplementation during pregnancy does not reduce the risk of allergic disease in childhood.
Prevention in pregnancy	Peanut, tree nuts, sesame	Cross-sectional	Hsu et al, 2013	^Citation47	Maternal consumption of tree nut and sesame seed during the first two trimesters was associated with a 60% higher risk of having a child sensitized to tree nut, peanut, or sesame seed. Children with asthma and environmental allergies had increased risk of sensitization.	Maternal consumption of tree nut and sesame seed leads to greater risk of having a child who is sensitized to tree nut, peanut, or sesame seed. This study did not evaluate allergy to these foods.
Prevention in infancy	Egg	Cross-sectional	Koplin et al, 2010	^Citation59	Compared with introduction at 4–6 months of age, later introduction was associated with higher risk of egg allergy (OR 1.6 for 10–12 months, 3.4 for >12 months). At age 4–6 months, first exposure to cooked egg (boiled, scrambled, fried, or poached) reduced the risk of egg allergy compared to first exposure to egg in baked goods (egg-containing cakes or biscuits or similar products) (OR 0.2). Duration of breastfeeding and age of introduction of solids were not associated with egg allergy.	Introduction of cooked egg between 4 and 6 months of age may be protective. Optimal timing of introduction of foods to induce tolerance remains under investigation.
Prevention in infancy	Milk	Prospective cohort	Katz et al, 2010	^Citation58	Incidence of IgE-mediated milk allergy was 0.5%. The mean age of introduction of cow’s milk was different between healthy infants (61.6 days) and milk-allergic infants (116.1 days).	Early exposure to cow’s milk may promote tolerance.
Prevention in infancy		RCT	Jensen et al, 2012	^Citation53	High-risk children randomized to receive probiotics or placebo for first 6 months of life. Long-term follow-up showed no significant difference in allergic disease between the groups at age 5 years.	Early probiotic supplementation does not reduce the risk of allergic disease in childhood.
Prevention in infancy		RCT	D’Vaz et al, 2012	^Citation56	There was no association between fish oil supplementation and allergic disease.	Fish oil supplementation does not prevent childhood allergic disease.
Prevention in infancy		Case-control	Grimshaw et al, 2013	^Citation57	Infants diagnosed with food allergy at 2 years were introduced to solids earlier (<16 weeks) and were less likely to be receiving breast milk when cow’s milk was introduced.	Optimal timing for introduction of foods to induce tolerance is unknown.
Prevention in infancy		RCT	Loo et al, 2014	^Citation55	Infants from birth to 6 months of age received cow’s milk formula with or without probiotic supplements. At the age of 5 years, there were no significant differences between the groups in the proportion of children who developed asthma, allergic rhinitis, eczema, or food allergy.	Probiotic supplementation during infancy does not protect against the development of allergic disease in childhood.
Prevention in infancy		RCT	West et al, 2013	^Citation54	25% of patients in the probiotic treatment group versus 35% of controls had some type of allergic disease.	Probiotic supplementation during infancy does not protect against allergic disease at age 8–9 years.
Prevention in childhood		Cross-sectional	DeMuth et al, 2013	^Citation60	Children presenting to allergy clinic with a history of parent-reported antacid use had a higher prevalence of food allergy (57%) compared to controls (32%). Patients who had taken antacids also had higher mean peanut-sIgE levels than controls (11.0 ± 5.0 kUA/L versus 2.0 ± 5.5 kUA/L; P= 0.01)	In a cohort of children presenting to allergy clinic, parent-reported antacid use was associated with an increased risk of food allergy.
Prevention – allergen avoidance	Milk	Cross-sectional	Boyano-Martínez et al, 2009	^Citation67	40% of children with milk allergy had accidental exposure resulting in allergic reactions: 53% mild, 32% moderate, 15% severe.	Accidental exposures to milk in milk-allergic children are common.
