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Keywords:

  • Crohn's disease;
  • ulcerative colitis;
  • proton pump inhibitors;
  • antibiotic exposure

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Background:

Epidemiological and microbiological data suggest that Clostridium difficile infection (CDI) plays a substantial role in the clinical initiation of inflammatory bowel disease (IBD). The aim of the present study was to investigate the prevalence and risk factors of CDI in newly diagnosed pediatric patients with IBD.

Methods:

The current investigation was a retrospective study. All patients newly diagnosed with IBD in the pediatric gastroenterology clinic in Warsaw between 2007 and 2010 were included in the present study. The patients were diagnosed according to Porto criteria and microbiology evaluation screening tests for CDI were conducted. Risk factors including prior hospitalization, use of antibiotics within 2 months of CDI detection, colonic involvement, and the duration of symptoms were evaluated. CDI diagnosis was based on a positive stool enzyme immunoassay.

Results:

In the present study, 134 patients were evaluated (54 patients with Crohn's disease, and 80 with ulcerative colitis; 87% of the patients had colonic disease). The average age of the patients was 12.3 years, and the prevalence of CDI was 47% (95% confidence interval [CI], 38%–56%). Significant differences in the prevalence of CDI between patients with Crohn's disease and ulcerative colitis (P = 0.72; odds ratio [OR] = 1.187, 95% CI, 0.56–2.52) were not observed. The risk of CDI was associated with an increase in the age of the patient and the severity of the disease.

Conclusions:

The prevalence of CDI in newly diagnosed IBD patients was high and was independent of the type of disease. (Inflamm Bowel Dis 2011;)

The etiology of inflammatory bowel disease (IBD) is poorly understood and its natural course is characterized by unpredictable exacerbations and remissions. On the basis of genetic disposition, IBD can develop after contact with exogenic environmental factors. The unknown antigen may be an infectious agent such as bacteria or a virus.1Clostridium difficile is an anaerobic, Gram-positive, spore-forming bacillus. Toxigenic strains produce toxins A and B, which bind to intestinal epithelial cells, leading to cell death and a proinflammatory state. Infection can cause a spectrum of illnesses including asymptomatic carriage, mild diarrhea, pseudomembranous colitis, and toxic megacolon.2

Recent epidemiological studies have suggested that the prevalence of C. difficile infection (CDI) in patients with IBD is greater than that of patients in the control group.2–4 Current studies have also suggested that the rate of CDI tended to increase in patients with IBD.5, 6 According to the limited pediatric data from Europe, the incidence of CDI in non-IBD patients varies from 5.5% in Zagreb, Croatia (mixed oncology and immunocompetent patients)7 to 8.9% in Naples, Italy (patients with diarrhea, constipation, irritable bowel syndrome, food allergy).8 Data regarding pediatric patients with IBD are also limited; however, the prevalence of CDI in these patients is greater than in adults.8, 9

Although epidemiological and microbiological studies suggest that C. difficile plays a substantial role in the clinical initiation of IBD,10 the exact relationship between the clinical assessment of IBD and the presence of C. difficile in the stool remains unknown. In the general population, several risk factors for CDI have been recognized.4 The most common risk factor is recent or current antibiotic use, which alters bowel microflora and leads to a loss of colonization resistance. The risk of CDI increases when multiple antibiotics are used or the treatment period is prolonged. Another well-known risk factor is recent or prolonged hospitalization or residence in a long-term care facility.11 IBD is an independent risk factor for CDI;6 however, it is unclear why this patient population is more susceptible to infection. Nevertheless, several risk factors have been identified in adults with IBD.4 In addition to antibiotic exposure and hospitalization, ulcerative colitis (UC), colonic involvement, disease activity, immunosuppressant maintenance therapy, initiation of corticosteroid therapy, non-summer month at the time of diagnosis, and acid-suppression therapy are also risk factors. Moreover, IBD patients may be at risk for infection due to an underlying disease, malnutrition, or immunosuppressive therapy.12 Other important clinical factors include host-susceptibility and the virulence of C. difficile; however, these factors are difficult to verify.

The aim of the present study was to evaluate the prevalence of CDI and to assess previously identified risk factors for CDI in pediatric patients with newly diagnosed IBD.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

The current investigation was a retrospective study and was conducted at the Department of Gastroenterology and Nutrition, Warsaw, Poland, between 2007 and 2010. Hospital admission records of newly diagnosed pediatric IBD (up to 18 years old) patients were reviewed. Crohn's disease (CD) and UC were diagnosed based on clinical signs and symptoms as well as on endoscopic, histologic, and radiologic results. In particular, the Porto criteria were applied13 and microbiology evaluation screening tests for CDI were conducted. Potential risk factors (previously reported for adult IBD patients) for CDI were recorded, including prior hospitalization, previous antibiotic exposure, use of proton pump inhibitors within 2 months of CDI detection, colonic involvement, duration of symptoms, disease activity, signs and symptoms of the gastrointestinal tract, abdominal pain, fever, diarrhea, blood in the stool, and the season at the time of IBD diagnosis. The severity of CD and UC was evaluated by determining the Pediatric Crohn's Disease Activity Index (PCDAI) and the Pediatric Ulcerative Colitis Activity Index (PUCAI), which included symptom evaluation, physical examination, and laboratory test results. Namely, a PCDAI score ≤10 and a PUCAI score <10 for CD and UC were defined as remission, respectively.

