Experienced Cytomegalovirus Infection Research Articles

Low-Dose Valganciclovir Prophylaxis Against Cytomegalovirus in Intermediate-Risk Liver and Dual-Abdominal Transplant Recipients.

Low-dose valganciclovir (VGC) for cytomegalovirus (CMV) prophylaxis post-transplant has been employed due to cost and safety. The incidence of CMV disease in CMV intermediate-risk liver recipients at 1-year after standard-dose prophylaxis is approximately 5%. However, there are limited data on outcomes after using a "true" low-dose VGC prophylaxis regimen in liver and dual-abdominal transplant recipients as VGC was not dose-adjusted in all patients with impaired renal function in prior studies. The objective was to assess the incidence of CMV associated with low-dose VGC prophylaxis in CMV intermediate-risk liver, simultaneous pancreas-kidney (SPK), and simultaneous liver-kidney (SLK) recipients with creatinine clearance (CrCl) >60 mL/min. This was a retrospective review of CMV intermediate-risk liver, SPK, and SLK recipients with CrCl >60 mL/min transplanted January 2018 to June 2022 who received VGC 450 mg daily for prophylaxis. The primary outcome was incidence of CMV infection 6-months post-transplant. Ninety-nine transplant recipients were included (79 liver, 11 SPK, 9 SLK). The primary outcome occurred in 13% of patients (liver 10%, SPK 36%, SLK 10%), including 1 case of CMV disease and 3 breakthrough infections. In addition, 6 patients experienced CMV infection between 6-months and 1-year. Recurrence occurred in 3 patients. There was no evidence of CMV resistance. Thirty patients experienced neutropenia within 1-year, 32 were prescribed granulocyte-colony stimulating factors, and 5 experienced thrombocytopenia. Two patients died due to graft-vs-host disease. Low-dose VGC prophylaxis led to comparable CMV infection rates at 6-months in CMV intermediate-risk liver and SLK recipients. However, as SPK recipients displayed higher rates of CMV infection, low-dose VGC should be avoided in this population.

Metabolic Profiling Early Post-Allogeneic Haematopoietic Cell Transplantation in the Context of CMV Infection.

Immune dysfunction resulting from allogeneic haematopoietic stem cell transplantation (aHSCT) predisposes one to an elevated risk of cytomegalovirus (CMV) infection. Changes in metabolism have been associated with adverse outcomes, and in this study, we explored the associations between metabolic profiles and post-transplantation CMV infection using plasma samples collected 7-33 days after aHSCT. We included 68 aHSCT recipients from Rigshospitalet, Denmark, 50% of whom experienced CMV infection between days 34-100 post-transplantation. First, we investigated whether 12 metabolites selected based on the literature were associated with an increased risk of post-transplantation CMV infection. Second, we conducted an exploratory network-based analysis of the complete metabolic and lipidomic profiles in relation to clinical phenotypes and biological pathways. Lower levels of trimethylamine N-oxide were associated with subsequent CMV infection (multivariable logistic regression: OR = 0.63; 95% CI = [0.41; 0.87]; p = 0.01). Explorative analysis revealed 12 clusters of metabolites or lipids, among which one was predictive of CMV infection, and the others were associated with conditioning regimens, age upon aHSCT, CMV serostatus, and/or sex. Our results provide evidence for an association between the metabolome and CMV infection post-aHSCT that is independent of known risk factors.

Evaluation of cytomegalovirus infection/disease in IgG positive renal transplantation recipients on valaciclovir prophylaxis

The reactivation of CMV (Cytomegalovirus) in renal transplant recipients may be manifested across a clinical spectrum from asymptomatic viraemia to organ rejection. The purpose of this study is to evaluate the patients who have experienced CMV infection after renal transplantation in the last twelve years, and to assess the efficacy of valacyclovir. Renal transplant recipients' demographic, clinical and laboratory data were evaluated retrospectively between 2006-2018. Valaciclovir was given at the standard prophylaxis dose of 2000 mg/daily. CMV Polymerase Chain reaction (PCR) was performed in 2-week intervals until 1 year after transplantation, and upon any symptoms attributable to CMV. The entire study group had D+/R+ (donor-positive, recipient-positive) serological status of the CMV virus. 171 (59.2%) patients had only CMV infection, 60 (20.8%) had overall CMV antigen positivity until the end of the follow-up period and 7 (2.4%) patients had CMV disease. Rejection episodes were diagnosed in 31 (10.8%) patients; 20 (64.5%) of those were PCR positive for CMV; mortality rate was 12 (4.2%) but those who died had a non-CMV related disease. Valaciclovir may be preferred in prophylaxis instead of valganciclovir as we used in our study since valganciclovir has prolonged treatment time, rapid development of drug resistance, drug toxicity and high cost.