Prevention – allergen avoidance	Milk	Prospective cohort	Tuokkola et al, 2010	^Citation66	85% of families adhered to the milk-elimination diet. Older children and those who were mono-sensitized were more likely to have some milk in their diet.	It is unclear whether the children in the study were avoiding milk for IgE-mediated allergy or intolerance. The participants in the study were receiving special infant formula reimbursement, so this may partially account for the high rate of adherence.
Prevention – allergen avoidance	Milk (cow versus camel)	Prospective cohort	Ehlayel et al, 2011	^Citation68	80% of cow’s milk-allergic children had a negative SPT response to camel milk and could safely ingest it. Children with a positive SPT response to camel milk were not challenged.	Patients in this study were not challenged to cow’s milk to confirm allergy; it is possible they acquired tolerance. Camel milk could be a safe alternative to cow’s milk, but this may not be practical depending on cultural influences.
Prevention – allergen avoidance		Cross-sectional	Sakellariou et al, 2010	^Citation71	The percentage of people able to correctly identify more than 50% of the terms associated with a given allergen were: 4.8% of the general population, 2.9% of parents of food-allergic children, and 39.5% of health care professionals without a history of food allergy. Females, those with higher education, and those with a history of food allergy scored more highly.	Consumer confusion regarding labeling for food allergies is prevalent. Labeling must state exact terms for each allergen, and “may contain” statements should be limited to avoid misleading labels.
Prevention – allergen avoidance		Review	Turner et al, 2011	^Citation73	A review of food-labeling practices detailing both the consumers’ and manufacturers’ perspectives. Overly stringent labeling measures reduce options for allergic individuals, leading to anxiety and affecting QOL.	The current system of food labeling is not beneficial for manufacturers, consumers, or health professionals. A standardized risk assessment tool such as VITAL could help improve food-labeling practices.
Prevention – allergen avoidance	Seafood	Cross-sectional	Ng et al, 2011	^Citation65	25% of seafood-allergic patients seen in allergy clinic were unable to recall dietary advice provided. Nonetheless 89% of all parents implemented a safe diet, but over half of the 89% followed a more stringent elimination diet than needed. 1/5 had allergic reactions to seafood after diagnosis. Prescription of an EAI was associated with improved adherence.	Food allergy has a detrimental effect on QOL. Many parents have difficulty recalling dietary advice given and implement more stringent diets than necessary.
Prevention – allergen avoidance		Prospective cohort	Pulcini et al, 2011	^Citation74	A survey of Mississippi, USA public school nurses found that 97% of schools had at least one food-allergic student. 30% of schools had food allergy action plans. Action plans were more likely to exist when the nurse had received information from a physician.	Most schools have food-allergic students, but relatively few have action plans for these students.
Prevention – allergen avoidance		Cross-sectional	Ben-Shoshan et al, 2012	^Citation72	Precautionary statement “not suitable” was most effective in deterring purchase of a product. Individuals directly affected by food allergy were more likely to avoid products with “may contain”, “may be processed on the same equipment as products containing”, and “not suitable for” on the label than indirectly affected subjects. Households reporting a moderate/severe allergy were more likely to avoid.	The effect of labeling on allergic patients is complex and multifactorial. A standardized labeling process with fewer variations may be helpful for consumers in identifying which products to avoid.
Prevention – allergen avoidance		Cross-sectional	Kim et al, 2012	^Citation75	71% of schools in Korea relied on parental reports of food allergy. 47% of participating schools had experienced student visits to a school health room due to food allergy within the previous year. >80% relied on self-care without school-wide measures for food allergies.	In Korea, most schools do not have a plan for managing food allergies among students. The authors suggest that such plans be implemented.
Prevention – allergen avoidance		Cross-sectional	Ercan et al, 2012	^Citation76	52% of teachers knew which of their students had allergic disease. Pollen was thought to be the most common agent to cause anaphylaxis (54%), followed by food (47%). Among foods, egg (30.4%) and strawberries (25.3%) were thought to be the two leading causes. Only 10% were aware of an EAI, and 4% knew where to apply it. 25% of teachers knew all of the symptoms of anaphylaxis and 6% reported there was a management plan for anaphylaxis in the school.	Primary school teachers are not well informed about food allergy and anaphylaxis. Training programs on the subject should be implemented.
