ARTICLE IN PRESS

THE JOURNAL OF PEDIATRICS • www.jpeds.com ORIGINAL

ARTICLES
Allergic Proctocolitis Is a Risk Factor for Functional Gastrointestinal
Disorders in Children
Giovanni Di Nardo, MD, PhD1,2,*, Cesare Cremon, MD3,*, Simone Frediani, MD4, Sandra Lucarelli, MD4, Maria Pia Villa, MD5,
Vincenzo Stanghellini, MD3, Giuseppe La Torre, MD6, Luigi Martemucci, MD1, and Giovanni Barbara, MD3

Objective To test the hypothesis that allergic proctocolitis, a cause of self-limiting rectal bleeding in infants, can
predispose to the development of functional gastrointestinal disorders (FGIDs) later in childhood.
Study design We studied a cohort of 80 consecutive patients diagnosed with allergic proctocolitis. Their sibling
or matched children presenting to the same hospital for minor trauma served as controls. Parents of the patients
with allergic proctocolitis and controls participated in a telephone interview every 12 months until the child was at
least 4 years old. At that time, they were asked to complete the parental Questionnaire on Pediatric Gastrointes-
tinal Symptoms, Rome III version.
Results Sixteen of the 160 subjects (10.0%) included in the study met the Rome III criteria for FGIDs. Among
the 80 patients with allergic proctocolitis, 12 (15.0%) reported FGIDs, compared with 4 of 80 (5.0%) controls (P = .035).
After adjustment for age and sex, the OR for FGIDs in allergic proctocolitis group was 4.39 (95% CI, 1.03-18.68).
FGIDs were significantly associated with iron deficiency anemia, duration of hematochezia, and younger age at
presentation. In a multivariate analysis, only the duration of hematochezia was significantly associated with the
development of FGIDs (OR, 3.14; 95% CI,1.72-5.74).
Conclusions We have identified allergic proctocolitis as a new risk factor for the development of FGIDs in chil-
dren. Our data suggest that not only infection, but also a transient early-life allergic inflammatory trigger may induce
persistent digestive symptoms, supporting the existence of “postinflammatory” FGIDs. (J Pediatr 2017;■■:■■-■■).

See editorial, p •••

F
unctional gastrointestinal disorders (FGIDs) are defined as symptoms that, after appropriate medical evaluation, cannot
be attributed to another medical condition.1 These disorders are characterized by a dysregulation of the brain-gut axis,
associated with psychosocial factors, changes in intestinal motility, and visceral hypersensitivity.1-4 In addition, several
other abnormalities have been identified in subgroups of patients, including genetic factors, enteroendocrine dysfunction, neuroplastic
changes, gastrointestinal infections, altered microbiota, dietary factors, mucosal and systemic immune activation, and in-
creased mucosal permeability.5,6 Infectious gastroenteritis is a common trigger of FGIDs, particularly irritable bowel syndrome
(IBS), also in children.7-11 A long-term, prospective, controlled, culture-proven, follow-up study examining the association between
a single episode of Salmonella gastroenteritis and new-onset FGIDs showed that Salmonella-induced gastroenteritis during child-
hood, but not adulthood, is a risk factor for IBS.9 These results suggest that disruption of gut homeostasis early in life by acute
triggers may predispose the individual to susceptibility to the development of FGIDs later in life.9
Animal studies also have stressed the importance of early-life events in the development of visceral hypersensitivity.12 Psy-
chological or biological stressful events occurring soon after birth result in increased intestinal permeability during both the
neonatal and adult period and favor the occurrence of FGIDs later in life.13 Studies have shown that colonic inflammation during
an early, vulnerable period of neural plasticity leads to long-lasting hypersensi-
tivity that outlasts the acute inflammation.14 This phenomenon was not seen in
a similar experiment conducted in adult rats.14 Taken together, these studies point
toward a predominantly neurogenic mechanism that is more pronounced when From the 1Pediatric Gastroenterology Unit, Santobono-
Pausilipon Children’s Hospital, Naples, Italy; 2Pediatric
the inflammation occurs early in life. Gastroenterology Unit, International Hospital Salvator
Mundi, Rome, Italy; 3Department of Medical and Surgical
Although animal data are of great value in understanding the basic mecha- Sciences, University of Bologna, S. Orsola-Malpighi
nisms underlying neuroimmune interactions in the pathogenesis of sensorimo- Hospital, Bologna, Italy; 4Pediatric Gastroenterology Unit,
Sapienza University of Rome, Umberto I Hospital, Rome,
tor dysfunction, their translation to humans is not always possible. Human data Italy; 5Pediatric Unit, School of Medicine and Psychology,
Sapienza University of Rome, S. Andrea Hospital, Rome,
Italy; and 6Department of Public Health and Infectious
Diseases, Sapienza University of Rome, Rome, Italy
*Authors contributed equally.
The authors declare no conflicts of interest.
FAP Functional abdominal pain
FGID Functional gastrointestinal disorder 0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights
IBS Irritable bowel syndrome reserved.
https://doi.org10.1016/j.jpeds.2017.10.073

