Cytomegalovirus Gastroenteritis Research Articles

Detection of cytomegalovirus (CMV) by digital PCR in stool samples for the non-invasive diagnosis of CMV gastroenteritis

BackgroundCMV gastroenteritis is common in patients receiving allogeneic hematopoietic stem cell transplantation and it is difficult to distinguish from acute graft-versus-host disease (aGvHD), which has very similar symptoms but needs quite different treatment. CMV gastroenteritis is caused by local infection or reactivation of CMV in the gastrointestinal tract while aGvHD is due to immune rejection. The gold standard of diagnosis of CMV gastroenteritis and aGvHD is gastrointestinal biopsy under endoscopy, which is invasive and can potentially lead to severe side effects. Stool samples testing with quantitative polymerase chain reaction (qPCR) may be an alternative, while the application in trace level measurements and precision are not all satisfactory enough in reported research.MethodsIn this study, we designed a novel method that extracted the cell free DNA (cfDNA) from the fecal supernatant to perform digital PCR (dPCR) for the detection of CMV, analyzed the performance and compared it with the total DNA extracted by the current procedure.ResultsTwenty-two paired stool samples using two DNA extraction methods proved that the cfDNA extraction method had markedly higher DNA concentrations and control gene copy number, suggesting that cfDNA may be more informative and more useful for the detection of CMV DNA segment. The dPCR approach in detecting CMV DNA segment also exhibit good linearity (R2 = 0.997) and higher sensitivity (limit of detection at 50% was 3.534 copies/μL). Eighty-two stool samples from 44 immunocompromised patients were analyzed, CMV-positive rate was 28%, indicating that more than one-quarter of the gastrointestinal symptoms within these patients may be caused by CMV infection or reactivation.ConclusionThe combined results suggest that detection of CMV by dPCR in cfDNA of stool supernatant is a powerful method to identify CMV gastroenteritis and helps in clinical treatment decision making.

Multiple polypoid lesions with erosion of the gastric mucosa in adult T-cell lymphoma/leukemia superimposed on cytomegalovirus infection.

We report here unique endoscopic findings of cytomegalovirus (CMV) gastritis associated with adult T-cell leukemia/lymphoma (ATLL). A 67-year-old Japanese man presented to a hematologist with a month history of appetite loss. Physical examination showed blurred consciousness (GCS E4V2M5) with labored breathing and hypotension. Blood examination revealed hypercalcemia (adjusted Ca: 3.24 mmol/L), anemia (Hb: 70 g/L), and leukocytosis (white blood cell count: 21.3 × 109/L) with abnormal lymphocytes (7%). Human T-cell lymphotropic virus type 1 antibody and provirus DNA monoclonality were positive. A blood transfusion was given, and noradrenaline and denosumab were administered. Upper gastrointestinal tract endoscopy showed multiple polypoid lesions with redness and erosive surface (upper left; see Figure 1). A gastric-biopsy specimen showed the presence of CD3+CD4+CD8− T cells, compatible with the gastric involvement by ATLL, and CMV gastritis presenting with inclusion bodies positive for anti-CMV antibody by immunohistochemistry (upper right and lower left; see Figure 1). CMV antigenemia was present, and soluble interleukin-2 receptor was markedly elevated at 119,194 U/ml. CMV enteritis was also observed. He was treated with ganciclovir for CMV gastroenteritis. One-month after repeated endoscopy revealed a significant regression of redness and erosion of polypoid lesions (lower right; see Figure 1). Two months later, he has been undergoing chemotherapy for ATLL. Since gastric involvement by ATLL presenting as multiple lymphomatous polyposis could only been observed in advanced stage [1, 2], we seldom encounter with this lesion nowadays. Although CMV antigenemia is frequently observed in ATLL patients [3], we rarely treat ATLL patients with CMV infections, particularly gastritis. The present case illustrates the rare complication of ATLL in these days (see Figure 1). This study was conducted by the support of the staffs at gastrointestinal department in the Uji Tokushukai Medical Center. All the authors have no conflict of interest. The authors received no specific funding for this work. All procedures performed in this study involving the patient were in accordance with the ethical standards of our institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Conceptualization, Methodology, Investigation, Data curation, Visualization, Writing-Reviewing and Editing: Yutaka Shimazu. Investigation, Data curation and Visualization: Fumihiko Kouno. Investigation, Writing-Reviewing and Editing: Shinsaku Imashuku. Investigation, Writing-Reviewing and Editing: Keisuke Shindo. Investigation, Supervision and Writing-Reviewing and Editing: Takashi Miyoshi.

