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Clinical Significance of Eosinophilia and Chronic Inflammatory Infiltrate in Children's Rectal Biopsies

Pacilli, Maurizio*; Eaton, Simon; Clarke, Alessandra*; Whitehead, Anita; Nagy, Anita; Brain, Jeffrey L.*

Journal of Pediatric Gastroenterology & Nutrition: November 2012 - Volume 55 - Issue 5 - p 519–522
doi: 10.1097/MPG.0b013e31825b3169
Original Articles: Gastroenterology

Aims: The aim of the present study was to determine the clinical significance of an incidental finding of eosinophilia (EOS) and chronic inflammatory infiltrate (CINF) in rectal biopsies of children investigated for suspected Hirschsprung disease (HSCR).

Methods: A retrospective study (2000–2010) of children incidentally found to have EOS and CINF was performed. HSCR cases were excluded. Presence of gastrointestinal (GI) symptoms and nutritional status (weight-for-age z score) were investigated and compared with a matched cohort with normal biopsy.

Results: Of 364 children undergoing rectal biopsy for suspected HSCR, 109 had confirmed HSCR, whereas 255 children had normal ganglia. Forty-four of 255 (17%) children had EOS and/or CINF incidentally reported and are the subject of the present study. In 13 of 44 (29%) children, the biopsy was performed neonatally. At follow-up (4.6 months [1–22]), 21 (48%) had food and/or milk allergy, 30 (68%) had constipation and/or other GI symptoms. There was no change in weight-for-age z score (P = 0.85) at follow-up and 8 (20%) had failure to thrive. Only 10 of 44 (P = 0.0001 vs patients with EOS and/or CINF) children with normal biopsy had persistent constipation at follow-up (9.7 months [0.5–84.7]) and 1 patient had atopy. Patients with normal biopsy exhibited an increase in weight-for-age z score at follow-up (P = 0.003) and only 3 patients (7%) had failure to thrive.

Conclusions: EOS and CINF are found in 17% of children who had rectal biopsies negative for HSCR. Half of these children will need further medical input for the presence of persisting GI symptoms, food/milk allergy and failure to thrive, and the possibility to develop inflammatory bowel disease later in life.

*Paediatric Surgery Unit, Cambridge University Hospital, Cambridge

Department of Surgery, UCL Institute of Child Health, London

Department of Histopathology, Cambridge University Hospital, Cambridge, UK.

Address correspondence and reprint requests to Maurizio Pacilli, MD, MRCS (Eng.), Paediatric Surgery Unit, Box 267, Cambridge University Hospital, Hills Rd, Cambridge CB2 0QQ, UK (e-mail:

Received 22 August, 2011

Accepted 18 April, 2012

The authors report no conflicts of interest.

In our surgical unit, we observed that the presence of eosinophilia (EOS) and chronic inflammatory infiltrate (CINF) is incidentally reported in rectal biopsies of children investigated for suspected Hirschsprung disease (HSCR), although the relevance of these findings is not clear. In the present study, we aimed to correlate the clinical symptoms with the incidental findings of EOS and CINF. There has been an increasing interest in defining the role of inflammatory infiltrate in GI disorders, both in adults and children, and inflammatory infiltrates, consisting of eosinophils and plasma cells, have been most commonly described in association with malignancy, infection, allergic disease, and intestinal pseudo-obstruction (1), but there is scanty information in children. Eosinophilic gastroenteritis was first described by Kaijser in 1937 (2) and since then several studies have focused on the distribution and significance of the eosinophils in the paediatric gastrointestinal (GI) tract. Recent studies (3–5) have documented an increasing prevalence of eosinophil-associated GI disorders parallel to the increased prevalence of allergic disorders (6). Allergy can cause inflammation of the rectal wall and the resulting eosinophilic infiltration leads to changes in the mucus composition, dysmotility, and ultimately to constipation (7). Cow's-milk protein allergy particularly has been associated with inflammation of the rectal mucosa and chronic constipation in children (8,9). DeBrosse et al (10) noticed that patients with a history of atopy have a trend towards greater eosinophilic infiltrates in the colon compared with those without history of atopy. Eosinophils infiltrating the intestinal surface and crypt epithelium have also been observed in inflammatory bowel disease, although the real implication is still unclear (11,12). In our unit, EOS and CINF have been incidentally reported by the pathologists in rectal biopsies of children investigated for HSCR in the neonatal period or in older children with chronic constipation. The significance of these findings is unknown and there are no studies that have evaluated whether further management is required. Our aim was to evaluate whether the incidental findings of EOS and CINF in rectal biopsies of children require further management.

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Following approval by the Cambridge University Hospital research ethics committee, a retrospective study of 364 children that underwent rectal biopsy for suspected HSCR (either for failure of passage of meconium in the neonatal period or for chronic constipation), between 2000 and 2010, was performed. Biopsies were either taken with a “suction” technique (rbi2 Aus Systems Pty Ltd, Allenby Gardens, Australia) in children younger than 3 months or via an open (full thickness) technique under general anaesthesia in older children. The suction biopsies were confirmed to have mucosa and submucosa to be comparable with the open (full thickness) biopsies. The biopsies were stained with haematoxylin and eosin and no specific neuronal or lymphocyte staining was performed. Histological findings were reviewed in all of the patients, who were then divided into 3 groups: patients with no ganglia (confirmed HSCR); patients with normal ganglia but with EOS and/or CINF (EOS/CINF group); patients with normal biopsy (normal ganglia and no EOS or CINF).

Children were followed up either in the surgical clinic or paediatric gastroenterology clinic. Patients’ characteristics and weight were reviewed from inpatient and outpatient records. All of the patients had weight measured by standard balance scales and recorded at the time of biopsy and at follow-up. To identify those children with failure to thrive, weight standard deviation scores (weight z score) were calculated for each individual patient and were derived using British 1990 standards (13). Incidence of GI symptoms (ie, constipation, diarrhoea, recurrent abdominal pain), and incidence of food/milk allergy were reviewed. Data, reported as median (range) and mean ± standard error mean, were compared by Fisher exact test, Mann-Whitney test, and paired t test.

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A total of 364 children underwent rectal biopsy and 109 (41%) were confirmed to have HSCR (Fig. 1). The remaining 255 children were found to have normal ganglion cells.

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Patients With EOS/CINF

Forty-four (17%) of the 255 had EOS or CINF (Fig. 1, Table 1); 3 patients had mixed eosinophilia and CINF. There were 24 boys (54%). The biopsy was carried out in the neonatal period for delayed passage of meconium and intestinal obstruction in 13 (29%) children. The remaining 31 children underwent rectal biopsy at a median of 21 months (2–145) for chronic constipation. In 18 (64%) children with EOS and 12 (75%) children with CINF, there was delayed passage of meconium for >24 hours (P = 0.5). The inflammatory infiltrate (Fig. 2A and B) was found in different sites (Table 2) including lamina propria, crypt epithelium, and submucosa. The median number of cells per high-power field (HPF) was 8 (4–15). Age at biopsy was significantly lower in children with EOS compared to children with CINF (P = 0.009). Follow-up was similar between the 2 groups (P = 0.6). Twenty-one (48%) were found to have food and/or milk allergy and 30 (68%) had persistent constipation and/or other GI symptoms at follow-up. Only 3 patients of the 13 that had the biopsy taken in the neonatal period continued to have constipation at follow-up (P = 0.0001 vs older children). At biopsy, patients with EOS or CINF had impaired growth, with a weight-for-age z score of −0.68 ± 0.25; 7 patients (18%) had failure to thrive (ie, a weight-for-age z score ≤−2.0) at biopsy. There was no significant catch-up growth (ie, increase in weight-for-age z score; Fig. 3) at follow-up (P = 0.8), and 8 (21%) had failure to thrive.

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Patients With Normal Biopsy

From the 211 children with normal biopsies, 44 were selected, matching for age and weight at biopsy and for sex with the 44 patients with EOS and CINF. Ten of these 44 children had persisting constipation at follow-up (P = 0.0001 vs patients with EOS/CINF) and only 1 patient was found to have atopy (P < 0.0001 vs patients with EOS/CINF). Four patients with persisting constipation were referred for psychological input because of associated behavioural problems. Growth was impaired at the time of biopsy, with a weight-for-age z score of −0.70 ± 0.25; 7 patients (18%) had failure to thrive, similar to those with EOS of CINF. However, in patients with normal biopsy, was significant catch-up growth, demonstrated by an increase in the weight-for-age z score at follow-up (P = 0.003), with only 3 patients (7%) continuing to have failure to thrive (Fig. 4).