Risk factors for CMV infection within 100 days posttransplantation in patients with acute leukemia

Three hundred fifty-nine patients with acute leukemia who received allo-HSCT at our center between January 2015 and January 2020 were retrospectively reviewed. Of 359 patients, 48.19% (173) patients experienced CMV infection within 100 days posttransplantation. In univariate and multivariate logistic analysis, haploidentical-related donor (HRD) (P < 0.001; odds ratio [OR], 5.542; 95% confidence interval [CI], 3.186-9.639), and ratio of CD3+CD8+ cells in lymphocytes <14.825% (P < 0.001; OR, 3.005; 95% CI, 1.712-5.275) were identified as 2 independent risk factors. One-year relapse rate (RR) between the CMV infection group and the non-CMV infection group was not statistically significant (18.5% vs 19.9%, P = 0.688). When we divided the total cohort into AML, ALL, and MAL subgroups, there were no significant differences as well (P = 0.138; P = 0.588; P = 0.117; respectively). In conclusion, donor type (HRD) and the insufficient recovery of CD3+CD8+ cells were independent risk factors for CMV infection within 100 days posttransplantation in patients with acute leukemia. CMV infection within 100 days did not influence the incidence of relapse in 1 year for patients with acute leukemia.

Optimal Use of Ganciclovir and Valganciclovir in Transplanted Patients: How Does It Relate to the Outcome?

Objective Organ transplant recipients receive immunosuppressive regimens to prevent transplant rejection, which put them at increased risk for opportunistic infections like cytomegalovirus (CMV). Ganciclovir and Valganciclovir are mostly used to prevent or treat CMV. Any incorrect use of the drug may have serious consequences for patients. In this study, the outcome of transplant recipients was assessed in relation to the optimal or suboptimal use of Ganciclovir or Valganciclovir. Methods This study was performed on 148 hospitalized patients who received Ganciclovir or Valganciclovir in the nephrology and kidney transplantation departments of our university hospitals, from March 2012 to December 2016. Patients' demographic and clinical data including dose and duration of treatment were collected and then analyzed in comparison with the standard CMV treatment protocols. Findings About 94.6% of patients received Ganciclovir or Valganciclovir therapy consistent with the standard defined indications. The mean ratio of prescribed daily dose to the optimal dose was 2.9 in the first dose, 2.0 in the second dose, 1.3 in the third dose, and 1.5 in the fourth dose. From 148 included patients, 26.5% experienced CMV infection once, 7.2% experienced CMV infection twice, and 1.2% had CMV infection for 3 times, within six-month follow-up after first episode of antiviral therapy during hospitalization. Conclusion In this study, empiric anti-CMV therapy was initially given. The doses used were generally higher than recommended but we could not find more adverse events in the patients receiving high initial doses. In any case, it seems necessary to advocate use of standard treatment guidelines to avoid adverse outcomes.

Long-term impact of CMV infection on allografts and on patient survival in renal transplant patients with protocol biopsies.

Cytomegalovirus (CMV) infection is a frequent complication of early posttransplantation. This study examines its impact on chronic allograft changes, long-term graft loss, and patient survival. We studied 594 patients who had protocol biopsies at 6 wk, and 3 and 6 mo posttransplantation. Chronic allograft changes were evaluated according to the updated Banff classification [interstitial fibrosis/tubular atrophy (IF/TA), vascular and glomerular lesions]. Follow-up data were available for up to 10 yr. CMV infection was diagnosed in 153 of 594 patients (26%) in the first year after transplantation, mostly within the first 3 mo. Graft survival was reduced in patients with CMV (P = 0.03) as well as the combined allograft/patient survival (P = 0.008). Prevalence of IF/TA at 6 wk after transplantation was already threefold higher in patients who experienced CMV infection later on compared with patients without CMV (P = 0.005). In multivariate analyses, CMV viremia or disease was not a significant factor for graft loss or death. In conclusion, patients with CMV infection posttransplantation show more chronic allograft changes early on, even before CMV infection, and development of IF/TA is not more prevalent in patients with CMV. Our data do not support a significant role of CMV in patient and graft outcomes.

