Alice Pong, MD

Clostridium difficile is the single most common cause of nosocomial diarrhea in both adults and children.[1, 2] C difficile infections (CDIs) can range from self‐limited diarrhea to severe pseudomembranous colitis. Though widely distributed in the environment, hospitals and child care facilities are major reservoirs for C difficile. Traditionally, hospitalization and antibiotic use have been the 2 major risk factors for acquiring CDI.

Recent studies suggest C difficile epidemiology is shifting. In 2005, the Centers for Disease Control and Prevention (CDC) reported CDIs in 33 otherwise low‐risk patients, 6 of whom were children.[3] Other studies have noted increasing incidence of pediatric CDIs,[4, 5, 6, 7] 1 identifying 43% with no prior antibiotic use.[4] This emerging data led to the recent American Academy of Pediatrics policy statement on pediatric CDIs.[8] Data regarding associated clinical risk factors of CDIs in pediatric patients in light of the changing epidemiology are limited. Only 1 recent study looked at 6 clinical factors and found that antibiotic use, history of solid organ transplantation, gastrointestinal (GI) devices, and acid suppressing medications increased risk for CDIs.[9]

Data regarding the source of these infections are also limited. Three pediatric studies evaluating source found a significant amount of community‐acquired disease (59%, 25%, and 19% of the study population, respectively).[4, 9, 10] However, only 1 of these studies provided clinical comparisons between community and hospital‐acquired cases.[10] To date, no study has examined a comprehensive list of potential risk factors that might differentiate hospitalized pediatric patients with CDIs from those with acute gastroenteritis (AGE).

PATIENTS AND METHODS

We conducted an investigator‐initiated, retrospective, case‐control study examining risk factors associated with CDIs in a hospitalized pediatric population at Rady Children's Hospital San Diego (RCHSD). Rady Children's is a tertiary‐care pediatric healthcare system and the sole pediatric referral center for San Diego, with a catchment of 850,000 children. RCHSD posts over 71,000 emergency department (ED) and 30,000 urgent care (UC) visits at 4 sites and over 15,000 admissions yearly. All system information is archived in 1 electronic database. We reviewed patient records for a 2‐year period from June 1, 2008 through May 31, 2010. The study protocol was reviewed and approved by the institutional review board at the University of California San Diego.

Cases of C difficile (CDs) included pediatric patients 18 years of age with all of the following: International Classification of Diseases, 9th Revision (ICD‐9) code for C difficile infection (08.45), a positive C difficile toxin A or B by enzyme immunoassay (EIA) (Meridian Bioscience, Inc., Cincinnati, OH), and the presence of diarrhea and/or abdominal pain. Randomly selected age‐matched controls from the same time period with a discharge diagnosis of AGE (APR‐DRG 249) and the presence of diarrhea served as controls (CTLs). In the 1 year age group, any patient with a positive C difficile toxin assay but no diagnosis of CDI was excluded from the CTL group to avoid potential confounding.

Records were reviewed for multiple potential risk factors based on limited past studies and other factors associated with CDI pathogenesis including age, race, ethnicity, antibiotic use within the previous 90 days (type, route, and duration), diarrhea type, abdominal pain, fever, proton pump inhibitor (PPI) use, sick contacts (diarrheal illness), recent travel, and hospitalization within the last 6 months. Diarrhea was defined as increase in stool frequency or volume. Past medical/surgical history abstracted included GI disease, past CDIs, abdominal surgery, immunodeficiency, renal disease, cardiac disease, nutritional deficiencies, and number of past hospitalizations (all cause). In addition, multiple factors during the hospital course were reviewed: length of stay (LOS), antibiotic therapy, diarrhea type, abdominal pain, fever, electrolyte levels, need for stool replacement fluid, and altered diet recommendations. Thirty‐day return to ED/UC or readmission and cause for the return were also retrieved on all patients. An objective data collection form was used, and all records were reviewed by 1 researcher (W.S.) with a second reviewer (E.F.) reviewing 20% of the charts, with 90% initial concordance. Consensus was reached on all elements abstracted.

Three additional subanalyses were completed. The first subanalysis compared antibiotic prophylaxis (defined as daily use of an antibiotic for >28 days) in CDs versus CTLs. We reviewed charts to ensure extended antibiotic use was for prophylaxis and not treatment. The second subanalysis compared CDs to those CTLs with a negative C difficile toxin assay. This was done to evaluate whether using this control group would highlight a different set of risk factors. The third subanalysis separated CDs into community‐acquired CD (CA‐CD) and hospital‐acquired CD (HA‐CD). We defined CA‐CD as any patient with symptoms either prior to or within the first 48 hours of the index admission and no past hospitalizations or with the last hospitalization >4 weeks prior to the index admission. Patients who developed symptoms at home or within 48 hours of the index admission, but had been hospitalized within the past 4 weeks, were defined as community‐onset HA‐CD. Patients who developed CDIs after 48 hours of the index admission were defined as hospital‐onset HA‐CD. These groupings are consistent with the CDI surveillance recommendations.[11]

All statistical analyses were performed with SPSS statistical software version 21.0 (SPSS Inc., Chicago, IL). Initial comparisons between CDs and CTLs were conducted using t tests for continuous variables and [2] tests for categorical variables. As CDI in infants is controversial, we analyzed our data with and without this cohort to eliminate extraneous, age‐related differences. After confirming that there were no issues with tolerance among possibly related factors, a saturated multiple logistic regression model was used to determine which of the independent variables identified in the initial comparison were predictors of having C difficile when controlling for factors associated with chronic disease.

