Jeffrey D. McCurdy

A Model for Identifying Cytomegalovirus in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS The presentation of cytomegalovirus (CMV) disease in patients with inflammatory bowel disease (IBD) can be similar to that of idiopathic IBD. It is a challenge to identify patients at highest risk for CMV. We investigated risk factors and generated a clinical score to identify patients with IBD at highest risk for CMV disease. METHODS We performed a retrospective case-control study of 68 patients with IBD (66% with ulcerative colitis, 31% with Crohns disease, and 3% with unclassified IBD) diagnosed with CMV disease on the basis of tissue analysis from January 2005 through December 2011 at Mayo Clinic, Rochester. The patients were each matched with 3 patients with IBD and suspected CMV disease (controls). An a priori set of the most objective variables was used to create a model to identify those with CMV disease. Scores were assigned to each significant factor from the multivariable analysis. Cutoff values that identified patients with CMV with ≥85% sensitivity and specificity were selected. RESULTS Patients with medically refractory IBD (odds ratio [OR], 3.69; P < .001) or endoscopic ulcers (OR, 3.06; P < .001) and those treated with corticosteroids (OR, 2.95; P < .001) or immunomodulators (OR, 1.86; P = .030) but not tumor necrosis factor antagonists (OR, 1.30; P = .376) were more likely to have CMV disease than patients with IBD without these features. In a multivariable model, refractory disease, treatment with immunomodulators, and age older than 30 years were independently associated with CMV disease. Use of tumor necrosis factor antagonists was an insignificant factor even after adjustment. CONCLUSIONS Clinical features can identify patients with IBD at risk for CMV disease. This model may help clinicians stratify patients on the basis of risk when CMV disease is suspected.

Effects of Antiviral Therapy for Patients With Inflammatory Bowel Disease and a Positive Intestinal Biopsy for Cytomegalovirus

BACKGROUND & AIMS Cytomegalovirus (CMV) is an opportunistic pathogen; documented tissue involvement of patients with inflammatory bowel disease (IBD) is associated with adverse outcomes. We quantified the density of CMV inclusions in biopsy specimens from patients with IBD and assessed their response to antiviral therapy. METHODS In a case-control study, we identified all small bowel and colon biopsy specimens collected from 1111 patients with IBD that had been submitted to the Department of Laboratory Medicine and Pathology, Mayo Clinic, to evaluate for CMV in intestinal tissue from 2005 through 2011. All positive cases were reviewed to confirm the diagnosis of CMV in tissue. We determined the number of viral inclusions in each processed biopsy sample. Biopsy specimens with 5 or more inclusions were considered to have high-grade CMV density. We collected data on response to antiviral therapy and history of surgical resection within 1 year after diagnosis of CMV in tissue. CMV-negative samples (controls) were selected from the same IBD population. Primary outcomes included clinical improvement, hospital admission, time to admission, need for surgical procedures, time to surgery, escalation of therapy, and relapse of CMV infection. RESULTS In our analysis of the biopsy samples, 68 (6%) were found to contain CMV. Follow-up data and treatment outcomes were available from 50 cases, including 16 patients with high-grade CMV density (all treated) and 34 with low-grade CMV density (20 treated). There was no overall difference in survival, free of surgery, between patients with or without CMV 1 year after diagnosis in tissue. Antiviral treatment improved surgery-free survival outcomes of patients with CMV infection—particularly of patients with high-grade CMV density. CONCLUSIONS Patients with IBD and a high density of CMV inclusions in intestinal biopsy specimens benefit from antiviral therapy. Patients with fewer viral inclusions in biopsy specimens also might benefit, but the severity of the IBD should be the prime consideration in determining treatment strategies.

Detection of Cytomegalovirus in Patients with Inflammatory Bowel Disease: Where to Biopsy and How Many Biopsies?

Background:The potential negative impact of cytomegalovirus (CMV) in ulcerative colitis (UC) and Crohns disease (CD) warrants efforts to improve the yield of diagnostic techniques. Methods:We retrospectively determined the optimal biopsy location and number from sixty-eight patients with inflammatory bowel disease (66% UC, 31% CD, and 3% inflammatory bowel disease-unclassified) with CMV disease between 2005 and 2011. Biopsies with endoscopic and histologic inflammation were analyzed by immunohistochemistry and/or in situ hybridization. The proportion of positive biopsies was determined, and using data from the 25th percentile, we assessed the number of biopsies required to achieve an 80% probability of a single positive biopsy. Results:Of the patients with a diagnosis by immunohistochemistry and/or in situ hybridization, 27 of 61 (44%; 95% confidence interval, 32–57) were positive by hematoxylin and eosin, and 11 of 36 (31%; 95% confidence interval, 16–46) had systemic CMV by polymerase chain reaction. Of the patients with biopsies proximal and distal to the splenic flexure, 1 of 11 with UC and 4 of 8 with CD had a diagnosis limited to the right colon. Twenty percent of biopsies were positive by immunohistochemistry or in situ hybridization (20% in UC and 17% in CD). Eleven biopsies in UC and 16 in CD were required to achieve an 80% probability of a positive biopsy. Conclusions:Biopsy location and number are important considerations when assessing for CMV. We recommend a flexible sigmoidoscopy with 11 biopsies in UC and a colonoscopy with 16 biopsies in CD.