Prevention – allergen avoidance	Milk	Cross-sectional	Berni Canani et al, 2013	^Citation114	Examined new amino acid formula in 60 patients with IgE or non-IgE-mediated reaction to milk. No patients had immediate or delayed reactions. Fecal concentration of calprotectin and eosinophil cationic protein remained stable after exposure to the new amino acid formula.	Provides a safe amino acid formula alternative for children with IgE- and non-IgE-mediated reactions to cow’s milk.
Prevention – allergen avoidance		Prospective cohort	Zurzolo et al, 2013	^Citation70	65% of products had warning labels for an allergen that was not listed in the ingredients. Most common were tree nuts (36.2%), followed by peanuts (34.1%), sesame (27.5%), and egg (22.6%). “May contain traces of” was the most common type of statement used (29%).	The use of precautionary labeling for food allergy is high, leading to restricted diets for consumers with allergies.
EAI		Telephone survey	Soller et al, 2011	^Citation115	Telephone survey that identified 3.2% of participants as having a probable food allergy. Of these, 45% had an EAI. Factors that increased the probability of having an EAI were: marriage/partner, children, female, multiple food allergies, history of being treated with epinephrine, and confirmatory testing.	Health care providers and patients need more education on the recognition and management of anaphylaxis.
EAI		Cross-sectional	DeMuth and Fitzpatrick, 2011	^Citation77	59% had an EAI in clinic on follow-up visit, of which 79% reported having received training in its use. Having EAI training was associated with having an EAI available. Fewer children aged >5 years reported having an EAI at school during lunch (25%) than those <5 years (42%).	Many children do not have an EAI available at all times. EAI training improves the likelihood of EAI carriage.
EAI		Cross-sectional	Segal et al, 2012	^Citation79	Evaluated 141 patients: 9.9% had used epinephrine previously. 37% had a valid device with them at follow-up visit. 62%–87% incorrectly performed steps in use of an EAI. 41 participants were reevaluated 1 year later, after which time the mean scores improved from 4.71 to 6.7.	Many patients do not carry valid EAIs and are not skilled in their use. Repeated instruction may improve this skill.
EAI		Prospective	Spina et al, 2012	^Citation78	Assessed influence of periodic checks by school nurse on EAI carrying among adolescents. Periodic checks did not influence the rate of carrying, but those who did carry EAIs were more likely to have unexpired medication with periodic reminders.	Carriages rates of EAIs are low among adolescents. We must work to develop effective interventions to improve this.
EAI		Cross-sectional	Simons et al, 2012	^Citation116	Most allergists expect patients aged 12–14 years to describe anaphylaxis symptoms (95.4%), demonstrate use of an EAI (93.1%), carry an EAI (88.1%), learn to self-inject an EAI (84.5%) and be able to self-inject (78.6%).	Most pediatric allergists expect their patients to be able to self-administer an EAI between the ages of 12 and 14 years. There are no patient data on optimal timing of transfer of responsibility.
EAI		Cross-sectional	Pinczower et al, 2013	^Citation80	Used FAQOL to assess impact of prescription of an EAI. Being aged 7–12 years, having four or more food allergies, and history of anaphylaxis had strongest impact on QOL. Patients issued an EAI reported lower QOL.	We must weigh the risks and benefits of prescribing EAIs as they are associated with reduced QOL.
EAI	Peanut	Prospective cohort	Chad et al, 2013	^Citation8	56% of parents of children with peanut allergy expressed fear about using EAI. Fear was attributed to concern about hurting the child, using the EAI incorrectly, or a bad outcome. Parents of children with a history of severe reaction, long duration of disease, or who were satisfied with EAI training were less likely to be afraid.	Many parents of peanut-allergic children are afraid to use an EAI. Parent training can help decrease fear associated with EAIs.