FLA 5.5.0 DTD ■ YMPD9576_proof ■ January 15, 2018

THE JOURNAL OF PEDIATRICS • www.jpeds.com
on the role of inflammation in the first weeks of life in the risk
of developing subsequent FGIDs could greatly advance our
knowledge on the pathogenesis of FGIDs. Saps et al15 sur-
veyed a large group of children with cow’s milk allergy early
in life several years after their initial diagnosis and found a
higher frequency of FGID symptoms in children diagnosed with
cow’s milk allergy compared with healthy controls.
Despite marked mucosal abnormalities, allergic proctoco-
litis is generally a cause of self-limiting rectal bleeding.16-23 Al-
lergic proctocolitis may provide a human model in which to
study the role of temporary colitis on the development of FGID,
thus supporting a role for noninfectious causes of inflamma-
tion as an early-life predisposing factor for the development
of FGIDs later in childhood.
The aim of this study was to prospectively evaluate the effect
of an early-life self-limiting human model of colitis on the de-
velopment of FGIDs, and the associated risk factors at least 4
years after the acute trigger.
Methods
This prospective controlled cohort study on the long-term
outcome of allergic proctocolitis on digestive functional symp-
toms and related risk factors comprised a cohort of consecu-
tive patients diagnosed with allergic proctocolitis at the Pediatric
Gastroenterology Unit of Sapienza, University of Rome between
October 2006 and November 2011. The diagnosis of allergic
proctocolitis was based on the American Gastroenterological
Association’s guidelines on the evaluation of food allergy in
gastrointestinal disorders.16
Owing to their similar genetic, environmental, and socio-
economic backgrounds, which can play a role in the preva-
lence of FGIDs, siblings aged <6 years without a history of cow’s
milk allergy were selected as controls. Each index case was as-
signed a unique control. If a patient did not have a sibling or
the sibling was aged >6 years or had a history of food allergy,
another child of similar age and sex presenting to the same
hospital in the emergency department for evaluation of minor
trauma in the absence of previous chronic gastrointestinal
symptoms was recruited as a control. Each control subject was
recruited within 4 weeks of the index case. A flow chart of re-
cruitment is provided in Figure 1 (available at www.jpeds.com).
The study was approved by the local Ethics Committee and
conducted in accordance with the Declaration of Helsinki. A
letter explaining the rationale of the present study was pro-
vided at all parents of the enrolled children, and written in-
formed consent was obtained in all eligible cases.
Consecutive patients referred to our unit for suspected al-
lergic proctocolitis underwent a screening visit including anal
inspection and stool culture to exclude other causes of rectal
bleeding. Blood tests, including concentrations of serum-
specific IgE antibody, skin prick tests, and fecal calprotectin,
were performed within 1 week before the endoscopy in all eli-
gible cases. Rectosigmoidoscopy was performed to confirm the
diagnosis and to exclude other entities. One pediatric gastro-
enterologist performed all endoscopic evaluation with a neo-
natal videogastroscope (Olympus, Tokyo, Japan), after deep
2 Di Nardo et al
FLA 5.5.0 DTD ■ YMPD9576_proof ■ January 15, 2018
Volume ■■ • ■■ 2017
sedation with midazolam (0.2 mg/kg). Endoscopic appear-
ance of rectal and left colonic mucosa (Figure 2, A and B) was
scored as reported previously.24 Mucosal biopsy specimens (at
least 2) were obtained from the left colon (splenic flexure to
the rectosigmoid junction) and the rectum. A pathologist
unaware of the clinical and laboratory data of the patients per-
formed all histological examinations. Histological grading was
assessed as described previously.24 The scoring for eosinophil
infiltration was adapted from previously described criteria
(Figure 2, C and D).25
Concentrations of serum-specific IgE antibody titers to
common foods (cow’s milk, soy, rice, wheat, egg) were mea-
sured using the immuno-CAP system with a detection limit
of 0.35 kU/L IgE.26 Prick tests for common food proteins (eg,
cow’s milk, soy, rice, wheat, egg) were performed as de-
scribed previously.27 Calprotectin was detected in the fecal
samples of allergic proctocolitis group by a commercially avail-
able enzyme-linked immunosorbent assay test (Calprest
Eurospital, Trieste, Italy).
Therapeutic Approach and Follow-Up
Cow’s milk protein maternal avoidance has been recom-
mended for breast-feeding infants. If rectal bleeding contin-
ues for 72-96 hours, an extensively hydrolyzed formula is
prescribed. Children unresponsive within 72-96 hours to the
extensively hydrolyzed formula are suggested an amino acid-
based formula.23 Children with allergic proctocolitis had a clini-
cal follow-up every month until stable remission of symptoms
and tolerance acquisition were achieved, and then a tele-
phone interview every 12 months until they reached at least
4 years of age, at which time they were mailed the validated
questionnaire. Healthy controls participated in a telephone in-
terview every 12 months until they reached at least 4 years of
age. The cutoff of 4 years was fixed because FGID cannot be
diagnosed according to the Rome III criteria until this age.
Participants who met the following criteria were eligible for
inclusion: at least 4 years of age at the time of mailing the ques-
tionnaire, and no diagnosis of organic chronic disorder (based
on self-report and review of medical records). Parents of all
invited participants received a postal questionnaire and were
asked to complete it and return it by mail. The questionnaire
was mailed up to 3 times to nonresponders. When no reply
was obtained, these individuals were contacted by telephone
to encourage participation in the study. No personal inter-
views were performed, to avoid interference with responses and
potential clinician assessment bias.
Parents were asked to review the child’s history and com-
plete the parental Questionnaire on Pediatric Gastrointesti-
nal Symptoms, Rome III version (QPGS-RIII), a validated
questionnaire for the diagnosis of FGIDs in children aged >4
years.28
Statistical Analyses
We estimated the sample size assuming that 2.0% of the sub-
jects in the control group29 and 19.2% of the subjects in the
exposed group15 would meet the criteria for FGIDs (ie, the
primary endpoint of the study). With this assumption, a sample
■■ 2017 ORIGINAL ARTICLES

