JPGN Journal of Pediatric Gastroenterology and Nutrition Publish Ahead of Print DOI : 10.1097/MPG.0000000000000737
Title: Clostridium difficile ileitis in pediatric inflammatory bowel disease: a case report and literature review. Authors: David Butler, MD, Department of Pediatrics*; Sanet Torres-Torres, MD, Department of Pediatrics*; Barbara Pahud, MD, Department of Pediatrics*; Angela Myers, MD, Department of Pediatrics*; Shawn D. St. Peter, MD, Department of Surgery*; Russell McCulloh, MD, Department of Pediatrics*. *Children’s Mercy Hospital, Kansas City, MO Corresponding author: David Butler, MD, Children’s Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108. Phone: (816)-234-3373. Email: [email protected] Conflicts of Interest: None Financial support: None Word Count: 1063 Number of Figures: 1 Number of Tables: 1
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Case Report
We present a case of Clostridium difficile ileitis in a 16 year old female with history of Crohn’s disease (CD). She was diagnosed with inflammatory bowel disease (IBD), initially thought to be ulcerative colitis, at age five. She underwent total colectomy with diverting ileostomy at age six due to persistent bloody stools, diarrhea, and weight loss. Her diagnosis was later changed to CD due to continued weight loss and diarrhea despite colectomy. At the time of presentation, her CD had been managed with adalimumab since nine years of age. She had a one month history of a “pulling sensation” at her stoma site and vague, crampy abdominal pain. She presented to the emergency department complaining of abdominal pain, yellow-green/nonbloody emesis, and increased stool output from her ileostomy. She denied fevers, rash, respiratory symptoms, or dysuria. Physical exam revealed diffuse abdominal tenderness with voluntary guarding, hypoactive bowel sounds, and brown stool output from the ileostomy. Abdominal CT scan showed distal small bowel mucosal enhancement—consistent with inflammatory changes—and fluid-filled small bowel loops concerning for obstruction or ileus, which prompted hospital admission (Figure 1). Laboratory findings on admission included white blood cell (WBC) count of 16.1 x 103/mcL with 76% neutrophils, C-reactive protein of 3.3mg/dL (normal 0-1 mg/dL), total bilirubin of 2.3mg/dL, and alkaline phosphatase of 167 units/L. Oral metronidazole (500mg every 8hrs) was initiated after positive C. difficile toxin assay [glutamate dehydrogenase (GDH)/toxin A&B enzyme immunoassay, Alere, Orlando, FL] was obtained from stool. The patient was similarly tested three times for the presence of toxigenic C. difficile during the previous two years for episodes of increased ostomy output and abdominal pain, all of which returned negative, thus decreasing the suspicion for toxin producing strain carriage at this most recent visit.
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On hospital day (HD) 1, oral antimicrobial therapy was changed to vancomycin (500mg every 6hrs) due to vomiting, thought to be due to metronidazole. Based on clinical and radiographic findings suggestive of small bowel obstruction, a catheter was placed in her stoma, her oral intake was restricted, and total parenteral nutrition (TPN) was started. She developed fever to 38.5°C on HD 3 and began complaining of sore throat and sinus pressure, and was clinically diagnosed with pharyngitis. Throat cultures for bacterial, viral and fungal pathogens were negative. Epstein-Barr virus and cytomegalovirus serologies showed no evidence of acute infection. Repeat laboratory studies on HD 7 revealed increasing WBC count of 20.8 x 103/mcL with 47% bands. Additional stool studies were obtained—including viral culture, Shigatoxin A antigen, and bacterial culture for Salmonella, Shigella, Yersinia, Escherichia coli 0157:H7, and Campylobacter—and all were negative. Following consultation with infectious diseases, IV metronidazole (10mg/kg/dose q6hrs) was added to oral vancomycin for treatment of severe C. difficile infection. The patient’s symptoms of possible small bowel obstruction were unchanged despite medical management, thus the patient underwent ileostomy exploration and revision on HD 8. The surgeon identified pseudomembranous plaques that were limited to the dilated segment upon direct visualization. The inflamed ostomy and adjacent dilated bowel segment were mobilized, explored, and resected. Histologic examination of the resected ileostomy and small bowel revealed focal erosion of the mucosal surface, mild villous atrophy, focal cryptitis, and rare crypt abscesses. The lamina propria showed increased plasma cells, histiocytic cells and multinucleated giant cells within the submucosa. These findings were determined by the pathologist to be consistent with chronic active ileitis. Given the presence of pseudomembranous plaques in the ileal mucosa and concerns for inadequate transit of enteral vancomycin; ostomy instillation of vancomycin (500 mg in 100 ml of normal saline) every 6 hours was initiated on
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HD 9. The patient was discharged on HD 11 with instructions to complete a total of 14 days of therapy, followed by a 2-week vancomycin taper (vancomycin 250mg PO twice a day for 1 week, then vancomycin 250mg PO once a day for 1 week). The patient completed a total of 28 days of oral vancomycin therapy, with marked improvement in abdominal pain and decrease in ostomy output by 50%. Repeat C. difficile testing six months after therapy completion was negative.
