Discussion
In this study, we investigated the natural history of IgE-mediated
immediate-type CMA in children aged 6–12 years. Forty-six of the 123
(37%) children with persisting CMA until the age of 6 years acquired CM
tolerance by the age of 12 years. Furthermore, we demonstrated that
higher CM-sIgE levels, previous anaphylaxis to CM, and complete CM
elimination from the diet were independent risk factors for persistent
CMA.
It has been reported that most children with CMA acquire tolerance
during the pre-school age.1, 8-12, 18-20 Half of
Korean children with CMA develop tolerance by the age of 8.7
years.19 A Danish birth-cohort study showed that the
tolerance acquisition rates in children with CMA, including
non-IgE-mediated CMA, were 92% and 97% at 5 and 15 years of age,
respectively.20 However, all of these studies
initiated follow-up in infancy, making it difficult to clarify the
tolerance acquisition rate in children with CMA persisting beyond school
age. Few studies on the natural history of CMA have focused on children
beyond school age. Our data demonstrated that the tolerance acquisition
rate in children with CMA between the ages of 6 and 12 years was 37%.
This rate is obviously higher than that for peanut allergy; however, it
seems to be lower than that for hen’s egg allergy
(HEA).21, 22 A previous study reported that the rate
of tolerance acquisition for peanut allergy in children aged 4–20 years
was 21.5%.21 Our institution reported a rate of
tolerance acquisition for HEA of 60.5%.22 However,
children with OIT were defined as dropouts in this previous study;
therefore, their rate may be overestimated. When we defined children
with OIT as dropouts, the tolerance acquisition rate was 58%
(Supplementary figure 1), which was similar to the results of the
previous HEA study.22 When we defined tolerance
acquisition as achieving short-term unresponsiveness to 200 mL of
unheated CM for children who underwent OIT after the age of 6 years, the
tolerance acquisition rate was 50% (Supplementary figure 1); this is
lower than the rate of 65.2% reported in the HEA
study.22 This difference would result from the poor
outcome of OIT to CMA compared to HEA.22 These
findings indicate that the “real” tolerance acquisition rate in
children aged 6–12 years with CMA might be between 37% and 50%. In
many previous studies, CMA persistence was not confirmed in annual
OFCs.8, 11, 12, 19 In our institution, children
usually undergo blood tests and OFCs annually, providing a more accurate
assessment of CMA tolerance.
In the present study, 88% of patients with CMA in the absence of the
identified risk factors (higher CM-sIgE levels, previous anaphylaxis to
CM, and complete CM elimination) acquired tolerance by the age of 12
years; therefore, these children should be proactively assessed by OFCs
for their tolerance acquisition. In contrast, none of the children with
CMA presenting all three risk factors acquired tolerance by the age of
12 years (Supplementary figure 3); therefore, these children should be
considered for OIT. Previous anaphylaxis and higher CM-sIgE levels were
common risk factors identified in the present and previous studies, and
both factors contributed to difficulties in acquiring tolerance (Figure
3A and 3C). This is the first report showing that complete CM
elimination from the diet is associated with CMA persistence. The
immunomodulatory effects of consuming baked milk proteins may accelerate
the progression to tolerance of non-baked milk.23 In
addition, continuous consumption of small amounts of heated milk has
been suggested to increase the safely ingestible amount of
CM.24 These results suggest that continuous small-dose
intakes of CM may induce immunological benefits for acquiring CM
tolerance.
In the present study, CM-sIgE levels in the persistent group were
significantly higher than those in the tolerant group at all ages from
6–12 years. Interestingly, CM-sIgE levels decreased annually, not only
in the tolerant group, but also in the persistent group. In previous
studies on the natural history of CMA, the CM-sIgE level in children
with persistent allergy was reported to increase over the first 3–4
years of life, followed by a plateau, and then a gradual decrease until
the age of 18 years.9, 10 These findings indicate that
decreasing CM-sIgE levels during school age may not be associated with
CM tolerance acquisition.
This study has some limitations. First, we defined children undergoing
OIT as having persistent CMA, not as dropouts. In children who received
OIT, 95% of the children eliminated CM completely, two-thirds had
previous anaphylaxis, and the median CM-sIgE level was 58.5
kUA/L at the age of 6; these characteristics were higher
than those in the persistent group who did not receive OIT
(Supplementary table 1). Since children with OIT should have difficulty
acquiring tolerance, we considered that children with OIT should be
defined as having persistent CMA rather than as dropouts. Second, this
study had a single-center design. Our facility is a tertiary center for
food allergies, and children with food allergies tend to be more
severely affected than the general population, which may have influenced
the study outcomes.
In conclusion, at least one-third of patients who still had IgE-mediated
CMA at the age of 6 years acquired tolerance by the age of 12 years. We
demonstrated that children with CMA whose CM-sIgE levels were higher
than the optimal cutoff value, who previously had anaphylaxis to CM, and
who eliminated CM from their diet at the age of 6 years have difficulty
acquiring tolerance by the age of 12 years. This study provides
important insights into the natural history of CMA persisting into
school age and identifies risk factors associated with persistent CMA.