Figure 2. Endoscopic (A and B) and histological (C and D) appearance of colonic mucosa in infants with allergic proctocolitis.
A, Partial lack of vascular pattern and mucosal friability with contact bleeding. B, Spontaneous bleeding and exudation. C, He-
matoxylin and eosin (H&E)-stained section (10× hpf) showing a prominent, full-thickness eosinophilic infiltrate in the lamina propria.
D, H&E-stained section at higher magnification (40× hpf) showing numerous eosinophils in the epithelium and lamina propria
with associated degenerative changes in the surface epithelium, focal goblet cell loss, and mucin depletion.

of at least 60 subjects would be needed in each group to have
80% power with a type I error of 0.05. The sample size was
estimated according to Dupont and Plummer30,31 using the “PS
Power and Sample Size Calculations” software of the Depart-
ment of Statistics, Vanderbilt University; version 3.0.12
(http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/Power
SampleSize). The analysis was conducted using frequency and
contingency tables. Differences between groups were as-
sessed using c2 and Mann-Whitney tests for categorical and
quantitative variables, respectively. A logistic regression analy-
sis was used to verify the association between FGID on aller-
gic proctocolitis, adjusted for age and sex. The results are
presented as OR and 95% CIs. The analysis was carried out
using SPSS for Windows, release 23.0 (IBM, Armonk, New
York). The statistical significance was set at P < .05.
Results
Of the 189 subjects potentially eligible to participate in the study,
29 subjects (15.3%) were not included, 8 who could not be
reached (change of address) and 21 who did not return the
questionnaire (Figure 1). One hundred and sixty subjects
(84.7%) completed the symptom questionnaire, including 80
in the allergic proctocolitis group and 80 in the control group.
Among these subjects, we were able to successfully match 53
patients with allergic proctocolitis with healthy siblings. All pa-
Allergic Proctocolitis Is a Risk Factor for Functional Gastrointestinal Disorders in Children
tients with allergic proctocolitis experienced complete reso-
lution of rectal bleeding, and their diagnosis was unchanged
during follow-up. In the control group, no patients devel-
oped an organic disorder during follow-up. Demographic data
were compared between the subjects who were successfully fol-
lowed up and completed the questionnaire and the eligible non-
participants. Sex (P = .635) and age (P = .951) were well
balanced between the 2 groups; thus, no selection bias was
present in the study population. The demographic data of the
participants in the present study are provided in Table I.
Overall, 16 of the 160 patients (10.0%) met the Rome III
criteria for FGIDs. In particular, among the 80 patients with
allergic proctocolitis, 12 (15.0%) reported FGIDs, compared
with 4 of 80 (5.0%) controls (P = .035). The univariate OR for
FGIDs in the patients was allergic proctocolitis was 3.35 (95%
CI, 1.03-10.89). In the allergic proctocolitis group, after ad-
justment for age and sex in the multivariate analysis, the OR
Table I. Demographic characteristics of all patients in-
cluded in the analysis
Allergic proctocolitis Control group
Characteristics group (n = 80) (n = 80)
Age, mean (SD) 5.96 (0.88) 7.66 (2.17)
Female sex: n (%) 43 (53.8) 38 (47.5)
3

FLA 5.5.0 DTD ■ YMPD9576_proof ■ January 15, 2018

THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Table II. Univariate and multivariate analysis of vari- Table III. Demographic, clinical, laboratory, endo-
ables associated with development of FGIDs scopic, and histologic characteristics of patients with al-
Characteristic Unadjusted OR (95% CI) aOR (95% CI) lergic proctocolitis included in the analysis
Mean age, wk 0.94 (0.70-1.26) 1.15 (0.80-1.67) No FGIDs FGIDs
Sex Characteristics (n = 68; 85%) (n = 12; 15%) P value
Female 1.28 (0.45-3.64) 1.22 (0.42-3.51) Continuous variables
Male (reference) 1 1 Age, wk, mean ± SD 16.56 (4.45) 12.25 (6.09) .017
Group Duration of hematochezia, 3.50 (1.70) 8.00 (1.86) <.001
Alergic proctocolitis 3.35 (1.03-10.89) 4.39 (1.03-18.68) wk, mean ± SD
Control (reference) 1 1 Fecal calprotectin, µg/g, 115.23 (71.21) 123.42 (60.45) .329
mean ± SD
Categorical variables
Sex, n (%)
Female 36 (83.7) 7 (16.3) .730
for developing FGIDs was 4.39 (95% CI, 1.03-18.68) (Table II). Male 32 (86.5) 5 (13.5)
Among the 80 patients with allergic proctocolitis, 8 (10%) re- Breast-fed, n (%)
ported IBS, 3 (3.7%) functional abdominal pain (FAP), and No 57 (85.1) 10 (14.9) .966
Yes 11 (84.6) 2 (15.4)
1 (1.3%) reported constipation. Among the 80 controls, 1 Family history of atopy, n (%)
patient (1.3%) reported IBS, 2 patients (2.5%) reported FAP, No 55 (84.6) 10 (15.4) .841
and 1 patient (1.3%) reported constipation. Yes 13 (86.7) 2 (13.3)
Increased IgE, n (%)
Univariate analysis was performed to identify factors asso- No 66 (84.6) 12 (15.4) .547
ciated with FGIDs in the allergic proctocolitis group. FGIDs Yes 2 (100) 0 (0)
was significantly associated with the presence of iron defi- Positive allergy tests, n (%)
No 67 (85.9) 11 (14.1) .160
ciency anemia (1 of 68 [1.5%] patients who did not develop Yes 1 (50) 1 (50)
FGIDs vs 4 of 12 [33.3%] who developed FGIDs; P < .001), Iron deficiency anemia, n (%)
mean duration of hematochezia (3.5 ± 1.7 weeks in the 68 pa- No 67 (89.3) 8 (10.7) <.001
Yes 1 (20) 4 (80)
tients who did not develop FGIDs vs 8.0 ± 1.9 weeks in the 12 Endoscopic score, n (%)
who developed FGIDs; P < .001), and younger age at presen- 1 47 (85.5) 8 (14.5) .611
tation (mean, 16.6 ± 6.4 weeks in the 68 patients who did not 2 17 (81) 4 (19)
3 4 (100) 0 (0)
develop FGIDs vs 12.3 ± 6.1 weeks in the 12 who developed Histologic score, n (%)
FGIDs; P = .017). We did not find any significant correlation 1 46 (85.2) 8 (14.8) .650
between FGIDs and family history of atopy, positivity of allergy 2 20 (87) 3 (13)
3 2 (66.7) 1 (33.3)
tests, fecal calprotectin, endoscopic score, histological score, or Eosinophilic score, n (%)
eosinophil score (Table III). Using a multivariate approach and 1 23 (82.1) 5 (17.9) .628
including only the variables with a P value < .25 on the uni- 2 38 (88.4) 5 (11.6)
3 7 (77.8) 2 (22.2)
variate analysis, the only variable significantly associated with
the development of FGIDs was the duration of hematochezia
(OR, 3.14; 95% CI, 1.72-5.74).
fecal calprotectin, and endoscopy with biopsies have been used
as tools to verify our hypothesis, but they should not be done
Discussion routinely.
Infectious gastroenteritis is the strongest risk factor for the
In this prospective controlled cohort study assessing the as- development of IBS and, to a lesser extent, functional dyspep-
sociation between allergic proctocolitis and new-onset FGIDs, sia, 2 of the main FGIDs.9,32,33 Here we have identified aller-
the novel main finding is evidence suggesting that an gic proctocolitis as a new risk factor for the development of
inflammatory/allergic self-limiting disorder occurring early in FGIDs, supporting the existence of “postinflammatory” FGIDs.
life, such as allergic proctocolitis, is a risk factor for the de- Allergic proctocolitis, a cause of rectal bleeding in exclusively
velopment later in life of digestive symptoms meeting the Rome breast-fed infants aged 1-6 months,17-23 may constitute an
III criteria for FGIDs. This was due especially to IBS, which elegant human model of colitis, with similarities to early-life
accounted for 66% of the new FGIDs in the allergic procto- inflammation in animal studies. In the rat model of neonatal
colitis group. Furthermore, we identified the duration of maternal separation, stress induces visceral hypersensitivity and
hematochezia as the only variable significantly associated with increased pain perception via mast cell degranulation, nerve
the development of FGIDs. These data suggest that not only growth factor, and transient receptor ion channel 1 modula-
infections, but also a self-limiting early-life allergic inflam- tion, in the absence of overt inflammation.34 Similar patho-
matory trigger, especially if prolonged, may induce digestive physiological mechanisms likely play a role also in our patients.
symptoms meeting the criteria for FGIDs. We did not find any In fact, adult studies suggest that an abnormal mucosal milieu
significant correlation between FGIDs and family history of and neuro-immune interactions, via mast cell activation and
atopy, positivity of allergy tests, fecal calprotectin, endo- nerve growth factor release, may be identified as key mecha-
scopic score, or histological score. We clarify that allergy tests, nisms in the pathophysiology of intestinal dysfunction and pain
4 Di Nardo et al

