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Clinical Features and Treatment Responses in Pediatric Lymphocytic and Collagenous Colitis

Narla, Nirmala P.*; Smyrk, Thomas C.; Pardi, Darrell S.; Tung, Jeanne§

Journal of Pediatric Gastroenterology and Nutrition: November 2013 - Volume 57 - Issue 5 - p 557–561
doi: 10.1097/MPG.0b013e3182a1df59
Original Articles: Gastroenterology

Objective: Microscopic colitis (MC) is prevalent in adults investigated for chronic watery diarrhea, yet characterization of pediatric MC is limited.

Methods: Our pathology database was searched from 1995 to 2011 for pediatric cases of lymphocytic colitis (LC) or collagenous colitis (CC). Those with diarrhea persisting for >2 weeks and visually normal colonoscopy were accepted as cases. Demographics, laboratory results, medication use within 3 months of presentation, medical and family history of autoimmune disease, and response to treatment were abstracted.

Results: A total of 27 cases were histologically consistent with MC on biopsy; 5 with concomitant enteric infection or isolated abdominal pain were excluded. Twenty-two cases of MC (female patients, 59%; median age at diagnosis, 15.3 years) were included (19 LC and 3 CC). Two had type 1 diabetes mellitus, 2 were anti-nuclear antibody positive, and 2 had common variable immunodeficiency. Of 20 patients who underwent an esophagogastroduodenoscopy, 1 had collagenous sprue and 4 had celiac disease. One presented after the clearance of recurrent Clostridium difficile infection. Previous drug exposures included nonsteroidal anti-inflammatory drugs (n = 7), proton pump inhibitors (n = 6), and selective serotonin reuptake inhibitors (n = 3). Common symptoms in addition to diarrhea included abdominal pain (77.3%) and weight loss (27.3%). Of 17 patients with follow-up, all of the 8 treated with steroids had some response: 57.1% (4/7) responded to mesalamine and 42.9% (3/7) responded to bismuth subsalicylate.

Conclusions: In this cohort of pediatric patients, LC was much more common than CC. As described in adults, we observed associations with celiac disease, type 1 diabetes mellitus, and medications; we additionally saw an association with immunodeficiency. Our patients showed greater response to steroids than mesalamine or bismuth.

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*Mayo Medical School

Department of Anatomic Pathology and Laboratory Medicine

Division of Gastroenterology and Hepatology

§Division of Pediatric Gastroenterology and Hepatology Mayo Clinic, Rochester, MN.

Address correspondence and reprint requests to Jeanne Tung, MD, Division of Pediatric Gastroenterology & Hepatology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905 (e-mail:

Received 16 June, 2013

Accepted 18 June, 2013

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

The authors report no conflicts of interest.

Microscopic colitis (MC) is an inflammatory condition of the colon, marked by chronic or intermittent watery diarrhea with a normal endoscopic appearance (1). Once regarded as a rare diagnosis, population-based studies in adults suggest a prevalence of 4% to 13% in patients investigated for chronic diarrhea (2,3). MC has traditionally been subdivided into lymphocytic (>20 intraepithelial lymphocytes per 100 colonocytes with mixed inflammation of the lamina propria and normal crypt architecture) and collagenous colitis (thickened subepithelial collagen band in addition to the inflammatory changes seen in LC) (4,5). MC affects adults of any age, although it is much more common in older adults, with a mean age of 60.7 years in recent large-center studies (6,7).

Although the etiology of MC is unclear, it has been associated with autoimmune disorders (including celiac disease, type 1 diabetes mellitus (DM), thyroiditis, rheumatoid arthritis, fibromyalgia, and CREST syndrome), immunodeficiency, infections, and medications (4–13). Medications associated with MC include nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, proton pump inhibitors (PPIs), ranitidine, selective serotonin reuptake inhibitors (SSRIs), ticlopidine, acarbose, and statins (1,4,7,12,13). Some studies suggest a female preponderance, with a female to male ratio ranging from 2.4:1 to 6:1 (1,3,6,7).

The pediatric prevalence of MC is unknown. Most reports are single-case descriptions (8,10,11,14–16), or case series of 3 to 7 children (ages 2–16 years) with diarrhea and colonic intraepithelial lymphocytosis in the absence of other organic disease (4,9,17). The youngest reported case is 2 years of age (9). Causes and associations of MC in the pediatric population are less clear, in part because of the relative paucity of cases in this age group. Possible etiologies postulated in previous reports of pediatric lymphocytic colitis include PPIs, immunodeficiency, celiac disease, and carbamazepine (4,8,9,11). In fact, the association of celiac disease with lymphocytic colitis has been well described in children and adults, with a reported prevalence of LC in patients with celiac disease ranging from 2% to 15% (6,18). A few cases of reported collagenous colitis in children have further suggested an association with Crohn disease, eosinophilic gastroenteritis, and juvenile scleroderma (10,14,15).

