Description of the condition
Clinical egg allergy is one of the most common food allergies in western countries, affecting up to approximately two per cent of young children (Savage 2007). A recent study has shown that the prevalence of challenge-proved egg allergy in 12-month-old infants in Australia was 8.9% (Osborne 2011). Natural tolerance, meant as a developing tolerance to egg over time, is frequent but some children will remain allergic until adulthood. Despite this trend, recent data has shown that milk and egg allergies are becoming more persistent and that children may not be outgrowing these allergies until adolescence, rather than during the first five to six years of life, as previously thought (Savage 2007).
IgE-antibody mediated allergic reaction to egg is based the soluble IgE, produced by B cells, and what circulates and binds to the surface of mast cells and basophils. Mast cells are found in the skin, gut, respiratory tract, and are situated adjacent to nerves and blood vessels. Among the most important of their immune functions is the propensity to bind IgE utilizing the high-affinity IgE receptor FcaR1. When egg allergen is re-encountered and recognized by cell-bound IgE, adjacent FcåR1-IgE complexes move closer together and bring their signalling machinery into close proximity, which sets off a cascade of phosphorylation, ultimately resulting in calcium influx. When calcium enters the cell, the activated mast cell undergoes degranulation, and the contents of these granules are released into the extracellular space. The immediate liberation of preformed powerful vasoactive compounds such as histamine, platelet activating factor, tryptase, carboxypeptidase, chymase, and heparin elicit the acute symptoms of type 1 hypersensitivity reactions in the skin, gut, respiratory, and cardiovascular systems (Galli 2010). These symptoms include urticaria, angioedema, flushing, nausea, vomiting, abdominal pain, diarrhoea, wheezing, coughing/ bronchospasm, rhinorrhoea, and hypotension / syncope, which can occur alone or in combination, and typically begin within minutes up to two hours of food ingestion (Burks 2008, Simons 2011).
There is no interventional therapy currently approved by the American Food and Drug Administration. Current management relies upon strict allergen avoidance, including the small quantities present in many foods, as well as more obvious sources such as dessert. In the United States, European Union, Australia, Japan and Singapore, food-labelling laws require food manufacturers to declare on packaging, in plain language, the presence of a common allergen or product. Similar laws are not in place in many other countries, and in these settings care is required to identify hidden forms of egg allergens, such as ovalbumin or ovomucoid (Burks 2012). Studies that evaluated growth measurements against diet records have suggested that food allergy puts children at risk for inadequate nutrition (Christie 2002). Especially in the case of paediatric food allergy, it is advisable to involve a dietician in formulating a nutritionally adequate, allergen-free diet. The quality of life of affected persons and their caregivers is reduced, due to fear of incorrect or accidental egg-containing food ingestion and the ever-present threat of anaphylaxis (Cummings 2010). The management of clinical egg allergy consists of teaching the patients and caregivers to recognize the symptoms and signs of severe reaction, use of epinephrine auto-injection promptly and activating emergency medicine (Simons 2009).
Thus, therapeutic interventions that might provide life-long protection against potential egg ingestion are needed. Traditional subcutaneous immunotherapy, (also known as 'allergy shots') had been studied over 10 years ago, and was able to induce desensitisation. However, this type of treatment is not appropriate due to the high rate of systemic reactions during immunotherapy (Oppenheimer 1992, Nelson 1997). Given the safety issues from subcutaneous immunotherapy, oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) have been studied recently as optional treatments. Although there have been scattered reports in the literature on the use of OIT for food allergy over the last 100 years, the majority of research on OIT has occurred in the last 25 years, beginning with work by Patriarca, who demonstrated the successful treatment of allergies to cow’s milk, egg, fish, and fruits with standardized OIT protocols (Patriarca 1984). In a pilot study of OIT for egg allergy in children, Buchanan demonstrated the safety of a 24-month egg OIT protocol involving a modified rush desensitization phase, build-up phase, and maintenance phase (Buchanan 2007). A randomised, double blind study by Burks 2012, showed that 75% of children in the oral-immunotherapy group were desensitised (Burks 2012). A small randomised controlled study (Lacono 2013) was published recently showing that 90% of children with severe egg allergy achieved the partial level of tolerance after six months of treatment. Similar results were published in Meglio 2013. The initial aim of OIT is therefore to provide clinical desensitisation - i.e. to achieve a state in which effector cells involved in a specific immune response develop reduced reactivity or become non reactive upon increased introduction of an allergen. In a desensitised state, an individual may be non-reactive while regularly receiving the allergen. However, when regular administration ends, the previous amount of reactivity returns. The goal of immunotherapy, is to reach a state of tolerance, where the non-reactive state remains present permanently through down-regulation of the Th2 response to egg, and which will endure irrespective of a previously clinically reactive patient continuing to consume egg products or not (Land 2011).