FAHF-2		RCT	Wang et al, 2010	^Citation63	Among 18 active intervention and placebo subjects, there were no significant differences in vital signs, physical examination, laboratory data, pulmonary function test results, and electrocardiogram data obtained before and after treatment visits.	FAHF-2 was safe and well tolerated in patients with food allergy.
FAHF-2		Open-label	Patil et al, 2011	^Citation64	14/18 patients completed the study, taking FAHF-2 for 6 months. There were no significant differences in laboratory parameters, PFT results, or electrocardiogram findings before or after treatment. There was a significant reduction in basophil CD63 expression at 6 months. There was a trend toward reduction of eosinophil and basophil numbers after treatment.	This study demonstrates further safety and tolerability of FAHF-2. There may be some immunologic modulatory effect.
FAHF-2		Review	Wang and Li, 2012	^Citation62	Review of FAHF-2 from development to Phase I clinical trials.
Complementary and alternative medicine		Survey	Nakano et al, 2012	^Citation61	8.4% of food-allergic children in Japan used complementary and alternative medicine. Herbal teas were most common (22%), followed by Chinese herbal medicine (18.5%) and lactic acid bacteria (16%). 13.6% felt that complementary and alternative medicine was very effective, and 11.1% thought it caused some type of side effect.	Among food-allergic Japanese children, 8.4% are using complementary and alternative medicine to treat their food allergy.
OIT	Peanut	RCT	Anagnostou et al, 2014	^Citation81	62% of patients receiving OIT and none of the control group achieved desensitization. The control patients went on to receive OIT in a second phase, during which 54% achieved desensitization. GI side effects were the most common.	This study demonstrates successful desensitization using peanut flour in a majority of participants; however, it does not evaluate long-term tolerance.
OIT	Peanut	RCT	Varshney et al, 2011	^Citation82	16 OIT patients ingested a maximum dose of 5 g of peanut (20 peanuts). Placebo subjects tolerated a median dose of 280 mg. OIT patients had reduced SPT wheal size and IL-13 and increased peanut-specific IgG4	Demonstrates desensitization and immunomodulation with peanut OIT, but does not examine long-term tolerance.
OIT	Peanut	RCT	Sampson et al, 2011	^Citation117	Of nine patients in the omalizumab treatment group, 44% tolerated >1 g peanut versus 20% in the placebo group (n=5). Mild and moderate adverse events were reported in both groups (88.9% placebo, 76.5% omalizumab).	The study was stopped early, and most did not meet predefined study endpoints. Some evidence to suggest that omalizumab helps to increase the threshold tolerated in peanut OIT.
SLIT	Peanut	RCT	Fleischer et al, 2013	^Citation83	After 44 weeks of treatment, 70% of subjects receiving SLIT tolerated peanut OFC compared with 15% of controls.	SLIT safely induced a modest level of desensitization in the majority of 40 subjects aged 12–37 years. A significant increase in dose was tolerated, but no correlation was found between clinical improvement and sIgE levels.
SLIT, OIT	Peanut	RCT	Chin et al, 2013	^Citation84	Comparison of two previously published trials (Varshney et al^Citation82 and Skripak et al^Citation99) regarding peanut OIT versus SLIT.	Retrospective comparison of two RCTs for OIT and SLIT in peanut-allergic children. OIT provided higher dose thresholds than SLIT.
OIT	Peanut	Prospective cohort	Vickery et al, 2014	^Citation88	Of 39 enrolled subjects, 24 completed a protocol involving 5 years of peanut OIT. Among them, 12 (50%) had sustained unresponsiveness to peanut 1 month after discontinuing OIT. Compared to those who failed challenge, those who passed had smaller SPT wheal diameters, and lower levels of sIgE, Ara h 1, and Ara h 2.	This study demonstrates that 50% of patients treated with peanut OIT for 5 years have sustained unresponsiveness 1 month after discontinuing treatment. While these results are promising, longer-term follow-up data would be helpful in determining acquisition of tolerance.