Discussion The incidence of Clostridium difficile infection is rising in both adult and pediatric populations [1]. C. difficile can cause pseudomembranous colitis via a toxin-mediated inflammatory process through production of toxins TcdA and TcdB [1]. Although previously thought to be limited to the colon, there is a growing body of evidence from adult studies demonstrating that C. difficile can also cause small bowel enteritis, particularly in patients with a history of IBD [2-7]. To our knowledge, this is the first reported case of C. difficile-positive small bowel enteritis in a pediatric patient with IBD. Acute infection due to C. difficile in a patient with IBD can be difficult to identify [1, 8]. The symptoms of both C. difficile intestinal infection and relapse of IBD include watery or bloody diarrhea, abdominal pain, and fever [1]. Complicating the diagnosis of infectious colitis/enteritis is the increased C. difficile carriage rate for IBD patients, which can be up to eight-fold higher than healthy volunteers [1]. In our patient’s case, high stool output from her ileostomy and abdominal pain were concerning for either a Crohn’s flare or infectious enteritis. On review of the literature, the majority of cases of C. difficile-positive small bowel enteritis presented with similar symptoms
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
(Table 1) [2-7]. Furthermore, the patients with history of colectomy and ileostomy frequently presented with high volume, watery ileostomy diarrhea and subsequent ileus [8]. After our patient had a positive test result for C. difficile GDH/toxin of her ileostomy output, one of the dilemmas was whether this represented true infection or carrier status. As our patient had previously had negative testing for C. difficile GDH/toxin several times over of the previous two years, true infection seemed more likely. Diagnosis of small bowel enteritis due to toxigenic C. difficile was supported by the findings of pseudomembranes during surgery. Our case demonstrates the importance of considering C. difficile infection in the setting of abdominal pain and diarrhea in pediatric IBD patients. This is particularly true for cases of C. difficile-positive small bowel enteritis, as mortality rates in adults have been reported to exceed 60% [8]. Our case also illustrates the importance of a multidisciplinary approach to treating children with complicated IBD. The involvement and collaboration of general pediatrics, pediatric surgery, gastroenterology, pathology, and infectious diseases was integral to the diagnosis and management for our patient.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
References 1. Banaszkiewicz A and Pituch H. Clostridium difficile infection in children with inflammatory bowel disease: current evidence. Curr Pharm Des 2014;20(28):4549-55. 2. Thomas K, Taylor J, Everitt L, Nelson R. Clostridium difficile does not only affect the colon: a case series. Colorectal Dis 2011;13(6):e156-7. 3. Pricolo VE, Chao S, Gregorian A. Clostridium difficile pouchitis after proctocolectomy with ileal pouch-anal anastamosis. Am Surg 2011;77(11):214-5. 4. Freiler JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clinical Infectious Diseases 2001;33(8):1429-31. 5. Lundeen SJ, Otterson MF, Binion DG, el al. Clostridium difficile enteritis: an early postoperative complication in inflammatory bowel disease patients after colectomy. J Gastrointest Surg 2007;11(2):138-42. 6. Yafi FA, Selvasekar CR, Cima RR. Clostridium difficile enteritis following total colectomy. Tech Coloproctol 2008;12(1):73-4. 7. Peacock O, Speake W, Shaw A, et al. Clostridium difficile enteritis in a patient after total proctocolectomy. BMJ Case Rep 2009 (Epub June 3, 2009). 8. Saidel-Odes L, Borer A, Odes S. Clostridium difficile infection in patients with inflammatory bowel disease. Ann Gastroenterol 2011;24(4):263-70.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Figure 1. Initial abdominal CT showing mildly increased mucosal enhancement of the distal small bowel loops (arrow), consistent with inflammatory changes. Also with multiple fluid-filled small bowel loops (arrow heads).
