Oral and sublingual immunotherapy for egg allergy

Olga Romantsik, Maria Angela Tosca, Simona Zappettini, Maria Grazia Calevo

Clinical egg allergy is a common food allergy. Current management relies upon strict allergen avoidance. Oral immunotherapy might be an optional treatment, through desensitization to egg allergen. To determine the efficacy and safety of oral and sublingual immunotherapy in children and adults with immunoglobulin E (IgE)-mediated egg allergy as compared to a placebo treatment or an avoidance strategy. We searched 13 databases for journal articles, conference proceedings, theses and trials registers using a combination of subject headings and text words (last search 31 March 2017). We included randomized controlled trials (RCTs) comparing oral immunotherapy or sublingual immunotherapy administered by any protocol with placebo or an elimination diet. Participants were children or adults with clinical egg allergy. We retrieved 97 studies from the electronic searches. We selected studies, extracted data and assessed the methodological quality. We attempted to contact the study investigators to obtain the unpublished data, wherever possible. We used the I² statistic to assess statistical heterogeneity. We estimated a pooled risk ratio (RR) with 95% confidence interval (CI) for each outcome using a Mantel-Haenzel fixed-effect model if statistical heterogeneity was low (I² value less than 50%). We rated the quality of evidence for all outcomes using GRADE. We included 10 RCTs that met our inclusion criteria, that involved a total of 439 children (oral immunotherapy 249; control intervention 190), aged 1 year to 18 years. Each study used a different oral immunotherapy protocol; none used sublingual immunotherapy. Three studies used placebo and seven used an egg avoidance diet as the control. Primary outcomes were: an increased amount of egg that can be ingested and tolerated without adverse events while receiving allergen-specific oral immunotherapy or sublingual immunotherapy, compared to control; and a complete recovery from egg allergy after completion of oral immunotherapy or sublingual immunotherapy, compared to control. Most children (82%) in the oral immunotherapy group could ingest a partial serving of egg (1 g to 7.5 g) compared to 10% of control group children (RR 7.48, 95% CI 4.91 to 11.38; RD 0.73, 95% CI 0.67 to 0.80). Fewer than half (45%) of children receiving oral immunotherapy were able to tolerate a full serving of egg compared to 10% of the control group (RR 4.25, 95% CI 2.77 to 6.53; RD 0.35, 95% CI 0.28 to 0.43). All 10 trials reported numbers of children with serious adverse events (SAEs) and numbers of children with mild-to-severe adverse events. SAEs requiring epinephrine/adrenaline presented in 21/249 (8.4%) of children in the oral immunotherapy group, and none in the control group. Mild-to-severe adverse events were frequent; 75% of children presented mild-to-severe adverse events during oral immunotherapy treatment versus 6.8% of the control group (RR 8.35, 95% CI 5.31 to 13.12). Of note, seven studies used an egg avoidance diet as the control. Adverse events occurred in 4.2% of children, which may relate to accidental ingestion of egg-containing food. Three studies used a placebo control with adverse events present in 2.6% of children. Overall, there was inconsistent methodological rigour in the trials. All studies enrolled small numbers of children and used different methods to provide oral immunotherapy. Eight included studies were judged to be at high risk of bias in at least one domain. Furthermore, the quality of evidence was judged to be low due to small numbers of participants and events, and possible biases. Frequent and increasing exposure to egg over one to two years in people who are allergic to egg builds tolerance, with almost everyone becoming more tolerant compared with a minority in the control group and almost half of people being totally tolerant of egg by the end of treatment compared with 1 in 10 people who avoid egg. However, nearly all who received treatment experienced adverse events, mainly allergy-related. We found that 1 in 12 children had serious allergic reactions requiring adrenaline, and some people gave up oral immunotherapy. It appears that oral immunotherapy for egg allergy is effective, but confidence in the trade-off between benefits and harms is low; because there was a small number of trials with few participants, and methodological problems with some trials.