Clostridium difficile and CMV in Inflammatory Bowel...

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Clostridium difficile and CMV inInflammatory Bowel Disease

David G. Binion, M.D.

Co-Director, Inflammatory Bowel Disease CenterDirector, Translational Inflammatory Bowel Disease Research

Division of Gastroenterology, Hepatology and NutritionUPMC Presbyterian Hospital

Visiting Professor of MedicineUniversity of Pittsburgh School of Medicine

Pittsburgh,PA

I. Background – C. difficile

II. Impact of C. difficile on IBD

III. Diagnostic considerations C. difficile

IV. Treatment considerations

V. CMV

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§ 1930’s - Bacillus difficillis first described as part of the normal flora of neonates.

§ 1974 - C. difficile recognized as complication of Clindamycin use.

§ 1978 - C. difficile identified as the cause of antibiotic-associated pseudomembranous colitis in humans.

§ Clinical syndrome may range from watery diarrhea, abdominal pain, pseudo-membranous colitis, toxic megacolon, sepsis, colonic perforation and death

* Hall, I. and E. O'Toole. Am J Dis Child, 1935. 48: p. 390-402.‡Tedesco, F.J et al. Ann Intern Med, 1974. 81(4): p. 429-33.

I. Clostridium difficile

§ In the past: C. difficile linked to antibiotic use. Most cases treated successfully with metronidazole

§ Doubling of C. difficile associated disease between 1996 - 2003.

§ Diminished therapeutic response to metronidazole (50% failure rate with initial course of treatment).

* McDonald LC et al. Emerg Infect Dis 2006;12:409-415.‡ Musher DM et al. Clin Infect Dis 2005;40:1586-1590.

C. difficile: Changing spectrum of clinical disease

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700 C. difficile related deaths in Quebec, Canadain one year (2003-4)

400 C. difficile related deaths annually in Quebecat the present time

§ Regional outbreaks - Pittsburgh, PA, Quebec, Canada and the mid-Atlantic and southeastern U.S.

§ C. difficile in low risk populations – young individuals, peripartum women, community dwelling and in individuals with no exposure to antibiotics.

Muto, C.A., et al., Infect Control Hosp Epidemiol, 2005. 26(3): p. 273-80.McDonald, L.C., et al.,N Engl J Med, 2005. 353(23): p. 2433-41.2005. MMWR Morb Mortal Wkly Rep, 2005. 54(47): p. 1201-5.

BI/NAP1 Epidemic strain C. difficile

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PR

AKHI

Centers for Disease Control and Prevention. Data & Statistics about Clostridium diff icile infections. w ww.cdc.gov/ncidod/dhqp/id_cdiff_data.html

DC

PR

AKHI

BI/NAP1 C. difficile in U.S. Nov. 2007 (n = 38)

BI/NAP1 C. difficile in U.S. Oct. 2008 IDSA Meetings

C. difficile Epidemic in U.S.

§ October 2008 – BI/NAP1 has been isolated in all 50 states (IDSA).

§ Total number of C. difficile cases annually in U.S. is >500,000. Cost of $1.1 billion.

§ Total number of C. difficile related deaths annually in the U.S. is >15,000.

§ Epidemic is predicted to worsen.

§ Cause?

Current burden of C. difficile in U.S.

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Where does the majority of antibiotic useoccur in the U.S.?

§ Poultry industry – antibiotic use to prevent diarrheal illness

§ Corn fed beef require antibiotics to prevent bacterial overgrowth

Antibiotic use in food animal industry

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§ Colonization and carriage with the epidemic strain C. difficile (B1 NAP1 strain) reported in cows.

§ C. difficile has been isolated from retail ground meat purchased in Canada.

Songer, J.G. and M.A. Anderson, Clostridium difficile: an important pathogen of food animals. Anaerobe, 2006. 12(1): p. 1-4.Rodriguez-Palac ios, A., et al., Clostridium difficile in retail ground meat, Canada. Emerg Infect Dis, 2007. 13(3): p. 485-7.

BI/NAP1 Epidemic strain C. difficileand food animals

Poutanen SM et al. CMAJ. July 6,2004;171(1).

C. difficile infectious inoculum is 10 spores

C. difficile spores may be resistant to cooking.Source of bacterial food poisoning?

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1) Antibiotic destroysnormal bacterial flora

3) Toxins inflameand ulcerate mucosa

2) C. difficile grows and secretes toxins

ColonicMucosa

Normal floraC. difficile

Toxin

PMN

Gut Lumen

4) Damaged mucosasecretes fluid causingdiarrhea

Antibiotic

Poutanen SM et al. CMAJ. July 6,2004;171(1).

C. difficile: Pathogenic mechanisms

Fluid secretion

Clostridium difficile

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§ 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, concluding “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;16:26-30.Bolton RP et al. Lancet 1980;1:383-384Trnka Y et al. Gastroenterology 1981;80:693-696.

Issa, M., et al. Clin Gastroenterol Hepatol, 2007. 5(3): p. 345-51.Rodemann, J.F., et al.Clin Gastroenterol Hepatol, 2007. 5(3): p. 339-44.Ananthakrishnan, et al. Gut, 2008. 57(2): p. 205-10.

Clostridium difficile and IBD

Increasing Impact of Clostridium difficile on IBD

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Increasing Proportion of Clostridium difficile Patients With IBD

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Complications: Clostridium difficileInfected Patients With IBD*

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Endoscopic appearance of C. diff in control patients

Endoscopic Appearance of C. difficile

Endoscopic appearance of C. diff in patients with IBD

Ulcerative Colitis Crohn’s DiseaseIssa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51.

Extensive cryptitis crypt abscesses in Crohn’s colitis pt with active C. difficile. No inflammatory pseudomembranes are identified.

Classic pseudomembrane on histology—mucin, fibrin, necrotic debris

Histologic appearance C. difficile in IBD

Issa M et al. Clin Gastro Hep. 2007 Mar;5(3):345-51.

Control patient Crohn’s disease patient

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91% Colonic IBD

61% Recent antibiotic exposure


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)

0.5%IBD alone

3.7%C. difficile alone

4.2% IBD pts with C. difficile

Ananthakrishnan, et al. Gut, 2008. 57(2): p. 205-10.

Clostridium difficile in IBD: Morbidity and Mortality

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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.

§ No prompt response to metronidazole, consider vancomycin p.o.


§ Laboratory

- Leukocytosis

- Hypoalbuminemia

§ Radiographic

§ Endoscopy - Pseudomembranes in 50% of patients with CDAD – rare in IBD patients.

III. Diagnostic considerations:C. difficile in IBD

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§ Cell culture toxin assay is the gold standard

- excellent sensitivity

- requires 24 – 48 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%.

Diagnosis of Clostridium difficile


Stool ELISA testing in IBD patients for C. Difficile toxins A and B

C. d

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Stool ELISA sample

0102030405060708090

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1st 2nd 3rd 4th

Positive C.difficileELISA

4 stool samples to reach90% detection with ELISA

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C. difficile in ileo-anal

PouchitisC. difficile in segments

of diverted bowel

Two case reports § Chronic refractory

pouchitis § Unresponsive to broad

spectrum antibiotics§ In both cases C. difficile

developed while patients were on metronidazole therapy

§ 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, 2003. 46(2): p. 267-70.Shen, B., et al. Dig Dis Sci, 2006. 51(12): p. 2361-4.

Tsironi, E., et al. Dis Colon Rectum, 2006. 49(7): p. 1074-7.

Special IBD scenarios with C. difficile

§ Rare but associated with significant morbidity with mortality rates ranging from 60-83%

§ MCW institutional series of six patients (2004-2006). C. difficile manifested in high volume watery ileostomy output, ileus and fever with leukocytosis. No mortality with prompt diagnosis and therapy.

Miller, D.L et al. Arch Surg, 1989. 124(9): p. 1082.Jacobs, A., et al. review of the literature. Medicine (Baltimore), 2001. 80(2): p. 88-101.Hayetian, F.D., et al. Arch Surg, 2006. 141(1): p. 97-9.Lundeen et al. J Gastroentest Surg (2007) 11:138-142

C. difficile enteritis: An early complication in IBD patients following colectomy

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IV. Therapeutic considerations:C. difficile in IBD

§ 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.

Approach for hospitalized IBD patients withSuspected/confirmed C. difficile

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METRONIDAZOLE

FDA-approved No

Colonic levels 0 -10 mcg/ml

EffectivityMildSevere

++++Inferior

Promotion of VRE Yes

Failure rate 13-16%*

Relapse rate 10-25%

Side effects Significant

Response(median time) 4.6 days

Cost +Zar, F.A., et al.. Clin Infect Dis, 2007. 45(3): p. 302-7. Lucas GM et al. Clin Infect Dis. 1998 May ;26 (5):1127-339Aslam et al. Lancet Infect Dis 2005;5:549-557.Wilcox, M.H. and R. How e, J Antimicrob Chemother, 1995. 36(4): p. 673-9.

Oral vancomycin vs metronidazole 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

Oral vancomycin for C. difficile

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§ Retrospective study from 20 ECCO investigators

§ 155 IBD patients with C difficile (59% UC)Antibiotics alone (n = 51)Combination Immunomodulator + antibiotic (n = 104)

§ 12 colectomies, all in combination group

§ Patients in combination group were sicker (more UC, abd pain, diarrhea, bleeding)

§ Among colectomy patients:Corticosteroids – 92%Thiopurine/MTX - 42%CsA - 33%Anti-TNF 25%Double/triple IS – 66%

Use of combination immunosuppression in setting of IBD and C. difficile

Ben-Horin S et al. Clin Gastro Hep. 2009; 7: 981-987.

