蛋过敏的口服和舌下免疫治疗

Oral immunotherapy protocols

Egg oral immunotherapy protocols differed. Nine studies included a build‐up phase in a hospital, day treatment centre, or research centre followed by gradual up‐dosing in hospital or at home, and a maintenance phase at home ( Burks 2012 ; Caminiti 2015 ; Dello Iacono 2013 ; Escudero 2015 ; Fuentes‐Aparicio 2013 ; Giavi 2016 ; Meglio 2013 ; Pérez‐Rangel 2017 ; Vazquez‐Ortiz 2014 ). Akashi 2017 reported that the oral immunotherapy protocol was carried out at home only. Burks 2012 was characterized by an increasing dose in research settings followed by an approximate doubling every 30 minutes, up to 50 mg. The maximum tolerated single dose of egg was given in the clinic on the following day and provided the starting dose for the build‐up phase. Attainment of a minimum dose of 3 mg of egg white powder was required to continue dosing. The children then continued a build‐up dosing at home. For children who did not achieve a dose of 50 mg on the first day, doses were doubled every two weeks up to 50 mg. Therefore, the dose was increased to 75 mg with following increases by 25% up to 2 g. The maximum time allowed for the build‐up phase was 10 months; the dose achieved at 10 months was considered to be the maintenance dose. After reaching their highest build‐up dose (maximum 2 g), children continued this dose daily for at least two months before the month 10 oral food challenge; children in the egg oral immunotherapy group continued maintenance dosing through to 22 months. The Fuentes‐Aparicio 2013 protocol included in‐hospital administration of 1 mg egg and was continued by tripling the dose every 30 minutes, up to 30 mg. On the second day, 30 mg was administered in one single dose, with treatment continuing at home at the same dose. Subsequently, weekly increases were made in the clinic until 10 g of powdered egg, the equivalent of one egg, was reached. In Dello Iacono 2013 children started with one drop of undiluted raw hen's egg emulsion (0.015 mL) in a day hospital then continued at home with gradually increasing doses. The doses were increased at six further day hospital visits (on days 8, 29, 64, 92, 134, 176). Dose increases were customized based on the frequency and severity of side effects and in cases of intercurrent illness or worsening asthma. The oral immunotherapy protocol in Meglio 2013 started with 0.27 mg of hen's egg protein in hospital and thereafter children doubled the dose at home every eight days until day 80. Subsequently, the doses were doubled every 16 days to achieve a total daily intake of 25 mL at six months. In the Vazquez‐Ortiz 2014 oral immunotherapy protocol, pasteurized liquid egg white containing 8.3 g of protein per 100 mL was used, in which allergenicity was equivalent to raw egg white. The induction phase involved 16 weeks and started with a 2‐day in‐hospital rush phase, in which doses were increased hourly, starting with 0.083 mg egg white protein. Children were then discharged home and continued receiving the last tolerated dose once daily throughout the week. Weekly increases were given at the outpatient clinic until the equivalent of one raw egg (60 g of fresh product) could be given. The Caminiti 2015 oral immunotherapy procedure consisted of weekly administration, at the hospital clinic, of increasing doses of dehydrated egg white, diluted with sterile saline, starting with 0.1 mg. The dose was doubled every week until week 16, to achieve a cumulative dose of 4 g in approximately four months. When the dose of 4 g was tolerated, the oral immunotherapy protocol was continued with cooked or boiled egg at home. The Escudero 2015 protocol followed the procedure described in Staden 2007 , which consisted of an initial dose escalation phase in hospital starting with 0.08 mg of egg white and subsequently increasing every 20 minutes up to 140 mg of egg white protein (cumulative dose was 280 mg). This was followed by a build‐up phase with a weekly increase of the last maximum tolerated dose in hospital up to 2.8 g of egg white protein and a maintenance phase, which consisted in consumption of at least one undercooked egg (defined by the authors as fried egg, scrambled or undercooked omelet) every 48 hours. Children were permitted to freely consume any other egg‐containing food. The Giavi 2016 oral immunotherapy protocol was characterized by an escalation phase in hospital increasing the dose of hydrolysed egg every 20 to 30 minutes to reach 9 ± 1 g of hydrolysed egg. In the absence of adverse events the child received the full dose of 9 ± 1 g of hydrolysed egg, and in the absence of adverse events occurring, the child received the full dose of hydrolysed egg daily for six months. The Pérez‐Rangel 2017 oral immunotherapy protocol involved a consecutive five day build‐up phase starting with a highest tolerated single dose at the baseline egg double‐blinded placebo‐controlled food challenge test (DBPCFC). This consisted in an escalation dose of egg white starting from 4 mg and finishing with 1.8 g of egg white every 20 minutes until objective IgE‐mediated manifestations or subjective mild‐to‐moderate symptoms occurred. The regimen was conducted in an outpatient clinic. The build‐up target was 3.6 g of dehydrated egg white with a cumulative dose of 5.4 g administered on the last day. The maintenance phase consisted in eating one undercooked egg every 48 hours. Moreover, children were permitted to freely consume any other egg‐containing food. In Akashi 2017 , oral immunotherapy was carried out at home with a starting dose of 0.1 mg of dried powdered egg and this was increased up to 4 g with three to four days interval. The escalation protocol was based on the method used in Patriarca 2003 . Children were permitted to continue oral immunotherapy in combination with antihistamines in case of recurrent allergic symptoms.