Cytomegalovirus gastroenteritis in patients with acute graft-versus-host disease

AbstractA preemptive strategy has successfully decreased cytomegalovirus (CMV) disease after allogeneic hematopoietic cell transplantation (HCT). However, some recipients still develop CMV gastroenteritis, especially after acute graft-versus-host disease (aGVHD), and its incidence, risk factors, and prognostic impact remain to be elucidated. We retrospectively analyzed 3759 consecutive adult patients who developed grade II-IV aGVHD using a Japanese registry database. The cumulative incidence of CMV gastroenteritis was 5.7% by day 365 from the development of grade II-IV aGVHD. Advanced age (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.16-2.22; P = .004), GVHD prophylaxis with mycophenolate mofetil and calcineurin inhibitor (HR, 1.73; 95% CI, 1.08-2.77; P = .024), lower-gut aGVHD (HR, 2.17; 95% CI, 1.58-2.98; P < .001), and the use of systemic steroids (HR, 1.78; 95% CI, 1.16-2.74; P = .008) were independent risk factors for CMV gastroenteritis. Development of CMV gastroenteritis was associated with an increased risk of nonrelapse mortality (HR, 1.89; 95% CI, 1.50-2.39; P < .001). Moreover, letermovir prophylaxis significantly reduced both the incidence of CMV gastroenteritis (HR, 0.50; 95% CI, 0.25-0.99; P = .047) and the risk of nonrelapse mortality (HR, 0.72; 95% CI, 0.52-0.99; P = .043). In summary, CMV gastroenteritis is a life-threatening complication that sets the need for preventive strategies with letermovir and targeted surveillance.

Cytomegalovirus Gastroenteritis in Patients with Acute Graft-Versus-Host Disease

Cytomegalovirus Gastroenteritis in Patients with Acute Graft-Versus-Host Disease

Cytomegalovirus colitis in inflammatory bowel disease and after haematopoietic stem cell transplantation: diagnostic accuracy, predictors, risk factors and disease outcome

BackgroundConcurrent cytomegalovirus (CMV) colitis in inflammatory bowel disease (IBD) and after haematopoietic stem cell transplantation (HSCT) is an important clinical entity associated with high rates of morbidity and mortality.MethodsA retrospective...

Preliminary Results of a Newly Established Organ Transplantation Program in a Teaching Hospital.

End-stage renal disease is the complete failure of kidney function; kidney transplant offers the best survival advantage. We analyzed data from Al-Basheer Hospital's newly established transplant program and present our kidney transplant results from the first year of operation. Between April 2015 and June 2016, 20 kidney transplants were performed (19 living-related donors and 1 deceased donor). We assessed the demographic data, surgical techniques employed, complications, immunosuppressive drugs used, and graft and patient survival rates. The mean recipient age was 32.8 years. There were 10 male and 10 female patients. Two patients underwent preemptive transplant, and 18 were on hemodialysis. Preparation of the donor and recipient employed an established transplant protocol. Induction immunosuppression therapy was used in 13.65% of patients. The left kidney was used from all living donors, and the right kidney was harvested from the deceased donor. The total ischemia time in the living-donor grafts ranged from 30 to 53 minutes; in the deceased donor, the ischemia time was 90 minutes. Intraoperative Doppler ultrasonography was used in most cases. There was no donor mortality, and no significant donor complications occurred, either intraoperatively or postoperatively. There was no recipient mortality, but there were complications in 6 patients. Intraoperative complications were reported in 2 patients: 1 with renal artery thrombosis and the other with external iliac artery dissection. Postoperative complications were reported in 4 patients: slow graft function in 1 patient with thrombotic thrombocytopenic purpura, 1 patient with acute cellular rejection treated with intravenous immunoglobulin, 1 patient with cytomegalovirus gastroenteritis, and 1 patient treated for varicella pneumonitis. The follow-up ranged from 1 week to 13 months. The first-year outcomes for our newly established transplant program at Al-Basheer Hospital are comparable to those of well-established programs.

