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\begin{document}

\title{FOOD PROTEIN--INDUCED ENTEROCOLITIS SYNDROME IN PRETERM NEWBORNS}



\author[1]{Enza D'Auria}%
\author[1]{Ilaria Cocchi}%
\author[2]{Giovanna Monti}%
\author[3]{Marco  Sartorio}%
\author[4]{Irene Daniele}%
\author[4]{Gianluca Lista}%
\author[1]{Gian Vincenzo Zuccotti}%
\affil[1]{University of Milan}%
\affil[2]{Ospedale Infantile Regina Margherita}%
\affil[3]{V. Buzzi Children’s Hospital, University of Milan}%
\affil[4]{Neonatal Pathology and Neonatal Intensive Care Unit, "V. Buzzi" Children's Hospital, University of Milano, 20154 Milano, Italy.}%


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  \date{May 19, 2024}


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\textbf{FOOD PROTEIN--INDUCED ENTEROCOLITIS SYNDROME IN PRETERM
NEWBORNS}

\textbf{Enza D'Auria\textsuperscript{1}, Ilaria
Cocchi\textsuperscript{2}, Giovanna Monti\textsuperscript{3}, Marco Ugo
Andrea Sartorio\textsuperscript{4}, Irene Daniele\textsuperscript{2},
Gianluca Lista\textsuperscript{2}, Gian Vincenzo
Zuccotti\textsuperscript{4}}

\textsuperscript{1} Allergy Unit-Vittore Buzzi Children's Hospital,
University of Milan, Milan, Italy

\textsuperscript{2}Neonatal Pathology and Neonatal Intensive Care Unit,
Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy.

\textsuperscript{3}Department of Pediatric Allergology, Regina
Margherita Children's Hospital, Turin, Italy.

\textsuperscript{4}Department of Pediatrics, Vittore Buzzi Children's
Hospital, University of Milan , Milan, Italy.

\textbf{Correspondence:} Enza D'Auria, Head Allergy Unit, Vittore Buzzi
Children's Hospital, University of Milan, Milan, Italy.

Email: enza.dauria@unimi.it

\textbf{CONFLICT OF INTEREST} : The authors declare that there are no
conflicts of interest.

\textbf{FINANCIAL SUPPORT:} None

\textbf{KEYWORDS:} FPIES, preterm newborns, twins, low birth weight,
atypical

\textbf{Key Messages statement:} Food-protein-induced enterocolitis
syndrome (FPIES) in preterm newborns may mimic necrotizing
enterocolitis. A combination of family history and laboratory findings,
e.g. eosinophilia plus leukocytosis with neutrophilia and
thrombocytosis, could help to discriminate between these two conditions.

A dietetic approach with an elemental diet based on amino acid formula
may be adopted as the first-line treatment when FPIES is suspected in
preterm newborns.

To the Editor,

Food-protein-induced enterocolitis syndrome (FPIES) was not recognized
as a specific disorder until the 1970s. While the European Academy of
Allergy and Clinical Immunology (EAACI) Guidelines addressed FPIES in
2014,it was only in 2017 that the first international consensus
guidelines for its diagnosis and treatment were published . The clinical
presentation of FPIES can mimic countless different conditions, making
its management challenging. In the neonatal period, especially in
preterm babies, FPIES should be carefully differentiated from
necrotizing enterocolitis (NEC), as its management, morbidity and
mortality are remarkably different . To date, only a few anecdotal case
reports of FPIES in preterm newborns and a case series from a US
Neonatal Unit have been published .

We report six cases of preterm, low-body-weight newborns born between
January 2014 and October 2020 at the Neonatal Intensive Care Unit (NICU)
of \emph{Vittore Buzzi} Children's Hospital in Milan or the Child
Illness and Care Department, \emph{Regina Margherita} Children's
Hospital in Turin.

Data on pregnancy and birth, family history of atopy, onset symptoms and
clinical course, laboratory and imaging findings, type of diet and
timing of symptom resolution are summarized in Table 1.