Cytomegalovirus infection of the ileoanal pouch: clinical characteristics and outcomes.

Background:Up to 30% of cases of pouchitis are felt to have a secondary cause. Cytomegalovirus (CMV) may represent a possible etiopathological agent. Here, we report our experience with CMV involvement of the pouch, including risk factors, clinical features, and pouch outcomes in patients with inflammatory bowel disease after proctocolectomy with ileal pouch–anal anastomosis. Methods:The pathology database at Mayo Clinic in Rochester was searched between January 1995 and October 2012 for patients with a tissue diagnosis of CMV of the pouch following ileal pouch–anal anastomosis. Results:Seven patients with CMV inclusions of the pouch were identified. The median age was 35 (range, 10–53) years, and the majority were female (71%). Five patients (71%) were on immunosuppressive medications including 4 who had undergone orthotopic liver transplantation for primary sclerosing cholangitis. The clinical presentation was similar among all patients: the majority had diarrhea (86%), fever (71%), and abdominal pain (57%). All had mucosal inflammation, with 71% having focal ulcerations in the pouch and 60% having inflammatory changes in the prepouch ileum. All patients improved with ganciclovir. None required pouch excision or had recurrent CMV infection. Three patients had recurrent nonspecific pouchitis. Conclusions:A high index of suspicion is needed to diagnose CMV of the pouch. An increase in stool frequency and fever in patients on immune suppression or in those who have failed empiric antibiotics should prompt assessment for CMV infection. Antiviral therapy seems to be effective, and postinfection pouch outcomes seem favorable, particularly in those presenting with their first episode of pouchitis.

Increased Rates of Clostridium difficile Infection and Poor Outcomes in Patients with IBD with Cytomegalovirus

Background:Clostridium difficile infection (CDI) and Cytomegalovirus (CMV) reactivation are associated with disease exacerbations and poor outcomes in inflammatory bowel disease (IBD). Therefore, we assessed the association between these organisms in patients with IBD and the impact on colectomy. Methods:A retrospective case–control study was conducted to assess CDI prevalence in patients with IBD with a tissue diagnosis of CMV compared with matched IBD controls without CMV from 2005 to 2011. We also assessed the impact of coinfection on colectomy risk for patients coinfected with CMV and CDI compared with IBD patients with CMV alone (CMV controls) or matched IBD patients with CDI alone (CDI controls). Colectomy-free survival was assessed using Kaplan–Meier methods, and statistical significance was determined using Log-rank analysis for unmatched comparisons and by generalized estimating equations in Cox regression for matched comparisons. Results:CDI was more common in IBD patients with CMV (n = 12/68; 17.6%) than in matched IBD controls (n = 12/144; 8.25%) (P = 0.046). A nonsignificant increase in high-grade disease (5 or more CMV inclusions by immunohistochemistry) was detected in coinfected patients compared with CMV controls (P = 0.15). Colectomy-free survival at 1 year was 30% (95% confidence interval, 12.0–74.7) for coinfected patients and was significantly less compared with 71.5% (95% confidence interval, 58.0–88.2) of CDI controls (P < 0.001) and was numerically less than 57.1% (95% confidence interval, 44.1–74.0) of CMV controls (P = 0.095). Conclusions:CDI occurs more frequently in IBD patients with CMV reactivation and is associated with poor outcomes. Patients with IBD with CMV should be tested for CDI and managed aggressively.

Clinical Benefit of Capsule Endoscopy in Crohn's Disease: Impact on Patient Management and Prevalence of Proximal Small Bowel Involvement.

