Discussion
In this study, we described the characteristics of a large population of
179 French children with FPIES according to international guidelines. We
found that i) culprit foods were ubiquitous as in other international
cohorts, but some specific characteristics existed, ii) persistent FPIES
was more frequent for fish than for other foods, and in case of severe
acute FPIES, but IgE sensitization was not associated with longer
duration of FPIES, iii) performing OFC within 12 months after the first
reaction increased the risk of failure.
In our study, the main culprit food was CM, followed by hen’s egg, and
fish, which differs from the findings in other
countries.13,16,18,23–29 The most frequent culprit
food was fish (54%) in Greece20 and Spain
(70.6%),28,30 rice in
Australia31–33 and the USA,19 and
oats (34.5%) in Taiwan.34 Soy is frequently reported
as a trigger food by North American, British, Australian and Israeli
cohorts4,10,12,17,33,35,36 and was infrequent in our
population. Food habits, geographic origins, genetic factors,
microbiota, and other environmental pre- or postnatal factors may
explain these differences.1,12,37
Among the 108 patients with FPIES to CM, only 2 had a documented FPIES
to beef or veal. One patient had single FPIES to beef. Cross-reactivity
between CM and beef is estimated at up to 20% in IgE-mediated
allergies.38 This meat is frequently avoided by
caregivers of FPIES-children.11 However, the
prevalence of FPIES to beef is estimated between 0.8% to 3.0% of
children with FPIES.2,4,10,12,19,26 Although beef is
considered as a “moderate-risk” food,21 our data
suggest that having FPIES to CM does not increase the risk of associated
FPIES to beef.33
The overall age of resolution of
FPIES was 2.2 years of age for all foods. The age at resolution was
based on the day of performance of an OFC and thus may be
overestimated.8 Some data suggests that tolerance
occurred later for solid foods than for CM, but results
diverge.4,6,17 Miceli Sopo et al . reported an
age of tolerance of 2.0 years for FPIES to CM and 4.4 years for other
foods (p<0.0006),6 whereas other authors did
not find any difference.4,17 We found that the
acquisition of tolerance was delayed by 6 months for solid foods
compared to CM. Previous studies suggested that the later age of
tolerance relates to the ingestion of seafood
products8,13,33,39 and may occur more frequently in
cases of multiple FPIES.8 Resolution of FPIES to fish
is around 18.8% to 57.0% of cases between 3 to 4.5 years of
age.20,32,39–41 We found a similar rate of 38%
tolerance at 4.0 years of age, with an older age of resolution for fish
than CM. Due to the low prevalence of multiple FPIES in our cohort, we
were unable to compare the age of resolution of single and multiple
FPIES.
The recurrence of repetitive vomiting, lethargy and pallor were the 3
most frequently observed minor criteria. Lethargy and pallor are
criteria with large variability in studies (from
3.8%20 to 100%18 for lethargy;
from 14%5 to 98.7%20 for pallor).
We did not find any hypothermia in FPIES histories, as is the case for
Dieme et al. 27 Hypothermia is indeed an
uncommon symptom, from 6% in Spain-Italy30 to 10% in
Australia,2,31 but up to 31.2% of patients according
to caregivers from the International FPIES
Association.11 Some minor criteria (such as
hypothermia, hypotension, pallor and lethargy) are difficult to identify
during the in-depth family interviews, and even worse in retrospective
reviews of medical records.30
We included patients suffering from acute and chronic presumptive FPIES
if the history was compatible with the diagnosis of FPIES without an
argument for a differential diagnosis, as previously
described.7,8 The hypothesis that this may affect our
results is unlikely because general characteristics and the prognosis in
children with confirmed and presumptive FPIES did not differ. Recent
data demonstrated how the different FPIES diagnostic criteria proposed
over time provide conflicting results in patients with a high clinical
suspected likelihood of acute FPIES.30 Despite
multiple reactions to the same offending food, one quarter of the cohort
of Vazquez-Ortiz et al. 30 did not meet the
criteria from the “2017 consensus”7, especially when
severity was mild,30 as was the case for us.
Accordingly, we cross-referenced our 145 acute FPIES patients to other
definitions. We found 61.4% of patients who fulfilled the Powell
criteria modified by Sicherer/1998,9 61.4% (up to
84.8% without the age criteria) according to
Leonard/2012,42 24.1% with Miceli Sopo’s 2013
definition (up to 27.6% without the age criteria),4391.1% according to Lee/2017.32 Different phenotypes
of FPIES may exist depending on geographic origins or culprit foods
which could explain the variability of the symptoms previously
described.30
Performing an OFC in the first year after the diagnosis resulted in an
increased risk of failure, confirming that an OFC should generally be
considered at least 12 months after the last
reaction.8 For fish, one must be even more patient,
because experts recommend postponing the performance of an OFC until 5
years of age or older,8 and testing tolerance to
alternative fish to avoid an unnecessarily fish-free
diet.39 Like Infante et
al., 39 we found that severe reactions at any moment
were associated with a risk of longer duration of FPIES.
Limited data suggest that atypical
FPIES with positive specific IgE is associated with delayed
tolerance.8,10,17 This was not confirmed in our
cohort, although sensitization (IgE and/or skin prick test) (14.7%)
were similar compared to other studies
(11.1%-34%).12,13,19,23,26,27 Atopic disorder was
found in 41% of patients and eczema in 29%. This is concordant with
American and Australian cohorts where eczema is reported in 11% to 57%
of patients with FPIES.7 Children with FPIES often
have associated atopic conditions (atopic dermatitis, IgE-food allergy,
asthma, allergic rhinitis).4 Even if FPIES is not an
atopic disease per se , this suggests that FPIES and other atopic
comorbidities share common pathophysiology.44,45
We reported a lower frequency of multiple FPIES (5.6%) than in the
literature which is commonly reported at around
30%.2,10,12,14,16,23,27,33 This may result from the
use of stringent criteria for the diagnosis of FPIES and the
retrospective design of the study. Despite medical charts studied, for
multiple FPIES in 13.4% of cases as per other
series,6,18,26,28,30,31 we only retained FPIES with a
specific clinical description. The prevalence of multiple FPIES ranges
from 5.1%20 to 69.0%.19 These
variations of prevalence could be explained by the fact that patients
had been referred to tertiary centers in the case of multiple and more
complex cases of FPIES. Secondly, it may be easier to diagnose multiple
FPIES in children with a previous diagnosis of FPIES.7It is interesting to note that, even if the incidence of single FPIES is
generally more prevalent than multiple FPIES, families report in 69.7%
of cases an avoidance of at least 2 food groups.11Consequently, the risk of developing food aversion is significantly
increased in FPIES triggered by 3 or more foods, by a factor of
3.34 Therefore, avoidance should be limited only to
the confirmed offending foods. Supervised introduction allows for the
prevention of unnecessary exclusion21 and
overdiagnosis of multiple FPIES.
Our study had certain limitations. The decision to include patients with
acute vomiting and only 2 minor criteria could be one such limit, as
previously explained. The retrospective aspect of our study is another
limitation, owing to missing data, and in particular in terms of the
description of minor criteria and multiple FPIES. Familial history of
atopic disease was self-reported, which leads to a typical bias of
over-reporting allergic symptoms.46 In terms of
further studies, researching a link between maternal feeding, mode of
delivery, previous anti-acid treatment and frequency of antibiotic use
and the occurrence of FPIES could be interesting, by exploring the field
of gut dysbiosis.