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We have observed that in our unit the findings of EOS and CINF are incidentally reported by the pathologists in rectal biopsy of children investigated for HSCR, either in the neonatal period for failed passage of meconium or in infancy for chronic constipation. Nonetheless, the clinical relevance of these findings is not clear. Eosinophilic infiltrates have been found in association with different GI conditions, including eosinophilic gastroenteritis, coeliac disease, inflammatory bowel diseases, drug-induced colitis, acute GI radiation injury, eosinophilic cryptitis, and autoimmune disorders (14,15,17,18). Furthermore, the presence of an eosinophilic infiltrate is common in biopsies taken from caecum and ascending colon (14–16), but there has been no study to document whether these findings in rectal biopsies of children require further management. We found a specific distribution of inflammatory infiltrates with eosinophils predominantly localised in the mucosa and the CINF mainly localised in the lamina propria. The implication of this finding is not clear, but it has been well documented that in normal subjects, eosinophils are present only in the lamina propria of the stomach, small intestine, caecum, and colon (4) but not in the mucosa; however, eosinophilic infiltration of the colonic mucosa, lamina propria, and muscularis is demonstrated in allergic proctocolitis in children (19). Eosinophils are also known to extend into submucosa in cow's-milk protein allergy, whereas lymphocytes extend into submucosa in ulcerative colitis and Crohn disease; however, in less severe conditions they may be confined to the mucosa. The presence of eosinophils in the surface and crypt epithelium has also been observed in inflammatory bowel disease (12) and focal eosinophilic infiltration in Crohn disease is an important parameter in the histological differentiation between colonic Crohn disease and ulcerative colitis. None of our patients was diagnosed with inflammatory bowel disease and this could be due to the young age of our population (median of 5.3 months) and the relative short follow-up period (median of 4.6 months), but we suggest that these children are possibly at risk for developing inflammatory bowel disease later in life and should be closely monitored. Another controversial issue is the number of inflammatory cells that should be present in normal subjects and, although we found a median of 6 cells per HPF, there is lack of consensus regarding the number of inflammatory cells to define EOS, and geographic variations in the number of eosinophils in the GI tract have also been described (20). Large numbers of eosinophils located in the muscularis mucosae or in crypt abscesses have been found to be significantly associated with allergy-related disease (25); however, Behjati et al (21) found no correlation between the change in number of colonic eosinophils and clinical symptoms. Similarly, other authors (12) found no correlation between total blood eosinophilic count, positivity of allergy tests, allergic history, and number of eosinophils in the biopsies. These authors concluded that in children with irritable bowel syndrome and patients with a variety of other diagnoses, including allergies, the distribution is mostly superficial, with a lower total cellularity.

Our study documents a significant incidence of GI symptoms at follow-up (68%) when compared with those with a normal biopsy (P = 0.0001). Similarly, Behjati et al (21) also reported a high incidence of GI symptoms, such as recurrent abdominal pain (50%), diarrhoea (30%), and constipation (20%), in children with eosinophilic colitis. The precise mechanism that could lead to constipation in children with eosinophilia is not clear, but it has been suggested that eosinophils interfere with the GI motility (22) and possibly have negative effects on the myenteric ganglion cells (23). There is also evidence that mast cells and eosinophils are key cells in the development of dysmotility, by mediating their action through release of potent granule constituents (24). We also found a high incidence of food/milk allergy when compared with the group with normal biopsy. Kaijser (2) initially proposed that the eosinophilic colitis was an allergic phenomenon, and other authors (21) have found an abnormal serum IgE levels in these patients but failed to find a significant association with a history of atopy. Because of the retrospective nature of our study, we do not have serum IgE levels data. Interestingly, we found that there was no significant change in the weight-for-age z score at follow-up (P = 0.8), and 8 (20%) patients had persistent failure to thrive (ie, a weight-for-age z score ≤−2.0). In contrast, in the group of patients with normal biopsies, there was significant catch-up growth, demonstrated by a change in the weight-for-age z score at follow-up (P = 0.003) with only 3 patients (7%) with failure to thrive.

The significance of the CINF is less clear and to the best of our knowledge, there are no studies that have investigated this histological finding in rectal biopsy of children. Interestingly, we found that patients with CINF were significantly older than patients with eosinophilia. It may be that patients with eosinophilia could subsequently develop a chronic inflammatory status because we found 3 patients with a combination of these histological findings.

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Our study demonstrates that EOS and/or CINF are found in 17% of children who undergo rectal biopsy to exclude HSCR. A significant number of these children (48%) will need further medical input for the presence of persisting GI symptoms, food/milk allergy, and failure to thrive and the possibility of developing inflammatory bowel disease later in life. Our findings indicate that children with EOS and CINF on rectal biopsy should be followed up by a specialist paediatrician for further management.

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constipation; eosinophilia; food allergy; rectal biopsy

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