Discussion
As we all know, there are more and more studies investigating the utility, effectiveness, and drawbacks of milk OIT in patients with IMCMA. On the other hand, it is also effective on partial desensitization, but according to different studies, the OIT protocol used and the duration time are varied in each study. The effort has been done to improve the usefulness of the technique and establishing protocols for more widespread use.
We conducted this systematic analysis of all RCTs in which OIT was used as a treatment for IMCMA. After comparing with the control group, we found that OIT with cow’s milk can be an effective and safe alternative therapy. Although there were three meta-analyses on milk OIT published previously[22-24], but the most recently published literature was seven years ago, so it is necessary to do an update meta-analysis that include the latest studies. In this meta-analysis, we included five new studies published after the year 2014. According to our analysis, we get conclusions on the efficacy of OIT similar to the previous Meta-analysis, but the number of patients in our meta-analysis is larger than the former three meta-analyses. Furthermore, we also analyzed the effect of OIT on partial desensitization, as well as Yeung and Brozek did. There was no study describing partial desensitization among the new five studies, so we included the same studies with Yeung, but we performed an intention-to-treat analysis. Although there was heterogeneity among included studies, it may be associated with patients’age, small patients’ number, different protcol and so on, so we did a subgroup analysis and sensitivity analysis, and obtained similar conclusions.In 2011, Fisher et al[25] published the first meta-analysis on the efficacy of OIT on food allergy and the authors concluded that OIT cannot be recommended in daily practice for desensitization in children with IgE-mediated food allergy. However, they evaluated the effect of OIT in all food allergies not just CMA. In 2017, Nurmatov et al[26] conducted a meta-analysis on allergen immunotherapy for IgE-mediated food allergy. In this article, the authors involved not only RCTs but also non-RCTs, and food allergies contained CMA, hen’s egg allergy, peanut allergy, and so on. The allergen immunotherapy used in this study was OIT, SLIT and EPIT. We didn’t include the other six randomized trials[27-32]. Staden et al[27] described the total efficacy of OIT on CMA or hen’s egg allergy together. Keet and colleagues[28] conducted a randomized trial to explore the safety and efficacy of OIT and SLIT for CMA. Wood and colleagues[29] examined the effect of OMB with OIT comparing with OIT alone. Flore et al[30]prospectively evaluated the efficacy and the safety of two OIT protocols in a cohort of children with persistent IMCMA: a cluster schedule starting immediately with raw milk versus a slow-progression schedule starting with baked milk and then less and less heated milk over time. In this context, the authors didn’t use placebo or milk avoidance as a control group, and they described the efficacy of the two treatment groups together. Chisato and colleagues[31]conducted a trial to evaluate the efficacy and safety of OIT with partially hydrolyzed cow’s milk protein-based formula (pHF) in CMA, they compared pHF-pHF to extensively hydrolyzed cow’s milk protein-based formula (eHF)-pHF. Nagakura et al[32] compared OIT with heated milk to OIT with unheated milk, the grouping of the latter two contexts was different from our study.
Adverse events during OIT are common, whereas most are mild-moderate and easily managed. Our analysis showed that there were only six patients with serious adverse events, and none was life-threatening. Comparing to the control group, the OIT group had an increased rate of epinephrine use and treatment discontinuation, but there were only 19 patients (17%) needing epinephrine use. The indications for epinephrine use in each study were not the same, especially in the studies which including patients with a history of life-threatening anaphylaxis, patients were asked to use epinephrine as soon as possible if there were any symptoms during OIT. We planned to analyze OIT on the impact of quality of life, but there were no RCTs. In 2012, Carraro et al[33]conducted a pilot study about the impact of OIT on quality of life (QoL) in children with CMA, the results showed that the QoL in emotional impact, food anxiety, social limitations, and dietary limitations domains were significantly improved after completing OIT and the improvement seemed particularly evident in children over 4 years old. Epstein-Rigbi et al[34] examined changes in QoL of children with food allergy during the up-dosing phase of OIT, the total Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) scores improved in 35%-50% of patient, but deteriorated in another 25%-30%. The same authors did another similar trial[35] on Food Allergy Quality of Life Questionnaire-Children Form (FAQLQ-CF) scores and FAQLQ-PF scores, they concluded that the total FAQLQ-CF score of children undergoing OIT improved significantly from the start of OIT to end of up-dosing (p<0.001), a greater improvement was noted in the children who reached a follow-up visit. Parents reported better quality of life (QOL) scores compared to their children at all stages of OIT, but these two articles included milk, egg, and other food allergies.
Desensitization to CM through immunotherapy has been associated with a decrease in CM-sIgE levels and an elevation in sIgG4 levels[30, 32, 36-37], suggesting that upregulation of allergen-specific IgG4 responses may be an important event in CM-specific immunotherapy. We intended to analyze the immunological changes before and after the intervention, but most of the included studies described IgE values differently, some in mean and some in the median, so it was impossible to do a combined analysis. On the other hand, only four studies described IgG4 level changes[13, 14, 17 18], whereas the values were expressed inconsistently.
To decrease the adverse actions of OIT, many adjuvant therapies combined with OIT were studied. Baked milk is likely to be hypoallergenic in part because of changes in the higher-order structure of conformational epitopes. In the retrospective analysis of Gruzelle et al[38], they found that 42.2% of children allergic to CM were desensitized after completing a course of baked milk OIT. This introduction seems to be safe and well-tolerated in most cases, but there were also 33.3% of patients had moderate reactions during OIT, with 18% OIT interruptions. In our included studies, Esmaeilzadeh and colleagues[19] concluded that OIT with baked milk had a higher rate of milk tolerance. However, in the study of Goldberg et al[39], the authors thought that baked milk-reactive subjects are at high risk of adverse allergic reactions throughout OIT. Furthermore, even in the few selected patients who reached the baked milk maintenance dose, only a limited increase in challenge threshold to unbaked milk was achieved. Caution must be exercised, and further studies especially RCTs are warranted before baked-milk OIT is used freely. Omalizumab (OMB) is a humanized monoclonal anti-IgE antibody that binds to the heavy chain constant CH3 domain of the free IgE molecule and prevents IgE from binding to FceRI effector cells. It was initially approved in 2003 for the treatment of severe allergic asthma in adolescents and adults. There were several studies of OMB with milk OIT[18, 29, 40-41], including one pilot study, two RCTs (one comparing to milk avoidance, the other comparing to OIT alone), and one case series. OIT with OMB may allow a shorter build-up phase or higher median tolerated dose, but adverse reactions, including the need for epinephrine, still occurred. So it needs more RCTs to examine the efficacy and safety of OMB.