Discussion:
A good understanding of the different trajectories of PA over time is
important to safely diagnose and manage PA. The prevalence of PA at both
the end of EAT and 7-11y was relatively stable with 2.1% at 7-11y and
1.9% at the end of EAT. There were two new cases of PA that developed
after 36m and only 1 child outgrew PA by 7-11y. Children with persistent
PA at 7-11y had significantly higher levels of SPT, peanut-sIgE, Ara h
2-sIgE and mast cell activation compared to children who were PS, with
many biomarkers being diagnostic of PA by 36m.
At 12m of age the persistent PA children already had median SPT and Ara
h 2-sIgE levels consistent with a PA diagnosis which only continued to
increase over time. Studies have reported SPT of ≥6mm and Ara h 2-sIgE
between 0.1-3kUA/L being predictors of persistent. (14, 15) Ara h 2-sIgE
and Ara h 6-sIgE are the peanut components most indicative of true
peanut allergy (16), which was consistent with our findings at the 7-11y
time-point. The IgG4:IgE ratios were significantly lower
in the PA group and specifically in the children with persistent PA at
36m and 7-11y. Overall, the MAT was suggestive of PA at the 36m and
7-11y time points in the children who had persistent PA at 7-11y. There
were only two persistent PA patients who had plasma available from their
3m EAT study visit who had MAT performed (Table 2). Their median CD63
activation was 10.7% which is suggestive of PA at such an early age.
The higher MAT at these time points reflected the higher levels of
peanut-sIgE levels, which we know from previous work induces greater
mast cell activation (7). These changes in biomarkers demonstrate that
biomarkers that are high early in childhood and increase over time are
indicative of persistent PA.
There were only 2 patients who developed new peanut allergy. Their SPT
and peanut-sIgE biomarkers were initially low until 36m but increased
over time so that by 7-11y they were consistent with a PA diagnosis.
They were consuming peanut in early childhood but by 7-11y had stopped
all peanut consumption which supports previous evidence that shows that
patients who do not consume peanut regularly after a negative OFC are at
higher risk of recurrent PA, which may have contributed to why these
patients developed new PA. (17) Interestingly, MAT remained negative
across time in these two children even at the 7-11y time point which
differed from the children with persistent PA who had higher MAT at 36m
and 7-11y. A possible explanation for this lower MAT in new PA is the
quality of the IgE. Hemmings et al showed that IgE functional
characteristics modify mast cell activation with higher mast cell
activation resulting from higher peanut-sIgE levels, higher specific
activity, higher diversity and higher avidity of IgE for peanut (18). It
is possible that for those who had new PA later in childhood, the
allergic immune response was not fully developed and sIgE had lower
levels, specific activity, diversity and avidity for peanut allergens.
There was only 1 child that outgrew their PA by 7-11y confirmed by
negative OFC. Although we cannot infer conclusions on trends in
biomarkers overtime based on their results alone, the patterns observed
were still interesting. This child had SPT and Ara h 2-sIgE suggestive
of PA at 12m of age; although the SPT remained high at 36m, Ara h 2-sIgE
level was negative. Their peanut-sIgE level was lower at all time points
with a peak of 1.3kUA/L at 12m and then was negative by 36m and remained
so until 7-11y. The IgG4:IgE ratio was also very high at
the 36m and 7-11y time points which would be consistent with tolerance
to peanut as seen in previous studies (12).
This study is unique in that it looks at the changes in PA in a
population-based cohort of children over the span of a decade. The
longitudinal nature of this study and the availability of biomarkers at
the different time points helps to explain how PA is largely stable in
later childhood. Our data demonstrates that high biomarkers in early
childhood are associated with PA persistence which is consistent with
previous findings (15). MAT has high specificity in identifying children
who will clinically react to peanut (19) but this is the first study
looking at MAT over time and for those with persistent PA, levels were
raised by 12m. The utility of MAT was limited in children with very low
levels of peanut-sIgE, like those who developed or resolved their PA.
The major limitation of this study is the small number of children in
the sub-group analysis. Only 2 children developed new PA and 1 child
outgrew PA which makes it difficult to draw conclusions. We had hoped to
compare biomarkers predicting resolution of PA with persistence of PA
but this was not possible in this cohort. There was also missing
biomarker data in terms of baseline SPT (i.e. these were not performed
for children randomised to the standard introduction group) and Ara h
component-sIgE data (i.e. was only performed if peanut
sIgE>0.1kUA/L). We were able to impute the component data
based on sIgE levels but there were still some children who did not have
data available. Also, as the children were all recruited from the EAT-On
Study, definitions for allergic status and tolerance were based on the
study protocol to allow for consistency in the data analysis. In an
ideal setting, all children selected for the biomarker work would have
had OFC to confirm their PA status at 7-11y of age.
To conclude, the rate of PA in this cohort of children was 2.1% at
7-11y. Children with PA at 36m and 7-11y have significantly higher SPT,
peanut-sIgE, Ara h2-sIgE and MAT compared to PS children. These
biomarkers are already raised between 12m and 36m of age. For those that
develop new PA or outgrow their PA, the timing at which this happens
likely occurred between 36m and 7-11 years of age but small numbers and
low biomarkers prevented additional conclusions.