Incidence, Risk Factors, and Outcome of Cytomegalovirus Viremia and Gastroenteritis in Patients with Gastrointestinal Graft-versus-Host Disease

Gastrointestinal (GI) graft-versus-host disease (GVHD) is one of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia at a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P < .001). The incidence of CMV viremia with relation to donor (D) and recipient (R) CMV serostatus subgroups was as follows: D+/R+, 73%; D−/R+, 67%; D+/R−, 19%; and D−/R−, 0. A total of 31 patients were diagnosed with a biopsy-proven CMV gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D−/R+, 31%; D+/R−, 12%; and D−/R−, 0. Median follow-up time for the 252 patients was 35.4 (95% CI 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P < .001) and development of CMV gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis.

Current characteristics and outcome of cytomegalovirus infections after kidney transplantation.

The clinical course of cytomegalovirus (CMV) infections in the current era is poorly described. We characterized the symptoms and outcome of all CMV infections in a large cohort of kidney transplant recipients. Among 1129 kidney transplant recipients transplanted between 2004 and 2011 in Charité Universitätsmedizin Berlin and Helsinki University Hospital, 297 patients with CMV infection were characterized. CMV disease occurred in 217/1129 patients (19.2%), and CMV infection in 297/1129 (26.3%). Gastrointestinal symptoms were recorded in 58% and fever in 47% patients with primary CMV disease, compared to 46% and 27% patients with symptomatic CMV reactivation, whereas leukopenia or thrombocytopenia were seen in only 17-28% patients, and malaise in 9-10%. Tissue-invasive CMV gastroenteritis was confirmed in 11% and CMV pneumonia in only 1% of patients with CMV disease. Only 1 patient died because of CMV infection (mortality 0.3%). Virus-related factors or the use of secondary prophylaxis did not predict the risk of recurrence, which occurred in 33% patients. In conclusion, CMV disease remains a common problem after kidney transplantation. Gastrointestinal symptoms were common, especially in patients with primary CMV infection, whereas bone marrow suppression, hepatopathy, or malaise were seen less frequently.

Mesenchymal Stem Cells for Treatment of Therapy-Resistant Graft-versus-Host Disease

Mesenchymal stem cells (MSC) have immunomodulatory effects. The aim was to study the effect of MSC infusion on graft-versus-host disease (GVHD). We gave MSC to eight patients with steroid-refractory grades III-IV GVHD and one who had extensive chronic GVHD. The MSC dose was median 1.0 (range 0.7 to 9)x10(6)/kg. No acute side-effects occurred after the MSC infusions. Six patients were treated once and three patients twice. Two patients received MSC from HLA-identical siblings, six from haplo-identical family donors and four from unrelated mismatched donors. Acute GVHD disappeared completely in six of eight patients. One of these developed cytomegalovirus gastroenteritis. Complete resolution was seen in gut (6), liver (1) and skin (1). Two died soon after MSC treatment with no obvious response. One of them had MSC donor DNA in the colon and a lymph node. Five patients are still alive between 2 months and 3 years after the transplantation. Their survival rate was significantly better than that of 16 patients with steroid-resistant biopsy-proven gastrointestinal GVHD, not treated with MSC during the same period (P = 0.03). One patient treated for extensive chronic GVHD showed a transient response in the liver, but not in the skin and he died of Epstein-Barr virus lymphoma. MSC is a very promising treatment for severe steroid-resistant acute GVHD.

