|
1
|
Tharmaraj D, Mulley WR, Dendle C. Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation. Front Immunol 2024; 15:1490472. [PMID: 39660122 PMCID: PMC11628869 DOI: 10.3389/fimmu.2024.1490472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
Infection and rejection are major complications that impact transplant longevity and recipient survival. Balancing their risks is a significant challenge for clinicians. Current strategies aimed at interrogating the degree of immune deficiency or activation and their attendant risks of infection and rejection are imprecise. These include immune (cell counts, function and subsets, immunoglobulin levels) and non-immune (drug levels, viral loads) markers. The shared risk factors between infection and rejection and the bidirectional and intricate relationship between both entities further complicate transplant recipient care and decision-making. Understanding the dynamic changes in the underlying net state of immunity and the overall risk of both complications in parallel is key to optimizing outcomes. The allograft biopsy is the current gold standard for the diagnosis of rejection but is associated with inherent risks that warrant careful consideration. Several biomarkers, in particular, donor derived cell-free-DNA and urinary chemokines (CXCL9 and CXCL10), show significant promise in improving subclinical and clinical rejection risk prediction, which may reduce the need for allograft biopsies in some situations. Integrating conventional and emerging risk assessment tools can help stratify the individual's short- and longer-term infection and rejection risks in parallel. Individuals identified as having a low risk of rejection may tolerate immunosuppression wean to reduce medication-related toxicity. Serial monitoring following immunosuppression reduction or escalation with minimally invasive tools can help mitigate infection and rejection risks and allow for timely diagnosis and treatment of these complications, ultimately improving allograft and patient outcomes.
Collapse
Affiliation(s)
- Dhakshayini Tharmaraj
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - William R. Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - Claire Dendle
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
| |
Collapse
|
|
2
|
Shirini K, Kamberi S, Drachenberg C, Haririan A, Saharia K, Meier RPH. Renal transplantation using kidneys from a donor with high grade cytomegalovirus viraemia: case report and literature review. THE LANCET. INFECTIOUS DISEASES 2024; 24:e718-e723. [PMID: 38991589 DOI: 10.1016/s1473-3099(24)00359-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/26/2024] [Accepted: 05/28/2024] [Indexed: 07/13/2024]
Abstract
Transplanting organs from cytomegalovirus-seropositive donors into cytomegalovirus-seronegative recipients is an accepted practice. However, outcomes following transplantation of organs from donors with active cytomegalovirus disease are unknown. We present a case involving a patient aged 61 years with end-stage renal disease, seropositive for cytomegalovirus, who underwent dual kidney transplant from a donor with high-grade cytomegalovirus viraemia. The donor was on immunosuppressive therapy for systemic lupus erythematosus and interstitial lung disease and had been admitted with respiratory failure. The donor had high-grade cytomegalovirus viraemia with probable cytomegalovirus pneumonitis (cytomegalovirus viral load >100 000 international units [IU]/mL in plasma and 319 000 IU/mL in bronchoalveolar lavage). Renal biopsy at organ procurement showed the absence of cytomegalovirus inclusions. Following transplantation, the recipient had delayed graft function, with renal recovery after 1 week. The patient received basiliximab induction and standard tacrolimus-based maintenance immunosuppression. He received ganciclovir and valganciclovir treatment for 1 month, followed by valganciclovir prophylaxis (or viral load monitoring, when prophylaxis had to be paused) for 2 additional months to prevent donor-derived cytomegalovirus infection. Transient cytomegalovirus viraemia (peaking at 4480 IU/mL) developed at 4 months and resolved with 1 month of valganciclovir treatment. The patient is doing well 1 year after transplantation, with adequate kidney function. This case highlights the successful and safe transplantation of kidneys from a donor with cytomegalovirus disease into a cytomegalovirus-seropositive recipient. Further research is needed to confirm our findings and define post-transplantation management.
Collapse
Affiliation(s)
- Kasra Shirini
- Division of Transplant Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Shani Kamberi
- Division of Transplant Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Cynthia Drachenberg
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Abdolreza Haririan
- Division of Nephrology, Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kapil Saharia
- Institute of Human Virology, Division of Infectious Diseases, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Raphael P H Meier
- Division of Transplant Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
3
|
Foca M, Demirhan S, Munoz FM, Valencia Deray KG, Bocchini CE, Sharma TS, Sherman G, Muller WJ, Heald-Sargent T, Danziger-Isakov L, Blum S, Boguniewicz J, Bacon S, Joseph T, Smith J, Ardura MI, Su Y, Maron GM, Ferrolino J, Herold BC. Multicenter Analysis of Valganciclovir Prophylaxis in Pediatric Solid Organ Transplant Recipients. Open Forum Infect Dis 2024; 11:ofae353. [PMID: 38979014 PMCID: PMC11229698 DOI: 10.1093/ofid/ofae353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 06/27/2024] [Indexed: 07/10/2024] Open
Abstract
Background Valganciclovir is the only approved antiviral for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation (SOT). Additional approaches may be needed to improve outcomes. Methods A multicenter retrospective study from 2016 to 2019 was conducted of pediatric SOT recipients in whom at least 3 months of valganciclovir prophylaxis was planned. Episodes of CMV DNA in blood (DNAemia), CMV disease, drug-related toxicities, as well as other infections in the first year posttransplant and demographic and clinical data were collected. CMV DNAemia in the first year after prophylaxis or during prophylaxis (breakthrough) was analyzed by multivariate hazard models. Results Among the 749 patients enrolled, 131 (17.5%) had CMV DNAemia at any time in the first year; 85 (11.4%) had breakthrough DNAemia, and 46 (6.1%) had DNAemia after prophylaxis. CMV disease occurred in 30 (4%). In a multivariate model, liver transplantation compared to kidney or heart, intermediate or high risk based on donor/recipient serologies, neutropenia, and valganciclovir dose modifications attributed to toxicity were associated with increased risk of total and/or breakthrough DNAemia. Bacteremia was also associated with increased hazard ratio for CMV DNAemia. In a separate multivariate analysis, rejection occurred more often in those with breakthrough CMV DNAemia (P = .002); liver transplants, specifically, had increased rejection if CMV DNAemia occurred in the first year (P = .004). These associations may be bidirectional as rejection may contribute to infection risk. Conclusions CMV DNAemia in the first year posttransplantation occurs despite valganciclovir prophylaxis and is associated with medication toxicity, bacteremia, and rejection. Pediatric studies of newer antivirals, especially in higher-risk subpopulations, appear to be warranted.
Collapse
Affiliation(s)
- Marc Foca
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Salih Demirhan
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Flor M Munoz
- Division of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Kristen G Valencia Deray
- Division of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Claire E Bocchini
- Division of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Tanvi S Sharma
- Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Gilad Sherman
- Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - William J Muller
- Division of Infectious Diseases, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Taylor Heald-Sargent
- Division of Infectious Diseases, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lara Danziger-Isakov
- Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Samantha Blum
- