During the past decade the incidence of Clostridium difficile infection and associated disease (CDAD) has increased (1). C difficile is an anaerobic, Gram-positive spore-forming bacillus responsible for a spectrum of diseases. Morbidity from infection ranges from diarrhea to life-threatening pseudomembraneous colitis. Although C difficile colonizes the colon, it is not invasive, and tissue injury and inflammation are mediated by exotoxins (toxin A and toxin B) generated by the bacteria. A number of CDAD outbreaks since 2003 have been associated with the emergence of a more virulent strain that exhibits increased production of toxin A and/or B, and a third binary toxin (2).
Although therapeutic use of antitoxin antibodies appears promising (3), usual treatment involves the use of vancomycin or metronidazole, although failure of both antibiotics has been reported. Recurrence of CDAD in patients treated with medications is common, as is failure to treat the infection. Kelly and LaMont (1) have recently reviewed data from several studies that took place before and after 2000 and demonstrated a decrease in the effectiveness of metronidazole to treat CDAD in the general population. Although the frequency of treatment failure with vancomycin remained relatively unchanged (3.5% vs 2.8%), the frequency of failure with metronidazole increased markedly (2.5% vs 18.2%). Recurrence of CDAD was similar after either metronidazole or vancomycin therapy (28.6% vs 19.9%).
The risk factors associated with CDAD include recent antibiotic therapy, prolonged hospitalization, advanced age, and immunosuppression (2). A mainstay of treatment for inflammatory bowel disease (IBD) is immunosuppressive therapy, and effective management can require long or frequent hospitalizations to manage problems associated with IBD. Recent studies have shown both an increased incidence and increased morbidity of CDAD in the adult IBD population compared with adults without IBD and increased frequency of carrier status (4–7). There is reason to believe that there is increased risk for CDAD among children with IBD, although this contention is supported by a single study at a pediatric IBD center in Italy (8). Our aim was to estimate the incidence of CDAD in a pediatric IBD population in the United States and to review antimicrobial treatment efficacy.
PATIENTS AND METHODS
We queried the database of patients with IBD at Cincinnati Children's Hospital Medical Center to identify subjects with IBD 18 years or younger who tested positive for C difficile toxin A and/or B between August 1, 2007 and December 31, 2008. Patients testing positive for C difficile toxin A and/or B in the 8 weeks before their initial IBD diagnosis were also included. All of the stool specimens were analyzed for the detection of C difficile toxins by ImmunoCard Toxins A & B (Meridian Bioscience, Cincinnati, OH) according to the manufacturer's instructions. This qualitative, horizontal-flow enzyme immunoassay has a sensitivity of 83% ± 6.7% and a specificity of 95% ± 1.6% for C difficile infection screening. After identifying study patients, a data dictionary of key concepts was constructed and a medical chart review on each patient was performed using a standardized case report form. Patient demographics, symptoms at the time of the positive test, treatments, hospitalizations, recurrence of C difficile infection, and date of infection relative to IBD diagnosis were extracted. Disease activity (quiescent, mild, moderate, severe) before the patient's positive C difficile test was also extracted from the medical charts. Whenever possible, data were cross-checked by reviewing electronic records. Spot checks of data extractions were performed by a second reviewer.
A functional definition was used to confirm that study patients exhibited symptoms indicative of CDAD: a self-reported or family-reported increase in the frequency of loose stools above baseline, often accompanied by blood in the stool, abdominal pain, or fever (Table 1). All of the patients with a positive test received antibiotic therapy and improved clinically. For each occurrence of C difficile infection, we defined treatment success as documented resolution of symptoms or C difficile toxin test negativity after treatment. In cases in which an initial antimicrobial drug was not tolerated or did not provide symptom relief and was changed and the next drug proved successful, it was coded as the success drug. In 1 case the initial treatment drug was not identified. Recurrence was defined as a second confirmed C difficile infection occurring after a treatment success for the prior infection. Hospital acquisition was surmised if the positive C difficile test occurred from 2 days to 6 weeks after hospital admission. This study was performed with the approval of the local institutional review board.