Decreasing colectomy rate amonghospitalized IBD patients with C. difficile

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Number of infections and rate of hospitalization remained constant, but significant decrease in colectomy rate.

- High index of suspicion-Use of oral vancomycin- Decreased corticosteroid dosing

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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, 2006. 101(4): p. 812-22.Mayfield, J.L., et al. Clin Infect Dis, 2000. 31(4): p. 995-1000.Wilcox, M.H., et al.J Hosp Infect, 2003. 54(2): p. 109-14. Leischner, J., et al., American Society for Microbiology, 2005. ((abstract # LB 29)).

Preventive strategies - C. difficile

Refractory C. difficile:- Intravenous immunoglobulin was used in a series of 14 patients (200 mg/kg).

64% responded. One patient required 2nd 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, 2006. 49(5): p. 640-5. Issa, M., et al. Am J Gastro, 2006. 101(9): p. S469. Johnson, S., et al. Clin Infect Dis, 2007. 44(6): p. 846-8.

Refractory and recurrent C. difficile

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Herpes virus family member.

Trophic to endothelial cells in microcirculation.

life long latency following a primary infection.

CMV infections in immunosuppressed patients are reactivation.

CMV may be a nonpathogenic bystander or true pathogen.

immunostain

HE staining

colonoscopy

Pro-inflammatory cytokines (i.e.TNF) increased in active IBD mucosa trigger reactivation of CMV.

CMV tropism for sites of severe inflammation.

CMV reactivation with immunosuppressive medications especially corticosteroids.

Soderberg-Naucler et al. J Clin Invest 1997Goodgame et al. Ann Intern Med 1993; 3154-63

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CMV infection in IBD - associated with poor outcomes including colectomy.

Prevalence of CMV infections 5-30%

- worst 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;96:773-775 Criscuoli V et al,Dig Liver Dis.2004,36;818-820Kishmore J et al.J Med Micro,2004;1155-1160 Wada Y et al.Dis Colon Rectum;2003;46:S59-65

Clinical findings:

High index of suspicion

AnemiaHypoalbuminemia

Endoscopic findings:

Punched out ulcers

Histologic biopsies:

H&E staining - viral inclusion bodies

Immunohistochemistry - CMV antibodyCMV DNA by PCR

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Indirect evidence of recent CMV infection based upon change in antibody titers

ELISA, latex agglutination, radioimmunoassay, complement-fixation

Diagnosis of recent or acute CMV is probable if:

CMV-specific IgM antibodies detected

4-fold increase in CMV-specific IgG titers in paired specimens 2 - 4 weeks apart

IgM antibody persists for several months and therefore can provide misleading information if a prior baseline test not available.

Requires paired serum samples (IgG) -

limits utility in establishing timely diagnosis.

Helpful in determining past exposure to CMV infections.

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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. Clin Inf Dis ;1998

Discontinue/decrease immunosuppressives and taper steroids.

Ganciclovir:

IV 5mg/kg BID X 14 days then

Oral Valganciclovir 450 mg BID X 4 Weeks.

Monitor response with CMV pp65 antigenemia assays.

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CMV – 6 cases from 2002 – 2007.

2 hospitalized

1 colectomy

C difficile - 29 cases from 2002 – 2007.

16 hospitalized

7 colectomies

§ C. difficile has doubled in North American Medical Centers in the past 5 years.

§ IBD colitis patients have been affected at highest rate.

§ C. difficile in IBD is associated with high rates of hospitalization and colectomy and increased mortality.

§ Antibiotic use may not be required to precipitate infection.

§ Endoscopic and Histologic appearance is frequently not classical – pseudomembranes not always present.

§ Multiple stool ELISA samples for toxin analysis are required to make a diagnosis.

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§ Metronidazole failure rate is 50%; Oral vancomycin may be superior in hopitalized patients.

§ C. difficile enteritis may occur in post-colectomy patients and patients with ileoanal reconstruction.

§ C. difficile recurrence rates are high.

§ Hand washing with soap and water is essential to prevent nosocomial transmission.

§ CMV in IBD patients – occurs in patients with maximum immunosuppression and steroids. Transplant patient setting.

§ Rate of infection is variable.§ Reactivation is most likely mechanism.§ Diagnosis based on punched out ulcers, histology

for CMV. § Treat with ganciclovir and decreased

immunosuppression.

Clostridium difficile and CMV in Inflammatory Bowel...

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