Parul Tandon

Diagnostic Accuracy of Blood-Based Tests and Histopathology for Cytomegalovirus Reactivation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Background: It is unclear if traditional histopathology and noninvasive blood-based tests are sufficiently accurate to detect cytomegalovirus (CMV) reactivation in inflammatory bowel disease. Therefore, we assessed the diagnostic accuracy of these tests compared with immunohistochemistry (IHC) and tissue polymerase chain reaction (PCR). Methods: A systematic search of electronic databases was performed from inception through January 2016 for observational studies comparing diagnostic tests for CMV reactivation in inflammatory bowel disease. IHC and tissue PCR were considered reference standards and were used to evaluate the accuracy of blood-based tests and hematoxylin and eosin histopathology. Weighted summary estimates with 95% confidence intervals (CIs) were calculated using bivariate analysis. Results: Nine studies examined the accuracy of blood-based tests for predicting colonic CMV reactivation: 5 studies by pp65 antigenemia and 4 studies by blood PCR. The overall sensitivity was 50.8% (95% CI, 19.9–81.6), the specificity was 99.9% (95% CI, 99–100), and the positive predictive value was 83.8% (95% CI, 58.6–95.0). The sensitivities of pp65 and blood PCR were 39.7% (95% CI, 27.4–52.1) and 60.0% (95% CI, 46.5–73.5), respectively. Nine studies examined the sensitivity of histopathology. The overall sensitivity was 12.5% (95% CI, 3.6–21.4), 34.6% by IHC (95% CI, 13.8–55.4), and 4.7% by tissue PCR (95% CI, 1.2–17.1). Conclusions: Although blood-based tests seem to predict colonic CMV reactivation, they are insensitive tests. Similarly, histopathology has poor sensitivity for detecting colonic CMV. In agreement with current guidelines, these tests should not replace IHC or tissue PCR for detecting CMV reactivation in inflammatory bowel disease.

Corticosteroids and Thiopurines, But Not Tumor Necrosis Factor Antagonists, are Associated With Cytomegalovirus Reactivation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Background: The association between cytomegalovirus (CMV) reactivation and individual immunosuppressive agents in inflammatory bowel disease (IBD) has not been clearly defined. Therefore, we performed a systematic review and meta-analysis to assess this association. Methods: Multiple electronic databases were searched systematically through July 2015 for observational studies reporting CMV reactivation (based on serum-based or tissue-based tests) in IBD patients stratified by medication exposure. We estimated summary odds ratios (ORs) and 95% confidence intervals (CI) using random-effects model. Study quality was assessed using the Newcastle-Ottawa scale. Results: Sixteen observational studies were identified. As compared with nonexposed patients, exposure to corticosteroids (CS) (12 studies, 1180 patients, 52.3% exposed; OR, 2.05; 95% CI, 1.40-2.99) and thiopurines (14 studies, 1273 patients, 24.1% exposed; OR, 1.56; 95% CI, 1.01-2.39) was associated with increased risk of CMV reactivation. In contrast, as compared with patients not exposed to tumor necrosis factor (TNF) antagonists, exposure to TNF antagonists was not associated with an increased risk of CMV reactivation (7 studies, 818 patients, 18.5% exposed; OR, 1.44; 95% CI, 0.93-2.24). The results remained stable for CS and thiopurines when the analysis was limited to hospitalized patients, and by a tissue-based diagnosis. Studies were limited in the ability to assess the impact of concomitant immunosuppressive therapy, duration of medication exposure, and disease severity. Conclusions: On the basis of 16 observational studies, exposure to CS or thiopurines, but not TNF antagonists, was associated with an increased risk of CMV reactivation in IBD patients.

Role of endoscopy in inflammatory bowel disease

Abstract Crohn’s disease (CD) and ulcerative colitis (UC) constitute the two most common phenotypes of inflammatory bowel disease (IBD). Ileocolonoscopy with biopsy has been considered the gold standard for the diagnosis of IBD. Differential diagnosis of CD and UC is important, as their medical and surgical treatment modalities and prognoses can be different. However, approximately 15% of patients with IBD are misdiagnosed as IBD unclassified due to the lack of diagnostic certainty of CD or UC. Recently, there has been increased recognition of the role of the therapeutic endoscopist in the field of IBD. Newer imaging techniques have been developed to aid in the differentiation of UC vs CD. Furthermore, endoscopic balloon dilation and stenting have become an integral part of the therapeutic armamentarium of CD stricture management. Endoscopic ultrasound has been recognized as being more accurate than magnetic resonance imaging in detecting perianal fistulae in patients with CD. Additionally, chromoendoscopy may help to detect dysplasia earlier compared with white-light colonoscopy. Hence, interventional endoscopy has become a cornerstone in the diagnosis, treatment and management of IBD complications. The role of endoscopy in the field of IBD has significantly evolved in recent years from small-bowel imaging to endoscopic balloon dilation and use of chormoendoscopy in dysplasia surveillance. In this review article, we discuss the current evidence on interventional endoscopy in the diagnosis, treatment and management of IBD compications.

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