Each study used a different egg preparation: Burks 2012 used raw white egg powder. Fuentes‐Aparicio 2013 used powdered pasteurized egg. Dello Iacono 2013 and Meglio 2013 used raw egg emulsion. Vazquez‐Ortiz 2014 used pasteurized liquid egg white. Caminiti 2015 , Escudero 2015 and Pérez‐Rangel 2017 used dehydrated egg white. Giavi 2016 used hydrolysed egg. Akashi 2017 used dried powdered egg.

There were also differences among included studies regarding the duration of oral immunotherapy to achieve full desensitization, defined as the ability to digest a small egg serving without adverse events. Burks 2012 reported desensitization in 75% of children after 22 months of oral immunotherapy; the target maintenance dose was 10 g egg white powder. Desensitization was evaluated by oral food challenge test. The duration of oral immunotherapy in Fuentes‐Aparicio 2013 varied between four and 28 weeks (average 10 weeks) targeted to achieve a tolerance of 10 g of whole egg. The Dello Iacono 2013 oral immunotherapy protocol duration, to achieve "maximum tolerance" by digesting 40 mL or raw egg emulsion without adverse events, was six months. Desensitization was evaluated by a DBPCFC test. The planned duration of oral immunotherapy for children to be able to tolerate 25 mL of raw egg in Meglio 2013 was 181 days. The actual duration of the oral immunotherapy was longer, with a mean duration of 215 days (range 178 to 287 days). None of the oral food challenge tests were performed for the intervention group at the end of the study; only children in the control group underwent DBPCFC at six months after enrolment. The duration of oral immunotherapy in Vazquez‐Ortiz 2014 was 12 months and desensitization was evaluated by oral food challenge to one raw egg, meaning 3.8 g of raw egg white or if not reached, the highest tolerated dose. The oral immunotherapy protocol in Caminiti 2015 aimed to achieve a tolerance a 4 g of dehydrated egg white in approximately four months and DBPCFC performed by the end of the study. Desensitized children received an egg‐containing diet with two to three eggs per week for six months, following a three‐month egg avoidance diet, after which a repeat DBPCFC was performed ( Caminiti 2015 ). In Escudero 2015 , the primary study outcome was to assess the induction of sustained unresponsiveness after three months of egg oral immunotherapy and an egg avoidance diet for one month, defined as the ability to consume 2808 mg of egg white protein without symptoms in a DBPCFC at four months. The oral immunotherapy duration in Giavi 2016 was six months with the target to tolerate 43.2 g of boiled egg on oral food challenge. The Pérez‐Rangel 2017 study was randomized for the first five months, during which an intervention group of children received egg oral immunotherapy shortly after randomization and control group children were on an egg avoidance diet; thereafter the control group was stopped and control group children who failed DBPCFC at five months began an oral immunotherapy treatment. The results reported here were extracted from the first five months of the randomized study period. No food challenge test was performed on children in the oral immunotherapy group at five months. Akashi 2017 used an oral immunotherapy protocol that lasted on average 6.5 months (range 5 to 8) aiming to achieve tolerance of 4 g dry egg powder on oral food challenge by the end of the oral immunotherapy protocol.

Clinical history of allergic reactions after egg digestion was an inclusion criterion for all studies. In two studies, positive clinical history was defined as development of symptoms within two hours after ingestion of egg ( Burks 2012; Escudero 2015 ), and in one study the definition was as an immediate (< 1 h) reaction following egg ingestion ( Giavi 2016 ).

Nine studies reported as one of the inclusion criteria a positive skin prick test (SPT) ( Burks 2012 ; Caminiti 2015 ; Dello Iacono 2013 ; Escudero 2015 ; Fuentes‐Aparicio 2013 ; Giavi 2016 ; Meglio 2013 ; Pérez‐Rangel 2017 ; Vazquez‐Ortiz 2014 ). Positive egg‐specific IgE (sIgE) levels was an inclusion criteria in all ten studies although the definition, if it was specified, varied among the studies. In Burks 2012 more than 5 kU/L for participants six years of age or older, or 12 kU/L or more for those five years old; in Giavi 2016 and in Giavi 2016 it was considered positive level of 0.35 kU/L or higher; Akashi 2017 , Escudero 2015 , Pérez‐Rangel 2017 defined IgE positivity if the levels were of 0.7 kU/L or higher. In seven studies DBPCFC was performed at baseline ( Akashi 2017 Caminiti 2015; Dello Iacono 2013; Escudero 2015; Meglio 2013; Pérez‐Rangel 2017 Vazquez‐Ortiz 2014 ). Two studies required oral food challenge at baseline ( Giavi 2016 and Fuentes‐Aparicio 2013 ); oral food challenge was not performed at baseline in Burks 2012 .

In seven studies a DBPCFC test was performed on all children in the control group at the end of the study ( Akashi 2017 ; Caminiti 2015 ; Dello Iacono 2013 ; Escudero 2015 ; Meglio 2013 ; Pérez‐Rangel 2017 ; Vazquez‐Ortiz 2014 ). In three of these seven studies, DBPCFC was also performed for oral immunotherapy group participants ( Akashi 2017 ; Dello Iacono 2013 ; Escudero 2015 ). An open oral food challenge was performed in oral immunotherapy group participants at the end of the study in five trials ( Burks 2012 ; Caminiti 2015 ; Fuentes‐Aparicio 2013 ; Giavi 2016 ; Vazquez‐Ortiz 2014 ) and in two trials it was performed in control group participants ( Burks 2012 ; Giavi 2016 ).

The follow‐up period varied for each study, and included: 36 months ( Escudero 2015 ), 24 months ( Burks 2012 ), 13 months ( Caminiti 2015 ), 12 months ( Vazquez‐Ortiz 2014 ), six months ( Akashi 2017 ; Dello Iacono 2013 ; Fuentes‐Aparicio 2013 , Giavi 2016 ; Meglio 2013 ) and five months ( Pérez‐Rangel 2017 ). All children were receiving daily maintenance at the time of follow‐up.

Study funding sources

Two included RCTs did not receive financial support ( Caminiti 2015 ; Dello Iacono 2013 ). Two studies were supported by national research grants ( Burks 2012 ; Vazquez‐Ortiz 2014 ). Pérez‐Rangel 2017 was supported by a Merck Sereno grant and by a grant from the ALK‐Abelló pharmaceutical company. Escudero 2015 was not funded, but the English language publication was financially supported by Stallergenes pharmaceutical company. Some authors of the Giavi 2016 study are or were employees for Nestec Ltd. Akashi 2017 declared that the study was partially supported by a grant from the Ministry of Health, Labour and Welfare Japan, and funds from a Research Center of Taiho Pharmaceutical Company. Study funding sources were not reported for two studies ( Fuentes‐Aparicio 2013 ; Meglio 2013 ).

Withdrawal rate

We calculated the withdrawal rate for each study. The main reason for withdrawal was the occurrence of adverse events. Interestingly, Giavi 2016 reported one dropout due to anxiety. In Burks 2012 the dropout rate was 15% for children in the oral immunotherapy group and 13% for placebo group children; the overall withdrawal rate for both study groups was 14.5%. Fuentes‐Aparicio 2013 reported a 4% overall dropout rate (7.5% for the oral immunotherapy group and 0% for the placebo group). Meglio 2013 reported an overall 5% dropout rate, with 10% in the oral immunotherapy group and 0% in the control group. There were no dropouts in Dello Iacono 2013 . Vazquez‐Ortiz 2014 reported 18% withdrawal in the oral immunotherapy group and none in the control group, resulting in an overall withdrawal of 11%. Caminiti 2015 reported an overall dropout rate of 13% (6% for the oral immunotherapy group and 21% for the placebo group). Escudero 2015 had a 7% dropout rate in the oral immunotherapy group and none in the control group, the overall withdrawal rate being 3%. Giavi 2016 reported a 27% withdrawal rate in the oral immunotherapy group and none in the control group; overall withdrawal: 14%. In Pérez‐Rangel 2017 , the overall withdrawal rate was 9%: 10.5% in the oral immunotherapy group and 7% in the placebo group. Akashi 2017 had an overall withdrawal rate of 17%: 22% in the oral immunotherapy group and 11% in the placebo group.

Studies awaiting classification

Our rsearch revealed abstracts for five studies with insufficient information to assess eligibility. See Characteristics of studies awaiting classification .

Ongoing studies

Searches of clinical trials registers identified two potentially relevant trials ( NCT02083471 ; NCT01846208 ; Characteristics of ongoing studies ). These will be assessed for inclusion in a future review update following completion of the studies.

Number of participants with serious adverse events (SAEs) (Analysis 1.3)

All 10 included trials (N = 439) reported occurrence of serious adverse events. A total of 21 children required epinephrine/adrenaline treatment ( Vazquez‐Ortiz 2014 , N = 13; Fuentes‐Aparicio 2013 , N = 5; 1 each in Caminiti 2015 ; Escudero 2015 and Akashi 2017 ). In total, 21 (8.4%) of the 249 children receiving oral immunotherapy required epinephrine. No children in the control group required epinephrine. Our GRADE assessment judged the quality of evidence to be low.

Number of participants with mild‐to‐severe adverse events (Analysis 1.4)

All included trials (N = 439) reported occurrence of mild‐to‐severe adverse events (RR 8.35, 95% CI 5.31 to 13.12; RD 0.67, 95% CI 0.61 to 0.73; children = 439; studies = 10; I² = 29% for RR and I² = 82% for RD). Although all studies provided detailed reports of adverse events, there was significant heterogeneity in methods of reporting. Adverse events occurred most frequently either in the oral immunotherapy escalation phase or in association with oral immunotherapy dosing. Seventy‐five per cent of children presented with mild‐to‐severe adverse events during oral immunotherapy treatment versus 6.8% of control group children. Based on available data, we could not comment on whether over‐ or under‐reporting of adverse events is a concern, although this is a possibility. Our GRADE assessment judged the quality of evidence to be low.

In Burks 2012 (N = 55) adverse events rates were highest during the first 10 months of oral immunotherapy. However, no serious adverse events or need for epinephrine were reported. Adverse events, most of which were oral or pharyngeal, were associated with 25% of 11,860 doses of oral immunotherapy with egg and 3.9% of 4018 doses of placebo. In the oral immunotherapy group 78% of children had oral or pharyngeal adverse events compared with 20% in the placebo group (P < 0.001). After 10 months, the rate of symptoms in the oral immunotherapy group decreased to 8.3% (15,815 doses). In addition to dosing‐related symptoms, 437 other adverse events were reported; 96% were considered to be unrelated to dosing on the basis of the timing and types of symptoms.

Fuentes‐Aparicio 2013 (N = 72) described 21 children (52.5%) who had symptoms at some stage of oral immunotherapy treatment. In eight children (20%) symptoms were very mild, and moderate‐to‐severe in 13 children. Eight children required treatment with antihistamines and corticosteroids and five children required epinephrine treatment.

