- Email: [email protected]
Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy?
Accepted Manuscript Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy? Kenji Matsumoto, MD, PhD, Rintaro Mori, MD, PhD, Celine Miyazaki, PhD, Yukihiro Ohya, MD, PhD, Hirohisa Saito, MD, PhD PII:
S0091-6749(18)30329-4
DOI:
10.1016/j.jaci.2018.02.033
Reference:
YMAI 13345
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 6 March 2017 Revised Date:
25 January 2018
Accepted Date: 14 February 2018
Please cite this article as: Matsumoto K, Mori R, Miyazaki C, Ohya Y, Saito H, Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy?, Journal of Allergy and Clinical Immunology (2018), doi: 10.1016/j.jaci.2018.02.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy?
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Kenji Matsumoto, MD, PhD,a Rintaro Mori, MD, PhD,b Celine Miyazaki, PhD,b
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Yukihiro Ohya, MD, PhD,c Hirohisa Saito, MD, PhDa
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National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
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157-8535, Japan
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Department of Allergy and Clinical Immunology, bDepartment of Health Policy,
Division of Allergy, National Center for Child Health and Development, Tokyo
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Key words: Food allergy, primary prevention, boiled egg, eczema, proactive treatment
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This study was supported in part by grants from the Food Safety Commission of Japan
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(#1506 and #1705 to KM, YO and HS) and from the National Center for Child Health
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and Development (#26-9 to KM).
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Corresponding author: Kenji Matsumoto, MD, PhD, Department of Allergy and Clinical
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Immunology, National Research Institute for Child Health and Development, 2-10-1
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Okura, Setagaya-ku, Tokyo 157-8535, Japan. E-mail: [email protected]
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Based on a number of epidemiological observations, the "dual-allergen-exposure
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hypothesis" was framed in 2008,1 postulating that oral antigen exposure tends to induce
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tolerance, whereas skin exposure tends to induce allergic sensitization leading to food
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allergy. The "LEAP" study proved that early introduction of peanut significantly
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prevented development of peanut allergy at 60M of age,2 and it became a landmark
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turning point for pediatric practice by providing us a glimpse of the ultimate goal:
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primary prevention.
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A previous issue of the Journal includes three randomized intervention trials for prevention of egg allergy.3-5 Although early introduction of egg did not show
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statistically significant effects on egg allergy in any of those studies, the number of
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subjects was likely insufficient for drawing a firm conclusion regarding whether early
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egg introduction is truly effective or not.
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In this review, we used those studies along with three previously published studies6-8 (Table 1) to perform a meta-analysis to re-evaluate the risk ratios (RRs) and subgroup
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analyses in an attempt to identify hidden factors that might be affecting the
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variability/heterogeneity of efficacy findings and safety issues among the trials. Our aim
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was to minimize the risk and maximize the efficacy of primary prevention strategies in
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the future. The details of our methods are shown in the Methods section in this article’s
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Online Repository at www.jacionline.org.
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Efficacy of early egg introduction on egg allergy and egg sensitization in infants at 12
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months of age
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Our meta-analyses of the six studies revealed that early egg introduction showed
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statistically significant benefits (40% and 22%) for prevention of both egg allergy (RR:
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0.60; 95% confidence interval (CI): 0.42-0.85; p = 0.004; Fig. 1A) and egg sensitization
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(RR: 0.78; 95% CI: 0.66-0.92; p = 0.004; Fig. 1B). However, the meta-analysis of egg
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allergy prevention showed moderate heterogeneity in the results of these studies (I2 =
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33%; p < 0.10 in the chi2 test for heterogeneity; Fig. 1A), suggesting that there may be
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some factors that affect the heterogeneity of the results among these studies.
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Food processing and the efficacy of early egg introduction on egg allergy and egg
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sensitization in infants at 12 months of age
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We performed subgroup analyses to further investigate the heterogeneity found in the
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aforementioned meta-analysis. Four of the six studies used pasteurized raw egg powder,
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whereas the remaining two used boiled egg or boiled egg powder for early introduction
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(Table 1). Subgroup analysis of the four studies using raw egg and two studies using
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boiled egg revealed that the efficacy of early egg introduction seemed to be greater in
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the boiled egg trials, but testing of the subgroup differences did not show statistical
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significance (p = 0.41; Fig. 1A). Further studies are needed to clarify whether raw egg
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or boiled egg is more beneficial.
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Egg dosage and the efficacy of early egg introduction on egg allergy in infants at 12
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months of age
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The EAT study demonstrated that the total intake of egg during the intervention period
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correlated significantly with lower risk of egg allergy.7 However, meta-regression
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analysis (see details in this article’s Online Repository at www.jacionline.org) found no
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statistically significant correlation between the dosage of egg and the logarithm of RR
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among the six studies (coefficient: -0.096; 95% CI: -0.18 to 0.037; p = 0.39; Fig. 1C).
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The optimal egg dosage for early introduction should be further explored.
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Relationship between food processing and egg dosage in the efficacy of early egg
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introduction on egg allergy in infants at 12 months of age
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We performed subgroup analyses to simultaneously investigate the relationship between
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food processing and the egg dosage. Among four possible combinations (food
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processing: raw or boiled; and egg dosage: ≥3 g/wk or <3 g/wk), the efficacy of early
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egg introduction reached statistical significance only in the subgroups using raw egg at
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≥3 g/wk and boiled egg at <3 g/wk (Figs. E1 and E2 in this article’s Online Repository
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at www.jacionline.org). Therefore, no firm relationship was identified between food
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processing and the egg dosage in regard to the efficacy of early egg introduction on egg
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allergy. However, because the number of subjects included in each combination was
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small, further studies are needed to draw a firm conclusion.