Cytomegalovirus-responsive γδ T cells: novel effector cells in antibody-mediated kidney allograft microcirculation lesions.

Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large γδ T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive γδ T cells express the Fcγ-receptor CD16, suggesting that γδ T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16(pos) γδ T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating γδ T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced γδ T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced γδ T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.

Cytomegalovirus infection and end-organ disease in Asian patients with lymphoma receiving chemotherapy

This study aimed to describe the epidemiology and risk factors for cytomegalovirus (CMV) infection and end-organ disease in patients with lymphoma undergoing potentially curative or salvage therapy. We retrospectively reviewed 534 patients with lymphoma treated at an Asian tertiary cancer center between January 2007 and December 2010. Overall, 48 patients (9.0%) experienced CMV infection, with 12 patients (25.0%) being further diagnosed with CMV end-organ disease. Many patients with CMV infection were male, with poor performance status, non-Hodgkin lymphoma and advanced disease, and received rituximab use. Moreover, patients receiving rituximab and HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) regimens had a high rate of CMV end-organ disease. In Asian patients with lymphoma receiving curative or salvage therapy, CMV infection was relatively common (9.0%). Most of these were likely to be reactivation in nature. A small group, especially those on rituximab or HyperCVAD, developed CMV end-organ disease (12/534). Such patients should be monitored closely for CMV end-organ disease. Alternatively, prophylaxis should be studied.

Factors Influencing Acute Rejection of Human Hand Allografts

Acute rejection (AR) of human hand allografts (HHAs) may carry a risk of graft loss and leads to the need for immunosuppressive treatment. The literature on HHAs was reviewed to determine and evaluate the factors that trigger AR of HHAs. Clinical case reports of hand allograft transplantation published between 1999 and 2011 in English, French, or German were reviewed systematically. The number of AR episodes was the main outcome measure. Sixty-eight episodes of AR were described in 28 recipients. Calcineurin inhibitor-based maintenance regimens were associated with significantly fewer AR episodes than non-calcineurin inhibitor-based regimens (mean 1.9 vs 3.2; P = 0.018). In recipients who experienced cytomegalovirus infection, the mean number of episodes of AR was 4, whereas in those who did not experience cytomegalovirus infection it was 2.25 (P = 0.024). The planning of hand allograft transplantation should take these factors into account to minimize the risk of AR.

Inflammatory bowel disease after liver transplantation: A role for cytomegalovirus infection

Objective. Despite the use of immunosuppressive drugs, recurrent and de novo inflammatory bowel disease (IBD) can develop after orthotopic liver transplantation (OLT). Cytomegalovirus (CMV) infection has been suggested to play a role in the pathogenesis of IBD. The aim of this study was to investigate the role of CMV infection in the development of IBD after OLT. Material and methods. All 84 patients who underwent transplantation for primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) in our center between May 1987 and June 2002 and who survived the first year after transplantation were included in the study. Diagnosis of active CMV infection was made using the pp65–antigenemia assay. Results. Thirty-one of the 84 patients (37%) had IBD prior to OLT. Eighteen patients (21%) experienced IBD after OLT, either as flare-up (n=12) or de novo (n=6), at a median of 1.4 years (range 0.3 to 6.3) after OLT. Forty-eight percent of all patients experienced CMV infection after OLT, at a median of 27 days (range 8 to 193). CMV infection was primary in half the patients. At 1, 3, and 5 years after OLT, active IBD-free survival without CMV infection was 91, 88, and 88%, respectively. With CMV infection these figures were 93, 82, and 67%. De novo IBD was seen only in those who had experienced a CMV infection (p=0.02). Conclusions. In patients transplanted for end-stage PSC or AIH, active IBD, especially de novo IBD, occurred more often in patients who experienced CMV infection in the postoperative period. This finding supports a pathogenic role for CMV in the development of IBD.