Dello Iacono 2013 (N = 20) reported that all children who received oral immunotherapy experienced adverse events (n = 53 events) although none resulted from accidental exposure to egg. According to Sampson’s classification, where grade 1 is the mildest anaphylactic reaction and grade 5 is severe anaphylactic reaction with loss of consciousness ( Sampson 2003 ), three (5.6%) were grade 1, 10 (18.9%) were grade 2, 35 (66%) were grade 3, and five (9%) were grade 4. No children in the oral immunotherapy group had a grade 5 reaction, needed oral or intramuscular steroids or epinephrine, or required access emergency services. Eighty‐one per cent of adverse events occurred during administration of the first 6 mL, and 100% occurred with first administration of 20 mL hen's egg, which means that all children experienced some adverse events while increasing the oral immunotherapy dosage. The children in the oral immunotherapy group had relative risk of 4.96 (95% CI 3.30 to 7.45) for incurring an adverse event, but there were no significant differences in severity of reactions. No children discontinued treatment because of adverse events. Three children (30%) in the control group had a total of five adverse events because of accidental ingestion of trace amounts of egg. The severity grade was 3 or 4; no children required intramuscular epinephrine.

In Meglio 2013 (N = 20) 70% of children presented with mild‐to‐severe adverse events. No serious adverse events were reported.

In Vazquez‐Ortiz 2014 (N = 82), 45 children (90%) had dose‐related events including 13 who required epinephrine treatment. There were 1024 adverse events detected, corresponding to 7.6% of oral immunotherapy doses. The highest incidence of events occurred during the induction phase. The symptom distribution of adverse events were: vomiting (19.7%); lower respiratory tract involvement (18.8%); abdominal pain (15.7%); mouth itchiness (13.7%); urticaria (13.1%); rhinoconjunctivitis (7.7%); angioedema (6.7%); hoarseness (2.1%); diarrhoea (1.5%) atopic dermatitis flare (0.7%); and dysphagia (0.5%). Delayed adverse events represented a total of 4.3% of all reactions (3.8% gastro‐ intestinal plus 0.5% skin symptoms). The severity distribution of adverse events (as classified by Sampson's anaphylaxis grading, Sampson 2003 ) was: grade 1 = 30%; grade 2 = 31.2%; grade 3 = 15.9%; and grade 4 = 22.9%. Grade 4 was experienced by 58% of children receiving oral immunotherapy, consisting of a mild cough/wheeze in 78% of occasions. One child experienced a grade 5 reaction during the induction phase, leading to discontinuation. Multisystem involvement represented a total of 11.5% of all dose‐related adverse events. Accidental adverse events occurred in five children (15.6%) in the control group, nevertheless no epinephrine or adrenaline was needed. There was a total of 1024 adverse events in the oral immunotherapy group and seven in the control group.

Caminiti 2015 (N = 31) reported that adverse events occurred in three children during the desensitization procedure, one of whom discontinued oral immunotherapy. In the egg‐containing diet arm, one child had abdominal pain with urticaria after exercise, and another had rhinitis and/or asthma during a respiratory tract infection. One participant (5.9%) required epinephrine treatment. No adverse events were observed in the control group.

Escudero 2015 (N = 61) reported 145 allergic reactions as adverse events during oral immunotherapy in 70% (N = 21) of children, presented mainly in the escalation phase (70%, N = 21), followed by the build‐up phase (53%, N = 16) and reducing to 33% (N = 10) in the maintenance phase. Ninty‐eight per cent (98%) of children experienced mild symptoms and 2% had a moderate allergic reaction. In one child (0.04%) epinephrine treatment was needed due to a systemic reaction (rhinitis, urticaria, and mild respiratory distress). The protocol was modified for this child by reducing the oral immunotherapy dose by 50%. The most common adverse events were gastro‐intestinal (82%), oropharyngeal symptoms (21.5%), rhinitis (11.4%), respiratory distress (6.3%), and generalized urticaria (3.8%). Moreover, 7% of children (N = 2) withdrew from the study for non‐severe repeated allergic reactions (abdominal pain and vomiting).

Giavi 2016 (N = 29) reported that all children, except one in the oral immunotherapy group, experienced at least one adverse event during the course of treatment. There was no significant difference between the hydrolysed egg and placebo groups with respect to type of adverse events.

In Pérez‐Rangel 2017 (N = 33), safety data during the first control randomized oral immunotherapy period, which was included in our analysis, was received from the authors following personal communication ( Ibanez Sandin MD 2017 [pers comm] ). Fifteen of 18 children presented with adverse events in the escalation phase (n = 40 adverse events). These included: oropharyngeal symptoms (n = 29); gastro‐intestinal symptoms (n = 17); cutaneous symptoms (n = 4); and rhinitis (n = 4). All adverse events were reported to be mild. At the beginning of the build‐up phase nine of 17 children presented with adverse events (n = 45 adverse events). All adverse events were mild, and the distribution among organ systems were similar to the build‐up phase: oropharyngeal symptoms (n = 37); gastro‐intestinal symptoms (n = 20); cutaneous symptoms (n = 10); rhinitis (n = 1); and asthma (n = 1). Five months after baseline in the maintenance phase, 45 mild adverse events were reported: oropharyngeal symptoms (n = 39); gastro‐intestinal symptoms (n = 10); cutaneous symptoms (n = 18); rhinitis (n = 4); and asthma (n = 2). Participants could present multiple symptoms in the same adverse event.

Akashi 2017 (N = 36) reported that 17 of 18 children in the oral immunotherapy group experienced adverse events: vomiting (N = 4), diarrhoea (N = 5), urticaria or angioedema (N = 6), and respiratory symptoms including coughing and wheezing (N = 3). Of the three children with respiratory symptoms, one developed persistent asthma. Eight children had oral cavity itchiness and six children had mild abdominal pain, but no children required an epinephrine injection. A total of 32 mild‐to‐severe adverse events were reported.

Skin prick test (SPT)

Nine studies (403 children; 231 oral immunotherapy; 172 control/placebo) reported performing SPT at baseline ( Burks 2012; Caminiti 2015; Dello Iacono 2013; Escudero 2015; Fuentes‐Aparicio 2013 ; Giavi 2016; Meglio 2013; Pérez‐Rangel 2017 ; Vazquez‐Ortiz 2014 ) and it was performed at the end of oral immunotherapy in seven studies (total number of children = 292; oral immunotherapy = 166; control/placebo = 126) ( Burks 2012; Caminiti 2015; Dello Iacono 2013; Escudero 2015 ; Fuentes‐Aparicio 2013 Meglio 2013; Pérez‐Rangel 2017 ). There were non‐significant differences between children in the oral immunotherapy and control groups before starting immunotherapy. A significant difference in SPT wheal size was found at the end of oral immunotherapy in all seven studies that performed the test ( Table 1 ). Moreover, Burks 2012 showed that a decrease in wheal size from baseline to 22 months (P = 0.009) was correlated with sustained unresponsiveness at 24 months (P = 0.005).

Serologic testing

Specific IgE (sIgE) levels at baseline and at the end of the oral immunotherapy protocol were investigated by using different laboratory methods in each study. However, there were no data available for sIgE levels at the end of the oral immunotherapy protocol in Vazquez‐Ortiz 2014 . For sIgE determination Burks 2012 , Caminiti 2015 , Escudero 2015 , Giavi 2016 , Pérez‐Rangel 2017 , Vazquez‐Ortiz 2014 used the Thermo Immuno‐CAP system (Fisher Scientific); Dello Iacono 2013 and Fuentes‐Aparicio 2013 used the Phadia CAP System fluorescence enzyme immunoassay (FEIA) (Phadia Diagnostics); Meglio 2013 used the Realtest Reverse Enzyme Allergo Sorbent Test (REAST) (Lofarma) and an allergen micro array assay (Immuno Solid‐phase Allergen Chip ISAC; VBC Genomics Bioscience Research, Vienna, Austria) in accordance with the manufacturer’s recommendations. A panel of 104 allergens (inhalants and foods), that also contained the following five purified natural hen's egg allergens: ovomucoid (Gal d 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3), lysozyme (Gal d 4), and serum albumin (Gal d 5), was used. Akashi 2017 used CAP system for sIgE determination. Because of the differences in the upper limit of measurement it was impossible to combine data.