Two of the six cases had a positive family history for allergic
diseases. Four babies were delivered by caesarean section (CS) and two
by vaginal delivery. Four cases were twins (of which one set was
monochorionic); in each set, only one sibling was affected. Three of the
cases were in males and three in females. The median gestational age
(GA) was 33\textsuperscript{+3} (range 28\textsuperscript{+2} --
36\textsuperscript{+6} weeks). All babies had a low birth weight, with a
median birth weight of 1902 g (range 1070 g --1980 g), and two (C1 and
C2) were small for gestational age. The median age of onset was 12 days
of life (median GA34\textsuperscript{+6}, min 30\textsuperscript{+5}).
In 3/6 cases, the first symptoms appeared in the first week of life, and
in one patient (C1) in the first hours after delivery. All cases
initially presented with vomiting (C1 bilious vomiting) and/or
pathological stools (4/6 bloody stools); 4/6 had a distended and painful
abdomen; 2/6 had unstable vital signs and a poor general condition. The
median serial WBC was 14920/mm\textsuperscript{3}(range 6840
--38780/mm\textsuperscript{3}); neutrophilia was also observed, with a
median count of 7371/mm\textsuperscript{3}(range 1370
--24025/mm\textsuperscript{3}). In 5/6 cases, concomitant eosinophilia
was observed (range 350- 3102/mm\textsuperscript{3}; 1.5\%-11.4\%). An
increase in C-reactive protein was observed in 4/6 cases. Culture
samples (blood, urine and stools) were negative in all cases. The median
platelet count was 357500/mm\textsuperscript{3}(range 250000 --
650000/mm\textsuperscript{3}). In 3/6 cases, anemia was also observed.
Only C1 had serum-specific IgE antibodies (to beta-lactoglobulin and
casein). Radiological findings were remarkable in 4/6 cases, mostly
showing bowel loop distension. Abdominal ultrasound showed intestinal
pneumatosis in one case and distended bowel loops in 2/6 cases.

Relapse on the reintroduction of the trigger food was observed in 5/6
cases, without vomiting in two of these. The mean time from symptom
onset to beginning the definitive diet was 23 days (range 5 -- 60). An
oral food challenge was performed in 3/6 cases and was positive in all
three, with profuse vomiting.

The diagnosis and management of FPIES has recently been addressed in
guidelines. Nevertheless, FPIES in preterm babies is still poorly
understood, and is often associated with misdiagnosis or delayed
diagnosis. Both FPIES and NEC often develop in infants fed with formula.
Although the exact pathogenetic mechanism is still unknown, cow's milk
has been hypothesized to act as a trigger of intestinal inflammation,
activating the immune innate system and enhancing the lymphocyte
response to cow's milk allergens. Many cases of NEC do not have a
fulminant course, and can be managed conservatively. It is therefore
important to differentiate between these conditions, as their management
is very different. We observed eosinophilia in 5/6 cases (three mild and
one severe at onset, three moderate at relapsing episodes) during the
clinical course of FPIES, in agreement with literature data. This
finding, which is even more frequent in premature babies and those with
low GA and low birth weight, may be an important indicator of FPIES,
especially if combined with other laboratory findings, e.g. leukocytosis
with neutrophilia and thrombocytosis. In contrast, thrombocytopenia and
neutropenia are mostly observed in classic NEC.

Case C1, the monochorionic twin, is of particular interest, as his
sibling was not affected and he showed serum-specific IgE antibodies to
cow's milk proteins. To our knowledge, this is the first report of FPIES
in a single affected monochorionic twin. A previous report described
monochorionic twins who both developed FPIES with positive
serum-specific IgE antibodies. Both our case C1 and the twins in the
previous report presented early onset, marked eosinophilia and the
presence of hematochezia.

It is well known that allergen sensitization can occur in utero. This
scenario has been described for IgE-mediated food allergy, but recent
reports point to the same background for FPIES .

Pneumatosis is recognized as a characteristic radiological feature of
NEC, although its presence is not constant. Pneumatosis was observed in
one of our cases (17\%), and in all 5 cases (100\%) in the US series
(5). In both our series and the US series, imaging also revealed bowel
loop distension, as is also seen in classic NEC. Imaging does not
therefore seem to help differentiate between NEC and FPIES.
Nevertheless, given the significant morbidity and mortality associated
with NEC, evaluation by imaging is necessary in clinical practice.

In summary, a combination of different features, including a family
history of atopy and laboratory findings such as eosinophilia,
especially in association with leukocytosis, neutrophilia and
thrombocytosis, could help to raise the suspicion of FPIES, although the
diagnosis primarily remains a clinical one.

Following a diagnosis of FPIES, a dietetic approach should be adopted.
It is worth noting that most of our patients failed to recover with an
extensively hydrolyzed formula, while all responded to amino acid
formula. This could have been due to their immature gastrointestinal
gut, as immature absorption function is common in preterm babies (5). In
premature infants, it may therefore be reasonable to start feeding with
an elemental diet based on an amino acid formula.

In our opinion, an OFC may be indicated or considered to confirm the
diagnosis in the event of a relapse-free course or a relapse without
vomiting. The timing of any OFC is at the clinician's discretion, taking
into account the patient's clinical condition and weight.

In conclusion, the diagnosis of FPIES in the neonatal period, even more
in preterm newborns, is challenging. Increasing clinicians' awareness of
FPIES in this specific population may help to avoid unnecessary
antibiotic therapies, protracted parenteral nutrition and a typical
relapsing course on reintroduction of the trigger food.

Further data are needed to differentiate FPIES from NEC more clearly and
to improve its diagnosis and management.

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