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Defining Eosinophilic Colitis in Children: Insights From aRetrospective Case Series

�Sam Behjati, yMatthias Zilbauer, yRobert Heuschkel, yAlan Phillips, yCamilla Salvestrini,yFranco Torrente, and �Alan W. Bates

Journal of Pediatric Gastroenterology and Nutrition49:208–215 # 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition andNorth American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

right © 2009 by

�Department o d NHS Trust,

rate, blood eosinophil

motility (5), possiblyganglion cells (6). Tdition mainly stems f

Received February 18,Address correspondenc

Consultant Pathologist, DHospital Pond Street, Loroyalfree.nhs.uk).

The authors report no

f Histopathology, and {Centre for Paediatric Gastroenterology, Royal Free Hampstea

Royal Free and University College Medical School Pond Street, London, UK

ABSTRACT

Objectives: Although it is a well-described syndrome in infants,eosinophilic colitis is a loosely defined and poorly understooddiagnosis in older children. The aims of this case series were tocharacterise colonic eosinophilia in children and to determinewhether it represents a distinct clinicopathological condition.Methods: We retrospectively reviewed symptomatic childrenolder than 12 months with the principal diagnosis of coloniceosinophilia who presented between January 2000 and February2007 (n¼ 38) and a further 10 children whose colonic biopsieswere reported as histologically normal. The eosinophil densityin all available gastrointestinal biopsies (n¼ 620) of thesechildren was determined using a validated quantitativemorphometric method. Patients were subdivided according tomean colonic eosinophil levels into 3 groups (marked,moderate, or minimal colonic eosinophilia). The followingpatient information was obtained and compared amongpatient groups: symptoms prompting endoscopy, atopic

Lippincott Williams & Wilkins.Un

count, and endoscopic findings.

through their effects on myenteriche uncertainty surrounding the con-rom the lack of consensus on normal

2009; accepted September 9, 2008.e and reprint requests to Alan W. Bates, MD,

epartment of Histopathology, Royal Freendon, NW3 2QG, UK (e-mail: alan.bates@

conflicts of interest.

208

Results: In all 3 patient groups, there was a colonic gradientof decreasing eosinophil density from caecum to rectum.Upper gastrointestinal tract biopsies did not exhibiteosinophilia. Although a significant association (P¼ 0.03)between abnormal total IgE levels and moderate or severecolonic eosinophilia was found, there was no significantdifference (P> 0.05) in other patient characteristics.Furthermore, follow-up data did not show a consistentrelation between eosinophil density and progression ofsymptoms.Conclusions: We find no association between ‘‘eosinophiliccolitis,’’ defined as a histologically demonstrated markedcolonic eosinophilia, and symptoms, history of atopy,inflammatory markers, or clinical outcome. JPGN49:208–215, 2009. Key Words: Allergic colitis—Coloniceosinophilia—Eosinophilic colitis—Eosinophilic gastro-intestinal disorders. # 2009 by European Society for

history, outcome, serum C-reactive protein and total

Pediatric Gastroenterology, Hepatolog immunoglobulin E (IgE) levels, erythrocyte sedimentation

y, and Nutrition andNorth American Society for Pediatric Gastroenterology,

Hepatology, and Nutrition

Although eosinophilic colitis is a well-recognisedsyndrome in infants (1), it is a loosely defined disorderin children older than 12 months of age (2). The con-dition, first described by Kaijser in 1937 (3), is charac-terised by the histological hallmark of colonic eosino-philia (1). Allergic hypersensitive reactions have beenimplicated in its pathogenesis (2,4), and it has beensuggested that eosinophils interfere with gastrointestinal

numbers of colonic eosinophils and on diagnostic criteria(2,7). Although eosinophilic colitis is encountered rela-tively frequently in paediatric gastroenterology practice,its true incidence is unknown. Reports suggestinggeographical variation in numbers of colonic eosinophilsin children add to the uncertainty (7,8). The relevantliterature comprises case reports of eosinophilic colitis(3,9–13), investigations into normal numbers of coloniceosinophils (7,14,15), and case series of eosinophilicganglionitis and eosinophilic gastroenteropathy (6,16).