CDI diagnosis was based on a positive stool enzyme immunoassay (C. difficile TOX A/B II, TechLab, Blacksburg, VA).

The odds ratio (OR) and confidence interval (CI) were used to measure the effect of each factor. To determine if time and therapy affected infection, McNemar's test with Yates' correction was employed. To identify significant factors affecting the risk of infection, an analysis of covariance (ANCOVA) was performed. The median was used as a location parameter and Sn was computed to determine the variability. Sn = 1.1926 × med{med|xi – xj|;j = 1n.14 Fisher's exact test was used to analyze the contingency tables and the results were considered statistically significant at P < 0.05. All data were analyzed using R v. 2.2.1 (www.r-project.org).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

In the present study 134 patients were evaluated, including 54 with CD and 80 with UC. Eight-seven percent of the patients had colonic disease and 73 were male. The average age of the patients was 12.3 years (range: 1.5–18 years).

The prevalence of CDI was 47% (95% CI, 38–56). Significant differences in the prevalence of CDI were not observed between patients with CD and UC (P = 0.72, OR = 1.187, 95% CI, 0.56–2.52).

The risk of CDI was associated with the age of the patient and the severity of the disease (Fig. 1). For patients with a disease severity index less than 35, the risk of CDI increased with an increase in age. Alternatively, the risk of CDI decreased with an increase in age when the disease severity index was greater than 35 points (Fig. 2). In patients with a disease severity index <35 points, the risk of CDI increased by 2% (OR = 1.02) as the diagnosis age increased by 1 month. A critical value of 35 points for the disease severity was statistically calculated on the basis of the Figure 1 model. Significant differences in antibiotic or proton pump inhibitor exposure, previous hospitalization, and colon involvement were not observed between IBD patients with and without CDI. The risk factors are summarized in Table 1.

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Figure 1. In newly diagnosed IBD patients, risk of CDI increased with the disease severity in children younger than 128 months of age at the IBD diagnosis time and decreased in children who were older. #Disease activity index: Pediatric Crohn's Disease Activity Index for patients with CD and Pediatric Ulcerative Colitis Activity Index for patients with UC.

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thumbnail image

Figure 2. Boxplots indicate that risk of CDI increased with age in children with a disease severity score of less than 35 points and decreased in children with a disease severity score of more than 35 points. #Disease activity index: Pediatric Crohn's Disease Activity Index for patients with CD and Pediatric Ulcerative Colitis Activity Index for patients with UC.

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Table 1. Risk Factors for Clostridium difficile Infection
 C. difficile P-value
AbsentPresentEffect Size
n% Infected95% CI
  • Sn, measure of scale based on pairwise differences; 95% CI, confidence interval with 1-α = 0.95; PPI, proton pump inhibitors.

  • a

    Disease activity index: Pediatric Crohn's Disease Activity Index for patients with Crohn's disease and Pediatric Ulcerative Colitis Activity Index for patients with ulcerative colitis.

  • b

    P-value for interaction between age at diagnosis and disease activity.

Number of Patients716347%38% – 56%
Significant factorsMedian ± SnOdds ratioCI95% 
Age (months)Disease activity indexa ≤ 35132 ± 48171 ± 331.021.002 – 1.0350.000353b
 Disease activity indexa > 35174 ± 30157 ± 360.970.936 – 0.999 
Disease activity indexaAge ≤ 128 mo25 ± 12.535 ± 121.081.005 – 1.159 
 Age > 128 mo42.5 ± 1830 ± 150.930.862 – 0.997 
Not significant factorsnOdds ratio95% CI 
Prior hospitalizationNo41420.6850.32–1.460.363
Yes3021
Previous antibiotic therapyNo55461.2680.53–3.010.688
Yes1617
PPINo69582.950.46–320.253
Yes25
Colonic involvementNo7100.5820.17–1.830.313
Yes6453

