Cytomegalovirus Inclusions Research Articles

2056 CMV Colitis Superimposed on Ischemic Colitis in an Immunocompetent Individual

INTRODUCTION: Cytomegalovirus (CMV) infections are more commonly seen in individuals with immunosuppressive diseases. We present a unique case of CMV colitis superimposed as ischemic colitis in an immunocompetent individual. CASE DESCRIPTION/METHODS: A 68-year-old man with history of PE (on Xarelto), pneumothorax & COPD presented with 10 weeks of diarrhea, associated with chills, lower abdominal discomfort, poor appetite, and weight loss of 15 pounds. Rectal exam showed dark stool and FOBT was positive Lab data showed elevated ESR and CRP. All stool studies were negative. CT Abdomen reported colonic findings suggestive of colitis with areas of active inflammation. Colonoscopy showed inflammation characterized by congestion (edema), erosions, granularity & ulcerations in a continuous and circumferential pattern from the sigmoid colon to the terminal ileum with sparing of mid & distal sigmoid colon and the rectum (Figures 1 and 2). Preliminary biopsies were suspicious for Crohns Disease. Patient was started on PO Prednisone 60 mgs daily & Pentasa TID and discharged for close follow up with GI. He kept on failing outpatient treatment, and was re-admitted twice with worsening of symptoms. Repeat CT scans showed worsening diffuse colitis. C Diff was checked, which was –ve. He was re-started on IV Abx, IV Steroids and supportive care. His symptoms continued to worsen, so Colorectal Surgery was consulted and, he underwent open subtotal colectomy. Pathology Slides from the Surgical Specimen were diagnostic for Ischemic looking bowel, and showed no features of IBD. So, decision was made to send the slides for second opinion. Meanwhile, he continued to deteriorate, so he was taken for emergent exploratory laparotomy and was found to have diffusely ischemic and distended bowel. Confirmation of pathology was not consistent with IBD. It showed Ischemic ileocolitis with possible superimposed CMV colitis with CMV inclusion bodies (Figure 3). IV Ganciclovir was initiated, steroids were discontinued. He began to improve, diet was advanced and was discharged with GI follow up. DISCUSSION: Suspicion of CMV colitis should be investigated by endoscopic evidence. The typical findings such as owl’s eye inclusion bodies on histology is specific for CMV. This is an unusual case of CMV associated ischemic colitis in an immunocompetent individual. This case report also should sound an alarm to GI physicians on thinking about CMV colitis infections even in immunocompetent individuals.

Analysis of 14 Patients With Congenital Nephrotic Syndrome.

From January 1995 to June 2018, 14 patients with congenital nephrotic syndrome (CNS) were diagnosed in the Department of Pediatrics, Peking University First Hospital. The clinical data were retrospectively studied. Eight patients underwent genetic testing; 7 of them had NPHS1 mutations (primary CNS), and 1 did not have a mutation. Of the 7 patients with NPHS1 mutations, 6 died, and 1 had proteinuria. Of the 14 patients, 8 had cytomegalovirus (CMV) infection, and anti-CMV therapy was administered to 7 of them. The other patient was hospitalized in critically ill condition and died before anti-CMV therapy administration. Of the 7 patients who were administered anti-CMV therapy, proteinuria disappeared in 2 patients; 2 patients died; 2 patients were lost to follow up; and 1 patient still had 3+ proteinuria. Three patients had both NPHS1 mutations and CMV infection. After anti-CMV therapy, proteinuria was resolved in 1 patient but relapsed to 3+ proteinuria due to a new infection. The other 2 patients died. Of 14 patients, only 1 patient underwent renal biopsy, with results showing mesangial proliferative glomerulonephritis pathology, negative CMV inclusion body, and CMV-DNA. In this study, genetic defect could play a primary role in CNS, and CMV could play a secondary role. Primary CNS with NPHS1 mutations has a poor prognosis. Primary CNS might be accompanied by CMV infection that responds poorly to antiviral treatment. Secondary CNS caused by CMV infection may be cured with antiviral therapy. However, genetic analysis is necessary to exclude genetic defects.