Background Ileocolonoscopy and computed tomography (CT) or magnetic resonance (MR) enterography (CTE/MRE) are utilized to evaluate patients with small bowel (SB) Crohns disease (CD). The purpose of our study was to estimate the impact of capsule endoscopy (CE) on patient management after clinical assessment, ileocolonoscopy, and CTE/MRE. Methods We prospectively analyzed 50 adult CD patients without strictures at clinically indicated ileocolonoscopy and CTE/MRE exams. Providers completed pre- and post-CE clinical management questionnaires. Pre-CE questionnaire assessed likelihood of active SBCD and management plan using a 5-point level of confidence (LOC) scales. Post-CE questionnaire assessed alteration in management plans and contribution of CE findings to these changes. A change of ≥2 on LOC scale was considered clinically meaningful. Results Of the 50 patients evaluated (60% females), median age was 38 years, median disease duration was 3 years, and median Crohns Disease Activity Index (CDAI) score was 238 points. All CTE/MRE studies were negative for proximal disease. CE detected proximal disease in 14 patients (28%) with a median Lewis score of 215 points. CE findings altered management in 17 cases (34%). The most frequent provider-perceived benefits of CE were addition of new medication (29%) and exclusion of active SB mucosal disease (24%). Conclusion CE is a safe imaging modality that alters clinical management in patients with established SBCD by adding incremental information not available at ileocolonoscopy and cross-sectional enterography.

Is Standard Histology Sufficient to Detect Cytomegalovirus Reactivation in Inflammatory Bowel Disease

We read with great interest the recent article by Solomon et al, who assessed the diagnostic accuracy of viral cytopathic effect (VCPE) for detecting routine viral infections in surgical specimens. The authors determined the sensitivity and specificity of VCPE from H&Estained surgical specimens compared with immunohistochemistry (IHC) as the reference standard and evaluated if changes in therapeutic decisions were required in cases of positive IHC in the absence of detectable VCPE. We were particularly interested in the results regarding the diagnostic accuracy of IHC for cytomegalovirus (CMV). From 59 positive samples by IHC, it was demonstrated that definitive VCPE had a sensitivity of 67.8%. Therefore, the authors concluded “the presence of VCPE on H&E sections is sufficient for diagnosis in most cases.” We have substantial concerns regarding the generalizability of these results in light of potential methodologic limitations and conflicting studies, particularly when considering patients with inflammatory bowel disease (IBD). The sensitivity of H&E histology for CMV reactivation in IBD is consistently poor. We previously demonstrated that H&E histology, when assessed prospectively, has an overall sensitivity of only 25% for detecting CMV reactivation compared with IHC. Even in patients with high-grade CMV disease, defined as five or more inclusions by IHC, the sensitivity of H&E histology was only 44%. Similarly, in a systematic review and metaanalysis assessing 373 patients with IBD from nine studies, the overall sensitivity of H&E histology was 12.5% (95% confidence interval [CI], 3.6%-21.4%), 34.6% (95% CI, 13.8%-55.4%) compared with IHC as the reference standard, and 4.7% (95% CI, 1.2%-17.1%) compared with tissue polymerase chain reaction (PCR) as the reference standard. The low diagnostic yield of CMV in IBD may be related to a “needle in a haystack” phenomenon. In keeping with this concept, we previously demonstrated that the diagnostic yield is greater when samples are re-reviewed. In the current study, the sensitivity of VCPE for CMV was determined retrospectively by re-reviewing tissue samples instead of from the original pathology reports and was determined by three pathologists. Both of these factors are likely to have increased the overall sensitivity of VCPE and do not reflect real-world practice. It has also been proposed that the typical histologic changes associated with CMV infection, including large cells with thickened nuclear membranes, granular cytoplasmic inclusions, and basophilic intranuclear inclusion bodies surrounded by a clear halo, classically described as the “owl’s-eye” appearance, may not necessarily occur in IBD. Although it is unclear how many patients in the current study had underlying IBD, only 53.2% of samples in the overall study were from a gastrointestinal origin. Therefore, the results from the current study cannot be generalized to patients with IBD. Recent studies have demonstrated the usefulness of ancillary testing for predicting the pathogenicity of CMV and response to antiviral therapy. Jones et al recently demonstrated that the degree of viral burden by IHC predicted surgery-free survival in patients treated with antiviral therapy. Similarly, high-grade disease by tissue PCR, defined as more than 370 IU/100,000 cells, predicted resistance to multiple lines of immunosuppressive agents in patients with IBD. Of particular importance, none of the patients in the latter study had evidence of VCPE. These findings underscore the importance of ancillary testing for CMV detection in IBD and support the recommendations of multiple gastroenterological societies, which state that IHC or tissue PCR be the tests of choice for diagnosing colonic CMV reactivation in IBD. We agree with the authors’ assertion that ancillary tests for CMV are costly and not always necessary. Therefore, identifying patients with IBD at highest c o r r e s p o n d e n c e