Discussion
In this study, we sought to identify potential biomarkers to
differentiate acute FPIES from mimicking diseases also associated with
vomiting, such as enterocolitis or IgE-mediated anaphylaxis. Our study
showed that the serum levels of IL-2 and IL-10 were both prominently
elevated in patients with acute FPIES compared with those with
enterocolitis or IgE-mediated anaphylaxis. Serum IL-2 and IL-10
increases were only detected in symptomatic FPIES patients. These
increases were also confirmed in the symptomatic phase by the OFC test.
The serum levels of these two cytokines were previously reported to be
elevated in OFC-positive FPIES patients,4, 5 which is
in line with our results.
Several studies on oral immunotherapy have demonstrated that IL-10
levels increase in the course of tolerance acquisition, suggesting a
role of this cytokine in the induction of oral
tolerance.5,9 Caubet et al.5reported increases in the serum levels of IL-10 in OFC-positive cases,
whereas this increase was not
observable in the supernatants of casein-stimulated peripheral blood
mononuclear cells skewing toward T cells obtained from FPIES patients
positive for milk OFC. This suggests that, in patients with active
FPIES, since T cells have a reduced capacity to secrete IL-10, other
cell populations such as monocytes produce compensatory IL-10 in
response to antigen exposure. It has been reported that the activation
of innate immune cells is involved in the pathogenesis of acute
FPIES.10 Thus, the increase in serum IL-10 levels that
we observed in symptomatic patients could be related to the activation
of innate immune cells such as monocytes.
IL-2 is a representative helper T (Th) 1 cytokine, produced by naive and
Th cells, that activates T cells, B cells, and
monocytes/macrophages.11 Our finding that serum IL-2
was elevated in patients with acute FPIES was consistent with the
results of Kimura et al.4, who reported that IL-2
elevation contributes to the activation of Th1 cells, which in turn
plays a significant role in FPIES pathophysiology. Several lines of
evidence suggest a key role of T cells in the secretion of
pro-inflammatory cytokines that have an impact on intestinal
permeability.12-16 On the other hand, the role of T
cells has been questioned by some studies.5,10,17,18It has been reported that IL-2 signaling might be required for
maintaining the homeostasis of regulatory T cells.19Zhou et al.20 recently reported that innate lymphoid
cell (ILC) 3-derived, but not T cell-derived, IL-2 is essential for
maintaining regulatory T cell immunological homeostasis throughout the
gastrointestinal tract. This suggests that increased IL-2 serum levels
observed in the very early phase of onset in acute FPIES patients could
reflect increased IL-2 production promoted by other mechanisms such as
ILC3 mediation in the gastrointestinal tract, although the
pathophysiological role of IL-2 remains unknown at the mechanistic
level.
Some studies have reported elevated serum IL-8 levels in symptomatic
acute FPIES patients.4,5 The serum level of IL-8 was
significantly elevated in the acute FPIES group compared with the
enterocolitis group. However, there were no significant differences
between patients with acute FPIES and IgE-mediated anaphylaxis,
suggesting that IL-8 was not a useful biomarker to differentiate acute
FPIES from mimicking diseases.
It has been reported that serum IL-2 and IL-10 levels are elevated in
severe anaphylactic reactions and correlate with the
severity.21 Furthermore, Jiang et
al.22 and Newman et al.23 reported
cytokine profiles in children with
rotavirus infection and patients with norovirus and observed a
significant increase in the IL-2 and IL-10 levels compared to that in
the corresponding healthy control group or individuals before illness
onset. The above-reported increases in IL-2 and IL-10 levels were not as
high as those in our acute FPIES patients. Because the half-life of
serum IL-2 is very short (6.9 min)24, the timing of
sample collection is very important to detect higher levels of serum
IL-2.
Lee et al.7 also sought features distinctive of acute
FPIES by comparing patients who presented to an emergency department
with FPIES symptoms and subjects with enterocolitis or sepsis. In their
study, the laboratory data characteristic of acute FPIES included less
pronounced CRP elevation, leukocytosis, lymphocytosis, and
thrombocytosis; and elevated albumin/globulin ratio. Thus, we compared
CRP as well as white blood cell, lymphocyte, and platelet counts in
patients with acute FPIES, enterocolitis, and IgE-mediated anaphylaxis,
and found no significant differences in these parameters among the three
groups (data not shown). This discrepancy might reflect differences in
the study design and timing of sample collection. Notably, in the study
by Lee et al.7, acute FPIES was determined
retrospectively based on the medical record database of an emergency
department, and the schedule of sample collection was not specified. In
contrast, in the present study, the diagnoses were made in suspected
cases by well-trained pediatric allergists based on recent international
consensus guidelines3, and the blood samples were all
obtained within 3 h after the onset of vomiting.
In this study, we suggest that serum IL-2 and IL-10 may be suitable
biomarkers for the diagnosis of acute FPIES. Acute FPIES can cause
lethal hypovolemic shock, and thus, the elimination of offensive foods
is crucial.25 However, causative foods may be
reintroduced to patients unless acute FPIES is diagnosed by reliable
biomarkers. We propose serum IL-2 and IL-10 as a convenient biomarker to
differentiate acute FPIES from other mimicking diseases, thus avoiding
the risk of lethal shock due to future accidental ingestion of the
offending foods by the patients.
There are some limitations in this study. First, it is a pilot study
conducted with a small sample size in a single center. Multicenter
studies from different regions are warranted to confirm the diagnostic
accuracy of serum IL-2 and IL-10 measurements for discrimination between
acute FPIES and mimicking diseases that are also associated with
vomiting. Second, we only considered infectious enterocolitis and
IgE-mediated anaphylaxis as non-FPIES conditions. Since there are many
other acute FPIES-mimicking diseases2, further
analyses need to include other conditions such as necrotizing
enterocolitis, sepsis, and lactose intolerance. Third, as we did not use
age-matched normal subjects, we have not adjusted the cytokine levels by
age.
To our knowledge, this is the first report to identify potential
biomarkers capable of discriminating between acute FPIES and other
diseases and, therefore, suitable for differential diagnosis. The
measurement of serum IL-2 and IL-10 levels may substantially improve the
diagnosis of acute FPIES, which now mainly relies on clinical
manifestations.