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This descriptive study was approved by the Mayo Clinic institutional review board. The Mayo Clinic pathology database was searched for pediatric colon biopsies given a diagnosis of “lymphocytic,” “collagenous,” or “microscopic” colitis between January 1, 1995 and December 31, 2011. Of 2381 colonoscopies performed with biopsies, 27 patient charts meeting inclusion criteria (1.1%) were formally reviewed. Pediatric patients were defined as younger than 18 years of age at the time of colonoscopy. Patients were included if they had diarrhea persisting for >2 weeks, visually normal colonoscopy, and histopathologic examination showing typical features of MC. Cases were excluded if there was an active enteric infection. The histopathologic diagnosis of LC was defined as >20 intraepithelial lymphocytes (IELs) per 100 colonocytes with a mixed inflammatory infiltrate in the lamina propria, and CC was defined as a subepithelial collagen band thickened to >10 μm, in addition to the inflammation seen in LC.

Data abstracted included demographics, clinical presentation, endoscopy and histology reports, laboratory results (hemoglobin, albumin, autoimmune and inflammatory markers, and stool tests for enteric pathogens), recent medications (within 3 months of symptom onset), underlying diagnoses, family history of gastrointestinal or autoimmune diseases, and treatment courses/responses.

All original hematoxylin and eosin–stained slides were reviewed by a single pathologist with expertise in gastrointestinal pathology in general and MC in particular. In addition, immunohistochemistry for CD3 was performed to highlight T cells on all biopsy specimens. The number of IEL in surface and crypt epithelium was recorded, along with the thickness of subepithelial collagen and a semiquantitative assessment of lamina propria lymphocytes, neutrophils, and eosinophils (0 = none; 1 = sparse; 2 = moderately dense; 3 = markedly increased). If concomitant biopsies of the stomach and duodenum were obtained, these were also reviewed for the evidence of celiac disease and collagenous gastritis.

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Colon biopsies of 27 patients were consistent with LC. Clinical review showed that 1 patient had Crohn disease, 1 had culture-positive Salmonella infection, and 3 presented with isolated abdominal pain only; these 5 patients were excluded. Twenty-two children fulfilled criteria (LC 19, CC 3), of whom 13 (59%) were girls. The median age at diagnosis was 15.3 years (range 2.0–17.8 years). The median follow-up time was 9.1 months (range 0.1–86.8 months). Patient characteristics are summarized in Table 1 (an expanded version with additional detail can be found at



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Clinical Presentation

In addition to chronic diarrhea, 17 patients (77.3%) had abdominal pain. Six patients (27.3%) lost weight, 3 (13.6%) had nausea, and 2 (9.0%) had vomiting. Of those with weight loss, 2 (33.3%) had celiac disease. The mean stool frequency was 4.5/day (range 2.5–11), and the median duration of symptoms at the time of diagnosis was 2.1 years (range 0.1–11.6). Patients self-reported diarrhea to be either “loose” (50%) or “watery” (50%). Four children (18.2%) reported nocturnal stools, and 5 (22.6%) described urgency. One child (4.5%) had bloody stools, which was attributed to hypertrophied papillae from straining with his diarrhea.

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Medical and Family History

Two patients (9%) had type 1 DM and 2 patients (9%) had common variable immunodeficiency. Of 20 patients who underwent an esophagogastroduodenoscopy with small bowel biopsy, 4 had celiac disease; 2 patients with known celiac disease presented in histologic remission. Two patients presented after clearance of an enteric infection: one after recurrent Clostridium difficile infection and the other after resolved Campylobacter jejuni. One patient had a diagnosis of hypothyroidism. Within 3 months of symptom onset, 7 patients (32%) had been taking nonsteroidal anti-inflammatory drugs, 6 patients (27%) were taking proton pump inhibitors for presumed gastroesophageal reflux, and 3 patients (14%) were taking SSRIs for either depression or anxiety (Table 1).

Detailed records of family history with respect to gastrointestinal and autoimmune diseases were available for 18 patients. Six patients (33%) had a family history of inflammatory bowel disease, and 1 (6%) had a family history of celiac disease. There was a family history of rheumatoid arthritis in 5 patients (28%), thyroid disease in 4 (22%), asthma in 1 (6%), systemic lupus erythematosus in 3 (17%), type 1 DM in 1 (6%), and mixed connective tissue disease in 1 patient (6%).

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Endoscopy and Laboratory Work

Nineteen patients had the typical picture of LC (Fig. 1) and 3 were consistent with CC, with a thickened collagen band ranging from 15 to 30 μm (Fig. 2). The mean number of surface IELs was 37.9 (range 20–100) per 100 colonocytes, and mean number of crypt IELs was 12.2 (range 2–40) per 100 crypt cells, by hematoxylin and eosin stain.





