Discussion
The clinical phenotype of FPIES is well described, with several
large-scale retrospective cohort studies published over the last two
decades. Despite this, the reason why there are prominent geographic
variations in types of food triggers, rates of multiple food FPIES and
why children outgrow FPIES remain unknown. Regional breastfeeding and
weaning practices have been proposed to influence these factors.
We have previously investigated the impact of infant feeding practices
on the development of FPIES to multiple triggers, in addition to the
associations among different food groups in infants with multiple food
FPIES 2. Rice was the most common food trigger in
Australian children, with 32% of the total cohort having FPIES to
multiple food triggers. Here, we demonstrate that rice is consistently
the most common trigger in Australian infants (in 45%). This is in
contrast to other regions with cow’s milk being the most common in the
United Kingdom, USA and Israel, and with fish being a predominant solid
food trigger in Italy and Spain 3, 5, 6, 8, 12. Only
one other study outside of Australia, in the USA, identified rice as
more frequent a trigger than cow’s milk 13.
Interestingly, in our cohort, infants with rice FPIES were unlikely to
react to cow’s milk or fish but were more likely to have FPIES to
multiple foods.
We identified a rate of FPIES to multiple food triggers within the whole
cohort of 36% in keeping with previous Australian data2, and in comparison with other countries, highest in
the USA (up to 50%) and United Kingdom (30%) 5, 14,
and lowest in Spain (16%) and Italy (15%) 6, 15.
Here we demonstrate a possible trend towards increased risk of FPIES to
multiple triggers in children who were delivered via caesarean section.
The mode of delivery has long been proposed to impact upon the
development of food allergy and atopy 16, with
delivery via caesarean section thought to disrupt the maternal
transference of microbiota to the infant. Katz et al. reported a higher
prevalence of delivery via caesarean section in infants with cow’s milk
FPIES, two times compared to vaginal delivery 3.
Our previous population-based study demonstrated that duration of
exclusive breastfeeding less than four months was associated with
increased risk of multiple food FPIES (11% versus 20%)2. This was not seen within this study’s cohort.
Instead, there was a weak association between increased duration of
breastfeeding and increased risk of multiple food FPIES. It may be that
mothers of children who have experienced multiple FPIES may choose to
breastfeed for longer duration, due to the perceived relative safety of
breastfeeding in triggering an FPIES reaction, thus a potential for
reverse causation. Few studies have examined infant feeding practices in
association with FPIES, and those which have, demonstrate similar or
mildly higher rates of FPIES in infants who are not breastfed, or have
shorter duration of breastfeeding 5, 6. Overall the
rate of breastfeeding in this population is high, compared to other
countries with well documented FPIES cohorts. Feeding practices and
their impact on FPIES development and phenotype warrant further
prospective investigation.
Co-associations between food triggers in children with multiple FPIES
were observed between rice and oats; cow’s milk and soy; and fish and
shellfish, consistent with previous data in reported case series17. We observed a co-association between eggs and
other grains (which included wheat and rye) in our cohort not previously
documented in other reports. Cow’s milk/soy cross-reactivity is commonly
seen in US populations (up to 50% in case series), as is rice/oats
cross-reactivity (up to 30%) in US and Australia 1.
Although fish and shellfish FPIES are more prevalent in Mediterranean
countries, the reported rates of cross-reactivity are similar18. Children with rice and cow’s milk FPIES had an
increased risk of FPIES to multiple foods. This may be due to rice and
cow’s milk being the most common food triggers within the cohort, in
addition to the higher prevalence of co-association between rice/oats
and cow’s milk/soy.
Atopy in siblings was another risk factor for multiple FPIES with a
1.6-fold risk. In contrast, a family history of FPIES was rare and not
associated with increased risk of multiple FPIES, although the numbers
for this analysis were small. This is similar to previous
epidemiological data demonstrating low familial risk of FPIES19. Both a family and personal history of atopy is
common in Australian infants and although not examined in local
populations, a US study has reported a higher rate of comorbid atopy in
infants with FPIES compared to healthy infants 20. In
our cohort, eczema was the most common comorbid atopy and was strongly
associated with IgE-mediated food allergy, particularly to eggs,
similarly demonstrated by Ruffner et al. 20.
Additionally, there is a risk of conversion from FPIES to IgE food
allergy, especially with cow’s milk FPIES 1. It would
be of interest to conduct a longitudinal study to observe for the rates
of development of IgE food allergy, given the apparent existing high
background risk.
Proposed definitions for severity of FPIES reactions have been
characterised by international guidelines 1, and few
descriptive case series have observed potential increased severity in
association with solid food triggers, however reports are varying. In
our cohort, the rate of experiencing at least one severe reaction was
high, at nearly 75% of the cohort, however no risk factors for severity
were identified.
We have previously reported variations in timing to acquisition of
tolerance to different causative food triggers 21.
Fifty five of 169 infants were participants in this previous study21. Here, we demonstrate similar findings of earlier
resolution for rice FPIES but delayed resolution for fish FPIES. Infants
who had their first reaction at a later age attained tolerance at a
later age, likely related to the sequence of exposure to different solid
foods. Although we did not find any predictive factors of tolerance from
feeding history, Sopo et al. demonstrated that earlier tolerance
acquisition in FPIES to eggs was achieved by the effect of cooking22, providing potential insight into how food protein
interactions with immune mechanisms may dictate responses. Despite a
proof of tolerance via supervised oral food challenge (OFC), a recent
study by Argiz et al. reported reactions upon re-exposure to trigger
foods following a negative OFC in 13% of infants, most likely to occur
with egg and fish FPIES 23. These findings aid in
recommendations for feeding practices and first weaning foods for
infants with FPIES.
Our study is limited by the retrospective nature, which is prone to
recall bias. In addition, our sample size is limited by selection of a
group of individuals known to a tertiary specialised centre, with
possible identification of a more severe cohort of patients with FPIES,
as illustrated by the high proportion of subjects who experienced at
least one severe episode. Missing data on mode of birth, and incomplete
feeding histories limit the conclusions which can be drawn about these
analyses.
Our findings over 20 years of children with FPIES managed at a large
single centre demonstrate many similarities with the published
population-based survey of Australian infants with FPIES, which examined
only FPIES presentations from 2012-14. Notably, we observed decreased
odds of the development of multiple food FPIES and severe reactions in
infants who were born via vaginal delivery, and a possible variable
effect of breastfeeding, with longer duration of breastfeeding seen in
infants with multiple food FPIES, but with a decreased risk of
development of severe reactions. Important clinical implications include
identifying that infants presenting with cow’s milk or rice FPIES may be
at greatest risk of the development of FPIES to other foods and that
severity of FPIES reactions appears not to be readily predictable by
food trigger or other baseline characteristics.