Assessment of Cytomegalovirus-Specific Cell-Mediated Immunity for the Prediction of Cytomegalovirus Disease in High-Risk Solid-Organ Transplant Recipients: A Multicenter Cohort Study

Manuel, Oriol; Husain, Shahid; Kumar, Deepali; Zayas, Carlos; Mawhorter, Steve; Levi, Marilyn E.; Kalpoe, Jayant S.; Lisboa, Luiz F.; Ely, Leticia; Kaul, Daniel; Schwartz, Brian S.; Morris, Michele; Ison, Michael G.; Yen‐Lieberman, Belinda; Sebastián, Anthony; Assi, Maha; Humar, Atul

doi:10.1093/cid/cis993

Cited by 247 publications

(203 citation statements)

References 23 publications

(37 reference statements)

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“…The incidence of CMV DNAemia in valacyclovir prophylaxis was comparable with that seen in the valganciclovir group (24 (Figure 2A). The median time to CMV DNAemia was likewise similar (137 versus 145 days; P=0.37).…”

Section: Primary End Points: CMV Dnaemia and Allograft Rejectionsupporting

confidence: 62%

“…Both protocols were effective in reducing the incidence of CMV disease to 5%, an effect to be considered in the context of the composition of our patients. In studies involving only patients who were donor positive/recipient negative, the incidence of late-onset CMV disease continues to be unsatisfactory and poses the main limitation to prophylaxis (12,14,23,24). Extending prophylaxis to 6 months would only partly eliminate the problem (12,14); hence, there are efforts to improve prophylactic regimens by determining CMV-specific T cell-mediated immunity (24).…”

Section: Discussionmentioning

confidence: 99%

“…In studies involving only patients who were donor positive/recipient negative, the incidence of late-onset CMV disease continues to be unsatisfactory and poses the main limitation to prophylaxis (12,14,23,24). Extending prophylaxis to 6 months would only partly eliminate the problem (12,14); hence, there are efforts to improve prophylactic regimens by determining CMV-specific T cell-mediated immunity (24). Another option is to use the preemptive therapy approach, where lateonset CMV disease does not pose a problem (10,25).…”

Section: Discussionmentioning

confidence: 99%

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Randomized Trial of Valganciclovir Versus Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

Reischig

Kacer

Jindra

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Both valganciclovir and high-dose valacyclovir are recommended for cytomegalovirus prophylaxis after renal transplantation. A head-to-head comparison of both regimens is lacking. The objective of the study was to compare valacyclovir prophylaxis with valganciclovir, which constituted the control group.Design, settings, participants, & measurements In a randomized, open-label, single-center trial, recipients of renal transplants (recipient or donor cytomegalovirus-seropositive) were randomly allocated (1:1) to 3-month prophylaxis with valacyclovir (2 g four times daily) or valganciclovir (900 mg daily). Enrollment occurred from November of 2007 to April of 2012. The primary end points were cytomegalovirus DNAemia and biopsy-proven acute rejection at 12 months. Analysis was by intention to treat. ResultsIn total, 119 patients were assigned to valacyclovir (n=59) or valganciclovir prophylaxis (n=60). Cytomegalovirus DNAemia developed in 24 (43%) of 59 patients in the valacyclovir group and 18 (31%) of 60 patients in the valganciclovir group (adjusted hazard ratio, 1.35; 95% confidence interval, 0.71 to 2.54; P=0.36). The incidence of cytomegalovirus disease was 2% with valacyclovir and 5% with valganciclovir prophylaxis (adjusted hazard ratio, 0.21; 95% confidence interval, 0.01 to 5.90; P=0.36). Significantly more patients with valacyclovir prophylaxis developed biopsy-proven acute rejection (18 of 59 [31%] versus 10 of 60 [17%]; adjusted hazard ratio, 2.49; 95% confidence interval, 1.09 to 5.65; P=0.03). The incidence of polyomavirus viremia was higher in the valganciclovir group (18% versus 36%; adjusted hazard ratio, 0.43; 95% confidence interval, 0.19 to 0.96; P=0.04).Conclusions Valganciclovir shows no superior efficacy in cytomegalovirus DNAemia prevention compared with valacyclovir prophylaxis. However, the risk of biopsy-proven acute rejection is higher with valacyclovir.