Given our poor understanding of eosinophilic colitis,the finding of colonic eosinophilia in children withotherwise unexplained gastrointestinal complaints isparticularly difficult to interpret and remains a challengeto manage. Should colonic eosinophilia be regarded as a

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pathological condition in its own right, that is, as eosi-nophilic colitis? Here we present the first case series ofsymptomatic children in whom colonic eosinophilia is

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the principal diagnosis to determine whether isolatedcolonic eosinophilia represents a distinct clinico-pathological entity.

METHODS

The pathology database of this paediatric gastroenterologytertiary referral centre was screened for histopathology reportsbetween January 2000 and February 2007 that commented onincreased numbers of eosinophils in colonic biopsies. Thereports were reviewed along with all case notes, previoushistopathology reports, and biopsies in November 2007 givinga follow-up time of between 8 months and 7 years. Adults (ages17 years or older) and infants (ages 12 months or younger) wereexcluded from further analysis, as were children who at the timeof, or before, review (November 2007) had been diagnosed withgastrointestinal disease other than ‘‘eosinophilic colitis’’ (eg,inflammatory bowel disease or gastrointestinal parasites). Allbiopsy series were reviewed but only the first colonic series,related to 38 children with a report of colonic eosinophilia, wereincluded in the initial analysis. A further 10 children were addedto the study, randomly chosen from a list of 24 patients whosecolonic biopsies had been reported as histologically normal andwith no current or subsequent diagnosis of gastrointestinaldisease. Upper gastrointestinal tract biopsies obtained on thesame occasion as the colonic biopsies, which were available in46 patients (96%), were also examined.

Histological Examination

The eosinophil density at each biopsy site was determinedfor each patient using an objective, quantitative morphometricmethod applicable to everyday pathology practice. An OlympusBH-2 microscope (Shinjuku-ku, Tokyo, Japan) with a high-power field (HPF) diameter of 0.5 mm2 (area of 0.196 mm2;magnification� 400) was used, and 3 HPFs were examined perbiopsy. The method of examining 3 HPFs in each biopsy wasadopted, because there was no statistically significant difference(P¼ 0.9854; median difference �0.05 eosinophils; range �5.8to 1.8 eosinophils) in a comparison of the mean number ofeosinophils in 3 HPFs with the mean number of eosinophils in10 HPFs in 20 randomly selected gastrointestinal biopsies. Inselecting HPF, areas of dense lymphocytic infiltration andartefact were avoided, and areas with preserved surface epi-thelium were included. According to a previously publishedmethod (7), eosinophils were counted where a portion of a cellcontaining eosinophilic granules was seen, irrespective ofwhether or not the nucleus was visible. The eosinophil densitywithin the lamina propria and within the surface and cryptepithelium was determined, and the presence or absence ofdegranulation was documented. Other histological changes ofnote were also recorded, for example, the presence of neutro-phils or eosinophilic crypt abscesses.

Review of Patient Characteristics

After collection of all histological data, and before further

DEFINING EOSINOPHILI

yright © 2009 by Lippincott Williams & Wilkins.U

analysis, the following information was obtained from patients’medical records using a standardised data proforma: symptomswhich led to endoscopy; medical history of asthma, eczema,

allergic rhinitis (seasonal and perennial), or urticaria; treatment;outcome; and macroscopic findings on endoscopy. Further-more, for each patient the age-specific results of the followingblood tests were reviewed: serum C-reactive protein (CRP),erythrocyte sedimentation rate (ESR), blood eosinophil count,and total serum immunoglobulin E (IgE) levels. CRP, ESR, andblood eosinophil count were only included in the study ifperformed on the day of or the day preceding endoscopy. TotalIgE levels measured within 12 months of endoscopy wereincluded in the study (median interval between total IgEmeasurement and colonoscopy was 2 months).

Patient Categorisation

To enable statistical analysis of patient characteristics inrelation to eosinophil density, the patients were arbitrarilydivided according to the mean colonic biopsy eosinophil countinto the following patient groups: <10 eosinophils per HPF(group I, minimal tissue eosinophilia); 10 to <20 eosinophilsper HPF (group II, moderate tissue eosinophilia); at least 20eosinophils per HPF (group III, marked tissue eosinophilia;Fig. 1).