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Role of food processing and egg dosage in the heterogeneity found in the
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aforementioned meta-analysis
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To further investigate the extent to which the heterogeneity in the aforementioned
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meta-analysis can be explained by the relationship between food processing and the egg
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dosage, we performed meta-regression analyses using the egg dosage as a continuous
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variable or as two groups (≥3 g/wk or <3 g/wk). No statistical significance was found,
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presumably due to the small sample size. However, these two analyses demonstrated
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that approximately 50% (49.8% and 41.2%, respectively) of the heterogeneity could be
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explained by food processing and the egg dosage (data not shown). Other factors
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affecting the heterogeneity are probably the family history of allergic diseases,
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presence/absence of eczema and so on.
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Food processing and the safety of early egg introduction
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Subgroup analyses showed several significant differences in terms of the safety. That is,
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at initial introduction, approximately 15 times more babies reacted to raw egg than to
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boiled egg (Fig. 1D). In the STAR study,6 five of six babies who reacted to raw egg
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powder at initial introduction were tolerant to boiled egg, suggesting that such reactions
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are mainly due to the higher allergenicity of raw egg powder. In addition, a total of
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eight anaphylaxis events were observed in three of the studies using raw egg powder,
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whereas no anaphylaxis was observed in the two studies using boiled egg (P<0.018 by
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Fisher's exact test; Table 1). These safety findings strongly recommend using boiled egg
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or exercising special caution when using raw egg powder in future studies. We would further like to point out a potentially harmful reaction to early egg
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introduction: food protein-induced enterocolitis syndrome (FPIES). FPIES is a
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non-IgE-mediated gastrointestinal food allergy that occurs most frequently during
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infancy. FPIES is not a common disease (0.34% in Israel,9 0.21% in Japan10 and 0.15%
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in Australia11), but seven babies in the early-introduction group developed symptoms
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consistent with FPIES, regardless of whether the egg was raw or boiled (Table 1). The
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offending food in the majority of FPIES babies was milk, whereas egg FPIES is much
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less common.9-11 When we calculate the predicted prevalence of egg FPIES, it is
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approximately 0.041% to 0.0018%, whereas the actual prevalence of egg FPIES among
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these 6 intervention studies was 0.61% (8/1314), which was significantly higher than
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the predicted prevalence (P < 10-5, by Fisher's exact test). Therefore, it can be thought
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that early egg introduction should be accompanied by careful monitoring for severe
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emesis within a couple of hours after egg ingestion, since it is a characteristic feature of
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FPIES.
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Eczema/atopic dermatitis
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Eczema prevalences at entry to these studies varied from 0% to 100% (Table 1). In this
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meta-analysis, the presence of eczema at entry was positively associated with the
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prevalence of allergy in the late-introduction (control) group, with very high statistical
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significance (Fig. 1E). This is consistent with previous epidemiological studies: a
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meta-analysis of those studies clearly demonstrated that eczema/atopic dermatitis is a
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robust risk factor for food allergy.12
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In eczematous lesions, Langerhans cells reportedly migrate right beneath the tight
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junctions, elongate their dendrites, and penetrate through the junctions so that they can
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uptake foreign proteins on the skin surface, even at sites of erythema, i.e., the early
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stage of eczema.13 In addition, two major cytokines—IL-33 and thymic stromal
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lymphopoietin (TSLP)—expressed at the sites of eczematous lesions reportedly activate
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antigen–presenting cells (APCs), and these cytokine-primed APCs facilitate naïve
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T–cell differentiation towards Th2. Therefore, exposure to foods via eczema lesions is
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likely to facilitate allergic sensitization.14 In fact, a couple of mouse studies provided
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clear evidence that the condition of skin that is exposed to exogenous protein is a
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critical deciding factor in immune responses: exposure of intact skin induces
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antigen-specific tolerance, whereas exposure of damaged skin (stripped skin) induces
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allergic sensitization.15-17 Therefore, primary prevention and appropriate treatment of
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eczema, i.e., damaged skin, should be recommended. However, although there is
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insufficient direct evidence for the effects of treatments of eczema/atopic dermatitis on
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the development of food allergy, it is probably unethical to test for such effects in a
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clinical intervention trial.
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Feeding egg to a baby with eczema may have another risk: the baby may already be
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sensitized to the trial food antigen due to the eczema12,14 and would react to the antigen
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even at the initial introduction. In fact, the prevalence of eczema at entry correlated
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strongly with the percentage of babies reacting to the raw egg powder at the initial
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introduction (Fig. 1F). In contrast, boiled egg was much safer than raw egg even for
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babies with eczema (Fig 1F), suggesting that it may be better to use boiled egg for
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introduction to babies with eczema. Notably, none of the babies who had eczema at
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recruitment and underwent extensive eczema treatment with a "proactive regimen"
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before egg introduction reacted at all to a small amount of boiled egg powder.8 However,
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it is yet to be clarified whether extensive eczema treatment also makes introduction to
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raw egg safer or not.
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A very recent guideline for prevention of peanut allergy recommended that specific
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IgE measurement or skin testing should be considered in babies with severe eczema.18 A
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similar recommendation for egg-specific IgE measurement should be considered for
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certain babies with severe eczema and/or allergy to any other foods.
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The optimal timing or "window" for the introduction of foods to prevent development
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of food allergy is still in debate. However, it may be too late to start egg introduction for
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babies who have eczema, and safer and effective methods (when, and how) for
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introducing egg to such babies should be further explored.
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Both “early boiled egg introduction” and “eczema treatment” are probably
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indispensable for primary prevention of egg allergy: Does it take two to “tango”?