Acyclovir plus CMV immunoglobulin prophylaxis and early therapy with ganciclovir are effective and safe in CMV high-risk renal transplant pediatric recipients

Abstract Cytomegalovirus (CMV) infection is still a major cause of morbidity in high-risk renal transplant recipients. In the present report, we have reviewed our records of renal transplant pediatric recipients (RTPR; mean age 14.1 ± 4.9 years) since 1991, when we started a policy of CMV prophylaxis constituting high-dose oral acyclovir plus CMV hyperimmune immunoglobulins (Hlg) followed by early i.v. ganciclovir therapy in high-risk patients (i.e., CMV donor +/ recipient -). Four patients received a kidney from a living relative (LR), 2 patients had one previous transplant, and 1 had a combined liver -kidney transplant. Thirty-three patients who were negative for CMV antibodies (ab) before transplantation received a kidney from CMV ab positive donors. The immunosuppressive regimen included cyclosporin A and steroids, with the addition of azathioprine in the 4 patients who received an LR kidney. Serial assessments for CMV antigenemia (pp 65) were routinely performed for 6 months after transplantation to define CMV infection. Among the 33 CMV seronegative recipients (R -) who received the graft from a CMV seropositive donor (D +), 18 (54.5 %) experienced CMV infection, whereas among the 28 CMV R +, who received a graft from a CMV D +, 11 (39.3 %) experienced CMV infection. With regard to CMV - related symptoms, only 2 patients suffered from a CMV syndrome (fever and leukopenia in 1 patient, fever and arthralgia in the other). In no case did the spectrum of CMV disease occur; only minor symptoms were present in 7 of the remaining CMV-infected patients (fever in 6 and leukopenia in 1). Rejection episodes and renal function did not differ between CMV-infected and non-CMV-infected patients. Our experiences support the use of prophylactic acyclovir plus CMV HIg followed by early therapy with i.v. ganciclovir to combat the risk of increased morbidity in high risk RTPR.

Cytomegalovirus infection and pneumonitis. Impact after isolated lung transplantation. Washington University Lung Transplant Group.

Using aggressive surveillance of blood, bronchoalveolar lavage (BAL) fluid, and lung tissue, we sought to determine the incidence of cytomegalovirus (CMV) pneumonitis in isolated lung transplant recipients and to characterize its impact on pulmonary function, chronic rejection, and survival. Forty-six lung transplant recipients who survived greater than 30 days had prospective documentation of CMV infection in blood and BAL fluid and regular surveillance with transbronchial lung biopsy. CMV infection was documented in 92% of patients who were D-/R+, D+/R+, or D+/R-, and the incidence of histologically confirmed CMV pneumonitis among these patients was 75%. No D-/R- patient experienced CMV infection or disease. D+/R- patients experienced more frequent and severe episodes, and ganciclovir prophylaxis during the first 2 wk was not useful. CMV pneumonitis was accompanied by detectable radiographic changes in less than one third of cases. The detection of CMV in BAL fluid was not predictive of CMV pneumonitis on biopsy, except in D+/R- patients during the first 90 days after transplantation. There was no evidence of an adverse impact because of CMV infection on pulmonary function during the first year after transplantation. A relationship between CMV infection and bronchiolitis obliterans could not be documented; however, D+/R- patients had higher morbidity and a trend toward lower survival. In a multivariate analysis, D+/R- status was an independent predictor of death.

Cytomegalovirus Infection in Burn Patients

We studied the seroepidemiology of cytomegalovirus (CMV) infection in 59 patients with thermal injuries. Among the 31 patients who were initially CMV seronegative, seven (22.5%) seroconverted. Patients who seroconverted had longer hospital stays (mean, 27 +/- 23.9 days v 14.9 +/- 8.8 days in seronegative patients [P = 0.03]) and they received more blood products (mean, 10.7 +/- 17.9 units v 1.8 +/- 2.8 units [P = 0.02]) than patients who remained seronegative. Among 18 patients who were initially seropositive for CMV, 10 (56%) had a fourfold or greater rise in CMV antibodies, evidence of CMV reactivation. Patients who had reactivated CMV infection tended to be younger, to have a larger burn area, and to have a longer hospital stay. No patient who experienced CMV infection, whether primary or reactivated, had serious complications attributable to CMV.