Of 20 patients with initial blood work available, 1 had anemia (hemoglobin 11.2 g/dL) and hypoalbuminemia (albumin 2.6 g/dL); the rest had values within the normal limits. Erythrocyte sedimentation rate was measured in 18 patients, and was within normal limits in all. Of 9 patients with a C-reactive protein drawn, 1 with type 1 DM had a slightly elevated level (15.5 mg/L, normal 8 mg/L) and the others were normal. Other autoimmune markers were assessed in 8 patients. Two patients were anti-nuclear antibody positive, and one of them was also positive for human leukocyte antigen-B27.

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Management Responses

Of 17 patients with available follow-up, 9 patients (52.9%) were given oral corticosteroids. Five patients were treated with oral prednisone (5–40 mg daily, average dose 0.55 mg · kg−1 · day−1) for a mean duration of 4.7 months (range 2–13 months), whereas 4 were treated with budesonide (3 mg capsules either daily or TID, or swallowed Pulmicort 1 μg daily) for a mean duration of 3.7 months (range 2–6 months). Four patients (44.4%) achieved remission with complete resolution of diarrhea, whereas 4 (44.4%) achieved partial response after 8 weeks.

Eight patients (47.1%) were treated with oral mesalamine (dose 30–50 mg · kg−1 · day−1) for a mean duration of 18.7 weeks (range 2–72 weeks). Three patients (37.5%) had complete response, 1 had partial response, and 3 had no response to the treatment course. Seven patients (39%) were treated with bismuth subsalicylate (1 tablet 3 times per day) for a mean duration of 6.8 weeks (range 2–13 weeks), of which 2 (29%) had a complete response, 1(14%) had partial response, and 4 (57%) had no response.

Other treatment trials included loperamide (n = 5) for symptomatic relief, with either partial or no response. One patient with minimal response to previous treatments showed some improvement with an 8-week course of oral azathioprine (1.44 mg · kg−1 · day−1). The patient's diarrhea resolved by 8 weeks, with a gradual return to 3 to 4 daily stools at 8 months while taking maintenance azathioprine. Another patient with CVID, celiac sprue, and type 1 DM, receiving intravenous Ig (20–30 mg every 3 weeks), insulin, and a strict gluten-restricted diet, proved difficult to manage medically, with frequent relapses. Interestingly, she had partial response to treatment with subcutaneous octreotide (150–300 μg/daily) after 2 months.

Complete resolution of symptoms was achieved in 2 patients. One patient with CC and collagenous sprue treated with oral corticosteroids for 11 weeks and following a gluten-free diet achieved histologic remission of both on repeat biopsies after 1.3 years; she subsequently remained asymptomatic through 2.5 years of follow-up. Another patient with LC treated with both budesonide and mesalamine for 6 weeks had complete resolution of diarrheal symptoms for the duration of the course, although longer follow-up data are missing. Relapse was otherwise common after treatment cessation, with no significant distinction in rates between patients with lymphocytic versus collagenous colitis.

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In this report, we describe the clinical features and clinicopathologic associations of MC in a cohort of 22 symptomatic pediatric patients. Because MC is typically a disease of older age groups, the pediatric literature remains limited. To our knowledge, this is the largest single-center cohort of pediatric patients with MC to date. As described in adults with MC, we observed associations with infections, medications, and comorbid conditions including celiac disease and type I DM. In the pediatric population, we also saw an association between lymphocytic colitis and CVID.

In our pediatric cohort, LC was more common than CC, as reported in several adult population-based studies (3,7). We show a slight female predominance with a ratio of 3:2, which is lower than what is described for both CC (7:1) and LC (2.4–2.7:1) in most adult reports (3,6,19,20).

Although the etiology of MC remains unknown, an autoimmune mechanism is a common theory (21,22). This rationale is related to the female predominance, frequently reported co-occurrence of other autoimmune diseases, and response to steroid therapy (22,23). In our pediatric cohort, the female to male ratio was not as high as described in adult population-based studies, but we did observe associations with celiac disease (18.2%) and type 1 DM (9.1%). In a case series of 7 children with CC from 3 institutions, Liu et al (17) reported 2 cases of concomitant celiac disease; however, this was not a population-based study, making it difficult to estimate the true prevalence of celiac disease or compare with rates in adults.

Furthermore, we observed 12 of 22 (55%) patients had a family history of autoimmune disease; however, given the retrospective nature of our study design, we are unable to clarify whether “thyroid disease” as reported was truly autoimmune thyroiditis. We also describe associations with a family history of inflammatory bowel disease (IBD) (27.3%) and RA (22.7%), which may further suggest a link between MC and other inflammatory conditions. The retrospective nature of our study precludes examination for human leukocyte antigen associations and other specific inflammatory markers. Our laboratory evaluations do not suggest that erythrocyte sedimentation rate or C-reactive protein would be useful markers in pediatric patients with MC.