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Exposure to foods via eczema lesions is likely to facilitate allergic sensitization.14
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Therefore, early introduction may provide little or no protective effect if eczema is left
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untreated. In particular, eczema treatment with a proactive regimen19 was reported to
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potently reduce further sensitization,20 suggesting that extensive control of eczema is
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critical for early introduction to successfully prevent food allergy. In fact, egg-specific
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IgE titers were significantly lower in the early-introduction group in the PETIT study, 8
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in which extensive eczema treatment had been performed, suggesting that—at
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present—primary prevention (aimed at preventing sensitization) can be achieved only
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by means of extensive concomitant eczema treatment.
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On the other hand, it is intriguing that even after the extensive eczema treatment
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using a proactive regimen in the PETIT study,8 the prevalence of egg allergy in the
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late-introduction (control) group was very high (37.7%). That suggests that early food
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introduction is necessary for effective food allergy prevention, even in eczema-treated
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babies and probably babies without eczema.
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These observations suggest that simultaneous performance of both "early introduction" and "eczema treatment" is the key to primary prevention of food allergy;
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performance of only one or the other is not sufficient.
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Other issues
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Regarding the specific food, a systematic review demonstrated that early introduction
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showed a preventive effect only for egg and peanut, not for milk.21 A similar tendency
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was observed in the EAT study.7 However, it remains to be clarified whether early food
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introduction combined with extensive eczema treatment is effective for other foods, as
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well. In addition, we need to determine if “eczema treatment” has the potential to
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enhance other antigen-specific immunotherapies administered by different routes, such
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as subcutaneous, sublingual and epicutaneous (SCIT, SLIT and EPIT).
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In summary, this rostrum updated and tried to provide a more solid foundation for
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the findings of the earlier systematic review.21 However, it is definitely true that the
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number of papers as well as the number of participants in each study are insufficient for
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drawing firm conclusions, especially regarding the optimal doses, raw/boiled, when to
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start and for whom to intervene. Therefore, we propose some studies that should be
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performed to generate stronger data and conclusions. However, on the basis of the most
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current results, we hypothesize that simultaneous intervention by both “early boiled egg
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introduction” and “eczema treatment” is probably indispensable for primary prevention
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of egg allergy. (2033 words)
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Allergy Clin Immunol 2013;132:387-92. Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. N Engl J Med 2016;374:1733-43. Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M, et al. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Lancet 2017;389:276-86. Katz Y, Goldberg MR, Rajuan N, Cohen A, Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study. J Allergy Clin Immunol 2011;127:647-53. Miyazawa T, Itabashi K, Imai T. Retrospective multicenter survey on food-related symptoms suggestive of cow's milk allergy in NICU neonates. Allergol Int 2013;62:85-90. Mehr S, Frith K, Barnes EH, Campbell DE; FPIES Study Group. Food protein-induced enterocolitis syndrome in Australia: A population-based study, 2012-2014. J Allergy Clin Immunol 2017;140:1323-30. Tsakok T, Marrs T, Mohsin M, Baron S, du Toit G, Till S, et al. Does atopic dermatitis cause food allergy? A systematic review. J Allergy Clin Immunol 2016;137:1071-8. Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, et al. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis. J Allergy Clin Immunol 2014;134:856-64. Matsumoto K, Saito H. Eczematous sensitization, a novel pathway for allergic sensitization, can occur in an early stage of eczema. J Allergy Clin Immunol 2014;134:865-6. Dioszeghy V, Mondoulet L, Dhelft V, Ligouis M, Puteaux E, Benhamou PH, et al. Epicutaneous immunotherapy results in rapid allergen uptake by dendritic cells through intact skin and downregulates the allergen-specific response in sensitized mice. J Immunol 2011;186:5629-37. Mondoulet L, Dioszeghy V, Puteaux E, Ligouis M, Dhelft V, Letourneur F, et al. Intact skin and not stripped skin is crucial for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT) in mice. Clin Transl Allergy 2012;2:22. Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE, et al. Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. J Allergy Clin Immunol 2014;133:1390-9. Togias A, Cooper SF, Acebal ML, Assa'ad A, Baker JR, Jr., Beck LA, et al. Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin Immunol 2017;139:29-44. Wollenberg A, Oranje A, Deleuran M, Simon D, Szalai Z, Kunz B, et al. ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol 2016;30:729-47
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Fukuie T, Hirakawa S, Narita M, Nomura I, Matsumoto K, Tokura Y, et al. Potential preventive effects of proactive therapy on sensitization in moderate to severe childhood atopic dermatitis: A randomized, investigator-blinded, controlled study. J Dermatol 2016;43:1283-92. Ierodiakonou D, Garcia-Larsen V, Logan A, Groome A, Cunha S, Chivinge J, et al. Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease: A Systematic Review and Meta-analysis. JAMA 2016;316:1181-92.
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Figure legend
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FIG. 1. Meta-analysis of six intervention trials for egg allergy prevention.
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Effect of early-introduction (Early intro.) versus late-introduction (control) of egg on
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risk of egg allergy (A) or egg sensitization (B) at 12 months of age. Data are from
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randomized clinical trials. “Events” refers to egg allergy (A) or egg sensitization (B).
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The size of each data marker is proportional to the study weight in the meta-analysis.
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(C) Meta-regression analysis of the egg dosage and log risk ratio. The size of each circle
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is proportional to the study weight in this analysis. Red and blue circles indicate studies
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using raw and boiled egg, respectively. (D) Percentages of babies and 95% confident
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interval in the early-introduction (Early intro.) group who reacted to raw (red column)
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or boiled (blue column) egg at the initial introduction. Statistical significance was
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calculated using the chi2 test. (E) Correlation between the prevalence of eczema at 4M
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and the prevalence of egg allergy at 12M in the late-introduction (control) group.
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Statistical significance was calculated after applying a linear regression model. (F)
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Correlation is shown between the prevalence of eczema at 4M and the percentage of
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babies in the early-introduction (Early intro.) group who reacted to raw (red dots) or
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boiled (blue dots) egg at the initial introduction. Statistical significance was calculated
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using the results from only the four studies that used raw egg, after applying a linear
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regression model.
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Table 1. Summary of recent intervention trials for prevention of egg allergy using Intention to Treat analysis Intervention
Eczema preva-
Safety*/
Risk ratio (95%CI)
Early introduction
Control
Allergy/
Egg allergy at 12M/
Egg allergy at 12M/
Sensitization
Sensitization at 12M Sensitization at 12M
at 12M 0% at 4M
6.1% (25/407)
15.1% (57/377)
11% at 12M
5 anaph. in EIG
0.6% (1/156)
9% at 4M
7.1% (13/184)
2.6% (4/156)
?
1 FPIES‡ 2 anaph. in EIG
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lence at entry/
Serious events
Palmer et al.3
6.3 g/wk
0.68 (0.42-1.09)
7.0% (26/371)
STEP-JACI 2017
Raw egg powder
0.71 (0.49-1.04)
10.8% (40/371)
Bellach et al.4
0.8-2.5 g/wk†
3.30 (0.35-31.32)
2.1% (3/142)
HEAP-JACI 2017
Raw egg powder
2.20 (0.68-7.14)
5.6% (8/142)
Wei-Liang Tan et al.5
2.45 g/wk
0.59 (0.25-1.37)
6.2% (8/130)
10.5% (13/124)
26% at 4M
8.5% (14/165)
BEAT-JACI 2017
Raw egg powder
0.52 (0.28-0.97)
10.7% (13/122)
20.5% (25/122)
37% at 12M
No anaph. in EIG
Palmer et al.6
6.3 g/wk
0.65 (0.38-1.11)
33.3% (13/42)
51.4% (18/35)
100% at 4M
20.4% (10/49)
STAR-JACI 2013
Raw egg powder
0.72 (0.47-1.09)
45.2% (19/42)
63.8% (22/35)
?
1 FPIES‡ 1 anaph. in EIG
Perkin et al.7
4 g/wk
0.69 (0.40-1.18)
3.7% (21/569)
5.4% (32/596)
24% at 3M
0.8% (3/569)
Boiled egg
0.80 (0.58-1.10)
10.4% (57/550)
13.0% (78/601)
17% at 12M
6 FPIES in EIG
0.35-1.75 g/wk§
0·22 (0·08–0·61)
8.3% (5/60)
37.7% (23/61)
100% at 4M
0% (0/60)
PETIT-Lancet 2017
Boiled egg powder
0.86 (0.85-1.13)
57.9% (33/57)
67.6% (46/68)
2% at 12M¶
No anaph. in EIG
Meta-analysis
Meta-analysis
0.56 (0.41-0.76)
5.9% (77/1314)
9.3% (126/1349)
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10.3% (39/377)
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*Reacted to egg powder at introduction in the Early Introduction Group (EIG). †Early Introduction Group received 0.8 g/wk in the first week, 1.7 g/wk in the second week, and then 2.5 g/wk from the third week of intervention until 12M.
‡FPIES: food protein-induced enterocolitis syndrome; anaph.: anaphylaxis. §Early Introduction Group received 0.35 g/wk from 6M through 8M, and 1.75 g/wk from 9M through 12M. ¶After corticosteroid ointment therapy with a "proactive regimen" and assessed by the POEM score at 12M.
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Supplementary Methods Selection of Studies We selected "randomized intervention trials" for "egg allergy". At the time we started the analysis (Jan 2017), three studies were found by PubMed search, while three other studies were not cited in PubMed but were found in Articles in Press of the JACI. Meta-analysis Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for
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dichotomous data using Mantel-Haenszel analysis. Random-effects meta-analysis was performed when between-study methodological heterogeneity undermined the compatibility of the quantitative results, or if substantial statistical heterogeneity was detected.
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Heterogeneity of the studies was assessed using both qualitative and quantitative measures. Statistical heterogeneity was determined for each meta-analysis using Tau2, I2 and chi2 statistics. Heterogeneity was deemed substantial if Tau2 was greater than zero and either I2 was greater than 50% or p < 0.10 in the chi2 test for heterogeneity.1 To further assess potential heterogeneity effects, both fixed- and random-effects models
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were compared for each outcome, when possible. Meta-regression analysis was performed to determine the extent of, and explanatory factors for, the heterogeneity identified in the above meta-analyses.
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All statistical analyses were performed using RevMan 5.0 software (Cochrane Collaboration, Oxford, UK) or STATA software (StataCorp LP, College Station, TX). 1. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–58.
Supplementary Figure E1
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Fig. E1. Effect of early introduction (Early Intro.) versus late introduction (control) of raw egg on the risk of egg allergy at 12 months of age. Data are from randomized clinical trials using ≥3 g/wk egg powder (2.1.1) or <3 g/wk egg powder (2.1.2). “Events” refers to egg allergy. The size of each data marker is proportional to the study weight in the meta-analysis.
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Fig. E2. Effect of early introduction (Early Intro.) versus late introduction (control) of boiled egg on the risk of egg allergy at 12 months of age. Data are from randomized clinical trials using ≥3 g/wk egg powder (2.2.1) or <3 g/wk egg powder (2.2.2). “Events” refers to egg allergy. The size of each data marker is proportional to the study weight in the meta-analysis.
S0091-6749(18)30329-4
DOI:
10.1016/j.jaci.2018.02.033
Reference:
YMAI 13345
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 6 March 2017 Revised Date:
25 January 2018
Accepted Date: 14 February 2018
Please cite this article as: Matsumoto K, Mori R, Miyazaki C, Ohya Y, Saito H, Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy?, Journal of Allergy and Clinical Immunology (2018), doi: 10.1016/j.jaci.2018.02.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy?