Nevertheless, two studies reported a statistically significantly decreased levels of egg sIgE antibody after oral immunotherapy compared to control ( Burks 2012 ; Dello Iacono 2013 ). In Dello Iacono 2013 (N = 20) the difference in the reduction of IgE between pre‐ and post‐oral immunotherapy was ‐14.4 kUA/L (range ‐27.6 to 0.1) in the oral immunotherapy group and 2 kUA/L (range ‐8.9 to ‐13.8) in the control group (P < 0.001). Futhermore, the median reduction in sIgE levels from baseline to the end of oral immunotherapy protocol for egg oral immunotherapy group was not statistically significantly greater than that for control group ( Akashi 2017 ; Burks 2012 ; Caminiti 2015 ; Escudero 2015 ; Fuentes‐Aparicio 2013 ; Giavi 2016 ; Pérez‐Rangel 2017 ). Meglio 2013 (N = 20) reported statistically significant reduction for sIgE before and after oral immunotherapy protocol for oral immunotherapy group: for ovomucoid (Gald1) by REAST (20.9 ± 45.6 versus 14.8 ± 30.7; P = 0.02), and for both ovomucoid (Gald1) (6.67 ± 8.36 versus 1.78 ± 1.74; P < 0.01) and ovalbumin (Gald2) measured by ISAC method (2.92 ± 5.05 versus 0.74 ± 1.22; P < 0.02), respectively. There were no differences in reduction of sIgE measured by REAST technique from baseline compared with the final point of the study in the control group. Interestingly, there was a statistically significant increase in ovomucoid (Gald1) measured using the ISAC method in the control group at the end of the study (5.32 ± 6.89 versus 7.81 ± 10.53; P < 0.05). In Caminiti 2015 (N = 31), the egg‐specific IgE level after oral immunotherapy was 34.2 kUA/L in the intervention group and 38.9 kUA/L in the placebo group. Of note, follow‐up of these children showed that at 10 months, formerly active oral immunotherapy children who continued with an egg‐containing diet for the following six months had significantly lower sIgE levels compared to baseline (37.6 versus 12.2 kUA/L, P = 0.02). Escudero 2015 (N = 61) reported a statistically significant decrease from baseline to the end of oral immunotherapy in both groups only for ovalbumin IgE (6.3 kUA/L (0.7 to 185) versus 2.2 kUA/L (0.3 to 192), P < 0.001) and 2.2 kUA/L (0.7 to 43.5) versus 1.3 kUA/L (0.3 to 32.3), P = 0.01); no differences were seen for ovomucoid or egg white IgE. Akashi 2017 (N = 36) reported a statistically significant decrease in sIgE levels from baseline to the end of the study in the control group (median 36.4 versus 30.6 kUA/mL; P < 0.05). It was not possible to extrapolate data for sIgE antibodies in Burks 2012 , Fuentes‐Aparicio 2013 , or Pérez‐Rangel 2017 . In Giavi 2016 (N = 29) no statistically significant difference was observed regarding sIgE levels (change over time expressed as median (min‐max) ‐3.230 kUA/L (‐8.90 to 0.42); P = 0.29).