Attenuated Preemptive Therapy Against Cytomegalovirus (CMV) Reactivation/Disease Consisting of a Higher Cutoff Point and a Lower Initial Dose of Ganciclovir after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with an HLA-Identical Sibling Donor.

CMV continues to be a major cause of morbidity following allogeneic HSCT. Although preemptive ganciclovir therapy is widely used to prevent CMV disease, the optimal initial dose and timing of ganciclovir administration have not yet been determined. Unnecessary routine ganciclovir therapy is not acceptable, since it can cause considerable neutropenia and may impair the de novo recovery of CMV-specific T cell immunity. We performed a prospective study to evaluate the safety and effectiveness of a novel preemptive protocol with a higher cutoff point to initiate therapy and a lower initial dose of ganciclovir. The primary endpoint of this study was defined as the occurrence of CMV disease. CMV antigenemia was measured weekly after engraftment. The decision to start ganciclovir was based on the detection of ≥10 positive cells per 50,000 cells by the antigenemia assay, or by the clinical diagnosis of CMV disease with apparent infection-related symptoms. Intravenous ganciclovir was started at 5 mg/kg/day three times per week, and was continued until the positive cell count had decreased to < 10 per 50,000 cells. If the number of positive cells increased or CMV-related symptoms worsened, the dose of ganciclovir was increased. Forty-six consecutive patients undergoing allogeneic HSCT from an HLA-identical sibling at National Cancer Center Hospital between April 2003 and March 2004 were enrolled. The median age of the patients was 51 years (range, 17 to 68 years). There were 40 cases of hematological malignancy and 6 solid tumor. The risk status of CMV was recipient (R) +/donor (D)+ in 39, R+/D- in 4, R−/D+ in 1, and R−/D− in 2. Fludarabine- or cladribine-based reduced-intensity regimens were used in 35 patients and conventional myeloablative in 11. All patients were given acyclovir 750 mg/day orally from day −7 to the discontinuation of GVHD prophylaxis. The median follow-up was 275 days (26 – 481). Twenty-six patients (57%) developed positive antigenemia at a median of 42 days (12 – 151) after transplantation. In 10 patients (22%), ≥10 positive cells per 50,000 cells were detected by the antigenemia assay, and these patients, except two with renal dysfunction, received low-dose ganciclovir. The dose of ganciclovir was increased in 5 patients. Three patients developed overt CMV gastroenteritis which was successfully treated with a regular therapeutic dose of ganciclovir at 10 mg/kg/day. No case of late CMV disease was observed in this study. Overall, the total dose of ganciclovir was significantly less than that in a previous protocol using a conventional double dose (5 mg/kg twice daily) of ganciclovir (111 mg/kg vs. 225 mg/kg on average, P=0.006), reducing the cost by as much as $ 1,500 per patient. The incidence of neutropenia after ganciclovir was significantly less than that in the previous approach (0% vs. 11% (4/36), P=0.038). In a multivariate analysis, factors associated with ≥10 positive antigenemia included grade II – IV acute GVHD (P < 0.0001), the use of systemic steroid of ≥1.0 mg/kg/day (P < 0.0001), and a reduced- intensity conditioning regimen (P =0.036). In conclusion, our attenuated preemptive treatment protocol appeared to be safe, better tolerated, less expensive, and effective at controlling CMV infection.