RESULTS

Descriptive characteristics of the 134 CDs and the 274 CTLs are provided in Table 1. CDs and CTLs were similar in gender and race. More CDs had recent hospitalization and antibiotic exposure, with 24% of CDs versus 3% of CTLs treated with 2 or more antibiotics. Watery stools were the most common type of diarrhea in both CDs and CTLs, and bloody stools did not differ significantly between the 2 groups. However, abdominal pain on admission was more common in CTLs. CDs were more likely to have a history of GI disease, abdominal surgery, and specifically GI surgery. Immunodeficiency and PPI use were far more frequent in CDs, whereas exposure to sick contacts was more common in CTLs. Although CDs had an overall higher rate of ED/UC return visits and readmissions, the rate of return due to GI symptoms was similar in both groups. Reanalysis of the data with the <1‐year cohort removed showed persistent statistically significant findings in these variables. Hospital course, including electrolyte levels, need for intravenous fluids, or modified diets, did not significantly differ between CDs and CTLs (data not shown).

Analysis of CDs without traditional risk factors was performed. To identify patients, we first selected the 46 (34%) without prior antibiotic exposure, then eliminated 19 who had been hospitalized within the past 6 months. Of the remaining 27 patients, 16 had a prolonged hospitalization (>5 days) at the time of CDI diagnosis. This left us with 11 patients (8% of CDs) without any common risk factors of antibiotic use, recent hospitalization, or prolonged hospitalization. None of these patients had a history of CDIs; 6 had significant medical histories. A detailed description of these 11 patients if provided in Table 2.

The first subanalysis evaluated antibiotic prophylaxis and found 51 (37%) in CDs versus 10 (4%) in CTLs. However, after controlling for immunodeficiency found in 40 of these CDs, we found no statistically significant difference. There were insufficient numbers of those on prophylaxis for other reasons (eg, vesicoureteral reflux) to analyze prophylaxis independently.

The second subanalysis compared controls with a negative C difficile toxin assay (21% of CTLs) to CDs on a number of clinical factors. Results were compared to the primary analysis. Many factors remained significant: antibiotic use in the past 90 days was still more frequent in CDs (66% vs 35%, P<0.001) as was immunodeficiency in CDs (46% vs 14%, P<0.001). However, immunodeficiency in this subset of the controls was represented over twice as often as that of the baseline CTLs (14% vs 6%), whereas GI disease was similar between the 2 groups (37% vs 31%, P<0.40). PPI use demonstrated a suggestive relationship (22% vs 11%, P<0.07).

Data for the third subanalysis between CA‐CD and HA‐CD are shown on Table 3. We initially compared CA‐CD, community‐onset HA‐CD, and hospital‐onset HA‐CD. However, when stratification was found to not be significant, we combined both categories of HA‐CD into 1 group. CA‐CD and HA‐CD did not demonstrate significant difference in antibiotic use, type, prophylaxis, history of abdominal surgery, immunodeficiency, or GI disease. Bloody stools were more common in CA‐CD.

Odds ratio (OR) was calculated for association of individual risk factors for disease between CDs and CTLs (Table 4). Our model controlled for antibiotics use in the past 90 days, PPI use, treatment with 2 or more antibiotics, recent hospitalization, past history of CDIs, history of GI disease, history of abdominal surgery, and being immunodeficient. Antibiotic use within the past 90 days (OR: 2.80, P=0.001), recent hospitalization (OR: 2.33, P=0.007), and immunodeficiency (OR: 6.02, P<0.001) were associated with having C difficile. A similar logistic regression was conducted using a model comparing community‐ and hospital‐acquired cases, but no difference was found among risk factors.

DISCUSSION/CONCLUSION

Our study shows that in addition to traditional risk factors of antibiotic use and recent hospitalization, immunodeficiency is a significant key factor associated with the diagnosis of CD. We found that traditional risk factors are not present in all hospitalized pediatric patients with CD. Our study does not support routine testing for C difficile in patients with diarrhea; however, it does suggest testing children with persistent or severe diarrheal symptoms even if traditional risk factors are absent, especially in the presence of immunodeficiency. The intervals we used for antibiotic exposure (past 90 days) and recent hospitalization (past 6 months) were longer compared to other studies,[9, 12] making our findings even more meaningful. Although some of the 11 patients without traditional risk factors had the presence of clinical factors shown in previous studies to be more common in patients with CDIs (GI disease, GI surgery, gastric tube/nasogastric feeding),[12, 13] we still find 4 patients >1 year of age with CDIs and no risk factors. This echoes the CDCs concerns of CDIs in low‐risk patients.[3]

Unlike clinical history, we found clinical symptoms and basic electrolyte testing may not help to distinguish CD from AGE patients. Although abdominal pain and diarrhea on admission were significantly more common in CTLs, when including abdominal pain and diarrhea during hospitalization, this finding was no longer valid. Additionally, although overall return rate was higher for CDs, the return rate for GI symptoms specifically was not different. The former was instead most often due to complications associated with comorbid conditions (GI disease, immunodeficiency). We did assess LOS for both CDs and CTLs; however, due to the high percentage of CDs with malignancy and other severe illnesses, it was difficult to ascertain the effect of CDIs on LOS. Severe CD is described as admission to the intensive care unit due to C difficile complications, colectomy, and death secondary to C difficile.[11] Although our study did not look at severe CDI as a direct outcome, we did not have any cases of colectomy or death secondary to CDI.