If no data on a particular variable were found in the medical chart review of a study patient, then the patient was excluded from that analysis. This type of censoring occurred for no more than 1 to 4 study patients for any given analysis. All of the other study subjects were included as evaluable. Chi-square and Fisher exact tests were used to compare categorical variables between groups, and the Student t test was used to compare continuous variables between groups. All of the analyses were conducted using SPSS 17.0 for Windows (SPSS Inc, Chicago, IL).
From our center's IBD database of 372 pediatric patients we identified 29 patients (7.8%, 95% confidence interval [CI] 5.5%–11.0%) with a positive C difficile stool test between August 2007 and December 2008. All of the exhibited symptoms were consistent with CDAD at the time of testing (Table 1) and showed clinical improvement after antimicrobial treatment. A single recurrence episode was documented in 11 (38%) of these patients, for a total of 40 cases. This represents an annualized incidence of 7.2%. In 5 of the 29 patients (17%), CDAD occurred from 2 to 8 weeks before the diagnosis of IBD was established. In 6 patients IBD diagnosis was followed by occurrence of CDAD within 8 weeks, whereas in the remainder, the duration of IBD varied from 4 months to more than 10 years before the occurrence of CDAD. For those patients studied for a minimum of 6 months before the occurrence of CDAD, 66% were considered to either have mild disease activity or be in remission (compared to 88.7% with similar disease activity in the IBD database).
There were no differences in age, sex, or type of IBD between patients with CDAD and patients without an occurrence of CDAD in the study time frame (Table 2). Furthermore, these parameters were not associated with recurrence of CDAD (data not shown). The majority of CDAD was community acquired because only 6 of 39 evaluable cases (15%) occurred during or in the 6-week period immediately after hospitalization. Prior antimicrobial exposure, a known risk factor for CDAD, was documented in half of the 40 episodes. These included 2 patients who contracted C difficile while prescribed metronidazole for nondiarrheal IBD symptoms.
Initial antimicrobial therapy was successful in 43% of evaluable cases (17/39). Metronidazole was the initial treatment in the majority of cases (27/38 evaluable cases), followed by vancomycin (9/38) and nitazoxanide (2/38). Age, sex, type of IBD, and the choice of initial antibiotic were not associated with initial treatment outcome (Table 3). Up to 5 treatment changes were needed to achieve treatment success. Final success was achieved in equal numbers when either metronidazole (41%, 15/37 evaluable cases) or vancomycin (43%, 16/37) was the final treatment drug. Nitazoxanide or a combination of vancomycin with metronidazole, nitazoxanide, intravenous immunoglobulin G, or rifaxamin was also used in 6 of 37 cases (16%).
Prior use of antibiotics, proton pump inhibitors (PPIs), probiotics, steroids, immune modulators, or biological treatments did not affect initial treatment success (Table 4). The use of anti-inflammatory medications (aminosalicylates) was associated with initial treatment success; 62% of patients taking anti-inflammatory medications before infection had initial CDAD treatment success (P = 0.02). No association was observed between type of IBD medication and CDAD recurrence (data not shown).
A number of retrospective studies have examined the incidence of CDAD in adult patients with IBD (summarized in Table 5). Although different parameters have been measured in each study, it is clear that adults with IBD have between 2 and 3 times higher incidence of CDAD than the adults without IBD. In the general pediatric population, 1 multicenter study (9) found the incidence of CDAD in children to be comparable with that of non-IBD adults. Using these historical data for context, the incidence of CDAD in pediatric patients with IBD in our retrospective study (7.2%) exceeds the incidence in children without IBD by 18- to 100-fold (9,10) and adults with IBD by 1.5-fold (4). Our center is thought to care for the vast majority of pediatric patients with IBD in our area, so it is likely that we were able to identify all or nearly all of the episodes of CDAD through our retrospective database review. Thus, our data give an approximate incidence based on a large and stable population of children with IBD, and is consistent with Pascarella et al (8) in Italy, who showed a 24.7% incidence of CDAD in children with IBD admitted to the hospital for diarrhea and abdominal pain.