FLA 5.5.0 DTD ■ YMPD9576_proof ■ January 15, 2018

■■ 2017
transmission of IBS.35 It is interesting to note that the type of
inflammation, as well as the period of life in which it occurs,
are crucial to defining its long-term effects. In fact, 2 re-
search groups have recently showed that celiac patients on a
gluten-free diet36 and patients with inflammatory bowel disease
in clinical remission37-39 have an FGIDs prevalence similar to
that of the general pediatric population.
The pathogenesis of FGIDs remains elusive and is likely
multifactorial.1 The new pathophysiological vision of FAP dis-
orders in children suggests that sensitizing medical factors, in-
cluding distention, inflammation, and motility disorders, on
a background of genetic predisposition and early-life events
may induce changes in pain processing and visceral hyper-
sensitivity, leading to abdominal pain and gastrointestinal
symptoms.1 Our data show that an early-life event of allergic/
inflammatory origin, such as allergic proctocolitis, occurring
in the first weeks of life may be the trigger for the develop-
ment of persistent digestive symptoms, particularly IBS. Early
in life, the intestine is characterized by an immature immune
system, altered intestinal permeability, and a delicate stage of
microbiotic development, with complex interactions between
host and microbiota.40,41 In this critical phase, which repre-
sents a window of vulnerability, an early disruption of gut ho-
meostatic equilibrium by an acute trigger, such as allergic
proctocolitis, might predispose to susceptibility to the devel-
opment of FGIDs later in life.
In most cases, allergic proctocolitis is due to cow’s milk pro-
teins transferred via breast milk. Diagnosis is based on clini-
cal features and recovery after dietetic therapy.17-19 Rectal
bleeding usually resolves within 72-96 hours of cow’s milk
protein maternal avoidance; however, approximately 7% of pa-
tients need an extensively hydrolyzed formula, and another 5%
require an amino acid-based formula.17,23 Recent data showed
that preschoolers with a history of allergic disease had an in-
creased risk of development of IBS on reaching school age, and
that this risk increased in the presence of concurrent allergic
disease and a higher clinical allergy burden.42 Saps et al15 pos-
tulated a link between food allergy and FGIDs, and studied a
large group of children with cow’s milk allergy early in life.
They found a higher frequency of FGIDs symptoms in chil-
dren diagnosed with cow’s milk allergy compared with the
healthy controls. Interestingly, our results are similar to those
reported by Saps et al, including the prevalence of new cases
of FGIDs (19.2% in their study vs 15% in our present study),
largely linked to IBS (70% in their study vs 66% in our study).
That pioneering study had some important limitations,
however. First, its retrospective design does not exclude the pos-
sibility of recall bias. Second, patients were categorized as having
cow’s milk allergy based on the physician’s clinical suspicion
following diagnostic recommendations by the American
Gastroenterological Association, and thus we cannot exclude
the possibility that some of the patients labeled as having cow’s
milk allergy may have a different, unspecified condition. Third,
a lack of histological confirmation of colonic inflammation is
lacking. In contrast, our study was prospective with a well-
selected and characterized control group and a long-term
follow-up period during which the 2 groups were surveyed
Allergic Proctocolitis Is a Risk Factor for Functional Gastrointestinal Disorders in Children
FLA 5.5.0 DTD ■ YMPD9576_proof ■ January 15, 2018
ORIGINAL ARTICLES
equally, the diagnosis of allergic proctocolitis was certain and
other organic disorders that could mimic allergic proctocoli-
tis were excluded, and colonic inflammation was evaluated and