Table 1. Literature review of Clostridium difficile small bowel enteritis and inflammatory bowel disease.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Figure 1
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Paper
Age
Diagnosis
Surgical History
Antibiotic Exposure
Diagnosis
Sample Site
Treatment
Outcome
Freiler et al. 2001
26 years
UC, LT
Colectomy, Ileostomy
amoxicillin-clavulanate
Toxin A EIA
Ileostomy
PO metronidazole
Resolution
Thomas et al. 2011
65 years
UC
Subtotal Colectomy, Ileostomy
unknown
PM by endoscopy
Ileum
PO metronidazole
Resolution
1
45 years
UC
PC, Ileoanal Pouch
cefuroxime, metronidazole
Stool C. diff toxin
Ileostomy
vancomycin
21 years
UC
PC, Ileostomy Reversal
cefuroxime, metronidazole
Stool C. diff2
NM
PO metronidazole
Resolution
Pricolo et al.
18 years
UC
PC, Ileoanal Anastomosis, Ileal Pouch
unknown
C. diff toxin titer2
Pelvic Pouch
PO & stoma vancomycin
Resolution
Yafi et al. 2008
21 years
UC
Subtotal Colectomy, Ileostomy
none
Toxin A/B EIA
Ileostomy
PO vancomycin
Resolution
Peacock et al. 2009
30 years
UC
PC, Ileostomy
unknown
Toxin A EIA
Ileostomy
PO metronidazole
Resolution
Lundeen et al. 2007
20 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
59 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
20 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
52 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
22 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
40 years UC Colectomy, Ileostomy Yes- specific drug NM Toxin A/B EIA Ileostomy PO metronidazole & vancomycin* Resolution UC= ulcerative colitis; LT= liver transplant; PC= proctocolectomy; PM= pseudomembrane; NM= not mentioned; *one patient received 1gm/L normal saline 250cc q12hr via ileostomy but specific patient not 1 2 mentioned; route not specified; not otherwise detailed in text
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Title: Clostridium difficile ileitis in pediatric inflammatory bowel disease: a case report and literature review. Authors: David Butler, MD, Department of Pediatrics*; Sanet Torres-Torres, MD, Department of Pediatrics*; Barbara Pahud, MD, Department of Pediatrics*; Angela Myers, MD, Department of Pediatrics*; Shawn D. St. Peter, MD, Department of Surgery*; Russell McCulloh, MD, Department of Pediatrics*. *Children’s Mercy Hospital, Kansas City, MO Corresponding author: David Butler, MD, Children’s Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108. Phone: (816)-234-3373. Email: [email protected] Conflicts of Interest: None Financial support: None Word Count: 1063 Number of Figures: 1 Number of Tables: 1
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Case Report
We present a case of Clostridium difficile ileitis in a 16 year old female with history of Crohn’s disease (CD). She was diagnosed with inflammatory bowel disease (IBD), initially thought to be ulcerative colitis, at age five. She underwent total colectomy with diverting ileostomy at age six due to persistent bloody stools, diarrhea, and weight loss. Her diagnosis was later changed to CD due to continued weight loss and diarrhea despite colectomy. At the time of presentation, her CD had been managed with adalimumab since nine years of age. She had a one month history of a “pulling sensation” at her stoma site and vague, crampy abdominal pain. She presented to the emergency department complaining of abdominal pain, yellow-green/nonbloody emesis, and increased stool output from her ileostomy. She denied fevers, rash, respiratory symptoms, or dysuria. Physical exam revealed diffuse abdominal tenderness with voluntary guarding, hypoactive bowel sounds, and brown stool output from the ileostomy. Abdominal CT scan showed distal small bowel mucosal enhancement—consistent with inflammatory changes—and fluid-filled small bowel loops concerning for obstruction or ileus, which prompted hospital admission (Figure 1). Laboratory findings on admission included white blood cell (WBC) count of 16.1 x 103/mcL with 76% neutrophils, C-reactive protein of 3.3mg/dL (normal 0-1 mg/dL), total bilirubin of 2.3mg/dL, and alkaline phosphatase of 167 units/L. Oral metronidazole (500mg every 8hrs) was initiated after positive C. difficile toxin assay [glutamate dehydrogenase (GDH)/toxin A&B enzyme immunoassay, Alere, Orlando, FL] was obtained from stool. The patient was similarly tested three times for the presence of toxigenic C. difficile during the previous two years for episodes of increased ostomy output and abdominal pain, all of which returned negative, thus decreasing the suspicion for toxin producing strain carriage at this most recent visit.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