OIT	Peanut	Prospective cohort	Jones et al, 2009	^Citation86	27/29 patients undergoing OIT were able to reach target dose of peanut. Throughout treatment, SPT wheal size and sIg E decreased, while IgG4 increased.	Demonstrated clinical desensitization and immune regulation with OIT to peanut.
OIT	Peanut	Prospective cohort	Hofmann et al, 2009	^Citation91	20/28 patients completed the study. On escalation day, 79% had URT, 68% GI symptoms, and 18% mild wheezing. After build-up phase, risk of reaction was 46% (29% URT, 24% cutaneous). Risk of reaction during home dosing was 3.5% (URT 1.2%, skin 1.1%). Treatment was given in 0.7% of the home doses.	This study examined the safety of peanut OIT. Most reactions occurred during escalation. Reactions with home dosing were rare.
OIT	Peanut	Prospective cohort	Blumchen et al, 2010	^Citation90	23 children received OIT with a rush protocol, after which a median dose of 0.15 g Peanut was tolerated. 22/23 patients received long-term protocol. After 7 months of treatment, 14 reached protective dose (0.5 g peanut).	Rush protocol was not effective and was associated with adverse reactions. Long-term build-up is safe and effective.
OIT	Peanut	Prospective cohort	Yu et al, 2012	^Citation92	24 patients received 6,662 doses. 84% of symptoms were mild, 13% moderate, and 3% severe (GI reactions requiring epinephrine).	In this study examining the safety of peanut OIT, most reactions were mild, though some patients had severe reactions requiring treatment with epinephrine.
OIT	Peanut	Retrospective cohort	Wasserman et al, 2014	^Citation89	352 patients received 240,351 doses of peanut OIT. There were 95 reactions requiring treatment with epinephrine; three required two doses. 298 patients achieved the target maintenance dose (85%).	This retrospective chart review examines data from five clinics conducting peanut OIT using different agents (peanut, peanut butter, or peanut flour). It demonstrates that a significant number of patients have reactions requiring epinephrine, and that most are able to reach the target maintenance dose.
OIT	Peanut	Editorial	Mansfield, 2013	^Citation87	Pro/con editorial of peanut OIT	The author argues that peanut OIT is ready for clinical practice.
OIT	Peanut	Systematic review	Sheikh et al, 2012	^Citation118	Systematic review of six case series studies with a total of 85 participants.	Many participants increase their threshold dose while on treatment. Adverse reactions were common and, though usually mild, some were life-threatening.
Novel immunotherapy	Peanut	Experimental technique	Pascal et al, 2013	^Citation119	Identified four regions of Ara h 2 that induced T-cell proliferation in peanut-allergic children. These could potentially be used for a peptide-based vaccine for food allergy.	Used a novel approach to treatment of food allergy, but requires further study before it is ready for clinical application.
OIT	Milk	RCT	Pajno et al, 2013	^Citation94	Children desensitized with OIT were randomized to one of two feeding regimens: daily or twice weekly. There was no difference in adverse reactions among the two groups.	Once desensitization is achieved, a twice-weekly maintenance regimen is as effective as daily maintenance.
OIT	Milk	Prospective cohort	Nadeau et al, 2011	^Citation95	Pilot study in eleven milk-allergic children, using omalizumab to perform rapid oral desensitization. 9/10 achieved target dose of 1 g during rush desensitization. Over 7–11 weeks, 9/10 reached 2 g target.	Rush milk desensitization with omalizumab was generally successful and well tolerated. All children had adverse events, but most were mild and did not require treatment. There was one event requiring epinephrine.
OIT	Milk	Prospective cohort	Vázquez-Ortiz et al, 2013	^Citation97	81 children enrolled. 71.6% had complete desensitization and 20.9% partial desensitization. 95% of children had reactions, of which 91% had a single affected organ system. 20 children (25%) accounted for 78% of reactions that were frequent, persistent, and unpredictable. sIgE >50, SPT wheal diameter of >9 mm, or Sampson severity grade 2, 3, or 4 at initial DBPCFC are risk factors for reaction persistence.	While many children can achieve desensitization with milk OIT, there is a high rate of adverse events. Development of tolerance was not discussed.