Longitudinal Analysis of Plasma Cytomegalovirus DNA in a Child with Crohn's Disease and Cytomegalovirus Gastroenteritis

Longitudinal Analysis of Plasma Cytomegalovirus DNA in a Child with Crohn's Disease and Cytomegalovirus Gastroenteritis

Cytomegalovirus disease of the gastrointestinal tract in AIDS

Disease of the gastrointestinal tract occurs in up to 100% of patients who are infected with the human immunodeficiency virus (HIV) (Quinn et al, 1987). Gastrointestinal tract disease results from infections with a wide variety of pathogens (including HIV) and tumours (CDC, 1987; Nelson et al, 1988). Cytomegalovirus (CMV), like all herpes viruses, can cause primary, latent or chronic persistent infections. Life-threatening disease due to CMV is less common than subclinical infection in patients with acquired immunodeficiency syndrome (AIDS), and because of the overlap between asymptomatic CMV infection and serious CMV disease, prevalence data is difficult to interpret. Although 50% or more of patients with AIDS may have CMV viraemia, only 2.2% of 761 patients presenting to San Francisco General Hospital had CMV gastrointestinal disease (Quinnan et al, 1984; Jacobson and Mills, 1988). Other studies have shown a higher incidence of gastrointestinal CMV disease (between 5 and 10%) but this may reflect selection of patients and referral to gastrointestinal clinics (Connolly et al, 1989; Francis et al, 1989). CMV is now well established as a major cause of specific gastrointestinal syndromes including oesophagitis, gastritis, enteritis and colitis (Knapp et al, 1983; Balthazar et al, 1985; Freedman et al, 1985; Meiselman et al, 1985). It is now thought that CMV can also cause perianal and perioral disease. The clinical recognition of these syndromes is important in patients with HIV disease because of the difficulty in interpretation of CMV serology and CMV excretion in the immunosuppressed in general and in AIDS patients in particular (Pass et al, 1984; Brodie et al, 1985). Although CMV infection is usually disseminated, clinical manifestations occur at specific sites. The main criteria of active CMV disease are based on histological changes present on biopsy specimens. Modern endoscopic techniques make it relatively easy to obtain biopsy specimens from most of the gastrointestinal tract and thus histological evidence, along with the response to recently introduced therapeutic agents, helps to define the various syndromes of CMV gastroenteritis (Reichert et al, 1983; Chachoua et al, 1987).

Ganciclovir does not appear to clinically benefit bone marrow transplant patients with cytomegalovirus gastroenteritis

Ganciclovir does not appear to clinically benefit bone marrow transplant patients with cytomegalovirus gastroenteritis

T-lymphocyte subsets in gut and blood of liver transplant recipients with and without cytomegalovirus gastroenteritis

The effects of orthotopic liver transplantation (OLTx) and cytomegalovirus (CMV) gastroenteritis on the type of mononuclear cells within the upper gastrointestinal tract were determined. Nineteen liver transplant recipients were studied both before and after transplantation. Each underwent a pan-upper gastrointestinal endoscopy with biopsy of the antrum and duodenum before and four weeks following liver transplantation. A panel of monoclonal antibodies prepared against HLA-DR, NK, IL-2R, T11, T4, T8, and B1 cell surface antigens was used to examine the tissues. Before OLTx, none of the 19 subjects studied had clinical or histologic evidence for CMV gastroenteritis. Following OLTx, five of the 19 subjects had CMV gastroenteritis. The number of HLA-DR positive staining lymphocytes present in biopsies obtained post-OLTx was significantly greater (P less than 0.005) than those present in biopsies obtained pre-OLTx regardless of the presence or absence of CMV gastroenteritis. No difference in the intensity of HLA-DR antigen expression between pre- and post-OLTx biopsies and those with and without CMV gastroenteritis was evident. No difference in the number of natural killer (NK) cells and the number of cells expressing the interleukin-2 receptor (IL-2R) was evident between biopsies obtained pre- and post-OLTx. In contrast, the number of T lymphocytes bearing the T11, T4, and T8 markers and the calculated T4/T8 ratio differed between biopsies obtained pre- and post-OLTx and between those positive for CMV gastroenteritis post-OLTx and those without evidence for CMV gastroenteritis either before or after OLTx, although these changes were not consistent throughout the gastrointestinal tract.(ABSTRACT TRUNCATED AT 250 WORDS)