Although 2 adult studies have documented increased incidence of CDAD in patients with ulcerative colitis (UC) compared with those with Crohn disease (CD) (5,6) we did not see a similar association. It is not known whether this represents a real difference between pediatric and adult UC or whether this is an artifact of the composition of our population that is typical of the distribution of CD in children (3:1 CD:UC). Issa et al (4) also found that the incidence of CDAD in adult patients with IBD (higher in patients with CD) matched the distribution of their IBD center population. Furthermore, Pascarella et al (8) showed that specific IBD type was also not associated with CDAD incidence in pediatric patients.
An important aspect of the changing epidemiology of CDAD is the increase in community-acquired cases (2,10). This is particularly true for patients with IBD. Similar to both adult and pediatric patients with IBD (4,5,8), the majority of CDAD in our pediatric patient population was community acquired. The increased number of community-acquired infections among those with IBD has important surveillance implications and dictates that even nonhospitalized patients are at risk for CDAD.
Symptoms of diarrhea and abdominal pain are common to both infectious colitis and progression of IBD, and may signal a need for more aggressive IBD therapy rather than antimicrobial treatment. It is known that there is a relatively high rate of carriage of C difficile in patients with IBD. In a prospective study, C difficile was detected in stool cultures from 8% of patients with IBD (in remission) compared to 1% of healthy controls, none of whom experienced clinical symptoms during a 6-month follow-up (7). Our use of retrospective data precludes knowledge of carrier status, and it is possible that C difficile–positive patients in our study who underwent multiple rounds of antimicrobial treatment before symptom resolution were indeed carriers whose symptoms were due to IBD exacerbation. Notably, Issa and coworkers (4) also reported initial antimicrobial treatment failure in 58% of adult patients with IBD, much higher than that reported in the general population (1). The role of C difficile carriage in subsequent CDAD or in relapse in patients with IBD is an important issue and remains to be elucidated.
The benefit of screening for C difficile toxin in patients with IBD with apparent relapse is therefore controversial. However, in 2 recent studies of adult patients with IBD during a relapse, from 5.5% to 19% of stool samples were found to be C difficile toxin positive, and these patients improved clinically after antimicrobial treatment (11,12). Likewise, in another study, 25% of pediatric patients with IBD admitted to the hospital had C difficile–positive stool samples (8). In the absence of a comprehensive prospective study, we would recommend C difficile toxin stool screening in all children with IBD experiencing an increase in disease symptoms to begin antimicrobial intervention in a timely fashion, with the caveat that failure may signal worsening of the underlying IBD.
Studies in adults with IBD have found either an increased risk of CDAD (4) or a worse outcome in patients (13) receiving immunomodulator treatments. In addition, PPI use has been found to be independently associated with CDAD risk (2). Although our study design did not allow us to look directly at these questions, we did examine risk in the context of recurrence and did not find any association in our pediatric population. Pascarella et al (8) did not find a correlation between CDAD and IBD therapy or PPI use in pediatric patients.
Of note, we found that the use of a common IBD anti-inflammatory medication (aminosalicylates) was associated with an improved response to treatment in patients with CDAD using these medications compared with patients not using these medications (P = 0.02). The biological basis of this finding is not known. The inflammatory effects of toxins A and/or B are required for at least part of the pathogenicity of C difficile, and it may be that the reduction in pro-inflammatory cytokines mediated by aminosalicyates (14) may aid in symptom resolution in certain individuals.
The limitations of our study include the use of retrospective data from a single-center tertiary care center, the absence of a control group, and the potential for type II errors due to sample size. However, our work does confirm the changing epidemiology of C difficile infection in a pediatric IBD population, including an increased incidence of CDAD acquired in the community and greatly reduced effectiveness of both metronidazole and vancomycin.
More must be understood about the unique epidemiology of CDAD in the IBD population, including the role of mucosal/immunological factors, before treatment strategies can be improved to yield better outcomes. To further our current understanding, prospective studies that include identification of C difficile carrier status, consistent definitions of treatment success and recurrence, and exploration of alternative therapies such as the use of probiotics, toxin binders, new antimicrobials, and monoclonal antibody therapy must be performed.
We thank Michael Cloughessy and RicJunette Addie-Carson for their assistance in compiling database reports and Cade Nylund, MD, for helpful discussions.
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