Statistical Methods

The Mann-Whitney U test was used for nonparametricindependent data and the Wilcoxon matched-pairs signed-ranksfor nonparametric paired data. When the number of pairs wasless than 20, exact probabilities were calculated. Fisher exacttest was applied to paired observations on 2 variables expressedin contingency tables. All tests were 2-sided. A P value of 0.05or less was considered to be statistically significant. Statisticalanalysis was performed using a software package (SPSS 15.0for Windows, Chicago, IL).

RESULTS

The age and sex distribution and eosinophil counts in48 children are summarised in Table 1. The mean coloniceosinophil density in 38 children with a diagnosis ofcolonic eosinophilia was 16.4 eosinophils per HPF. All10 children with colonic biopsies reported as histologi-cally normal had a mean eosinophil density of <10eosinophils per HPF (mean of 6.7 colonic eosinophilsper HPF).

Table 2 lists all of the clinical symptoms documentedin 3 or more children. Symptoms reported by only 1 or 2patients included food avoidance, anaemia, offensivestools, belching, and nausea. No significant differenceswere found in symptoms among the 3 patient groups(P> 0.05); 40% of patients reported a history of 1 ormore of the following: seasonal or perennial allergicrhinitis, eczema, asthma, or urticaria. There was nosignificant difference in allergic symptomatology among

LITIS IN CHILDREN 209

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the 3 patient groups. In contrast, we found statisticallysignificant differences in total serum IgE levels as sum-marised in Table 3.

J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

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FIG. 1. Examples of colonic biopsies. (A) Minimal tissue eosinophilia (group I); (B) moderate tissue eosinophilia (group II); (C) marked tissueeosinophilia (group III) with eosinophilic crypt abscess (arrow).

210 BEHJATI ET AL.

Serum CRP levels and ESR were normal in all ofthe patients except for 2 in group III (1 patient with CRP

right © 2009 by Lippincott Williams & Wilkins.Un

of 13 mg/L and ESR of 43 mm/hour; 1 patient with raisedCRP 43 mg/L and normal ESR), 1 patient in group II(CRP of 13 mg/L and normal ESR), and 1 patient in

J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

group I (CRP of 5 mg/L and normal ESR). The differ-ences between patient groups were not statistically

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significant (P> 0.05). To assess whether the coloniceosinophilia occurred in the context of systemic eosino-philia, we reviewed the blood eosinophil count at the time

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TABLE 2. Symptoms prompting endoscopy

Patient groups

I II III

Eosinophilia Mild Moderate Markedn�

15 21 11Abdominal pain 7 10 4Diarrhoea 4 8 2Constipation 4 3 3Rectal bleeding 4 3 1Vomiting 0 4 3Failure to thrive 2 2 1Weight loss 2 1 1Melaena 2 2 0Mouth ulcers 0 2 2Soiling 0 0 3Bloating 1 2 0

Only symptoms that were reported by 3 or more patients are listed.

TABLE 1. Patient characteristics and categorisation

Patient groups

I�<10 II 10–<20 III �20

Mean colonic eosinophils per HPF Total

No. patients 15 21 12 48Male 9 14 6 29Female 6 7 6 19Median age, y 9 8 6.5 7Age range, y 1.3–16 2.0–14 1.2–14

Data are number of patients unless otherwise specified. HPF¼ high-power field.�

DEFINING EOSINOPHILIC COLITIS IN CHILDREN 211

of endoscopy. This was mildly raised in only 1 patientfrom group III (0.80� 109 eosinophils/L, upper limit ofnormal 0.62� 109 eosinophils/L).

Colonoscopic findings with histological correlationare presented in Table 4. All documented macroscopicabnormalities were mild and included the presence ofcolonic lymph follicles, erythema, or loss of vascularpattern; no overt ulceration or haemorrhage was seen inany case. Histological analysis of the colonic biopsiesrevealed that the crypt architecture was preserved in allbut 3, in which minor distortion was found. Furthermore,eosinophilic crypt abscesses were seen in 5 biopsies (2 ingroup III and 3 in group II), and 5 biopsies contained aminimal neutrophilic infiltrate (3 in group II and 2 ingroup I).