OIT	Milk	Prospective cohort	García-Ara et al, 2013	^Citation96	36 patients were classified according to milk-sIgE and treated with two dosing protocols. 100% of patients with sIgE <3.5 kUA/L and 88% of patients with sIgE >3.5 kUA/L were desensitized. 75% of patients had adverse events during induction, and 60% during maintenance.	Tolerance was achieved earlier with lower sIgE. Adverse events were more frequent with higher sIgE.
OIT	Milk	Prospective cohort	Keet et al, 2013	^Citation98	5-year follow up of 32 patients from two studies (Skripak et al^Citation99 and Keet et al^Citation100). 31% were tolerating full servings of milk with minimal to no symptoms.	Achievement of long-term tolerance through milk OIT is low.
OIT – formula	Milk	Prospective cohort	Berni Canani et al, 2013	^Citation69	260 milk-allergic children evaluated. Rate of acquisition of tolerance was higher in groups that received extensively hydrolyzed casein formula (43.6%) or EHCF + Lactobacillus rhamnosus GG (78.9%) compared to rice, soy, and amino acid formulas.	ECHF accelerates acquisition of tolerance in milk-allergic children.
OIT – formula	Milk	RCT	Reche et al, 2010	^Citation101	92 infants with IgE-mediated milk allergy were randomized to receive hydrolyzed rice formula or EHCF. One infant in the EHCF group had an immediate reaction. No statistically significant difference in acquisition of milk tolerance between the two groups.	Hydrolyzed rice formula is a safe alternative for children with milk allergy.
OIT	Milk	Review	Yeung et al, 2012	^Citation93	Cochrane Review examining five studies with a total of 196 participants (106 treatment, 90 control). Primary outcome of studies was desensitization; tolerance was not assessed. 62% of the OIT group were able to tolerate a full serving of milk versus 8% of controls. 25% of the OIT group could ingest a partial serving of milk versus none in the control group.	Side effects in milk OIT are common, but the majority are mild. Long-term tolerance has not yet been assessed. Maintaining desensitization requires regular consumption of the highest tolerated dose of milk.
OIT	Egg	RCT	Burks et al, 2012	^Citation103	After 10 months of egg OIT, 55% of the treatment group and none of the placebo group passed OFC. After 22 months, 75% of the OIT group were desensitized. After 2 months of avoiding egg consumption, only 28% passed OFC.	Egg OIT can successfully desensitize most children, but sustained unresponsiveness is achieved only in a small subset.
OIT	Egg	RCT	Meglio et al, 2013	^Citation104	Of a group of ten egg-allergic children treated with raw egg OIT, 80% achieved the target dose over a 6-month period. One failed and another achieved partial desensitization. 20% of the control group achieved tolerance after 6 months.	This study demonstrates effective desensitization but does not examine long-term tolerance. While this study is encouraging, it had small numbers and a short duration.
OIT	Egg	Prospective cohort	Itoh et al, 2010	^Citation106	Rush OIT in six egg-allergic children, whereby after 12 days all participants reached the target dose of one whole egg, after which they remained on maintenance twice a week. At 12 months, there was decreased egg-sIgE and increased IgG4. There were no serious reactions and no participants required epinephrine.	Rush OIT to egg was well tolerated in the group of six children.
OIT	Egg	Prospective cohort	García Rodríguez et al, 2011	^Citation107	In rush OIT in 23 egg-allergic children over 5–10 days, 78.3% had reactions, but none were serious. 20/23 were successfully desensitized. At 6 months, there were decreases in sIgE and SPT size and increases in IgG4 and CD4+ FoxP3+ cells.	Describes a protocol for egg desensitization that is tolerated by most egg-allergic patients as well as immunologic changes possibly associated with desensitization.