True cytomegalovirus colitis is a poor prognostic indicator in patients with ulcerative colitis flares: the 10-year experience of an academic referral inflammatory bowel disease center

Background and aims: The impact of cytomegalovirus (CMV) colitis on long-term outcomes of ulcerative colitis (UC) flares remains controversial.Methods: A total of 257 UC patients with moderate-to-severe flares were observed for a mean follow-up of 41.2 months. CMV colitis was defined as histopathologic confirmation of CMV inclusions obtained from macroscopic endoscopic lesions in patients with UC flares. An independent gastrointestinal pathologist prospectively reviewed all specimens. A poor outcome was defined as any of hospitalization, colectomy or death during the follow-up period.Results: The prevalence of CMV colitis was 14% (36/257) over the 10-year study period (2007–2016). When compared to the controls, patients with CMV colitis were characterized by older age, higher disease activity, endoscopic deep ulcerations and more frequent use of immunosuppressive drugs (all p < .05). In total, 57 outcome events (50 hospitalizations, seven colectomies) were observed among the study population (44.7% in patients with CMV colitis vs. 18.9% in controls). The cumulative probability of a poor outcome was significantly greater in the patients with CMV colitis than in the controls (log-rank test p < .001). In a multivariable analysis, CMV colitis remained as an independent predictor of a poor outcome (hazard ratio; 2.27; 95% confidence interval: 1.12–4.60). Despite a generally favorable response to antiviral therapy (79%), the risk of recurrent CMV colitis remained quite high (57%). Most of the recurrences developed within 8 months (75%).Conclusions: True CMV colitis is a poor prognostic indicator among patients with UC flares. An effective strategy for managing recurrent CMV colitis is urgently needed (KCT0003296).

Immunological damage effects of cytomegalovirus infection on bone marrow hematopoietic cells

Objective: Toobserve the damage effects of cytomegalovirus (CMV) infection on hematopoietic cells and to investigate the clinical significance. Methods: (1) ELISA assay wasused to detect IL-17 and IFN-γ levels in the peripheral blood serum of 36 patients on pretherapy and posttherapy. (2) Changes of peripheral blood lymphocyte subsets were detected by FACS. (3) Cytological observation of cervical lymph nodes was executed by needle aspiration cytology. (4) Cellular immunochemistry and immunofluorescence staining were performed to observe the POX release, HLA-DR expression, IL-17A and IFN-γ secretion-like expression status of activated immune cells in the bone marrow hematopoietic microenvironment. Serum samples from healthy individuals were used as controls. Bone marrow smears from patients without iron deficiency anemia were compared as bone marrow immunostaining. Results: (1) Serum levels of IL-17 and IFN-γ were significantly increased in CMV-infected patients [IL-17 (48.23±3.86) ng/L vs (20.16±1.05) ng/L,respectively; IFN-γ (40.16±3.11) vs (8.17±1.92) ng/L,P<0.01]. (2) The proportion of CD16+/CD56+NK cells was significantly increased in patients [(43.54±6.01)% vs (14.01±3.25)%, P<0.01]. The proportion of CD3+CD4+T and CD3+CD8+T cells decreased,(20.91±53.15)% vs (35.10±4.88)%, and (15.41±5.13)% vs (25.11±3.92)%,respectively,P<0.05. (3) Large numbers of abnormal lymphocytes and macrophages (MΦ) that engulf large quantities of CMV inclusion bodies were observed in bone marrow and lymph nodes. CMV infected and destroied the hematopoietic cells of various lines in the bone marrow. The activated MΦ phagocytizedthe CMV inclusion bodies and also phagocytosed CMV-infected blood cells. (4) Activated MΦ in bone marrow hematopoietic microenvironment released POX strongly positive, highly expressed class Ⅱ HLA-DR, and highly expressed inflammatory factors IL-17A and IFN-γ. (5) Twenty-twopatients with elevated WBC were treated with ganciclovir combined with antibiotics for 2 weeks after the disappearance of the foci, WBC counts and CMV-IgM levels of 16 cases were reduced to normal.Six patients with CMV who were not turned negative were tprolonged,and the granulocyte and/or platelet counts fell below normal range. Fourteenpatients withreduced granulocyte or platelet count, CMV-IgM levels were slow descend,and the ganciclovir treated more than 4 weeks. Conclusions: CMV can infect hematopoietic bone marrow nucleated blood cells and destroy hematopoiesis. NK and MΦ cells are important effector cells against CMV infection. Activated macrophages are dual in nature, they can engulf CMV virus and virus-infected blood cells,and also aggravate bone marrow immune damage by releasing inflammatory factors such as POX and IL-17A and IFN-γ.