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

The results of the present study suggested that the prevalence of CDI in children recently diagnosed with IBD was nearly 50%, which is significantly higher than that of adults and children.15 Several factors could explain our results. Namely, the incidence of CDI in children is higher than in adults (26% vs. 10%, respectively).15 Moreover, the rate of CDI at initial presentation of adult IBD is greater than that of patients in relapse and varies from 15% to 31%.5, 16 As a result, high prevalence rates were observed in newly diagnosed pediatric patients with IBD. In addition, a wide variety of tests are used to diagnose CDI.8, 16, 18 Enzyme immunoassays (EIAs) that detect toxin A and B are recommended for the diagnosis of CDI. The sensitivity and specificity of different types of EIAs range from 50%–90% and 70%–95%, respectively.17 The prevalence of CDI in children may be higher because feco-oral ingestion of spores is more common in children than adults.15 Finally, geographical variations are also important. Single-center studies conducted in the United States and India demonstrated that the rate of CDI in relapsing UC patients was 15% and 32%, respectively.18, 19 The higher prevalence of CDI in newly diagnosed IBD patients compared to those observed during the course of the disease suggests that dysbiosis due to CDI plays an essential role in the pathogenesis of IBD.

In the present study the risk of infection in UC and CD patients was identical. This result is in accordance with those of previous studies conducted on children;8, 9 however, in studies performed on adults CDI was more common in patients with UC.5, 15 Children are more likely than adults to have colonic CD; thus, in the present study nearly 70% of patients with CD had colonic involvement. Because the prevalence of CDI is higher in children than adults, the predilection of C. difficile in the colon was confirmed.

In children with IBD the association between common risk factors previously reported in adults (disease severity, previous hospitalization, antibiotic and proton pump inhibitors exposure, and colonic involvement) and CDI was evaluated. The only risk factor that affected the prevalence of CDI was the interaction between the age at the time of diagnosis and the severity of disease. Young children with high severity scores had the highest risk of CDI because pediatric-onset IBD is more likely to display a severe course.20 The results of the present study are in line with the findings of most studies conducted on children8, 9 and adults.4 In the general population, exposure to a healthcare environment, including recent hospitalization, increases the risk of CDI; however, this effect was not observed in IBD patients.2 Moreover, a statistically significant association between previous hospitalization and risk of CDI was not observed in the present study. Our results are similar to those of a previous pediatric study that compared CDI in children with and without IBD.8 In the aforementioned study, risk factors for recurrent CDI were evaluated and the results suggested that patients in the control group were admitted to the hospital prior to infection more frequently than patients with IBD.21 These results further support the theory that patients with IBD are more likely to develop a community-acquired CDI than the general population, for which infections are predominantly nosocomial.6, 10 In the general population, previous antibiotic exposure is a key risk factor for the acquisition and development of CDI. Antibiotic use may increase the risk of CDI by disrupting normal intestinal flora, allowing the proliferation of C. difficile, a more resistant organism. However, in patients with IBD the contribution of antibiotic use to the development of CDI was minimal.15 In the present study, statistically significant differences in previous antibiotic use were not observed between IBD patients with and without CDI (26% vs. 22% respectively, OR = 1.268, 95% CI, 0.53–3.01). These results confirm previous pediatric data.8, 21 Other potential offending drugs include proton pump inhibitors. However, recent studies on CDI in the pediatric8, 21 and adult22 IBD population did not confirm this association. Our results are consistent with those described in the literature. Similar to the results of a previous pediatric study,21 colonic involvement was not a risk factor for CDI in the present study. In adults, the rate of CDI in patients with UC and colonic CD was greater than that of patients with isolated small bowel manifestations of the disease.15, 24 Our findings may be attributed to the fact that the majority of pediatric patients with CD have colon disease.

To the best of our knowledge, this is the first study to specifically address the prevalence of CDI in children with new-onset IBD. In studies conducted by Kelsen et al21 and Pascarella et al,8, 9 the prevalence of CDI in patients recently diagnosed with IBD was 44% and 32%, respectively; however, subanalyses were not performed in the aforementioned investigations. Although only a few studies have been conducted to assess the prevalence of CDI in the IBD pediatric population, the results suggest that the prevalence of CDI is much higher in children than in adults and may play a crucial role in the course and etiology of the disease.8, 9, 21 Therefore, prospective studies evaluating the role of CDI in IBD patients must be conducted.

The main advantage of the present study is that the patients were homogenous. Moreover, patients were not excluded from the study, and all newly diagnosed patients were analyzed. Because patients were assessed at the initial presentation of IBD, the relationship between CDI and IBD therapy could not be evaluated. Immunosuppressants are suspected to increase the risk of CDI;5 however, this result has not been confirmed.23, 24 The most significant shortcoming of the present study is the retrospective design.

Although the amount of data on the prevalence and impact of CDI in patients with IBD has increased, several issues remain unclear. Most studies on CDI and IBD are retrospective; thus, the data are not complete. Moreover, controlled therapeutic trials on initial and recurrent CDI in patients with IBD have not yet been conducted.

CONCLUSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

In conclusion, the results of the present study demonstrated that the prevalence of CDI in new-onset pediatric IBD patients was high. In this study the only risk factors for CDI were the age of the patient and the severity of disease at the time of IBD diagnosis.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES