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.
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.
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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