On hospital day (HD) 1, oral antimicrobial therapy was changed to vancomycin (500mg every 6hrs) due to vomiting, thought to be due to metronidazole. Based on clinical and radiographic findings suggestive of small bowel obstruction, a catheter was placed in her stoma, her oral intake was restricted, and total parenteral nutrition (TPN) was started. She developed fever to 38.5°C on HD 3 and began complaining of sore throat and sinus pressure, and was clinically diagnosed with pharyngitis. Throat cultures for bacterial, viral and fungal pathogens were negative. Epstein-Barr virus and cytomegalovirus serologies showed no evidence of acute infection. Repeat laboratory studies on HD 7 revealed increasing WBC count of 20.8 x 103/mcL with 47% bands. Additional stool studies were obtained—including viral culture, Shigatoxin A antigen, and bacterial culture for Salmonella, Shigella, Yersinia, Escherichia coli 0157:H7, and Campylobacter—and all were negative. Following consultation with infectious diseases, IV metronidazole (10mg/kg/dose q6hrs) was added to oral vancomycin for treatment of severe C. difficile infection. The patient’s symptoms of possible small bowel obstruction were unchanged despite medical management, thus the patient underwent ileostomy exploration and revision on HD 8. The surgeon identified pseudomembranous plaques that were limited to the dilated segment upon direct visualization. The inflamed ostomy and adjacent dilated bowel segment were mobilized, explored, and resected. Histologic examination of the resected ileostomy and small bowel revealed focal erosion of the mucosal surface, mild villous atrophy, focal cryptitis, and rare crypt abscesses. The lamina propria showed increased plasma cells, histiocytic cells and multinucleated giant cells within the submucosa. These findings were determined by the pathologist to be consistent with chronic active ileitis. Given the presence of pseudomembranous plaques in the ileal mucosa and concerns for inadequate transit of enteral vancomycin; ostomy instillation of vancomycin (500 mg in 100 ml of normal saline) every 6 hours was initiated on
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
HD 9. The patient was discharged on HD 11 with instructions to complete a total of 14 days of therapy, followed by a 2-week vancomycin taper (vancomycin 250mg PO twice a day for 1 week, then vancomycin 250mg PO once a day for 1 week). The patient completed a total of 28 days of oral vancomycin therapy, with marked improvement in abdominal pain and decrease in ostomy output by 50%. Repeat C. difficile testing six months after therapy completion was negative.
Discussion The incidence of Clostridium difficile infection is rising in both adult and pediatric populations [1]. C. difficile can cause pseudomembranous colitis via a toxin-mediated inflammatory process through production of toxins TcdA and TcdB [1]. Although previously thought to be limited to the colon, there is a growing body of evidence from adult studies demonstrating that C. difficile can also cause small bowel enteritis, particularly in patients with a history of IBD [2-7]. To our knowledge, this is the first reported case of C. difficile-positive small bowel enteritis in a pediatric patient with IBD. Acute infection due to C. difficile in a patient with IBD can be difficult to identify [1, 8]. The symptoms of both C. difficile intestinal infection and relapse of IBD include watery or bloody diarrhea, abdominal pain, and fever [1]. Complicating the diagnosis of infectious colitis/enteritis is the increased C. difficile carriage rate for IBD patients, which can be up to eight-fold higher than healthy volunteers [1]. In our patient’s case, high stool output from her ileostomy and abdominal pain were concerning for either a Crohn’s flare or infectious enteritis. On review of the literature, the majority of cases of C. difficile-positive small bowel enteritis presented with similar symptoms
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
