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.