Challenges and Clinical Implications of the Diagnosis of Cytomegalovirus Lung Infection in Children.

Pulmonary cytomegalovirus (CMV) infection is a potential lethal disease in children, but it remains a diagnostic challenge. The differentiation between latent CMV infections with viral shedding and active infections is difficult and may lead to false positives in bronchoalvolar lavage (BAL) PCR detection. This review summarizes current diagnostic approaches for CMV lung infection in children including progress in the identification of underlying immune defects linked to this condition. There is increasing literature supporting that the combined assessment of host risk factors and lung disease pattern is essential for the diagnosis of pulmonary CMV infection in children. The most important host risk factor is an immunecompromised state that has expanded from primary or acquired immunodeficiency (e.g., HIV) to include a myriad of immune-dysregulation syndromes (e.g., CTLA4, PIK3 defects). Newborns, paricularly those born premature, are also a high-risk group. At the pulmonary level, active CMV infection is typically characterized by alveolar compromise leading to hypoxemia, ground-glass opacities, and intra-alveolar infiltrates with CMV inclusions in lung biopsy. The identification of active CMV lung infection should trigger additional evaluation of immune defects (primary or secondary) impairing T and NK cell function or innate antiviral responses as well as other immune dysregulation disorders. Lung CMV infections in children are more prevalent in immunocompromised hosts and premature newborns. Lung CMV infections should prompt further investigation into conditions altering immune mechanisms usually in place to contain CMV infections. Common clinical and radiological patterns such as hypoxemia and ground-glass pulmonary opacities may allow early identification and treatment of CMV lung infection and underlying causes in the pediatric population.

The Bug Blockade: CMV-Induced Terminal Ileum Stricture

Cytomegalovirus (CMV) colitis is typically found in patients that are immunocompromised and is rarely found in immunocompetent patients. Patients with CMV colitis present with nonspecific GI symptoms mainly abdominal pain, nausea, vomiting, and diarrhea. CMV ileitis has been primarily described in AIDS patients and is found in 4% of CMV cases affecting the GI tract. In this case, we present an immunocompetent patient who presented with a high grade small bowel obstruction (SBO) secondary to CMV ileocolitis causing a terminal ileum stricture. The patient is a 60-year-old immunocompetent, HIV-negative black male recently admitted with SBO. CT scan of his abdomen showed several centimeters of circumferential wall thickening of his terminal ileum (TI), and colonoscopy was unsuccessful due to bowel prep. He was a poor candidate for surgery given CHF with an EF of 20%. He was planned for outpatient colonoscopy after two weeks of Prednisone for presumed Crohn's disease. Patient had persistent abdominal pain requiring re-hospitalization. Colonoscopy showed ulcerations and erosions in the TI and cecum with a TI stricture that could not be traversed with biopsies taken. Repeat CT showed high grade SBO. He underwent successful laparotomy and ileocecal resection and resection of stenosis with side-to-side functional end-to-end anastomosis. Colonoscopy biopsy samples showed crypt distortion, ulceration and immunohistochemical staining was positive for CMV inclusions. The resected specimen confirmed viral cytopathic change with multiple superficial ulcerations and vasculature containing stromal cells with viral inclusions positive for CMV. There was no histologic features to support IBD. Patient had symptom resolution and was discharged home.1475_A Figure 1. Colonoscopy showing high grade stricture in the terminal ileum through which the colonoscope could not be traversedCMV ileitis is rare in immunocompetent patients. A systematic review on immunocompetent patients with CMV in any organ in 2008 described 60 patients with CMV colitis. This study found no significant difference in mortality for patients with CMV colitis treated with antiviral agents. There is only one other case report of a patient with a CMV-induced colonic stricture presenting as an acute bowel obstruction in an immunocompetent adult. This is the only case of CMV terminal ileocolitis with primary ileal involvement that caused acute SBO in an immunocompetent adult. There are no clear guidelines in the management of CMV ileocolitis; however, surgical intervention of bowel obstruction provided good outcomes in both cases.1475_B Figure 2. Colonoscopy biopsy showing evidence of CMV inclusion (arrow).1475_C Figure 3. Histology with positive immunohistochemical staining for CMV intranuclear viral inclusions.