Two recent studies[9, 14] showed a high percentage of acid suppression medication use in patients with CDIs, with 1 study reporting 60% using PPIs and 21% using histamine blockers. Our study initially found similar high levels of PPI use among patients with CDIs; however, no significance was found when controlling for chronic disease. Prescriptions of PPIs for pediatric patients have risen dramatically recently,[15] as have reported all‐cause complications.[16] Further studies are needed to evaluate the independent risks of PPI use and CDIs in children. We were unable to analyze the influence of antibiotic use at prophylactic levels on CD rates, as the majority our CDs were on prophylaxis due to immunodeficiency.

Our study is unique in many ways. It is the first study to evaluate hospitalized pediatric patients with a comprehensive list of potential risk factors for CDIs, looking at clinical data on admission and during hospitalization. Additionally, as our site archives all clinical information in 1 database, we were able to identify ED/UC return and hospital readmissions. Although it is possible patients may have been evaluated outside of our healthcare system, this would be uncommon due to our referral patterns and UC sites. Our study used age‐matched patients with diarrheal symptoms and AGE discharge diagnosis as the control group. This differs from the 1 previous study looking at risk factors for CDIs in children.[9] In that study, researchers used patients with negative C difficile toxin testing as controls. Our subanalysis of CTLs with a negative toxin assay found much higher rates of underlying GI disease and immunodeficiency. Whereas previous studies compared patients already at high risk for CDI and assessed the differences between those with and without the infection, our study looked at what clinical factors distinguish CDI from AGE in a hospitalized population.

Similar to other pediatric studies, our study found a significant number of CA‐CD. However our study is 1 of the first to compare pediatric CA‐CD with HA‐CD based on clinical factors. Of the 9 demographic and clinical variables assessed, the only significant difference found was presence of bloody diarrhea. It may be that bloody diarrhea prompted the patients to be admitted as opposed to evaluated in the ambulatory setting.

Our study had some limitations. We used ICD‐9 discharge diagnosis codes to identify our patients; however, thorough chart review found clinical indices (diarrhea and abdominal pain) that correlated well with CDI diagnosis in addition to positive laboratory test. The EIA C difficile toxin assay was the standard of care during our study period. However, a recent study has shown false positives using EIA testing in pediatric populations.[17] In our primary analysis, we did not exclude patients with a past history of CDIs. Recurrent CDI is defined as having symptoms within 8 weeks after the primary infection. Of our patients with a history of CDIs, only 2 met this definition. Due to the small number, excluding these patients would not have changed our results significantly. Last, as with any retrospective study, we relied on caregiver reports regarding clinical history, especially in the CA‐CD cohort.

Based on our comprehensive analysis of pediatric patients, there should be increased suspicion for CDI in children with baseline immunodeficiency. Our study also supports testing children with persistent or severe GI symptoms even in the absence of traditional risk factors. These elements, coupled with history of antibiotic use, recent hospitalization, GI disease, and abdominal surgery could be used to create an assessment tool to assist clinicians in the diagnosis of CDIs in pediatric patients. A significant percentage of CDIs continues to be CA‐CD. HA‐CD and CA‐CD patients have similar clinical features. Further studies are needed to determine the effect of PPI use and prophylactic antibiotics on CDIs in children.

Clostridium difficile is the single most common cause of nosocomial diarrhea in both adults and children.[1, 2] C difficile infections (CDIs) can range from self‐limited diarrhea to severe pseudomembranous colitis. Though widely distributed in the environment, hospitals and child care facilities are major reservoirs for C difficile. Traditionally, hospitalization and antibiotic use have been the 2 major risk factors for acquiring CDI.

Recent studies suggest C difficile epidemiology is shifting. In 2005, the Centers for Disease Control and Prevention (CDC) reported CDIs in 33 otherwise low‐risk patients, 6 of whom were children.[3] Other studies have noted increasing incidence of pediatric CDIs,[4, 5, 6, 7] 1 identifying 43% with no prior antibiotic use.[4] This emerging data led to the recent American Academy of Pediatrics policy statement on pediatric CDIs.[8] Data regarding associated clinical risk factors of CDIs in pediatric patients in light of the changing epidemiology are limited. Only 1 recent study looked at 6 clinical factors and found that antibiotic use, history of solid organ transplantation, gastrointestinal (GI) devices, and acid suppressing medications increased risk for CDIs.[9]

Data regarding the source of these infections are also limited. Three pediatric studies evaluating source found a significant amount of community‐acquired disease (59%, 25%, and 19% of the study population, respectively).[4, 9, 10] However, only 1 of these studies provided clinical comparisons between community and hospital‐acquired cases.[10] To date, no study has examined a comprehensive list of potential risk factors that might differentiate hospitalized pediatric patients with CDIs from those with acute gastroenteritis (AGE).

