12/14/2009. Diagnostic considerations: C. difficile in IBD

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1 Diagnosis and treatment of Gastrointestinal Tract Infections in IBD Case Studies Leonard Baidoo,MD David Binion,MD University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Case 1 46yr old man,1 year after a heart attack, when he stopped smoking presents with diarrhea after a trip to Mexico.PCP puts him on antibiotics. A week later he develops bloody diarrhea(10-14/day) with cramps. Had colonoscopy and diagnosed with moderately severe ulcerative colitis. Treated with 5ASA 2.4gm,then 4.8gm 4 weeks later still bloody diarrhea(12-16/day),weak, tired and dehydrated. Admitted. 1

2 Work up and Management Diagnostic considerations Treatment considerations Prevention Summary CASE 1 1 st 2 samples of stool for C difficile toxin A & B negative. Labs normal except WCC of 11 Flexible sigmoidoscopy 2

3 Flex Sigmoidoscopy finding Diagnostic considerations: C. difficile in IBD Laboratory - Leukocytosis -Greater than Creatinine Doubling during admission - Hypoalbuminemia less than 2 Radiographic CT scan -Toxic megacolon,perforation,ileus,ascitis Endoscopy - Pseudomembranes in 50% of patients with CDAD rare in IBD patients. 3

4 Role of Endoscopy Flexible sigmoidoscopy provides rapid diagnosis in presence of pseudomembranes Colonoscopy preferred if can be done safely because in 30% of cases involves right colon only No indication in patient with classic symptoms and positive assay Risk of perforation espcially in fulminant disease Negative endoscopy does not rule out C Diff Endoscopic Appearance of Clostridium difficile Endoscopic appearance of C. diff in control patients Endoscopic appearance of C. diff in patients with IBD Ulcerative Colitis Crohn s Disease Issa M et al. Clin Gastroenterol Hepatol. 2007;5:

5 Diagnosis of Clostridium difficile Testing for the toxin Cell culture toxin assay is the gold standard - excellent sensitivity - requires hrs; labor intensive and expensive ELISA for toxin A and B - More rapid, less expensive and requires less expertise - Sensitivity varies from 79% to 97%. Stool ELISA testing in IBD patients for C. Difficile toxins A and B C. difficile confirmed st 2nd 3rd 4th 4 stool samples to reach 90% detection with ELISA Positive C. difficile ELISA Stool ELISA sample Issa M et al. Clin Gastro Hep Mar;5(3):

6 Diagnosis Clostridium Difficile Diarrhea in patient with Ulcerative Colitis. Clostridium difficile IBD and Clostridium difficile Issa M et al. Clin Gastroenterol Hepatol. 2007;5:

7 The Clostridium difficile Epidemic Clostridium difficile is an anaerobic spore forming bacillus associated with pseudomembranous colitis that produces 2 endotoxins,toxins A and B Causes disease by toxin mediated damage to the colonic mucosa. Increasing incidence and severity throughout North America. Doubling of cases in past 5 years. Metronidazole failure rate = 50% >500,000 cases annually in U.S. Mortality: >15,000 cases annually Loo VG et al. N Engl J Med. 2005;353:2442. McDonald LC et al. Emerg Infect Dis. 2006;12:409. Musher DM et al. Clin Infect Dis. 2005;40:1586. New particularly virulent strain of C Difficile BI/NAP1/027 associated with severe symptoms, significant mortality and high relapse rates -Produces 16x more toxin A and 23x more toxin B -Also produces 3 rd toxin Binary toxin, clinical significance currently unknown - Colonization by C diff occurs when antibiotic therapy disrupts normal colonic bacteria AND the patient ingests C diff spores which are ubiquitous Sunenshine,RH et al Cleve Clin J 2006;73(2) Loo VJ et al N Engl J Med 2005 ;353(23) 7

8 Clostridium difficile is acquired exogenously % patients who acquired C Diff Length of Hospital Stay (wks) Adapted from Johnson S, Gerding DN, Clin Infect Dis, 1998, 26: CDI Pathogenesis Hospitalization Antibiotics Asymptomatic colonization Exposure C diff Diarrhea Exposure to a low inoculum of Cdiff is likely all what is required to infect Adapted from Johnson S, Gerding DN, Clin Infect Dis, 1998, 26:

9 Clostridium difficile and IBD C. difficile and IBD present in identical fashion ranging from mild diarrhea to fulminant colitis. Early studies performed 2 decades ago indicated little overlap between C. difficile and IBD. it concluded No need for routine screening for C. difficile in IBD population. Recent studies: Increasing incidence and severity of C. difficile in IBD population C. difficile recently identified to have a significant negative impact on IBD morbidity. Kochlar R et al. J Clin Gastroenterol 1993;16: Bolton RP et al. Lancet 1980;1: Trnka Y et al. Gastroenterology 1981;80: Issa, M., et al. Clin Gastroenterol Hepatol, (3): p Rodemann, J.F., et al.clin Gastroenterol Hepatol, (3): p Ananthakrishnan, et al. Gut, (2): p Increasing Impact of Clostridium difficile on IBD 50 Number of Patients P Issa M et al. Clin Gastroenterol Hepatol. 2007;5:

10 Increasing Proportion of Clostridium difficile Patients with IBD p=<0.01 Number of Patients % 7% 16% Total C. diff patients IBD patients with C. diff P.01 Issa M et al. Clin Gastroenterol Hepatol. 2007;5: Complications: Clostridium difficile Infected Patients With IBD* Hospitalizations Colectomies % Number of Patients Number of Patients % # of Patients With IBD With C. diff # of Colectomies Issa M et al. Clin Gastroenterol Hepatol. 2007;5:

11 Clostridium difficile in IBD: Morbidity and Mortality IBD patients with C. difficile compared with IBD alone: Longer hospital stay Increased hospitalization costs Higher colectomy rates Increased mortality rate 118 IBD C.diff deaths in NIS 2004 (>500 IBD C.diff deaths in U.S. 2004) 4.2% 3.7% IBD pts with C. C. difficile alone difficile 0.5% IBD alone Ananthakrishnan, et al. Gut, (2): p C. difficile and IBD: Summary Clostridium difficile and IBD Patients with colitis are at increased risk Maintenance immunosuppression correlated with infection (purine analogs, methotrexate) 10% of cases were new IBD presentations Contributes to flare in setting of new and longstanding disease in remission Recommend multiple stool samples for ELISA toxin A, B analysis. 54% of patients detected on first stool sample. Issa M et al. Clin Gastroenterol Hepatol. 2007;5:

12 Work up and Management Diagnostic considerations Treatment considerations Prevention Summary Treatment Considerations High Index of Suspicion No prompt response to Flagyl try Vancomycin Steroids increase the risk of relapse Immunosuppresives + Antibiotics leads to worse outcome compared to antibiotics alone Multiple IMM + Antibiotics even worse Anti TNFs do not seem to have the same bad outcomes as the immunosuppresives Shamoun Ben Horim et al:clin Gastro & Hep:2009:7 12

13 Approach for hospitalized IBD patients with Suspected/confirmed C. difficile C. difficile isolation and contact precautions. Daily stool testing for C. difficile (until positive sample). Possibility for in-hospital acquisition. Empiric oral vancomycin from day 1, alone or in combination with metronidazole (IV or po). Maintain oral diet! Decrease corticosteroid dosing steroids blunt humoral immunity and IgG response to toxin A is necessary to resolve CDAD. Oral vancomycin vs metronidazole for C. difficile METRONIDAZOLE FDA-approved Colonic levels Effectivity Mild Severe Promotion of VRE No 0-10 mcg/ml ++++ Inferior Failure rate 13-16%* Relapse rate 10-25% Side effects Response(median time) Yes Significant 4.6 days Cost + Zar, F.A., et al.. Clin Infect Dis, (3): p Lucas GM et al. Clin Infect Dis May ;26 (5):

14 Oral vancomycin for C. difficile Only FDA approved drug for the treatment of C. difficile Tablets of vancomycin shortages in past, high cost Parenteral (intravenous formulation) vancomycin for oral use Decreased cost involves hospital pharmacy formulation Palatability can be improved mouthwash chaser Apple juice chaser Parenteral vancomycin for enema formulation Preventive strategies - C. difficile Prophylaxis Limit exposure to antibiotics MacFarland et al.. Probiotics (Saccharomyces boulardii, Lactobacillus rhamnosus GG,, and probiotic mixtures) effective for the prevention of CDAD (OR 0.59). data was strongest in S. boulardii Environmental decontamination requires 10% sodium hypochlorite solutions. Alcohol based hand gels are in-effective against spore-forming organisms. Soap and water dislodges spores from skin. Educate parents of newborns regarding handwashing following diaper changing. McFarland, L.V. Am J Gastroenterol, (4): p Mayfield, J.L., et al. Clin Infect Dis, (4): p Wilcox, M.H., et al.j Hosp Infect, (2): p Leischner, J., et al., American Society for Microbiology, ((abstract # LB 29)). 14

15 Refractory and recurrent C. difficile Refractory C. difficile: - Intravenous immunoglobulin was used in a series of 14 patients (200 mg/kg). 64% responded. One patient required 2 nd dose. - Consideration for hypogammaglobulinemia associated IBD. Recurrent C. difficile: - 59% of IBD patients (27 out of 46) had a recurrence. Of the recurring patients, one-quarter required colectomy. C. difficile treatment regimens used: 1- Prolonged courses of vancomycin with or without pulse dosing (2 months) 2- Initial course of vancomycin followed by rifaximin maintenance course. McPherson, S., et al. Dis Colon Rectum, (5): p Issa, M., et al. Am J Gastro, (9): p. S469. Johnson, S., et al. Clin Infect Dis, (6): p Special IBD scenarios with C. difficile C. difficile in ileo-anal Pouchitis Two case reports Chronic refractory pouchitis Unresponsive to broad spectrum antibiotics In both cases C. difficile developed while patients were on metronidazole therapy C. difficile in segments of diverted bowel One case report of C. difficile in UC pt following subtotal colectomy with end-ileostomy. Treated successfully with 10 day course of metronidazole suppositories. Mann, S.D., et al. Dis Colon Rectum, (2): p Shen, B., et al. Dig Dis Sci, (12): p Tsironi, E., et al. Dis Colon Rectum, (7): p

16 Other treatments and future Stool Transplant or fecal bacteriotherapy administered by fecal enema C difficile vaccine Monoclonal antibodies to C difficile toxin A&B Non toxigenic C difficile usually after antibiotic treatment Case 2 A 21 year-old Ohio woman with a 5yr history of Crohn s disease presented with diffuse abdominal pain,nausea,vomiting,and watery diarrhea that had persisted for 10 days in spite of being on her usual maintenance treatment with 6MP.She was hospitalized 2 weeks prior for a Crohn s flare that required IV solumedrol then oral corticosteroids. 16

17 Case 2 On admission she had a temperature of 99F, BP 110/50, HR of 92,RR 18/min. P/E. She had diffuse abdominal tenderness with any rebound tenderness Hb 8.2g/dl,WCC 12.4,Albumin 2.1g/l Stool for C difficile toxin x3 were negative So she had a colonoscopy Colonoscopy 17

18 HE stain show inclusion body 18

19 Immunostaining-Positive for CMV Cytomegalovirus Infection and IBD Human Cytomegalovirus(CMV) is a member of the Herpes virus family which has a life long latency following a primary infection. Most CMV infections reported in IBD patients or other immunosuppressed patients are a consequence of reactivation. Most cases and studies are of transplant patients. CMV may be a nonpathogenic bystander or true pathogen 19

20 Why IBD patients are at high risk Proinflammatory cytokines(eg TNF) are increased in the mucosa of active IBD patients and these are known as triggering factors for reactivation of CMV CMV tropism for sites of severe inflammation. Treatment with immunosuppressive medications especially corticosteroids Soderberg-Naucler et al,j Clin Invest,1997 Goodgame et al,ann Intern Med,1993; CMV and IBD CMV infection in IBD patients is associated with poor outcomes including colectomy Prevalence of CMV infections has been reported as 5-30%,worse in steroid refractory patients Although prevalence is high in active IBD it has been difficult to evaluate the real clinical impact of CMV infections Cottone M et al,am J Gastrol,2001;96: Criscuoli V et al,dig Liver Dis.2004,36; Kishmore J et al.j Med Micro,2004; Wada Y et al.dis Colon Rectum;2003;46:S

21 Diagnosis Clinical:- High index of suspicion, anemia and hypoalbuminemia Endoscopic Findings :- Punched out ulcers Histologic biopsies -H & E staining for viral inclusion bodies -Immunohistochemistry for CMV antibody -CMV DNA by PCR Serology Provides indirect evidence of recent CMV infection based upon changes in antibody titers Techniques include :-ELISA, latex agglutination, radioimmunoassay, complement-fixation Diagnosis of recent or acute CMV is probable though not definite if; 1.Detection of CMV-specific IgM antibodies 2.Four fold increase in CMV-specific IgG titers in paired specimens 2-4 weeks apart 21

22 IgM antibody can persist for several months and therefore can provide misleading information if a prior baseline test not available The requirement for paired serum samples (IgG) limits the utility of these tests in establishing a timely diagnosis Helpful in determining past exposure to CMV infections Other tests CMV antigenemia assays-rapid detection of CMV proteins in peripheral leukocytes using tagged monoclonal antibodies to the pp65 matrix protein of CMV in peripheral blood. Reported as # of cells with staining per total # of cells counted(low # of positive cells) Sensitivity and specificity are 90 and 96 Results in 24 hrs Lesprit et al-using CMV antigenemina,clin Inf Dis ;

23 Treatment Discontinue immunosuppressive and taper off steroids IV Ganciclovir 5mg/kg BID X 14days then Oral Valganciclovir 450mg BID X 4 Weeks Monitor response with CMV pp65 antigenemia assays CMV C difficile UPMC Infections in IBD cases 2 hospitalized 1 colectomy 29 cases 16 hospitalized 7 colectomies 23