There are different types of OIT protocols. Oral immunotherapy involves the regular administration of small amounts of allergen by the oral route to first rapidly induce desensitization, then over time induce tolerance to the allergen. Some reports have considered immunotherapy that is ingested and immunotherapy that is administered sublingually as two forms of oral immunotherapy. For the purposes of this review, oral immunotherapy (OIT) will refer specifically to ingested immunotherapy and sublingual immunotherapy (SLIT) will refer to immunotherapy that is administered under the tongue. Patients undergoing OIT generally ingest a mixture of protein powder in a vehicle food such as apple sauce. Patients undergoing SLIT generally receive a small amount of liquid extract under their tongue. Both treatments are typically initiated in a controlled setting where gradually increasing doses of allergen are given up to a targeted dose. Following this, in standard protocols, the majority of dosing is done at home.
Description of the intervention
Therapeutic interventions that may provide lifelong protection against accidental allergen ingestion are needed. Oral immunotherapy (OIT) is of particular interest as a possible treatment for egg allergy. The aim of the treatment is initially to desensitise patients to egg allergen, which by increasing the threshold dose of exposure reduces the risk of anaphylaxis. However, the goal is to induce a state of tolerance of an allergen following the completion of treatment. More importantly, Jones 2009 demonstrated that underlying the clinical benefits of OIT, were changes to multiple aspects of the immune system, leading to a dampened allergic response. These changes included, not only, the decrease in allergen-specific IgE and increase in allergen-specific IgG4 previously demonstrated (Patriarca 2003, Buchanan 2007, Staden 2007, Itoh 2010), but also a suppression of mast cells and basophils, an increase in T regulatory cells (TRegs), and a change in cytokine profile. Additionally, microarray analysis of patient T cells revealed changes in several apoptotic pathways, although the significance of this result is still unknown (Jones 2009). Cytokine analysis demonstrated a clear decrease in TH2 cytokines without a concomitant increase in TH1 cytokines arguing against OIT, causing a shift in the TH1/TH2 skewing. Rather a decrease in IL-2 was noted, possibly suggesting clonal anergy or deletion as a possible mechanism of OIT (Land 2011). However, one should be cautious of interpreting these results, as the cohort of both studies was small and the selection criteria for the immunological studies are not clear enough.
How the intervention might work
OIT involves the administration of initially very small doses (usually micro or milligrams) of food allergen to food-allergic patients in a controlled clinical setting. The dose of the administered food allergen is then systematically increased until a maximum tolerated dose is achieved (Jones 2009). Regular dosing with this maximal dose is then maintained at home by the patient. Successful desensitisation is thought to induce immunological tolerance by generating allergen specific IL-10 secreting Tr1 and/or TGF-secreting Th3 regulatory T-cells (Sicherer 2010). OIT is intended for patients with IgE- mediated egg allergy.
Why it is important to do this review
Food allergy is an IgE-mediated immediate type hypersensitivity that is thought to be a result of a breakdown in the normal process of oral tolerance. Although the prevalence of food allergy continues to rise, avoidance remains the standard of care as no disease modifying treatments are readily available. Although questions regarding the safety of the treatments and the potential for the development of long-term immunological tolerance remain, OIT and SLIT offer a potential hope for the future treatment of egg allergy. Thus, there is a need to systematically identify, critically appraise and summarise available evidence on the benefits and risks associated with OIT and SLIT for the management of persons with egg allergy.
To assess the clinical effectiveness and safety of egg oral and sublingual immunotherapy in children and adults with IgE-mediated egg allergy.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCT), quasi-RCT and controlled clinical trials (CCT) will be included.
Types of participants
Children and adults diagnosed with an immediate-type egg allergy will be included. Egg allergy is defined as: a history of systemic clinical reaction within minutes to hours after the ingestion of egg in patients with objective evidence of sensitization to egg. Objective evidence is:
- positive SPT (skin prick test) or specific IgE;
- a positive open challenge or double–blind, placebo controlled food challenge. The positive reaction to the challenge should be the immediate onset of symptoms suggestive of IgE-mediated mechanisms, such as urticaria, angioedema, vomiting, diarrhoea, abdominal pain, and any alteration in the level of consciousness.
Types of interventions
Egg OIT or SLIT administered by any protocol compared with a placebo group, with an alternative way of administering desensitization therapy or treatment with continued avoidance diet.
Types of outcome measures
Successful desensitization or achieved tolerance defined as:
- an increase in the amount of egg that can be ingested and tolerated (absence of adverse reactions) while receiving allergen-specific OIT /SLIT (i.e. evidence od desensitization)
- a complete recovery from egg allergy after completion of OIT whether or not egg is eaten (i.e. induction of immunologic tolerance)
- Immunological changes suggestive of the induction of tolerance (e.g. decreased wheal diameter on SPT testing with egg, decreased egg-specific IgE levels, increased egg-specific IgG4 levels)
- Serious adverse events
- Mild to severe adverse reactions
- Change in quality of life
We will present the main outcomes of the review in a Summary of Findings table.
Search methods for identification of studies
EMBASE, PubMed, MEDLINE, Cochrane library, ISI Web of Science, Google Schoolar, AMED, BIOSIS, CAB, CINAHL, Global Health, TRIP, and WHO Global Health Library will be searched for the studies.
Searching other resources
Unpublished studies and ongoing work and research in progress will be found by searching key internet-based relevant databases: Current Controlled Trials (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), The Australian and New Zealand’s trial repository (http://www.anzctr.org.au) we will contact experts in the field for ongoing work and unpublished work. Thereafter a search for grey literature will be performed (http://opensigle.inist.fr).
Data collection and analysis
Selection of studies
Titles and abstracts of records retrieved will be screened by one author (OR) and irrelevant records excluded. Full texts of reports of potentially relevant studies will be retrieved. Multiple reports from the same study will be identified and grouped under a single study identifier. Examination of these studies and selection based on the eligibility criteria will be undertaken by two authors (OR, MAT), independently. If required, study investigators will be contacted to clarify eligibility. If the two authors do not agree on inclusion of a study even following discussion, the third author will act as an arbiter (MB).
Data extraction and management
A data collection form will be created and piloted using two to three sample studies. Data extraction will be undertaken by two authors (OR; MAT), independently. Correspondence with study investigators may be required if not all information is available from reports. Disagreements between reviewers will be resolved with discussion and, if required, arbitration by the third author (MB).
Assessment of risk of bias in included studies
The Cochrane Collaboration’s tool for assessing risk of bias will be used by two authors (OR, MGC), independently, to evaluate each included study. We will consider the following types of potential bias: selection bias (adequacy of randomisation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors) and attrition bias (loss to follow up). Any disagreements will be discussed, and the third author will act as an arbiter if necessary. The results of the assessments will be summarized in a 'Risk of Bias' table. To determine the influence on the results of the meta-analysis of the studies with a high risk of bias, sensitivity analyses will be performed.
Measures of treatment effect
The outcomes will be collected and analysed as dichotomous data e.g. presence or absence of tolerance, partial tolerance, adverse effects. The effect measure of choice is the risk ratio.
Unit of analysis issues
We do not anticipate that with this particular intervention that we will likely come across unit of analysis issues. For example, cross-over trials would not be a rational approach to assessing immunotherapy as the goal of treatment is to induce tolerance, and a patient would not be able to serve as their own control if their immune response has been altered. We also do not expect large numbers of egg-allergic patients to arise from various cohorts, and so cluster-randomization is unlikely to be encountered.
Dealing with missing data
We will attempt to contact study investigators and request missing data. When possible, missing data will be classified as random and non-random. For the non-random missing data, it may be necessary to input replacement values based on reasonable clinical assumptions. If this is required, sensitivity analysis will be performed to ensure assumptions do not greatly change the results. Data will be analysed on an intention-to-treat basis whenever possible.
Assessment of heterogeneity
We anticipate clinical heterogeneity in the studies that are reviewed, including ages of the study population, and differences in immunotherapy protocol. However, despite these potential differences we feel that we may be able to analyse the studies together, to examine the principle of whether oral immunotherapy is efficacious. Statistical heterogeneity will be assessed using the I² test (Higgins 2011), where an I
Assessment of reporting biases
If appropriate a funnel plot will be created to assess whether there is evidence of asymmetry indicative of possible publication or other types of bias.
We intend to use the Mantel-Haenszel fixed-effect model for meta-analysis, and we will summarize the evidence in a Summary of Findings table. All analyses will be conducted using Review Manager (RevMan 5).
Subgroup analysis and investigation of heterogeneity
Depending on the data available, we hope to undertake subgroup analyses for presence of asthma, other food allergies, history of previous anaphylaxis, OIT and SLIT regimen, duration of treatment, time since completion of treatment, RCT versus non-RCT.
Sensitivity analyses will be performed for studies reviewed that are deemed at high risk of bias.
Contributions of authors
Protocol draft: OR, MB, ODCA, MGC
Develop a search strategy: MB, MGC
Search for trials (usually 2 people): OR, MAT
Obtain copies of trials: OR
Select which trials to include: OR, MAT; arbiter: MB
Extract data from trials (2 people): OR, MAT
Enter data into RevMan: OR, MB
Carry out the analysis: MB, MGC
Interpret the analysis: OR, ODCA, MGC
Draft the final review: OR, MB, MAT, ODCA, MGC
Update the review: OR, MB
Declarations of interest