PATIENTS AND METHODS

We conducted an investigator‐initiated, retrospective, case‐control study examining risk factors associated with CDIs in a hospitalized pediatric population at Rady Children's Hospital San Diego (RCHSD). Rady Children's is a tertiary‐care pediatric healthcare system and the sole pediatric referral center for San Diego, with a catchment of 850,000 children. RCHSD posts over 71,000 emergency department (ED) and 30,000 urgent care (UC) visits at 4 sites and over 15,000 admissions yearly. All system information is archived in 1 electronic database. We reviewed patient records for a 2‐year period from June 1, 2008 through May 31, 2010. The study protocol was reviewed and approved by the institutional review board at the University of California San Diego.

Cases of C difficile (CDs) included pediatric patients 18 years of age with all of the following: International Classification of Diseases, 9th Revision (ICD‐9) code for C difficile infection (08.45), a positive C difficile toxin A or B by enzyme immunoassay (EIA) (Meridian Bioscience, Inc., Cincinnati, OH), and the presence of diarrhea and/or abdominal pain. Randomly selected age‐matched controls from the same time period with a discharge diagnosis of AGE (APR‐DRG 249) and the presence of diarrhea served as controls (CTLs). In the 1 year age group, any patient with a positive C difficile toxin assay but no diagnosis of CDI was excluded from the CTL group to avoid potential confounding.

Records were reviewed for multiple potential risk factors based on limited past studies and other factors associated with CDI pathogenesis including age, race, ethnicity, antibiotic use within the previous 90 days (type, route, and duration), diarrhea type, abdominal pain, fever, proton pump inhibitor (PPI) use, sick contacts (diarrheal illness), recent travel, and hospitalization within the last 6 months. Diarrhea was defined as increase in stool frequency or volume. Past medical/surgical history abstracted included GI disease, past CDIs, abdominal surgery, immunodeficiency, renal disease, cardiac disease, nutritional deficiencies, and number of past hospitalizations (all cause). In addition, multiple factors during the hospital course were reviewed: length of stay (LOS), antibiotic therapy, diarrhea type, abdominal pain, fever, electrolyte levels, need for stool replacement fluid, and altered diet recommendations. Thirty‐day return to ED/UC or readmission and cause for the return were also retrieved on all patients. An objective data collection form was used, and all records were reviewed by 1 researcher (W.S.) with a second reviewer (E.F.) reviewing 20% of the charts, with 90% initial concordance. Consensus was reached on all elements abstracted.

Three additional subanalyses were completed. The first subanalysis compared antibiotic prophylaxis (defined as daily use of an antibiotic for >28 days) in CDs versus CTLs. We reviewed charts to ensure extended antibiotic use was for prophylaxis and not treatment. The second subanalysis compared CDs to those CTLs with a negative C difficile toxin assay. This was done to evaluate whether using this control group would highlight a different set of risk factors. The third subanalysis separated CDs into community‐acquired CD (CA‐CD) and hospital‐acquired CD (HA‐CD). We defined CA‐CD as any patient with symptoms either prior to or within the first 48 hours of the index admission and no past hospitalizations or with the last hospitalization >4 weeks prior to the index admission. Patients who developed symptoms at home or within 48 hours of the index admission, but had been hospitalized within the past 4 weeks, were defined as community‐onset HA‐CD. Patients who developed CDIs after 48 hours of the index admission were defined as hospital‐onset HA‐CD. These groupings are consistent with the CDI surveillance recommendations.[11]

All statistical analyses were performed with SPSS statistical software version 21.0 (SPSS Inc., Chicago, IL). Initial comparisons between CDs and CTLs were conducted using t tests for continuous variables and [2] tests for categorical variables. As CDI in infants is controversial, we analyzed our data with and without this cohort to eliminate extraneous, age‐related differences. After confirming that there were no issues with tolerance among possibly related factors, a saturated multiple logistic regression model was used to determine which of the independent variables identified in the initial comparison were predictors of having C difficile when controlling for factors associated with chronic disease.

RESULTS

Descriptive characteristics of the 134 CDs and the 274 CTLs are provided in Table 1. CDs and CTLs were similar in gender and race. More CDs had recent hospitalization and antibiotic exposure, with 24% of CDs versus 3% of CTLs treated with 2 or more antibiotics. Watery stools were the most common type of diarrhea in both CDs and CTLs, and bloody stools did not differ significantly between the 2 groups. However, abdominal pain on admission was more common in CTLs. CDs were more likely to have a history of GI disease, abdominal surgery, and specifically GI surgery. Immunodeficiency and PPI use were far more frequent in CDs, whereas exposure to sick contacts was more common in CTLs. Although CDs had an overall higher rate of ED/UC return visits and readmissions, the rate of return due to GI symptoms was similar in both groups. Reanalysis of the data with the <1‐year cohort removed showed persistent statistically significant findings in these variables. Hospital course, including electrolyte levels, need for intravenous fluids, or modified diets, did not significantly differ between CDs and CTLs (data not shown).

Analysis of CDs without traditional risk factors was performed. To identify patients, we first selected the 46 (34%) without prior antibiotic exposure, then eliminated 19 who had been hospitalized within the past 6 months. Of the remaining 27 patients, 16 had a prolonged hospitalization (>5 days) at the time of CDI diagnosis. This left us with 11 patients (8% of CDs) without any common risk factors of antibiotic use, recent hospitalization, or prolonged hospitalization. None of these patients had a history of CDIs; 6 had significant medical histories. A detailed description of these 11 patients if provided in Table 2.