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Kenji Matsumoto, MD, PhD,a Rintaro Mori, MD, PhD,b Celine Miyazaki, PhD,b
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Yukihiro Ohya, MD, PhD,c Hirohisa Saito, MD, PhDa
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a
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National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
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157-8535, Japan
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Department of Allergy and Clinical Immunology, bDepartment of Health Policy,
Division of Allergy, National Center for Child Health and Development, Tokyo
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Key words: Food allergy, primary prevention, boiled egg, eczema, proactive treatment
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This study was supported in part by grants from the Food Safety Commission of Japan
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(#1506 and #1705 to KM, YO and HS) and from the National Center for Child Health
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and Development (#26-9 to KM).
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Corresponding author: Kenji Matsumoto, MD, PhD, Department of Allergy and Clinical
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Immunology, National Research Institute for Child Health and Development, 2-10-1
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Okura, Setagaya-ku, Tokyo 157-8535, Japan. E-mail: [email protected]
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Based on a number of epidemiological observations, the "dual-allergen-exposure
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hypothesis" was framed in 2008,1 postulating that oral antigen exposure tends to induce
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tolerance, whereas skin exposure tends to induce allergic sensitization leading to food
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allergy. The "LEAP" study proved that early introduction of peanut significantly
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prevented development of peanut allergy at 60M of age,2 and it became a landmark
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turning point for pediatric practice by providing us a glimpse of the ultimate goal:
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primary prevention.
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A previous issue of the Journal includes three randomized intervention trials for prevention of egg allergy.3-5 Although early introduction of egg did not show
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statistically significant effects on egg allergy in any of those studies, the number of
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subjects was likely insufficient for drawing a firm conclusion regarding whether early
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egg introduction is truly effective or not.
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In this review, we used those studies along with three previously published studies6-8 (Table 1) to perform a meta-analysis to re-evaluate the risk ratios (RRs) and subgroup
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analyses in an attempt to identify hidden factors that might be affecting the
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variability/heterogeneity of efficacy findings and safety issues among the trials. Our aim
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was to minimize the risk and maximize the efficacy of primary prevention strategies in
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the future. The details of our methods are shown in the Methods section in this article’s
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Online Repository at www.jacionline.org.
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Efficacy of early egg introduction on egg allergy and egg sensitization in infants at 12
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months of age
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Our meta-analyses of the six studies revealed that early egg introduction showed
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statistically significant benefits (40% and 22%) for prevention of both egg allergy (RR:
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0.60; 95% confidence interval (CI): 0.42-0.85; p = 0.004; Fig. 1A) and egg sensitization
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(RR: 0.78; 95% CI: 0.66-0.92; p = 0.004; Fig. 1B). However, the meta-analysis of egg
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allergy prevention showed moderate heterogeneity in the results of these studies (I2 =
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33%; p < 0.10 in the chi2 test for heterogeneity; Fig. 1A), suggesting that there may be
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some factors that affect the heterogeneity of the results among these studies.
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Food processing and the efficacy of early egg introduction on egg allergy and egg
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sensitization in infants at 12 months of age
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We performed subgroup analyses to further investigate the heterogeneity found in the
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aforementioned meta-analysis. Four of the six studies used pasteurized raw egg powder,
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whereas the remaining two used boiled egg or boiled egg powder for early introduction
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(Table 1). Subgroup analysis of the four studies using raw egg and two studies using
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boiled egg revealed that the efficacy of early egg introduction seemed to be greater in
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the boiled egg trials, but testing of the subgroup differences did not show statistical
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significance (p = 0.41; Fig. 1A). Further studies are needed to clarify whether raw egg
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or boiled egg is more beneficial.
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Egg dosage and the efficacy of early egg introduction on egg allergy in infants at 12
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months of age
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The EAT study demonstrated that the total intake of egg during the intervention period
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correlated significantly with lower risk of egg allergy.7 However, meta-regression
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analysis (see details in this article’s Online Repository at www.jacionline.org) found no
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statistically significant correlation between the dosage of egg and the logarithm of RR
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among the six studies (coefficient: -0.096; 95% CI: -0.18 to 0.037; p = 0.39; Fig. 1C).
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The optimal egg dosage for early introduction should be further explored.
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Relationship between food processing and egg dosage in the efficacy of early egg
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introduction on egg allergy in infants at 12 months of age
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We performed subgroup analyses to simultaneously investigate the relationship between
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food processing and the egg dosage. Among four possible combinations (food
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processing: raw or boiled; and egg dosage: ≥3 g/wk or <3 g/wk), the efficacy of early
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egg introduction reached statistical significance only in the subgroups using raw egg at
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≥3 g/wk and boiled egg at <3 g/wk (Figs. E1 and E2 in this article’s Online Repository
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at www.jacionline.org). Therefore, no firm relationship was identified between food
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processing and the egg dosage in regard to the efficacy of early egg introduction on egg
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allergy. However, because the number of subjects included in each combination was
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small, further studies are needed to draw a firm conclusion.
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Role of food processing and egg dosage in the heterogeneity found in the
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aforementioned meta-analysis
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To further investigate the extent to which the heterogeneity in the aforementioned
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meta-analysis can be explained by the relationship between food processing and the egg
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dosage, we performed meta-regression analyses using the egg dosage as a continuous
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variable or as two groups (≥3 g/wk or <3 g/wk). No statistical significance was found,
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presumably due to the small sample size. However, these two analyses demonstrated
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that approximately 50% (49.8% and 41.2%, respectively) of the heterogeneity could be
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explained by food processing and the egg dosage (data not shown). Other factors
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affecting the heterogeneity are probably the family history of allergic diseases,
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presence/absence of eczema and so on.
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Food processing and the safety of early egg introduction
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Subgroup analyses showed several significant differences in terms of the safety. That is,
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at initial introduction, approximately 15 times more babies reacted to raw egg than to
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boiled egg (Fig. 1D). In the STAR study,6 five of six babies who reacted to raw egg
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powder at initial introduction were tolerant to boiled egg, suggesting that such reactions
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are mainly due to the higher allergenicity of raw egg powder. In addition, a total of
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eight anaphylaxis events were observed in three of the studies using raw egg powder,
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whereas no anaphylaxis was observed in the two studies using boiled egg (P<0.018 by
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Fisher's exact test; Table 1). These safety findings strongly recommend using boiled egg
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or exercising special caution when using raw egg powder in future studies. We would further like to point out a potentially harmful reaction to early egg
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introduction: food protein-induced enterocolitis syndrome (FPIES). FPIES is a
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non-IgE-mediated gastrointestinal food allergy that occurs most frequently during
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infancy. FPIES is not a common disease (0.34% in Israel,9 0.21% in Japan10 and 0.15%
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in Australia11), but seven babies in the early-introduction group developed symptoms
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consistent with FPIES, regardless of whether the egg was raw or boiled (Table 1). The
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offending food in the majority of FPIES babies was milk, whereas egg FPIES is much
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less common.9-11 When we calculate the predicted prevalence of egg FPIES, it is
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approximately 0.041% to 0.0018%, whereas the actual prevalence of egg FPIES among
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these 6 intervention studies was 0.61% (8/1314), which was significantly higher than
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the predicted prevalence (P < 10-5, by Fisher's exact test). Therefore, it can be thought
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that early egg introduction should be accompanied by careful monitoring for severe
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emesis within a couple of hours after egg ingestion, since it is a characteristic feature of
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FPIES.
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Eczema/atopic dermatitis
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Eczema prevalences at entry to these studies varied from 0% to 100% (Table 1). In this
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meta-analysis, the presence of eczema at entry was positively associated with the
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prevalence of allergy in the late-introduction (control) group, with very high statistical
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significance (Fig. 1E). This is consistent with previous epidemiological studies: a
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meta-analysis of those studies clearly demonstrated that eczema/atopic dermatitis is a
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robust risk factor for food allergy.12
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In eczematous lesions, Langerhans cells reportedly migrate right beneath the tight
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junctions, elongate their dendrites, and penetrate through the junctions so that they can
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uptake foreign proteins on the skin surface, even at sites of erythema, i.e., the early
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stage of eczema.13 In addition, two major cytokines—IL-33 and thymic stromal
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lymphopoietin (TSLP)—expressed at the sites of eczematous lesions reportedly activate
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antigen–presenting cells (APCs), and these cytokine-primed APCs facilitate naïve
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T–cell differentiation towards Th2. Therefore, exposure to foods via eczema lesions is
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likely to facilitate allergic sensitization.14 In fact, a couple of mouse studies provided
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clear evidence that the condition of skin that is exposed to exogenous protein is a
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critical deciding factor in immune responses: exposure of intact skin induces
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antigen-specific tolerance, whereas exposure of damaged skin (stripped skin) induces
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allergic sensitization.15-17 Therefore, primary prevention and appropriate treatment of
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eczema, i.e., damaged skin, should be recommended. However, although there is
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insufficient direct evidence for the effects of treatments of eczema/atopic dermatitis on
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the development of food allergy, it is probably unethical to test for such effects in a
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clinical intervention trial.
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Feeding egg to a baby with eczema may have another risk: the baby may already be
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sensitized to the trial food antigen due to the eczema12,14 and would react to the antigen
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even at the initial introduction. In fact, the prevalence of eczema at entry correlated
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strongly with the percentage of babies reacting to the raw egg powder at the initial
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introduction (Fig. 1F). In contrast, boiled egg was much safer than raw egg even for
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babies with eczema (Fig 1F), suggesting that it may be better to use boiled egg for
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introduction to babies with eczema. Notably, none of the babies who had eczema at
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recruitment and underwent extensive eczema treatment with a "proactive regimen"
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before egg introduction reacted at all to a small amount of boiled egg powder.8 However,
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it is yet to be clarified whether extensive eczema treatment also makes introduction to
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raw egg safer or not.
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A very recent guideline for prevention of peanut allergy recommended that specific
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IgE measurement or skin testing should be considered in babies with severe eczema.18 A
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similar recommendation for egg-specific IgE measurement should be considered for
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certain babies with severe eczema and/or allergy to any other foods.
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The optimal timing or "window" for the introduction of foods to prevent development
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of food allergy is still in debate. However, it may be too late to start egg introduction for
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babies who have eczema, and safer and effective methods (when, and how) for
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introducing egg to such babies should be further explored.
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Both “early boiled egg introduction” and “eczema treatment” are probably
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indispensable for primary prevention of egg allergy: Does it take two to “tango”?
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Exposure to foods via eczema lesions is likely to facilitate allergic sensitization.14
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Therefore, early introduction may provide little or no protective effect if eczema is left
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untreated. In particular, eczema treatment with a proactive regimen19 was reported to
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potently reduce further sensitization,20 suggesting that extensive control of eczema is
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critical for early introduction to successfully prevent food allergy. In fact, egg-specific
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IgE titers were significantly lower in the early-introduction group in the PETIT study, 8
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in which extensive eczema treatment had been performed, suggesting that—at
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present—primary prevention (aimed at preventing sensitization) can be achieved only
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by means of extensive concomitant eczema treatment.
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On the other hand, it is intriguing that even after the extensive eczema treatment
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using a proactive regimen in the PETIT study,8 the prevalence of egg allergy in the
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late-introduction (control) group was very high (37.7%). That suggests that early food
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introduction is necessary for effective food allergy prevention, even in eczema-treated
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babies and probably babies without eczema.
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These observations suggest that simultaneous performance of both "early introduction" and "eczema treatment" is the key to primary prevention of food allergy;
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performance of only one or the other is not sufficient.
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Other issues
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Regarding the specific food, a systematic review demonstrated that early introduction
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showed a preventive effect only for egg and peanut, not for milk.21 A similar tendency
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was observed in the EAT study.7 However, it remains to be clarified whether early food
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introduction combined with extensive eczema treatment is effective for other foods, as
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well. In addition, we need to determine if “eczema treatment” has the potential to
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enhance other antigen-specific immunotherapies administered by different routes, such
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as subcutaneous, sublingual and epicutaneous (SCIT, SLIT and EPIT).
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In summary, this rostrum updated and tried to provide a more solid foundation for
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the findings of the earlier systematic review.21 However, it is definitely true that the
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number of papers as well as the number of participants in each study are insufficient for
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drawing firm conclusions, especially regarding the optimal doses, raw/boiled, when to
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start and for whom to intervene. Therefore, we propose some studies that should be
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performed to generate stronger data and conclusions. However, on the basis of the most
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current results, we hypothesize that simultaneous intervention by both “early boiled egg
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introduction” and “eczema treatment” is probably indispensable for primary prevention
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of egg allergy. (2033 words)
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Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol 2008;121:1331-6. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 2015;372:803-13. Palmer DJ, Sullivan TR, Gold MS, Prescott SL, Makrides M. Randomized controlled trial of early regular egg intake to prevent egg allergy. J Allergy Clin Immunol 2017;139:1600-7. Bellach J, Schwarz V, Ahrens B, Trendelenburg V, Aksunger O, Kalb B, et al. Randomized placebo-controlled trial of hen's egg consumption for primary prevention in infants. J Allergy Clin Immunol 2017;139:1591-9. Wei-Liang Tan J, Valerio C, Barnes EH, Turner PJ, Van Asperen PA, Kakakios AM, et al. A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. J Allergy Clin Immunol 2017:139;1621-8. Palmer DJ, Metcalfe J, Makrides M, Gold MS, Quinn P, West CE, et al. Early regular egg exposure in infants with eczema: A randomized controlled trial. J
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Allergy Clin Immunol 2013;132:387-92. Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. N Engl J Med 2016;374:1733-43. Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M, et al. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Lancet 2017;389:276-86. Katz Y, Goldberg MR, Rajuan N, Cohen A, Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study. J Allergy Clin Immunol 2011;127:647-53. Miyazawa T, Itabashi K, Imai T. Retrospective multicenter survey on food-related symptoms suggestive of cow's milk allergy in NICU neonates. Allergol Int 2013;62:85-90. Mehr S, Frith K, Barnes EH, Campbell DE; FPIES Study Group. Food protein-induced enterocolitis syndrome in Australia: A population-based study, 2012-2014. J Allergy Clin Immunol 2017;140:1323-30. Tsakok T, Marrs T, Mohsin M, Baron S, du Toit G, Till S, et al. Does atopic dermatitis cause food allergy? A systematic review. J Allergy Clin Immunol 2016;137:1071-8. Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, et al. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis. J Allergy Clin Immunol 2014;134:856-64. Matsumoto K, Saito H. Eczematous sensitization, a novel pathway for allergic sensitization, can occur in an early stage of eczema. J Allergy Clin Immunol 2014;134:865-6. Dioszeghy V, Mondoulet L, Dhelft V, Ligouis M, Puteaux E, Benhamou PH, et al. Epicutaneous immunotherapy results in rapid allergen uptake by dendritic cells through intact skin and downregulates the allergen-specific response in sensitized mice. J Immunol 2011;186:5629-37. Mondoulet L, Dioszeghy V, Puteaux E, Ligouis M, Dhelft V, Letourneur F, et al. Intact skin and not stripped skin is crucial for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT) in mice. Clin Transl Allergy 2012;2:22. Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE, et al. Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. J Allergy Clin Immunol 2014;133:1390-9. Togias A, Cooper SF, Acebal ML, Assa'ad A, Baker JR, Jr., Beck LA, et al. Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin Immunol 2017;139:29-44. Wollenberg A, Oranje A, Deleuran M, Simon D, Szalai Z, Kunz B, et al. ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol 2016;30:729-47
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Fukuie T, Hirakawa S, Narita M, Nomura I, Matsumoto K, Tokura Y, et al. Potential preventive effects of proactive therapy on sensitization in moderate to severe childhood atopic dermatitis: A randomized, investigator-blinded, controlled study. J Dermatol 2016;43:1283-92. Ierodiakonou D, Garcia-Larsen V, Logan A, Groome A, Cunha S, Chivinge J, et al. Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease: A Systematic Review and Meta-analysis. JAMA 2016;316:1181-92.
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Figure legend
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FIG. 1. Meta-analysis of six intervention trials for egg allergy prevention.
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Effect of early-introduction (Early intro.) versus late-introduction (control) of egg on
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risk of egg allergy (A) or egg sensitization (B) at 12 months of age. Data are from
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randomized clinical trials. “Events” refers to egg allergy (A) or egg sensitization (B).
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The size of each data marker is proportional to the study weight in the meta-analysis.
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(C) Meta-regression analysis of the egg dosage and log risk ratio. The size of each circle
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is proportional to the study weight in this analysis. Red and blue circles indicate studies
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using raw and boiled egg, respectively. (D) Percentages of babies and 95% confident
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interval in the early-introduction (Early intro.) group who reacted to raw (red column)
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or boiled (blue column) egg at the initial introduction. Statistical significance was
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calculated using the chi2 test. (E) Correlation between the prevalence of eczema at 4M
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and the prevalence of egg allergy at 12M in the late-introduction (control) group.
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Statistical significance was calculated after applying a linear regression model. (F)
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Correlation is shown between the prevalence of eczema at 4M and the percentage of
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babies in the early-introduction (Early intro.) group who reacted to raw (red dots) or
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boiled (blue dots) egg at the initial introduction. Statistical significance was calculated
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using the results from only the four studies that used raw egg, after applying a linear
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regression model.
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Table 1. Summary of recent intervention trials for prevention of egg allergy using Intention to Treat analysis Intervention
Eczema preva-
Safety*/
Risk ratio (95%CI)
Early introduction
Control
Allergy/
Egg allergy at 12M/
Egg allergy at 12M/
Sensitization
Sensitization at 12M Sensitization at 12M
at 12M 0% at 4M
6.1% (25/407)
15.1% (57/377)
11% at 12M
5 anaph. in EIG
0.6% (1/156)
9% at 4M
7.1% (13/184)
2.6% (4/156)
?
1 FPIES‡ 2 anaph. in EIG
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lence at entry/
Serious events
Palmer et al.3
6.3 g/wk
0.68 (0.42-1.09)
7.0% (26/371)
STEP-JACI 2017
Raw egg powder
0.71 (0.49-1.04)
10.8% (40/371)
Bellach et al.4
0.8-2.5 g/wk†
3.30 (0.35-31.32)
2.1% (3/142)
HEAP-JACI 2017
Raw egg powder
2.20 (0.68-7.14)
5.6% (8/142)
Wei-Liang Tan et al.5
2.45 g/wk
0.59 (0.25-1.37)
6.2% (8/130)
10.5% (13/124)
26% at 4M
8.5% (14/165)
BEAT-JACI 2017
Raw egg powder
0.52 (0.28-0.97)
10.7% (13/122)
20.5% (25/122)
37% at 12M
No anaph. in EIG
Palmer et al.6
6.3 g/wk
0.65 (0.38-1.11)
33.3% (13/42)
51.4% (18/35)
100% at 4M
20.4% (10/49)
STAR-JACI 2013
Raw egg powder
0.72 (0.47-1.09)
45.2% (19/42)
63.8% (22/35)
?
1 FPIES‡ 1 anaph. in EIG
Perkin et al.7
4 g/wk
0.69 (0.40-1.18)
3.7% (21/569)
5.4% (32/596)
24% at 3M
0.8% (3/569)
Boiled egg
0.80 (0.58-1.10)
10.4% (57/550)
13.0% (78/601)
17% at 12M
6 FPIES in EIG
0.35-1.75 g/wk§
0·22 (0·08–0·61)
8.3% (5/60)
37.7% (23/61)
100% at 4M
0% (0/60)
PETIT-Lancet 2017
Boiled egg powder
0.86 (0.85-1.13)
57.9% (33/57)
67.6% (46/68)
2% at 12M¶
No anaph. in EIG
Meta-analysis
Meta-analysis
0.56 (0.41-0.76)
5.9% (77/1314)
9.3% (126/1349)
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10.3% (39/377)
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*Reacted to egg powder at introduction in the Early Introduction Group (EIG). †Early Introduction Group received 0.8 g/wk in the first week, 1.7 g/wk in the second week, and then 2.5 g/wk from the third week of intervention until 12M.
‡FPIES: food protein-induced enterocolitis syndrome; anaph.: anaphylaxis. §Early Introduction Group received 0.35 g/wk from 6M through 8M, and 1.75 g/wk from 9M through 12M. ¶After corticosteroid ointment therapy with a "proactive regimen" and assessed by the POEM score at 12M.
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Supplementary Methods Selection of Studies We selected "randomized intervention trials" for "egg allergy". At the time we started the analysis (Jan 2017), three studies were found by PubMed search, while three other studies were not cited in PubMed but were found in Articles in Press of the JACI. Meta-analysis Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for
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dichotomous data using Mantel-Haenszel analysis. Random-effects meta-analysis was performed when between-study methodological heterogeneity undermined the compatibility of the quantitative results, or if substantial statistical heterogeneity was detected.
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Heterogeneity of the studies was assessed using both qualitative and quantitative measures. Statistical heterogeneity was determined for each meta-analysis using Tau2, I2 and chi2 statistics. Heterogeneity was deemed substantial if Tau2 was greater than zero and either I2 was greater than 50% or p < 0.10 in the chi2 test for heterogeneity.1 To further assess potential heterogeneity effects, both fixed- and random-effects models
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were compared for each outcome, when possible. Meta-regression analysis was performed to determine the extent of, and explanatory factors for, the heterogeneity identified in the above meta-analyses.
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All statistical analyses were performed using RevMan 5.0 software (Cochrane Collaboration, Oxford, UK) or STATA software (StataCorp LP, College Station, TX). 1. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–58.
Supplementary Figure E1
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Fig. E1. Effect of early introduction (Early Intro.) versus late introduction (control) of raw egg on the risk of egg allergy at 12 months of age. Data are from randomized clinical trials using ≥3 g/wk egg powder (2.1.1) or <3 g/wk egg powder (2.1.2). “Events” refers to egg allergy. The size of each data marker is proportional to the study weight in the meta-analysis.
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Fig. E2. Effect of early introduction (Early Intro.) versus late introduction (control) of boiled egg on the risk of egg allergy at 12 months of age. Data are from randomized clinical trials using ≥3 g/wk egg powder (2.2.1) or <3 g/wk egg powder (2.2.2). “Events” refers to egg allergy. The size of each data marker is proportional to the study weight in the meta-analysis.