OIT	Egg	Prospective cohort	Leonard et al, 2012	^Citation102	89% of patients challenged to baked egg were tolerant. 53% of those became regular egg tolerant as well. Among those who reacted to baked egg, 61% subsequently tolerated it and 26% tolerated regular egg. Those who tolerated baked egg had lower egg-sIgE. In subjects ingesting baked egg, egg SPT wheal size and ovalbumin- and ovomucoid-sIgE all decreased, while ovalbumin and ovomucoid-specific IgG4 increased.	Baked egg challenges should be performed among egg-allergic children, as most egg-allergic children tolerate baked egg and inclusion of baked egg in the diet may hasten the resolution of egg allergy.
OIT	Egg	Prospective cohort	Ojeda et al, 2012	^Citation108	80.6% of the subjects in the intention-to-treat group achieved desensitization to egg. Four cases required treatment with epinephrine at home. Baked egg-tolerant patients were more likely to achieve raw egg tolerance.	This study demonstrates effective desensitization but does not examine long-term tolerance. The authors’ definition of anaphylaxis as involving three or more organ systems may explain why there were few cases of anaphylaxis.
OIT	Egg	Prospective cohort	Tortajada-Girbés et al, 2012	^Citation105	19 egg-allergic children were given increasing amounts of egg at weekly intervals. 89.5% of subjects achieved tolerance to the target dose. There was no anaphylaxis during the OIT phase, though two participants withdrew from the study as they had anaphylaxis with the initial dose.	This study demonstrates effective desensitization to egg but does not examine long-term tolerance.
SLIT	Peach	RCT	García et al, 2010	^Citation110	In describing sensitization profiles of peach-allergic individuals, rPru p 3 was the most recognized (83.3%), followed by nArt v 3 (25.9%), rMal d 4 (24.1%), and rMal d 1 (18.5%). sIgE to rPru p 3 rose in both groups but remained elevated only in the treatment group. Peach SPT wheal size decreased in the treatment group.	rPru p 3 was the most common antigen recognized by peach-allergic individuals. This study demonstrates a decrease in SPT wheal size in the treatment group, but they did not perform OFC.
SLIT	Peach	RCT	Fernández-Rivas et al, 2009	^Citation109	After 6 months of SLIT with Pru p 3 extract, the treatment group tolerated higher doses of peach, had smaller SPT, and increased IgG4. No systemic reactions were observed, but local reactions were common.	Demonstrates effective desensitization and safety of SLIT to peach using Pru p 3 extract.
Effect of cooking method on peanut allergens	Peanut	Experimental technique	Kim et al, 2013	^Citation120	Examined effect of cooking method on peanut proteins. Ara h 2 and 3 were the most important epitopes. Ara h 2 was enhanced by boiling, roasting, and frying peanuts and decreased by pickling (vinegar). Also, there was less IgE binding in vinegar. Ara h 3 was enhanced by all treatments.	Cooking methods will alter epitopes in peanut, although the clinical significance of this is not established.
	Milk	Review	Restani et al, 2009	^Citation121	Choices in cow’s milk (filtration not effective); alternatives to cow’s milk (donkey, mare, camel, etc); comorbid beef allergy.	Milk allergy is an increasing problem in infancy. Further research should be targeted to evaluating management of milk allergy.
		Review	Sanz et al, 2011	^Citation5	Use of microarray component-based diagnosis in food allergy.	Microarray technology to evaluate sIgE to foods is a helpful advance in food allergy diagnosis.

Abbreviations: DBPCFC, double-blind, placebo-controlled food challenge; EAI, epinephrine autoinjector; EHCF, extensively hydrolyzed cow’s milk formula; FAHF-2, food allergy herbal formula 2; FAQOL, food allergy health–related quality of life; GI, gastrointestinal; IgE, immunoglobulin E; IgG₄, immunoglobulin G, type 4; OFC, open food challenge; OIT, oral immunotherapy; OR, odds ratio; PFT, pulmonary function test; QOL, quality of life; RCT, randomized controlled trial; sIgE, specific IgE; SLIT, sublingual immunotherapy; SPT, skin prick test; URT, upper respiratory tract; VITAL, Voluntary Incidental Trace Allergen Labelling.

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