The first subanalysis evaluated antibiotic prophylaxis and found 51 (37%) in CDs versus 10 (4%) in CTLs. However, after controlling for immunodeficiency found in 40 of these CDs, we found no statistically significant difference. There were insufficient numbers of those on prophylaxis for other reasons (eg, vesicoureteral reflux) to analyze prophylaxis independently.

The second subanalysis compared controls with a negative C difficile toxin assay (21% of CTLs) to CDs on a number of clinical factors. Results were compared to the primary analysis. Many factors remained significant: antibiotic use in the past 90 days was still more frequent in CDs (66% vs 35%, P<0.001) as was immunodeficiency in CDs (46% vs 14%, P<0.001). However, immunodeficiency in this subset of the controls was represented over twice as often as that of the baseline CTLs (14% vs 6%), whereas GI disease was similar between the 2 groups (37% vs 31%, P<0.40). PPI use demonstrated a suggestive relationship (22% vs 11%, P<0.07).

Data for the third subanalysis between CA‐CD and HA‐CD are shown on Table 3. We initially compared CA‐CD, community‐onset HA‐CD, and hospital‐onset HA‐CD. However, when stratification was found to not be significant, we combined both categories of HA‐CD into 1 group. CA‐CD and HA‐CD did not demonstrate significant difference in antibiotic use, type, prophylaxis, history of abdominal surgery, immunodeficiency, or GI disease. Bloody stools were more common in CA‐CD.

Odds ratio (OR) was calculated for association of individual risk factors for disease between CDs and CTLs (Table 4). Our model controlled for antibiotics use in the past 90 days, PPI use, treatment with 2 or more antibiotics, recent hospitalization, past history of CDIs, history of GI disease, history of abdominal surgery, and being immunodeficient. Antibiotic use within the past 90 days (OR: 2.80, P=0.001), recent hospitalization (OR: 2.33, P=0.007), and immunodeficiency (OR: 6.02, P<0.001) were associated with having C difficile. A similar logistic regression was conducted using a model comparing community‐ and hospital‐acquired cases, but no difference was found among risk factors.

DISCUSSION/CONCLUSION

Our study shows that in addition to traditional risk factors of antibiotic use and recent hospitalization, immunodeficiency is a significant key factor associated with the diagnosis of CD. We found that traditional risk factors are not present in all hospitalized pediatric patients with CD. Our study does not support routine testing for C difficile in patients with diarrhea; however, it does suggest testing children with persistent or severe diarrheal symptoms even if traditional risk factors are absent, especially in the presence of immunodeficiency. The intervals we used for antibiotic exposure (past 90 days) and recent hospitalization (past 6 months) were longer compared to other studies,[9, 12] making our findings even more meaningful. Although some of the 11 patients without traditional risk factors had the presence of clinical factors shown in previous studies to be more common in patients with CDIs (GI disease, GI surgery, gastric tube/nasogastric feeding),[12, 13] we still find 4 patients >1 year of age with CDIs and no risk factors. This echoes the CDCs concerns of CDIs in low‐risk patients.[3]

Unlike clinical history, we found clinical symptoms and basic electrolyte testing may not help to distinguish CD from AGE patients. Although abdominal pain and diarrhea on admission were significantly more common in CTLs, when including abdominal pain and diarrhea during hospitalization, this finding was no longer valid. Additionally, although overall return rate was higher for CDs, the return rate for GI symptoms specifically was not different. The former was instead most often due to complications associated with comorbid conditions (GI disease, immunodeficiency). We did assess LOS for both CDs and CTLs; however, due to the high percentage of CDs with malignancy and other severe illnesses, it was difficult to ascertain the effect of CDIs on LOS. Severe CD is described as admission to the intensive care unit due to C difficile complications, colectomy, and death secondary to C difficile.[11] Although our study did not look at severe CDI as a direct outcome, we did not have any cases of colectomy or death secondary to CDI.

Two recent studies[9, 14] showed a high percentage of acid suppression medication use in patients with CDIs, with 1 study reporting 60% using PPIs and 21% using histamine blockers. Our study initially found similar high levels of PPI use among patients with CDIs; however, no significance was found when controlling for chronic disease. Prescriptions of PPIs for pediatric patients have risen dramatically recently,[15] as have reported all‐cause complications.[16] Further studies are needed to evaluate the independent risks of PPI use and CDIs in children. We were unable to analyze the influence of antibiotic use at prophylactic levels on CD rates, as the majority our CDs were on prophylaxis due to immunodeficiency.

Our study is unique in many ways. It is the first study to evaluate hospitalized pediatric patients with a comprehensive list of potential risk factors for CDIs, looking at clinical data on admission and during hospitalization. Additionally, as our site archives all clinical information in 1 database, we were able to identify ED/UC return and hospital readmissions. Although it is possible patients may have been evaluated outside of our healthcare system, this would be uncommon due to our referral patterns and UC sites. Our study used age‐matched patients with diarrheal symptoms and AGE discharge diagnosis as the control group. This differs from the 1 previous study looking at risk factors for CDIs in children.[9] In that study, researchers used patients with negative C difficile toxin testing as controls. Our subanalysis of CTLs with a negative toxin assay found much higher rates of underlying GI disease and immunodeficiency. Whereas previous studies compared patients already at high risk for CDI and assessed the differences between those with and without the infection, our study looked at what clinical factors distinguish CDI from AGE in a hospitalized population.