Eight studies (total number of children = 337; oral immunotherapy = 189; control/placebo = 148) evaluated changes in egg‐specific IgG4 antibodies and all eight showed a statistically significant increase in the level of these antibodies after oral immunotherapy ( Akashi 2017 ; Burks 2012 ; Caminiti 2015 ; Escudero 2015 ; Fuentes‐Aparicio 2013 ; Giavi 2016 ; Meglio 2013 ; Pérez‐Rangel 2017 ). Akashi 2017 (N = 36) demonstrated a statistically significant increase of egg white‐specific IgG4 in the oral immunotherapy group after completing the oral immunotherapy protocol (median, 13 U/mL at baseline to 94 U/mL at the end of oral immunotherapy; P < 0.01), whereas such a change was absent in the control group (median, 13 U/mL at baseline to 13 U/mL; P = 1.00). In Burks 2012 (N = 55) the median reduction of egg‐specific IgG4 by the end of oral immunotherapy for the oral immunotherapy group was significantly higher (median, 48.5 kU/L range ‐0.1 to 162.1; P < 0.01) compared to the placebo group (there were no numerical data available for the placebo group). Caminiti 2015 (N = 31) reported a significant increase of the mean egg‐specific IgG4 levels by the end of oral immunotherapy in intervention group children (29.2 µg/mL versus 0.9 µg/mL, P = 0.001). In Escudero 2015 (N = 61) there was an increase in median egg‐specific IgG4 observed from baseline to the end of oral immunotherapy in the oral immunotherapy group (0.4 mg/L (0.1 to 6.2) versus 4.4 mg/L (0.1 to 30), P = 0.0001). Giavi 2016 (N = 29) reported a significant increase over time from baseline to the end of oral immunotherapy in specific IgG4 in the active group (expressed as change over time, median (range): for egg yolk IgG4 (0.10 mg/L, 0.00 to 1.71, P = 0.01) and for ovalbumin IgG4 (0.11 mg/L, ‐0.00 to 3.59, P = 0.04); there were no differences observed in the median change of IgG4 levels for egg white (0.07 mg/L, ‐0.31 to 2.54, P = 0.07) and for ovomucoid (0.00 mg/L, ‐0.56 to 1.04, P = 0.14). Meglio 2013 (N = 20) found a statistically significant increase in the level of IgG4 only for ovalbumin (Gald2) at the end of oral immunotherapy (average, ± SD 2.6 mg/L (± 0.4) versus 2.95 mg/L (± 0.4); P = 0.02), but not for ovomucoid (Gald1) (average, ± SD 0.9 mg/L (± 0.7) versus q.8 mg/L (± 1.5). Data for the egg‐specific IgG4 levels were presented graphically in two studies and could not be extracted for analysis ( Fuentes‐Aparicio 2013 ; Pérez‐Rangel 2017 ).

In addition, six studies (281 children; oral immunotherapy = 161; control/placebo = 120) showed a statistically significant increase in IgG4 compared to the control group ( Burks 2012 ; Caminiti 2015 ; Escudero 2015 ; Fuentes‐Aparicio 2013 ; Giavi 2016 ; Pérez‐Rangel 2017 ). In Caminiti 2015 (N = 31) egg‐specific IgG4 levels after oral immunotherapy were statistically significantly higher in the intervention group (29.2 µg/mL) than in the placebo group (1.5 µg/mL, P = 0.001). Follow‐up of these children showed that at 10 months, formerly active oral immunotherapy children who continued with egg‐containing diet for the following six months had significantly higher sIgG4 levels compared to baseline (32.4 versus 0.9 µg/mL, P = 0.001). Median sIgG4 levels in Escudero 2015 (N = 61) were higher in the oral immunotherapy group by the end of oral immunotherapy than in the control group (4.4 mg/L (0.1 to 30) versus 0.4 mg/L (0.1 to 7.5); P = 0.001). Giavi 2016 (N = 29) reported that a greater increase of egg‐specific IgG4 occurred in the oral immunotherapy group compared to placebo by the end of oral immunotherapy, however these data were not reported. It was not possible to extrapolate precise data for sIgG4 from Burks 2012 , Fuentes‐Aparicio 2013 and Pérez‐Rangel 2017 because data were reported graphically.

Two studies reported a significant reduction in basophil activation test in the oral immunotherapy group compared to placebo at the end of treatment ( Burks 2012 ; Giavi 2016 ) (84 children; oral immunotherapy group = 55; placebo group = 29): in Burks 2012 the differences in CD63 activation were statistically significant (0.01 μg/mL, P = 0.002; 0.1 μg/mL, P = 0.001). In Giavi 2016 a significant decrease in percentage of CD203c+ cells (P = 0.04) occurred and there was a trend for a lower percentage of CD63+ cells (P = 0.07).

Meglio 2013 (N = 20) performed cytokines (IL‐4, IL‐5, IL‐6, IL‐10, IL‐12, IL‐13), interferon‐gamma and tumour necrosis factor‐alfa analysis and found a statistically significant increase of IL‐5 levels in the oral immunotherapy group at the end of treatment (mean, 19.00 ± 9.4 pg/mL; range = 5.00 to 32.00 versus 28.13 ± 14.7 pg/mL; range, 12.00 to 56.00; P = 0.03).