Double Hit: CMV-Related Toxic Megacolon in a Poorly Controlled Diabetic Patient

A 58 year old man with uncontrolled type 2 diabetes mellitus presented with 1 week of worsening lower abdominal pain, constipation, decreased appetite, and unintentional weight loss. He had recently been admitted to the hospital with diabetic ketoacidosis (DKA) four weeks previously when he was recorded to have a hemoglobin A1c of greater than 17.4%. His physical exam was most significant for cachexia and a tense, diffusely tender abdomen. Basic laboratory data including complete blood count, complete metabolic panel (including liver tests), amylase and lipase were normal. Computed tomography (CT) of the abdomen and pelvis revealed distal sigmoid colitis and diffuse colonic dilatation, greatest in the transverse colon with a diameter of 10 cm consistent with toxic megacolon. Flexible sigmoidoscopy was then performed and revealed edematous, ulcerated mucosa in the rectum, sigmoid, and descending colon. Biopsies and pathological evaluation were positive for cytomegalovirus (CMV) inclusions. The patient was treated with a 14-day course of valgancyclovir 900 mg twice daily with subsequent symptom improvement. CT abdomen and pelvis 8 days later showed decreased colonic distension. CMV-associated toxic megacolon is a diagnosis usually only observed in immunocompromised patients, such as those with inflammatory bowel disease or human immunodeficiency virus. There is little evidence of CMV-induced toxic megacolon in immunocompetent individuals, with case reports limited to those patients with other acute conditions such as C. difficile infection or severe trauma. Our patient had no concomitant acute illness or identifiable etiology of immunocompromise aside from diabetes. Diabetic patients are prone to opportunistic infections such as CMV due to deleterious effects of blood glucose on neutrophil and T-cell function, which is pronounced in the setting of HgA1c elevation. To our knowledge, this is one of the first reports in the literature of CMV-associated toxic megacolon identified in setting of diabetes. It is important to recognize the risk of CMV colitis and associated megacolon in this patient cohort especially when diabetes is poorly controlled.Figure: CT Abdomen and Pelvis showing a 10 cm dilatation of the transverse colon.Figure: Ulcer bed with granulation tissue showing a stromal cell with CMV inclusion (arrow).Figure: Edematous and ulcerated mucosa found in the sigmoid colon on flexible sigmoidoscopy.

A rare case of cytomegalovirus presentation in a hemodialysis patient

Background: Cytomegalovirus (CMV) infection is a common viral infection in humans with a diverse manifestation, mostly dependent on the host. CMV infection in the immunocompetent host is generally asymptomatic or may present as a mononucleosis syndrome. Infection in immunocompromised patients cause substantial morbidity and mortality.Case representation: We report a rare manifestation of a CMV infection in a 87-year-old male with end-stage renal failure with dialysis dependency and diabetes who presents with diffuse abdominal pain and nausea. Further assessment with a CT scan of the abdomen showed a thickening of the wall of the preterminal ileum, suggestive of focal enteritis. Ileocolonoscopy showed a partial circular ulcerated mucosa of the preterminal ileum, biopsies showed ulcerations, etiology was unknown. A few days later he develops melena and anemia of 7.2 g/dl. Further exploration with gastroscopy was normal. A new colonoscopy showed no abnormalities; however the terminal ileum could not be visualized. An urgent laparotomy was performed because of hemodynamic instability and showed an ulcus of 7 cm with a thickened terminal ileum. An enterectomy of the inflammated part of the ileum was performed. Histopathology of the ulceration showed the presence of CMV inclusions in the vascular endothelium of the capillaires of the ileal segment. Serologic examination showed nonreactive CMV IgM antibodies and IgG antibodies were positive. PCR CMV showed 300 copies/ml (whole blood). Treatment with intravenous ganciclovir was started with good clinical and biochemical response.Conclusions: In the differential diagnosis CMV disease should be considered in any ulceration in the gastro-intestinal tract in the immunocompromised patient.

Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade.

Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

The Association Between CMV Viremia or Endoscopic Features and Histopathological Characteristics of CMV Colitis in Patients with Underlying Ulcerative Colitis

Cytomegalovirus (CMV) infection has been shown to be related to severe or steroid-refractory ulcerative colitis (UC) flare-ups. The aim of this study was to evaluate the endoscopic and pathological characteristics of CMV colitis in patients with UC and to assess the predictive value of the endoscopic and pathological features of CMV colitis. A total of 50 consecutive UC patients with CMV infection who were admitted to Peking Union Medical College Hospital from 2010 to 2015 were enrolled in this study. Twenty-five UC patients with CMV infection (50.0%) had concurrent CMV colitis. When the cutoff value was set at 1150 copies, the sensitivity and specificity of blood CMV DNAq polymerase chain reaction for predicting CMV colitis were 44.4% and 78.9%, respectively. A higher proportion of endoscopic punched-out ulcers, irregular ulcers, and cobblestone-like appearance were observed among the patients in the CMV colitis group than those in the non-CMV colitis group (52.0% versus 20.0%, 60.0% versus 16.0%, and 20.0% versus 0%, respectively, P < 0.05). The number of CMV inclusion bodies per high-power field was significantly higher in those with punch-out ulcerations (25.7% versus 60.0%, P < 0.05). A higher grade of pathological inflammation was observed in the CMV colitis group than in the control group (68.0% versus 44.0%). Characteristic endoscopic features with punch-out ulcers and high CMV viremia load may be useful for predicting the presence of CMV colitis in histology. Punch-out ulcers were found to be associated with a higher number of inclusion bodies on histology, suggesting a role of targeted biopsy for endoscopist.

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

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. 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. 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). 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.

Cytomegalovirus (CMV) in gastrointestinal mucosal biopsies: should a pathologist perform CMV immunohistochemistry if the clinician requests it?

Cytomegalovirus (CMV) causes clinically significant gastrointestinal (GI) injury. CMV inclusions can be identified on routine hematoxylin and eosin (H&E) stain, but immunohistochemistry (IHC) is also available for identifying CMV in tissue. The advent of accountable care organization models of care bring into question whether it is cost-effective for immunohistochemistry to be performed upfront at the request of clinicians and whether the quality of viral detection is compromised when the diagnosis of CMV is predicated on histologic review. In this study, a retrospective review of GI biopsies with CMV evaluations was performed. There were 449 cases with clinical requests to rule out CMV and 238 CMV analyses initiated by the pathologist without a clinical request. Among the cases that included a clinician's request, 37 had CMV detected. Immunostaining was performed on 26 cases, while a diagnosis based on readily identifiable viral inclusions on H&E-stained slides was made in 11. Among pathologist-initiated work-ups, 15 were CMV+, 3 of which had inclusions identified by H&E only. Among 38 CMV cases for which IHC had been performed, 27 had overt viral inclusions obvious on H&E. Seventy-two cases revealed uninflamed GI mucosa, and although a clinical concern about CMV infection was present, a CMV IHC work-up was not initially performed; all were negative for CMV by IHC and H&E. Clinical suspicion for CMV has a high yield for CMV detection, but "upfront" testing is likely unnecessary. Careful histopathologic review by a pathologist remains critical in the efficient and cost-effective detection of CMV.

Cytomegalovirus encephalitis: Undescribed diffusion-weighted imaging characteristics. Original aspects of cases extracted from a retrospective study, and from literature review

There is paucity of studies analyzing DWI in MRI sequences when imaging cytomegalovirus (CMV) meningoencephalitis. The main objective of this study is to demonstrate that DWI sequence is mandatory when imaging immunocompromised patients presenting with encephalitic symptoms, as this sequence can reveal very peculiar lesions in the setting of CMV encephalitis. Three CSF PCR CMV positive cases were identified in a 13-year retrospective study with MRI scans including T1, FLAIR, DWI with automated ADC calculation, and T1 with contrast injection, and were reviewed by a senior neuroradiologist. Our three cases presented multiple high-signal intensity punctiform lesions in DWI, which uniformly were in restricted diffusion. Each patient had multiple lesions (mean 19.3, range 12-30): 96.5% were supratentorial and 3.5% were infratentorial. Among supratentorial lesions, 62.5% were subependymal, 28.6% were periventricular and 8.9% were subcortical. Some lesions remained in a long lasting restricted diffusion state. All cases had FLAIR curvilinear periventricular high signal intensities. No contrast uptake was found. Punctiform DWI lesions had a clear ventricle wall tropism, consistent with classical autopsy findings. The classical histological knowledge-compatible explanation for long lasting diffusion restriction is non-lethal cytotoxic edema owing to CMV inclusions. Subependymal and periventricular punctiform restricted diffusion lesions in the setting of meningoencephalitis in immunocompromised patients seem highly evocative of CMV encephalitis. The diffusion sequence probably reveals focal lesions constitutive of cellular viral inclusions.