Similar to other pediatric studies, our study found a significant number of CA‐CD. However our study is 1 of the first to compare pediatric CA‐CD with HA‐CD based on clinical factors. Of the 9 demographic and clinical variables assessed, the only significant difference found was presence of bloody diarrhea. It may be that bloody diarrhea prompted the patients to be admitted as opposed to evaluated in the ambulatory setting.

Our study had some limitations. We used ICD‐9 discharge diagnosis codes to identify our patients; however, thorough chart review found clinical indices (diarrhea and abdominal pain) that correlated well with CDI diagnosis in addition to positive laboratory test. The EIA C difficile toxin assay was the standard of care during our study period. However, a recent study has shown false positives using EIA testing in pediatric populations.[17] In our primary analysis, we did not exclude patients with a past history of CDIs. Recurrent CDI is defined as having symptoms within 8 weeks after the primary infection. Of our patients with a history of CDIs, only 2 met this definition. Due to the small number, excluding these patients would not have changed our results significantly. Last, as with any retrospective study, we relied on caregiver reports regarding clinical history, especially in the CA‐CD cohort.

Based on our comprehensive analysis of pediatric patients, there should be increased suspicion for CDI in children with baseline immunodeficiency. Our study also supports testing children with persistent or severe GI symptoms even in the absence of traditional risk factors. These elements, coupled with history of antibiotic use, recent hospitalization, GI disease, and abdominal surgery could be used to create an assessment tool to assist clinicians in the diagnosis of CDIs in pediatric patients. A significant percentage of CDIs continues to be CA‐CD. HA‐CD and CA‐CD patients have similar clinical features. Further studies are needed to determine the effect of PPI use and prophylactic antibiotics on CDIs in children.

Clostridium difficile is the single most common cause of nosocomial diarrhea in both adults and children.[1, 2] C difficile infections (CDIs) can range from self‐limited diarrhea to severe pseudomembranous colitis. Though widely distributed in the environment, hospitals and child care facilities are major reservoirs for C difficile. Traditionally, hospitalization and antibiotic use have been the 2 major risk factors for acquiring CDI.

Recent studies suggest C difficile epidemiology is shifting. In 2005, the Centers for Disease Control and Prevention (CDC) reported CDIs in 33 otherwise low‐risk patients, 6 of whom were children.[3] Other studies have noted increasing incidence of pediatric CDIs,[4, 5, 6, 7] 1 identifying 43% with no prior antibiotic use.[4] This emerging data led to the recent American Academy of Pediatrics policy statement on pediatric CDIs.[8] Data regarding associated clinical risk factors of CDIs in pediatric patients in light of the changing epidemiology are limited. Only 1 recent study looked at 6 clinical factors and found that antibiotic use, history of solid organ transplantation, gastrointestinal (GI) devices, and acid suppressing medications increased risk for CDIs.[9]

Data regarding the source of these infections are also limited. Three pediatric studies evaluating source found a significant amount of community‐acquired disease (59%, 25%, and 19% of the study population, respectively).[4, 9, 10] However, only 1 of these studies provided clinical comparisons between community and hospital‐acquired cases.[10] To date, no study has examined a comprehensive list of potential risk factors that might differentiate hospitalized pediatric patients with CDIs from those with acute gastroenteritis (AGE).

PATIENTS AND METHODS

We conducted an investigator‐initiated, retrospective, case‐control study examining risk factors associated with CDIs in a hospitalized pediatric population at Rady Children's Hospital San Diego (RCHSD). Rady Children's is a tertiary‐care pediatric healthcare system and the sole pediatric referral center for San Diego, with a catchment of 850,000 children. RCHSD posts over 71,000 emergency department (ED) and 30,000 urgent care (UC) visits at 4 sites and over 15,000 admissions yearly. All system information is archived in 1 electronic database. We reviewed patient records for a 2‐year period from June 1, 2008 through May 31, 2010. The study protocol was reviewed and approved by the institutional review board at the University of California San Diego.

Cases of C difficile (CDs) included pediatric patients 18 years of age with all of the following: International Classification of Diseases, 9th Revision (ICD‐9) code for C difficile infection (08.45), a positive C difficile toxin A or B by enzyme immunoassay (EIA) (Meridian Bioscience, Inc., Cincinnati, OH), and the presence of diarrhea and/or abdominal pain. Randomly selected age‐matched controls from the same time period with a discharge diagnosis of AGE (APR‐DRG 249) and the presence of diarrhea served as controls (CTLs). In the 1 year age group, any patient with a positive C difficile toxin assay but no diagnosis of CDI was excluded from the CTL group to avoid potential confounding.

Records were reviewed for multiple potential risk factors based on limited past studies and other factors associated with CDI pathogenesis including age, race, ethnicity, antibiotic use within the previous 90 days (type, route, and duration), diarrhea type, abdominal pain, fever, proton pump inhibitor (PPI) use, sick contacts (diarrheal illness), recent travel, and hospitalization within the last 6 months. Diarrhea was defined as increase in stool frequency or volume. Past medical/surgical history abstracted included GI disease, past CDIs, abdominal surgery, immunodeficiency, renal disease, cardiac disease, nutritional deficiencies, and number of past hospitalizations (all cause). In addition, multiple factors during the hospital course were reviewed: length of stay (LOS), antibiotic therapy, diarrhea type, abdominal pain, fever, electrolyte levels, need for stool replacement fluid, and altered diet recommendations. Thirty‐day return to ED/UC or readmission and cause for the return were also retrieved on all patients. An objective data collection form was used, and all records were reviewed by 1 researcher (W.S.) with a second reviewer (E.F.) reviewing 20% of the charts, with 90% initial concordance. Consensus was reached on all elements abstracted.

Three additional subanalyses were completed. The first subanalysis compared antibiotic prophylaxis (defined as daily use of an antibiotic for >28 days) in CDs versus CTLs. We reviewed charts to ensure extended antibiotic use was for prophylaxis and not treatment. The second subanalysis compared CDs to those CTLs with a negative C difficile toxin assay. This was done to evaluate whether using this control group would highlight a different set of risk factors. The third subanalysis separated CDs into community‐acquired CD (CA‐CD) and hospital‐acquired CD (HA‐CD). We defined CA‐CD as any patient with symptoms either prior to or within the first 48 hours of the index admission and no past hospitalizations or with the last hospitalization >4 weeks prior to the index admission. Patients who developed symptoms at home or within 48 hours of the index admission, but had been hospitalized within the past 4 weeks, were defined as community‐onset HA‐CD. Patients who developed CDIs after 48 hours of the index admission were defined as hospital‐onset HA‐CD. These groupings are consistent with the CDI surveillance recommendations.[11]

All statistical analyses were performed with SPSS statistical software version 21.0 (SPSS Inc., Chicago, IL). Initial comparisons between CDs and CTLs were conducted using t tests for continuous variables and [2] tests for categorical variables. As CDI in infants is controversial, we analyzed our data with and without this cohort to eliminate extraneous, age‐related differences. After confirming that there were no issues with tolerance among possibly related factors, a saturated multiple logistic regression model was used to determine which of the independent variables identified in the initial comparison were predictors of having C difficile when controlling for factors associated with chronic disease.

RESULTS

Descriptive characteristics of the 134 CDs and the 274 CTLs are provided in Table 1. CDs and CTLs were similar in gender and race. More CDs had recent hospitalization and antibiotic exposure, with 24% of CDs versus 3% of CTLs treated with 2 or more antibiotics. Watery stools were the most common type of diarrhea in both CDs and CTLs, and bloody stools did not differ significantly between the 2 groups. However, abdominal pain on admission was more common in CTLs. CDs were more likely to have a history of GI disease, abdominal surgery, and specifically GI surgery. Immunodeficiency and PPI use were far more frequent in CDs, whereas exposure to sick contacts was more common in CTLs. Although CDs had an overall higher rate of ED/UC return visits and readmissions, the rate of return due to GI symptoms was similar in both groups. Reanalysis of the data with the <1‐year cohort removed showed persistent statistically significant findings in these variables. Hospital course, including electrolyte levels, need for intravenous fluids, or modified diets, did not significantly differ between CDs and CTLs (data not shown).

Analysis of CDs without traditional risk factors was performed. To identify patients, we first selected the 46 (34%) without prior antibiotic exposure, then eliminated 19 who had been hospitalized within the past 6 months. Of the remaining 27 patients, 16 had a prolonged hospitalization (>5 days) at the time of CDI diagnosis. This left us with 11 patients (8% of CDs) without any common risk factors of antibiotic use, recent hospitalization, or prolonged hospitalization. None of these patients had a history of CDIs; 6 had significant medical histories. A detailed description of these 11 patients if provided in Table 2.

The first subanalysis evaluated antibiotic prophylaxis and found 51 (37%) in CDs versus 10 (4%) in CTLs. However, after controlling for immunodeficiency found in 40 of these CDs, we found no statistically significant difference. There were insufficient numbers of those on prophylaxis for other reasons (eg, vesicoureteral reflux) to analyze prophylaxis independently.

The second subanalysis compared controls with a negative C difficile toxin assay (21% of CTLs) to CDs on a number of clinical factors. Results were compared to the primary analysis. Many factors remained significant: antibiotic use in the past 90 days was still more frequent in CDs (66% vs 35%, P<0.001) as was immunodeficiency in CDs (46% vs 14%, P<0.001). However, immunodeficiency in this subset of the controls was represented over twice as often as that of the baseline CTLs (14% vs 6%), whereas GI disease was similar between the 2 groups (37% vs 31%, P<0.40). PPI use demonstrated a suggestive relationship (22% vs 11%, P<0.07).

Data for the third subanalysis between CA‐CD and HA‐CD are shown on Table 3. We initially compared CA‐CD, community‐onset HA‐CD, and hospital‐onset HA‐CD. However, when stratification was found to not be significant, we combined both categories of HA‐CD into 1 group. CA‐CD and HA‐CD did not demonstrate significant difference in antibiotic use, type, prophylaxis, history of abdominal surgery, immunodeficiency, or GI disease. Bloody stools were more common in CA‐CD.

Odds ratio (OR) was calculated for association of individual risk factors for disease between CDs and CTLs (Table 4). Our model controlled for antibiotics use in the past 90 days, PPI use, treatment with 2 or more antibiotics, recent hospitalization, past history of CDIs, history of GI disease, history of abdominal surgery, and being immunodeficient. Antibiotic use within the past 90 days (OR: 2.80, P=0.001), recent hospitalization (OR: 2.33, P=0.007), and immunodeficiency (OR: 6.02, P<0.001) were associated with having C difficile. A similar logistic regression was conducted using a model comparing community‐ and hospital‐acquired cases, but no difference was found among risk factors.