staged by means of endoscopy, histology, and fecal calprotectin.
Furthermore, the study was planned based on sample size cal-
culation, and the number of subjects who returned the ques-
tionnaires exceeded the calculated sample size, thus ensuring
a correctly powered primary endpoint of the study.
A systematic review and meta-analysis assessing new-
onset IBS in 21 421 subjects with infectious enteritis showed
an estimated pooled point prevalence of postinfectious IBS of
11%.33 The overall risk of new IBS is 4.2-fold higher in exposed
subjects compared with nonexposed subjects, and remains high
beyond the first year of exposure and stable across adults and
children. In adult patients, factors associated with an in-
creased risk of postinfectious IBS include female sex, psycho-
logical distress at the time of infection, use of antibiotics, and
severity of the initial illness.33
Interestingly, this study shows for the first time that the du-
ration of rectal bleeding in infants with allergic proctocolitis
is the sole variable significantly associated with the develop-
ment of FGIDs. This suggests that even in postinflammatory
FGIDs, the severity of the acute trigger is a determinant of per-
sistent digestive sequels. This could be explained by the pro-
longed release of inflammatory mediators during an early,
vulnerable period of neural plasticity, leading to altered enteric
nervous system physiology. Recent data support the concept
that the release of factors with known effects on nerves in the
intestinal milieu not only might have functional effects, but
also might affect the enteric nervous system and sensory fibers
in a structural manner, inducing long-lasting neuroplastic
changes.35
This study does have some limitations. Potential weakness
includes the fact that all subjects were recruited in a single
center, and no information was collected on psychological status
and family dynamics, which may play a role in the pathogen-
esis of FGIDs in children. Finally, although 66% of our new
cases of FGIDs were linked to IBS, this study was not powered
for statistical comparisons among single FGIDs in patients with
allergic proctocolitis.
In conclusion, we have identified allergic proctocolitis as a
new risk factor for the development of FGIDs, particularly IBS,
in early stages of life, and we have shown that the severity of
this illness is the most relevant factor in symptom develop-
ment. If confirmed in future large-scale, multicenter studies,
our findings may have important clinical implications. Because
allergic proctocolitis is usually seen as a brief and self-
limited illness, its long-term effects are not considered. Future
studies are warranted to evaluate whether different interven-
tion strategies could potentially minimize the development of
FGIDs in allergic proctocolitis patients at higher risk. ■
Submitted for publication Jul 24, 2017; last revision received Sep 23, 2017;
accepted Oct 30, 2017
Reprint requests: Giovanni Barbara, MD, Department of Medical and Surgical
Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Pavilion 5, Via
Massarenti 9, Bologna, 40138, Italy. E-mail: giovanni.barbara@unibo.it
5
THE JOURNAL OF PEDIATRICS • www.jpeds.com
References
1. Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg
M. Childhood functional gastrointestinal disorders: child/adolescent. Gas-
troenterology 2016;150:1456-68.
2. Zhou Q, Fillingim RB, Riley JL 3rd, Malarkey WB, Verne GN. Central and
peripheral hypersensitivity in the irritable bowel syndrome. Pain
2010;148:454-61.
3. Faure C, Wieckowska A. Somatic referral of visceral sensations and rectal
sensory threshold for pain in children with functional gastrointestinal dis-
orders. J Pediatr 2007;150:66-71.
4. Chumpitazi BP, Shulman RJ. Underlying molecular and cellular mecha-
nisms in childhood irritable bowel syndrome. Mol Cell Pediatr 2016;3:11.
5. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl
J Med 2012;367:1626-35.
6. Barbara G, Feinle-Bisset C, Ghoshal UC, Quigley EM, Santos J, Vanner
S, et al. The intestinal microenvironment and functional gastrointesti-
nal disorders. Gastroenterology 2016;150:1305-18.
7. Saps M, Pensabene L, Di Martino L, Staiano A, Wechsler J, Zheng X, et al.
Post-infectious functional gastrointestinal disorders in children. J Pediatr
2008;152:812-6, 816.e1.
8. Thabane M, Simunovic M, Akhtar-Danesh N, Garg AX, Clark WF, Collins
SM, et al. An outbreak of acute bacterial gastroenteritis is associated with
an increased incidence of irritable bowel syndrome in children. Am J
Gastroenterol 2010;105:933-9.
9. Cremon C, Stanghellini V, Pallotti F, Fogacci E, Bellacosa L, Morselli-
Labate AM, et al. Salmonella gastroenteritis during childhood is a risk
factor for irritable bowel syndrome in adulthood. Gastroenterology
2014;147:69-77.
10. Pensabene L, Talarico V, Concolino D, Ciliberto D, Campanozzi A, Gentile
T, et al. Postinfectious functional gastrointestinal disorders in children:
a multicenter prospective study. J Pediatr 2015;166:903-7.e1.
11. Dupont AW. Post-infectious irritable bowel syndrome. Curr Gastroenterol
Rep 2007;9:378-84.
12. Barreau F, Ferrier L, Fioramonti J, Bueno L. New insights in the etiol-
ogy and pathophysiology of irritable bowel syndrome: contribution of
neonatal stress models. Pediatr Res 2007;62:240-5.
13. Klooker TK, Braak B, Painter RC, de Rooij SR, van Elburg RM, van den
Wijngaard RM, et al. Exposure to severe wartime conditions in early life
is associated with an increased risk of irritable bowel syndrome: a
population-based cohort study. Am J Gastroenterol 2009;104:2250-6.
14. Al-Chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral
hypersensitivity in adult rats induced by colon irritation during postna-
tal development. Gastroenterology 2000;119:1276-85.
15. Saps M, Lu P, Bonilla S. Cow’s milk allergy is a risk factor for the devel-
opment of FGIDs in children. J Pediatr Gastroenterol Nutr 2011;52:166-
9.
16. Sampson HA, Sicherer SH, Birnbaum AH. AGA technical review on the
evaluation of food allergy in gastrointestinal disorders. American
Gastroenterological Association. Gastroenterology 2001;120:1026-40.
17. Lucarelli S, Di Nardo G, Lastrucci G, D’Alfonso Y, Marcheggiano A, Federici
T, et al. Allergic proctocolitis refractory to maternal hypoallergenic diet
in exclusively breast-fed infants: a clinical observation. BMC Gastroenterol
2011;11:82.
18. Maloney J, Nowak-Wegrzyn A. Educational clinical case series for pedi-
atric allergy and immunology: allergic proctocolitis, food protein-
induced enterocolitis syndrome and allergic eosinophilic gastroenteritis
with protein-losing gastroenteropathy as manifestations of non IgE-
mediated cow’s milk allergy. Pediatr Allergy Immunol 2007;18:360-7.
19. Pumberger W, Pomberger G, Geissler W. Proctocolitis in breast-fed infants:
a contibution to differential diagnosis of haematochezia in early child-
hood. Postgrad Med J 2001;77:252-4.
20. Xanthakos SA, Schwimmer JB, Melin-Aldana H, Rothenberg ME, Witte
DP, Cohen MB, et al. Prevalence and outcome of allergic colitis in healthy
infants with rectal bleeding: a prospective cohort study. J Pediatr
Gastroenterol Nutr 2005;41:16-22.
6 Di Nardo et al
FLA 5.5.0 DTD ■ YMPD9576_proof ■ January 15, 2018
Volume ■■
21. Dupont C, Heyman M. Food protein-induced enterocolitis syndrome: labo-
ratory perspectives. J Pediatr Gastroenterol Nutr 2000;30 Suppl:S50-7.
22. Odze RD, Wershil BK, Leichtner AM, Antonioli DA. Allergic colitis in
infants. J Pediatr 1995;126:163-70.
23. Molnár K, Pintér P, Győrffy H, Cseh A, Müller KE, Arató A, et al. Char-
acteristics of allergic colitis in breast-fed infants in the absence of cow’s
milk allergy. World J Gastroenterol 2013;19:3824-30.
24. Oliva S, Di Nardo G, Ferrari F, Mallardo S, Rossi P, Patrizi G, et al.
Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC
55730 rectal enema in children with active distal ulcerative colitis. Aliment
Pharmacol Ther 2012;35:327-34.
25. Casella G, Villanacci V, Fisogni S, Cambareri AR, Di Bella C, Corazzi N,
et al. Colonic left-side increase of eosinophils: a clue to drug-related colitis
in adults. Aliment Pharmacol Ther 2009;29:535-41.
26. Sampson HA. Utility of food-specific IgE concentrations in predicting
symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6.
27. Verstege A, Mehl A, Rolinck-Werninghaus C, Staden U, Nocon M, Beyer
K, et al. The predictive value of the skin prick test weal size for the outcome
of oral food challenges. Clin Exp Allergy 2005;35:1220-6.
28. Caplan A, Walker L, Rasquin A. Validation of the pediatric Rome II cri-
teria for functional gastrointestinal disorders using the questionnaire on
pediatric gastrointestinal symptoms. J Pediatr Gastroenterol Nutr
2005;41:305-16.
29. Miele E, Simeone D, Marino A, Greco L, Auricchio R, Novek SJ, et al. Func-
tional gastrointestinal disorders in children: an Italian prospective survey.
Pediatrics 2004;114:73-8.
30. Dupont WD, Plummer WD Jr. Power and sample size calculations. A
review and computer program. Control Clin Trials 1990;11:116-28.
31. Dupont WD, Plummer WD Jr. Power and sample size calculations for
studies involving linear regression. Control Clin Trials 1998;19:589-601.
32. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroen-
terology 2009;136:1979-88.
33. Klem F, Wadhwa A, Prokop L, Sundt WJ, Farrugia G, Camilleri M, et al.
Prevalence, risk factors, and outcomes of irritable bowel syndrome after
infectious enteritis: a systematic review and meta-analysis. Gastroenter-
ology 2017;152:1042-54.e1.
34. van den Wijngaard RM, Klooker TK, Welting O, Stanisor OI, Wouters MM,
van der Coelen D, et al. Essential role for TRPV1 in stress-induced (mast
cell-dependent) colonic hypersensitivity in maternally separated rats.
Neurogastroenterol Motil 2009;21:1107-94.
35. Dothel G, Barbaro MR, Boudin H, Vasina V, Cremon C, Gargano L, et al.
Nerve fiber outgrowth is increased in the intestinal mucosa of patients
with irritable bowel syndrome. Gastroenterology 2015;148:1002-11.e4.
36. Saps M, Sansotta N, Bingham S, Magazzu G, Grosso C, Romano S, et al.
Abdominal pain-associated functional gastrointestinal disorder preva-
lence in children and adolescents with celiac disease on gluten-free diet:
a multinational study. J Pediatr 2017;182:150-4.
37. Diederen K, Hoekman DR, Hummel TZ, de Meij TG, Koot BG, Tabbers
MM, et al. The prevalence of irritable bowel syndrome-type symptoms
in paediatric inflammatory bowel disease, and the relationship with bio-
chemical markers of disease activity. Aliment Pharmacol Ther 2016;44:181-
8.
38. Zimmerman LA, Srinath AI, Goyal A, Bousvaros A, Ducharme P, Szigethy
E, et al. The overlap of functional abdominal pain in pediatric Crohn’s
disease. Inflamm Bowel Dis 2013;19:826-31.
39. Watson KL Jr, Kim SC, Boyle BM, Saps M. Prevalence and impact of func-
tional abdominal pain disorders in children with inflammatory bowel dis-
eases (IBD-FAPD). J Pediatr Gastroenterol Nutr 2017;65:212-7.
40. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Mo-
lecular analysis of commensal host-microbial relationships in the intes-
tine. Science 2001;291:881-4.
41. Hooper LV, Littman DR, Macpherson AJ. Interactions between the
microbiota and the immune system. Science 2012;336:1268-73.
42. Tan TK, Chen AC, Lin CL, Shen TC, Li TC, Wei CC. Preschoolers with
allergic diseases have an increased risk of irritable bowel syndrome when
reaching school age. J Pediatr Gastroenterol Nutr 2017;64:26-30.
■■ 2017 ORIGINAL ARTICLES

Figure 1. Flowchart of study participants.

Allergic Proctocolitis Is a Risk Factor for Functional Gastrointestinal Disorders in Children 6.e1

FLA 5.5.0 DTD ■ YMPD9576_proof ■ January 15, 2018