A few of our cases showed slightly increased eosinophils in the lamina propria, but that phenomenon has been well described as a feature of MC, particularly CC (24). The youngest patient (age 2 years) diagnosed as having LC in our cohort was also found to have cryptitis. Cryptitis has been commonly described in adult patients with MC (34% in 1 large series), so the paucity of cryptitis in our children may actually be of more interest than its appearance in 1 patient (25).

Routine laboratory work in adult patients with MC is typically normal. Similarly, we reported laboratory abnormalities in only 1 patient with a diagnosis of CC, who had anemia and hypoalbuminemia with no other comorbidities, including celiac sprue. Two patients with LC also had a positive anti-nuclear antibody, a nonspecific autoimmune marker that has been reported in the adult literature (21); however, neither patient had a defined rheumatologic condition.

In adult MC, treatment of mild symptoms includes loperamide and diphenoxylate/atropine. Treatment of more significant symptoms includes bismuth and cholestyramine. Corticosteroids are commonly used for severe or refractory symptoms, and immunomodulators are suggested for corticosteroid-refractory disease (26); however, knowledge of treatment responses in children is limited. Although budesonide is presently the best-studied treatment for MC in adults, with assessment in 5 randomized, placebo-controlled studies, there are no controlled studies or large series in the pediatric population (13,21). The substantial proportion of children in our study was treated with steroids (9/17), 8 of which had follow-up data. Of those 8 children, 4 (44%) had a complete response and 4 (44%) had a partial response.

Two patients had a complete response to budesonide, whereas 1 had a partial response. This is consistent with case reports suggesting excellent response to oral budesonide in children (22). Our study showed a similar response to prednisone, with 2 patients achieving complete response and 3 achieving partial response. Sustained remission (for >2 years following discontinuation of therapy) was achieved in 1 patient treated with 11 weeks of budesonide, despite high relapse rates upon discontinuation as reported in adult randomized, double-blind, placebo-controlled trials (13); however, a recent population-based case series of adult MC patients treated with corticosteroids by Gentile et al (21) indicates that those treated with budesonide may in fact have a higher response rate and lower risk of recurrence than those treated with prednisone (hazard ratio 0.38). Similarly, a Cochrane review of 10 adult randomized clinical trials for MC concluded that budesonide is effective and well tolerated in inducing a response in both CC and LC and effective in maintenance in CC. The evidence for prednisolone, bismuth subsalicylate, and mesalamine, however, is weaker (27).

In our study, 42.7% of patients failed treatment with mesalamines. This is in contrast to another pediatric MC cohort of 11 children, in which all 5 patients treated with oral mesalamine preparations had complete resolution of symptoms (4). Mesalamine is sometimes used in adults, but several large case series in both LC and CC showed disappointing results, and a recent controlled trial in adult patients with CC showed no benefit of mesalamine over placebo (1,28).

Finally, we also observed histologic evidence of MC in patients with isolated abdominal pain. Liu et al (17) described 2 pediatric cases of CC presenting as isolated abdominal pain and weight loss. These patients with histologic features of MC but no diarrhea were not included in our results because it is presently unclear whether this represents a nonspecific histologic finding, for example, related to postinfectious changes, or whether MC in children may in fact cause abdominal pain without diarrhea. Several other conditions are characterized by abnormal histology without macroscopic lesions, including spirochetosis and other infections, and inactive IBD (19). T cells have also been observed in rectal biopsies from patients following acute C jejuni enteritis and in postdysenteric irritable bowel syndrome (19,23). Further analysis indicated that our patients with abdominal pain only had partial response to mesalamine, as reported in other pediatric cases of conventional MC (4). Although many studies indicate abdominal pain as a commonly associated adjunct symptom in MC, atypical presentations with normal bowel movement may not exclude the possibility of MC in pediatric patients. This important question deserves additional study.

The retrospective nature of our study is an important limitation. Loss to follow-up made it difficult to assess long-term treatment outcomes in some patients, and may have precluded analysis of comorbid conditions that take longer to become apparent.

In summary, our study demonstrates that, although extremely uncommon, MC should be considered in children with chronic diarrhea, after appropriate investigation for more common conditions such as dietary factors, enteric infections, celiac disease, and IBD has been unrevealing. In these patients, biopsies should be obtained even when the colon is endoscopically normal. For patients with more severe symptoms, corticosteroids may be considered. Because of lower risk of steroid-related adverse effects, budesonide is favored over prednisone. Compared with mesalamine, steroids are associated with a higher response rate. Large, multicenter pediatric studies are needed to better elucidate treatment responses and generate standardized treatment algorithms in pediatric MC.

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chronic diarrhea; collagenous colitis; lymphocytic colitis; microscopic colitis; pediatric

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