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Section: Primary End Points: CMV Dnaemia and Allograft Rejectionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Randomized Trial of Valganciclovir Versus Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

Reischig

Kacer

Jindra

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…The use of less toxic drugs for prophylaxis and the introduction of biomarkers for individualizing prevention in each patient (e.g. based on the use of cell-mediated immune assays for assessing the risk for CMV infection) may further reduce the clinical importance of this once feared viral complication (200). Clinical trials assessing the different preventive strategies for CMV should incorporate, in addition to CMV infection and disease, allograft function and survival as primary clinical end points.…”

Section: Resultsmentioning

confidence: 99%

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

Martín-Gandul

Mueller

Pascual

et al. 2015

American Journal of Transplantation

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129

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Infectious diseases after solid organ transplantation (SOT) are a significant cause of morbidity and reduced allograft and patient survival; however, the influence of infection on the development of chronic allograft dysfunction has not been completely delineated. Some viral infections appear to affect allograft function by both inducing direct tissue damage and immunologically related injury, including acute rejection. In particular, this has been observed for cytomegalovirus (CMV) infection in all SOT recipients and for BK virus infection in kidney transplant recipients, for community-acquired respiratory viruses in lung transplant recipients, and for hepatitis C virus in liver transplant recipients. The impact of bacterial and fungal infections is less clear, but bacterial urinary tract infections and respiratory tract colonization by Pseudomonas aeruginosa and Aspergillus spp appear to be correlated with higher rates of chronic allograft dysfunction in kidney and lung transplant recipients, respectively. Evidence supports the beneficial effects of the use of antiviral prophylaxis for CMV in improving allograft function and survival in SOT recipients. Nevertheless, there is still a need for prospective interventional trials assessing the potential effects of preventive and therapeutic strategies against bacterial and fungal infection for reducing or delaying the development of chronic allograft dysfunction.

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“…[4][5][6][7] As these cellular immune responses are restricted by HLA Class I alleles for peptide recognition, in addition to determining the CMV seroprevalence rate in Ireland, the association of CMV seropositivity with HLA Class I alleles was also examined.…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus infection in Ireland: Seroprevalence, HLA Class I alleles and implications

Hassan

O'Neill

Honari

et al. 2015

Journal of Clinical Virology

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Cytomegalovirus (CMV) infections occur worldwide and primary infection usually occurs in early childhood and is often asymptomatic whereas primary infection in adults may result in symptomatic illness. CMV establishes a chronic latent infection with intermittent periods of reactivation. Primary infection or reactivation associate with increased mortality and morbidity in those who are immunocompromised. Transplacental transmission may result in significant birth defects or long-term sensorineural hearing loss.We performed a study to determine the CMV seroprevalence and the association between HLA Class I alleles and frequency of CMV infection in Ireland. The presence of CMV IgG, a marker of previous CMV infection, was determined for a cohort of 1849 HLA typed solid organ transplant donors between 1990 and 2013. The presence of CMV IgG was correlated with HLA type.The CMV seroprevalence in solid organ transplant donors was 33.4% (range 22-48% per annum) over the time period 1990 to 2013. Multivariate logistic regression analysis showed that both age and HLA alleles were associated with CMV seropositivity. A significant and positive relationship between age and CMV seropositivity was observed (OR ¼ 1.013, P < 0.001, CI [1.007, 1.019]). Chi-square analysis revealed that the female gender was independently associated with CMV seropositivity (P < 0.01). Seroprevalence in women of reproductive age (20-39 years) was significantly higher than men of the same age (37% vs 26%, P < 0.01). The frequencies of HLA-A1, HLA-A2, and HLA-A3 in our cohort were 40.8%, 48.8%, and 25.9%, respectively. Logistic regression analysis showed that the presence of HLA-A1 but not HLA-A2 or HLA-A3 was independently associated with CMV seronegativity (P < 0.01). Interestingly, individuals who coexpressed HLA-A2 and HLA-A3 alleles were significantly more likely to be CMV seropositive (P < 0.02). The frequencies of HLA-B5, HLA-B7, and HLA-B8 in our cohort were 6.1%, 31.2%, and 30.8%, respectively. The presence of the most common inherited haplotype in the Irish population, HLA-A1, B8 was significantly associated with CMV seronegativity (OR ¼ 1.278, P < 0.001, CI [1.049, 1.556]).CMV seroprevalence is lower in Ireland compared with other countries. The high frequency of HLA-A1 in the Irish population may, in part, have a role in the reduced susceptibility to CMV infection.(Medicine 95(6):e2735)Abbreviations: CI = confidence interval, CMV = cytomegalovirus, HLA = human leucocyte antigen, IFN = interferon, Ig = immunoglobulin, OR = odds ratios.

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Assessment of Cytomegalovirus-Specific Cell-Mediated Immunity for the Prediction of Cytomegalovirus Disease in High-Risk Solid-Organ Transplant Recipients: A Multicenter Cohort Study

Abstract: NCT00817908.

Cited by 247 publications

References 23 publications

Randomized Trial of Valganciclovir Versus Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

Randomized Trial of Valganciclovir Versus Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

Cytomegalovirus infection in Ireland: Seroprevalence, HLA Class I alleles and implications

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