DISCUSSION/CONCLUSION

Our study shows that in addition to traditional risk factors of antibiotic use and recent hospitalization, immunodeficiency is a significant key factor associated with the diagnosis of CD. We found that traditional risk factors are not present in all hospitalized pediatric patients with CD. Our study does not support routine testing for C difficile in patients with diarrhea; however, it does suggest testing children with persistent or severe diarrheal symptoms even if traditional risk factors are absent, especially in the presence of immunodeficiency. The intervals we used for antibiotic exposure (past 90 days) and recent hospitalization (past 6 months) were longer compared to other studies,[9, 12] making our findings even more meaningful. Although some of the 11 patients without traditional risk factors had the presence of clinical factors shown in previous studies to be more common in patients with CDIs (GI disease, GI surgery, gastric tube/nasogastric feeding),[12, 13] we still find 4 patients >1 year of age with CDIs and no risk factors. This echoes the CDCs concerns of CDIs in low‐risk patients.[3]

Unlike clinical history, we found clinical symptoms and basic electrolyte testing may not help to distinguish CD from AGE patients. Although abdominal pain and diarrhea on admission were significantly more common in CTLs, when including abdominal pain and diarrhea during hospitalization, this finding was no longer valid. Additionally, although overall return rate was higher for CDs, the return rate for GI symptoms specifically was not different. The former was instead most often due to complications associated with comorbid conditions (GI disease, immunodeficiency). We did assess LOS for both CDs and CTLs; however, due to the high percentage of CDs with malignancy and other severe illnesses, it was difficult to ascertain the effect of CDIs on LOS. Severe CD is described as admission to the intensive care unit due to C difficile complications, colectomy, and death secondary to C difficile.[11] Although our study did not look at severe CDI as a direct outcome, we did not have any cases of colectomy or death secondary to CDI.

Two recent studies[9, 14] showed a high percentage of acid suppression medication use in patients with CDIs, with 1 study reporting 60% using PPIs and 21% using histamine blockers. Our study initially found similar high levels of PPI use among patients with CDIs; however, no significance was found when controlling for chronic disease. Prescriptions of PPIs for pediatric patients have risen dramatically recently,[15] as have reported all‐cause complications.[16] Further studies are needed to evaluate the independent risks of PPI use and CDIs in children. We were unable to analyze the influence of antibiotic use at prophylactic levels on CD rates, as the majority our CDs were on prophylaxis due to immunodeficiency.

Our study is unique in many ways. It is the first study to evaluate hospitalized pediatric patients with a comprehensive list of potential risk factors for CDIs, looking at clinical data on admission and during hospitalization. Additionally, as our site archives all clinical information in 1 database, we were able to identify ED/UC return and hospital readmissions. Although it is possible patients may have been evaluated outside of our healthcare system, this would be uncommon due to our referral patterns and UC sites. Our study used age‐matched patients with diarrheal symptoms and AGE discharge diagnosis as the control group. This differs from the 1 previous study looking at risk factors for CDIs in children.[9] In that study, researchers used patients with negative C difficile toxin testing as controls. Our subanalysis of CTLs with a negative toxin assay found much higher rates of underlying GI disease and immunodeficiency. Whereas previous studies compared patients already at high risk for CDI and assessed the differences between those with and without the infection, our study looked at what clinical factors distinguish CDI from AGE in a hospitalized population.

Similar to other pediatric studies, our study found a significant number of CA‐CD. However our study is 1 of the first to compare pediatric CA‐CD with HA‐CD based on clinical factors. Of the 9 demographic and clinical variables assessed, the only significant difference found was presence of bloody diarrhea. It may be that bloody diarrhea prompted the patients to be admitted as opposed to evaluated in the ambulatory setting.

Our study had some limitations. We used ICD‐9 discharge diagnosis codes to identify our patients; however, thorough chart review found clinical indices (diarrhea and abdominal pain) that correlated well with CDI diagnosis in addition to positive laboratory test. The EIA C difficile toxin assay was the standard of care during our study period. However, a recent study has shown false positives using EIA testing in pediatric populations.[17] In our primary analysis, we did not exclude patients with a past history of CDIs. Recurrent CDI is defined as having symptoms within 8 weeks after the primary infection. Of our patients with a history of CDIs, only 2 met this definition. Due to the small number, excluding these patients would not have changed our results significantly. Last, as with any retrospective study, we relied on caregiver reports regarding clinical history, especially in the CA‐CD cohort.

Based on our comprehensive analysis of pediatric patients, there should be increased suspicion for CDI in children with baseline immunodeficiency. Our study also supports testing children with persistent or severe GI symptoms even in the absence of traditional risk factors. These elements, coupled with history of antibiotic use, recent hospitalization, GI disease, and abdominal surgery could be used to create an assessment tool to assist clinicians in the diagnosis of CDIs in pediatric patients. A significant percentage of CDIs continues to be CA‐CD. HA‐CD and CA‐CD patients have similar clinical features. Further studies are needed to determine the effect of PPI use and prophylactic antibiotics on CDIs in children.