Characteristic endoscopic findings and risk factors for cytomegalovirus-associated colitis in patients with active ulcerative colitis.

To identify characteristic endoscopic findings and risk factors for cytomegalovirus (CMV)-associated colitis in patients with active ulcerative colitis (UC). A total of 149 UC patients admitted to the Department of Gastroenterology, Nagoya University Hospital, from January 2004 to December 2013 with exacerbation of UC symptoms were enrolled in this retrospective study. All medical records, including colonoscopy results, were reviewed. CMV infection was determined by the presence of CMV antigen, CMV inclusion bodies in biopsy specimens, or positive specific immunohistochemical staining for CMV. Multivariate analysis was used to identify independent risk factors for CMV colitis. Multivariate analysis indicated independent associations with the extent of disease (pancolitis) and use of > 400 mg corticosteroids for the previous 4 wk. In contrast, no association was seen with sex, age at UC diagnosis, immunomodulator use, or infliximab use. Punched-out ulceration was also significantly associated with CMV infection in patients with active UC (odds ratio = 12.672, 95%CI: 4.210-38.143). Identification of a total corticosteroid dose > 400 mg for 4 wk, extensive colitis and a specific endoscopic finding of punched-out ulcer might facilitate the more rapid diagnosis and timely initiation of antiviral therapy for CMV-associated colitis in patients with active UC.

Inflammatory Bowel Disease Patients With High-Grade Cytomegalovirus Infection May Benefit From Antiviral Therapy

Introduction: Patients with inflammatory bowel disease (IBD) have an increased risk of cytomegalovirus (CMV) colitis, but can also have incidental CMV identified on mucosal biopsies. Identifying IBD patients with CMV who may benefit from antiviral therapy thus remains a challenge. Increasing evidence support that patients with a “higher grade” of CMV infection may benefit most from antiviral therapy, but there is no consensus in defining high versus low grade infection. We aim to investigate the effect of antiviral treatment in high and low grade infection by CMV cell number. Methods: Patients with IBD and CMV infection were identified by searching the pathology database. Slides were re-reviewed blinded to clinical outcome and the number of CMV cells on immunohistochemical (IHC) staining was quantified. The distribution of CMV cell counts were determined, and patients were stratified into “high grade” and “low grade” infection, based on the median cell number (high grade: > median, low grade: < median). Charts were reviewed for clinical outcomes and laboratory data including serum CMV PCR. Results: Forty-four patients with IBD and CMV by IHC were identified. Cell count ranged from 1 to 25 cells (median 5); high grade infection was defined as ≥5 cells. Serum CMV polymerase chain reaction (PCR) was significantly higher in patients with high vs low grade infection (167 vs 16 copies, p < 0.05). There were no differences in hospitalization rate, length of stay, and inflammatory markers between high and low grade infection, and between treated versus untreated subgroups (Table 1). Although not statistically significant, there was decreased colectomy rate in patients with high CMV load receiving antiviral treatment, compared to patients not receiving treatment (Table 1). The colectomy rates of treated versus untreated patients with low grade CMV appear to be similar.Table 1Conclusion: Our study indicates that serum CMV PCR correlates with colonic CMV burden and may be used to predict CMV colitis with “high grade” CMV infection. Our data suggests that treating patients with high CMV burden (≥5 CMV inclusion cells) may improve important clinical outcomes, notably colectomy. Further studies are warranted.