The distribution of eosinophils along the colorectumwas characterised in 30 complete colonic biopsy series,that is, cases including biopsies from caecum, ascending,transverse, descending, and sigmoid colon, as well asrectum: 11 from group I, 12 from group II, and 7 fromgroup III. As illustrated in Figure 2, a gradient ofdecreasing eosinophil density from the caecum to the

The 10 children whose colonic biopsies were reported as normal areincluded in this group.

yright © 2009 by Lippincott Williams & Wilkins.U

rectum with relative rectal sparing was present in all 3patient groups. In all 3 patient groups, we found signifi-cantly (P< 0.02) lower eosinophil density in the distal

TABLE 3. Total ser

Eosinophilian�

Total IgE raised (age-dependent upper limit of normal 63–75 kU/L)Median of raised IgE levels (kU/L)

Data are number of patients unless otherwise specified.�Number of patients with information available.yP¼ 0.024 comparing II with I.zP¼ 0.023 comparing III with I; P> 0.05 for comparison between II and§Median IgE level in group I: 13 kU/L.

colon (ie, descending colon, sigmoid colon, and rectum)compared with the proximal colon (ie, caecum, ascend-ing colon, and transverse colon), and colonic eosinophillevels were lowest in the rectum (P< 0.05; comparingrectum with all other colonic biopsy sites). Figure 2further shows that the ileal eosinophil density in patientsfrom group III was significantly higher (mean countof 19 eosinophils per HPF) than in patient groups II(mean count of 12.1/HPF; P¼ 0.047) and I (mean countof 11.1/HPF; P¼ 0.048). There was no significant differ-ence in ileal eosinophil density between groups I and II(P¼ 0.172).

The mean number of eosinophils counted in a totalof 46 oesophageal biopsies was 0.5 per HPF (range0–8 eosinophils/HPF) with no significant differencesamong patient groups (P> 0.05). In biopsies from gastricantrum (n¼ 45) and fourth part of duodenum (n¼ 46),the eosinophil density was 0.9 per HPF (n¼ 45; range

Data are number of patients.�Number of patients with information available.

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0–3.7 eosinophils/HPF) and 7.7 eosinophils per HPF(n¼ 46; range 1–22.3 eosinophils/HPF), respectively.There was no significant difference in gastric and

um IgE levels

Patient groups

I II III

Mild Moderate Marked10 14 80 6y 4z

254 402

III.

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TABLE 4. Endoscopic appearance of colonic mucosa with histological correlation

Patient groups

I II III

Eosinophilia Mild Moderate MarkedEndoscopic findingsn�

14 19 12Endoscopic appearance abnormal 5 6 5Histological findingsn�

15 21 12Degranulation present (%) 33 39 73y,z

Intraepithelial eosinophils present (%)y 18y 22y 39y,§

Range of number of intraepithelial eosinophils per HPF 0.3–1.7 0.3–3 0.3–2.7

Data are number of patients unless indicated otherwise. HPF¼ high-power field.�Number of patients with information available.

anulatir I; P

212 BEHJATI ET AL.

duodenal eosinophil density among children in groups I,II, or III (P> 0.05).

A subgroup of 6 patients from groups II and IIIunderwent more than 1 endoscopy because of persistingsymptoms (Table 5) and required various treatments(detailed in Table 5). In this series, we found no corre-lation between the change in number of colonic eosino-phils and clinical symptoms at follow-up endoscopy(Table 5).

DISCUSSION

y For each patient group the percentage of biospsies containing degrzP< 0.001 and §P< 0.03 comparing group III with either group II o

right © 2009 by Lippincott Williams & Wilkins.Un

In this retrospective case series, we aimed to determinethe significance of isolated colonic eosinophilia in chil-

FIG. 2. Distribution of eosinophils in colorectum. Columns represent mean(bar). TI¼ terminal ileum; Cae¼ caecum; AC¼ascending; TC¼ transver

J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

dren experiencing otherwise unexplained gastrointestinalsymptoms. Although colonic eosinophilia is a featureof various pathological conditions (15,17), the findingsfrom our case series question whether this strikinghistological finding per se represents a distinctclinicopathological entity.

Most reports of normal colonic eosinophil levels inchildren have been on the basis of either rectal (18,19) ortransverse colonic biopsies (20) and may not be repre-sentative of pancolonic eosinophil density. Two previousstudies of pancolonic eosinophil density suggested that

on or intraepithelial eosinophils was determined.> 0.05 for comparison of all other results.

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marked colonic eosinophilia may be a normal finding.DeBrosse et al (7) observed a mean colonic eosino-phil density of 15 eosinophils per 0.28 mm2 HPF

number of eosinophils per high-power field with standard deviationse; DC¼descending; SC¼ sigmoid colon; Rec¼ rectum.

Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.

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DEFINING EOSINOPHILIC COLITIS IN CHILDREN 213

J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

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children with colonic eosinophilia to identify possible

JATI

(54 eosinophils per mm2) in histologically normal colonicbiopsies of children. Lowichik and Weinberg (14) founda mean colonic eosinophil count of 17 eosinophils per0.19 mm2 HPF (89 eosinophils per mm2) in postmortemtissue of asymptomatic children who died in road trafficaccidents. In our series, the mean colonic eosinophil countin children with the diagnosis of colonic eosinophilia was16 eosinophils per 0.196 mm2 HPF (82 eosinophils permm2) and 7 eosinophils per 0.196 mm2 HPF (34 eosino-phils per mm2) in biopsy series were reported as histo-logically normal. The difference between studies may bepartly attributable to geographical variation in the coloniceosinophil density of children (8).

Given the lack of a definition of normal coloniceosinophil density in children, we opted to analyseclinical and laboratory findings in relation to eosinophildensity to determine whether findings in children withmarked colonic eosinophilia (group III) are specific tothis patient group. These children presented with non-specific gastrointestinal symptoms and showed no sig-nificant difference in terms of systemic inflammatorymarkers or blood eosinophil counts at the time of endo-scopy from children with lower colonic eosinophilcounts. Furthermore, marked colonic eosinophilia wasnot associated with abnormal colonoscopic or additionalabnormal histological findings. Degranulation of eosino-phils and intraepithelial eosinophilia was significantlymore common in children with marked colonic eosino-philia, but these changes are of unknown significance.This may reflect the increased number of eosinophils orindicate pathologically increased activity.

We found no association between colonic eosinophiliaand eosinophilic oesophagitis, gastritis, or duodenitis inthose patients who had upper endoscopic series. Therewas, however, a significantly raised eosinophil density inthe ileal biopsies of children with marked colonic eosi-nophilia, perhaps a consequence of high eosinophildensity in the neighbouring caecum, akin to the phenom-enon of backwash ileitis described in ulcerative colitis.The previously reported histological finding of a gradientof decreasing eosinophil density from caecum to rectumwas found to be preserved in moderate and markedcolonic eosinophilia (7,9).

In his original article, Kaijser (3) proposed thateosinophilic colitis was an allergic phenomenon. Ourobservation that moderate and marked colonic eosino-philia was significantly associated with abnormal totalserum IgE levels supports this hypothesis. Yet, we didnot find a significant association between a history ofatopy and colonic eosinophilia, which may be expectedif colonic eosinophilia was driven by an allergicprocess.

In our study, we retrospectively followed up the sub-

214 BEH

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group of children who underwent repeat colonoscopiesafter the initial diagnosis of colonic eosinophilia. Ourdata document the various treatments used in our centre

J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

for the treatment of eosinophilic colitis, which includeeosinophil-specific agents (eg, montelukast (21)) andsystemic immunosuppression. Furthermore, the follow-up data in this subgroup of children showed no relationbetween change in eosinophil density and progression ofsymptoms, although the validity of this finding is limitedby the treatment and the small size (n¼ 6) of the sub-group. Nevertheless, the finding raises the question thatwhether there is a relation between the degree of color-ectal eosinophilia and severity of symptoms, whichshould be addressed in prospective longitudinal follow-up studies.

In summary, although the validity of our case series islimited by its retrospective design (22), our findings donot demonstrate that colonic eosinophilia necessarilyrepresents a distinct clinicopathological entity currentlytermed ‘‘eosinophilic colitis.’’ Prospective follow-up andinterventional studies are urgently required to clarifywhether colonic eosinophilia does indeed cause gastro-intestinal complaints in children, and whether the degreeof eosinophilic infiltration is a useful marker of diseaseseverity. Until such evidence from prospective studiesbecomes available, the clinical management of sympto-matic children with the sole diagnosis of colorectaleosinophilia cannot be accurately defined. We recom-mend that management of these children be based on andtargeted at symptom control, rather than at modificationof colonic eosinophilia. Moreover, it would seem appro-priate to consider further assessment of symptomatic

ET AL.

upstream mechanisms that may explain their clinicalpresentation.

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