(Table 1) [2-7]. Furthermore, the patients with history of colectomy and ileostomy frequently presented with high volume, watery ileostomy diarrhea and subsequent ileus [8]. After our patient had a positive test result for C. difficile GDH/toxin of her ileostomy output, one of the dilemmas was whether this represented true infection or carrier status. As our patient had previously had negative testing for C. difficile GDH/toxin several times over of the previous two years, true infection seemed more likely. Diagnosis of small bowel enteritis due to toxigenic C. difficile was supported by the findings of pseudomembranes during surgery. Our case demonstrates the importance of considering C. difficile infection in the setting of abdominal pain and diarrhea in pediatric IBD patients. This is particularly true for cases of C. difficile-positive small bowel enteritis, as mortality rates in adults have been reported to exceed 60% [8]. Our case also illustrates the importance of a multidisciplinary approach to treating children with complicated IBD. The involvement and collaboration of general pediatrics, pediatric surgery, gastroenterology, pathology, and infectious diseases was integral to the diagnosis and management for our patient.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
References 1. Banaszkiewicz A and Pituch H. Clostridium difficile infection in children with inflammatory bowel disease: current evidence. Curr Pharm Des 2014;20(28):4549-55. 2. Thomas K, Taylor J, Everitt L, Nelson R. Clostridium difficile does not only affect the colon: a case series. Colorectal Dis 2011;13(6):e156-7. 3. Pricolo VE, Chao S, Gregorian A. Clostridium difficile pouchitis after proctocolectomy with ileal pouch-anal anastamosis. Am Surg 2011;77(11):214-5. 4. Freiler JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clinical Infectious Diseases 2001;33(8):1429-31. 5. Lundeen SJ, Otterson MF, Binion DG, el al. Clostridium difficile enteritis: an early postoperative complication in inflammatory bowel disease patients after colectomy. J Gastrointest Surg 2007;11(2):138-42. 6. Yafi FA, Selvasekar CR, Cima RR. Clostridium difficile enteritis following total colectomy. Tech Coloproctol 2008;12(1):73-4. 7. Peacock O, Speake W, Shaw A, et al. Clostridium difficile enteritis in a patient after total proctocolectomy. BMJ Case Rep 2009 (Epub June 3, 2009). 8. Saidel-Odes L, Borer A, Odes S. Clostridium difficile infection in patients with inflammatory bowel disease. Ann Gastroenterol 2011;24(4):263-70.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Figure 1. Initial abdominal CT showing mildly increased mucosal enhancement of the distal small bowel loops (arrow), consistent with inflammatory changes. Also with multiple fluid-filled small bowel loops (arrow heads).
Table 1. Literature review of Clostridium difficile small bowel enteritis and inflammatory bowel disease.
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Figure 1
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
Paper
Age
Diagnosis
Surgical History
Antibiotic Exposure
Diagnosis
Sample Site
Treatment
Outcome
Freiler et al. 2001
26 years
UC, LT
Colectomy, Ileostomy
amoxicillin-clavulanate
Toxin A EIA
Ileostomy
PO metronidazole
Resolution
Thomas et al. 2011
65 years
UC
Subtotal Colectomy, Ileostomy
unknown
PM by endoscopy
Ileum
PO metronidazole
Resolution
1
45 years
UC
PC, Ileoanal Pouch
cefuroxime, metronidazole
Stool C. diff toxin
Ileostomy
vancomycin
21 years
UC
PC, Ileostomy Reversal
cefuroxime, metronidazole
Stool C. diff2
NM
PO metronidazole
Resolution
Pricolo et al.
18 years
UC
PC, Ileoanal Anastomosis, Ileal Pouch
unknown
C. diff toxin titer2
Pelvic Pouch
PO & stoma vancomycin
Resolution
Yafi et al. 2008
21 years
UC
Subtotal Colectomy, Ileostomy
none
Toxin A/B EIA
Ileostomy
PO vancomycin
Resolution
Peacock et al. 2009
30 years
UC
PC, Ileostomy
unknown
Toxin A EIA
Ileostomy
PO metronidazole
Resolution
Lundeen et al. 2007
20 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
59 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
20 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
52 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
22 years
UC
Colectomy, Ileostomy
Yes- specific drug NM
Toxin A/B EIA
Ileostomy
PO metronidazole & vancomycin
Resolution
40 years UC Colectomy, Ileostomy Yes- specific drug NM Toxin A/B EIA Ileostomy PO metronidazole & vancomycin* Resolution UC= ulcerative colitis; LT= liver transplant; PC= proctocolectomy; PM= pseudomembrane; NM= not mentioned; *one patient received 1gm/L normal saline 250cc q12hr via ileostomy but specific patient not 1 2 mentioned; route not specified; not otherwise detailed in text
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