A Risk Score to Predict CMV Viremia within the First 100 Days after Allogeneic Stem Cell Transplantation Based on Pre-Transplant Parameters

▪Introduction:Cytomegalovirus (CMV) is a major infectious complication following allogeneic hematopoietic stem cell transplantation (HSCT). Risk of CMV infection varies between patients and individualized strategies for monitoring and therapy for CMV are needed. In this study, we attempted to establish a clinical score based on patient and transplant characteristics in order to predict the probability for early CMV viremia (CMV-V) within the first 100 days after HSCT.Methods:A total of 548 patients were evaluated after receiving HSCT between 2005 and 2012 at Princess Margaret Cancer Centre. CMV sero-negative recipients with CMV sero-negative donors (R-D-) were excluded. CMV-V was diagnosed in peripheral blood samples obtained on two occasions either by PCR (>200 IU/ml) or antigenemia testing (>2 positive cells/100000). A total of 378 patients were included into the study. Uni- and multivariable analyses were performed to identify risk factors for CMV-V. A weighted score was assigned to each factor based on the odds ratios determined by the multivariable analysis. A total score was calculated for each patient and used for assignment into one of 4 risk categories, the low risk (score 0-1), the intermediate (score 2-3), the high (score 4-5) and the very high (score 6-8).Median age for all patients was 51 years (range 17-71) and 173 (46%) were female. Matched related donors were used for two hundred fifteen patients (57%). Two hundred forty-three patients (64%) were transplanted for myeloid and 108 (29%) for lymphoid malignancies. One hundred thirteen patients (30%) were CMV sero-positive with a negative donor (R+D-) while 191 (51%) were recipient and donor CMV sero-positivity (R+D+). Graft versus host disease (GVHD) prophylaxis included CSA/MMF (n=200, 52%), and CSA/MTX (n=178, 48%). Myeloablative conditioning regimens were administered to 220 patients (58%), 158 patients (42%) were treated with a reduced intensity regimen. Three hundred-thirty seven patients (89%) received peripheral blood stem cells as a stem cell source. In vivo T cell depletion (TCD) with alemtuzumab was used in 138 (37%).Results: CMV-V occurred in 246 (64%) patients by day 100 post HSCT. The impact of patient and HSCT characteristics on the risk of CMV-V was assessed by multivariable analysis. The significant factors were CMV sero-status R+D- and R+D+, TCD, GVHD prophylaxis with MMF administration of myeloablative preparative regimens (Table 1). [Display omitted] CMV-V rates on the 4 new risk categories amounted to 93% in the very high-risk, 78% in high-risk, 41% in intermediate-risk and 11% in low-risk group (Fig 1). The risk score was also predictive for the occurrence of multiple CMV-V reactivations with rates of 71%, 45%, 19% and 4% for the very high, high, intermediate and low-risk groups, respectively.The overall survival (OS) rate at 2 years was 33%(n=56) in the very high-risk group compared to 50% in other-risk groups (n=147) (P=0.01) (Fig 2). Non-relapse mortality (NRM) was 53% in the very high-risk versus 33% in other-risk groups (P<0.001). However, there was no difference on cumulative incidence of relapse between the groups (P=0.3).The cumulative incidence of grades 1-4 acute GVHD, grades 2-4, grades 3-4 at day 120 and overall chronic GVHD at 2 years was 68%, 47%, 25% and 39% in very high-risk group versus 65%, 52%, 21% and 52% in other-risk groups, suggesting slightly lower incidence of chronic GVHD in very high-risk vs other-risk groups.Conclusion: We present a new clinical scoring system to stratify the risk of early CMV viremia after allogeneic HSCT based on patients and HSCT characteristics. Identifying the risk for each patient would facilitate decision making with respect to strategies including CMV prophylaxis, pre-emptive treatment or inclusion into clinical trials, as well directing the CMV monitoring policy post-transplant. In addition, the risk score was associated with higher risk of overall mortality and NRM in the very high-risk versus other-risk groups. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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

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. 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. 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. 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.

Long-term outcome of inflammatory bowel diseases with cytomegalovirus colitis: effect of antiviral treatment.

The role of cytomegalovirus (CMV) reactivation in the outcome of inflammatory bowel diseases (IBDs) is unclear. Uncertainties remain on the treatment of CMV infection, especially in patients with a viral load just above the normal value in the blood or with very few positive cells in colonic biopsies. This retrospective cohort study reports the long-term outcome of 38 active IBD patients with CMV infection, 13 of whom received an antiviral treatment. Thirty patients with ulcerative colitis (UC) and eight patients with Crohn's colitis with active colitis and CMV infection, diagnosed by detection of at least one CMV inclusion by histology and immunohistochemistry and/or with the CMV antigen test or the CMV DNA test, were studied. Their clinical history at 6 months and up to 1 year following hospital discharge was reviewed. Clinical remission at hospital discharge and recurrences requiring new treatments or colectomy were considered major outcomes of the study. The features of treated and untreated patients were compared using the Fisher exact test and the Student t-test. All patients showed rare CMV inclusions, and only three had positive blood CMV PCR. Thirteen patients received antiviral treatment, whereas 25 patients did not. No patient underwent colectomy during the hospitalization. The 12-month cumulative rate of clinical relapse requiring new treatment or colectomy was 23% in patients treated with antivirals and 50% in untreated patients (P=0.165). However, in patients with UC and in those with steroid-dependent/refractory disease, antiviral treatment was associated with a significantly higher clinical remission rate at 12 months (77.8 vs. 45%, P=0.049, and 77.8 vs. 19.4%, P=0.038, respectively). In IBD patients with active CMV colitis, antiviral treatment seems to have a marginal impact in the short term, during the treatment of the acute phase, but it may have some beneficial effect in maintaining remission up to 1 year of follow-up in patients with UC and steroid-dependent/refractory disease.

Clinical significance of isolated cytomegalovirus-infected gastrointestinal cells.

Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract is associated with high mortality in immunosuppressed patients. However, few studies have correlated blood CMV load with GI histopathological findings. Furthermore, there have been few studies determining the clinical significance of isolated CMV infection. Cases were selected for the diagnosis of GI CMV infection by searching the information system of a tertiary hospital. The electronic medical record was reviewed for each case to determine blood viral load, clinicopathological features at the time of diagnosis and clinical outcomes after discharge. In all, 30 patients with CMV-positive intestinal biopsies confirmed by immunohistochemistry (IHC) were identified. All were immunosuppressed. CMV inclusions were also recognized by hematoxylin and eosin stain in 27% of the cases, and the remaining cases were identified by IHC alone. CMV blood load was only positive in 17% of the cases; 8 cases had only isolated CMV-infected cells (0.1-0.5 IHC count/high-power field), with the following outcomes: worsening symptoms that responded to antiviral therapy (n = 5); clinical improvement without treatment (n = 1); death without treatment (n = 2). CMV infection of the intestines is clinically significant but will not always present with classic viral cytopathic changes. IHC should be considered in any case where there is a clinical suspicion for CMV infection. Identification of isolated CMV infection by IHC should be considered clinically significant. Current blood viral load tests have poor sensitivity in detecting CMV intestinal infection. Future studies will investigate the predictive value of positive peripheral blood viral load in patients with intestinal symptoms.

Cytomegalovirus reactivation following hematopoietic stem cell transplantation

There is a high prevalence of cytomegalovirus (CMV) seropositivity in developing countries. An apparent risk of CMV reactivation increases following hematopoeitic stem cell transplantation. With effective surveillance and timely treatment using anti-viral therapy, morbidity and mortality associated with CMV reactivation can be reduced. To evaluate the incidence and morbidity associated with CMV reactivation following hematopoeitic stem cell transplantation. We retrospectively analysed 136 hematopoeitic stem cell transplant recipients at our centre for CMV reactivation and their complications. Quantification of CMV-DNA was done by PCR. CMV disease was confirmed histologically via CMV inclusion bodies or immunostaining of biopsy of the affected organ, mainly the gastrointestinal tract. A total of 13 out of 136 patients (9.56%) had CMV reactivation. 6 out of 13 patients had CMV disease, 3 of which died (23.1% of patients with CMV reactivation). CMV reactivation occurred at a median duration of 52.5 days post transplantation (range 35-178 days). The gastrointestinal tract was the organ most commonly affected by CMV. The median follow-up was 14 months (range 6 - 64 months). Through a higher rate of sero-prevalance in developing countries, the incidence of CMV infection following hematopoeitic stem cell transplantation is comparable to that reported in Western literature. Oral valganciclovir was an effective pre-emptive therapy for CMV disease.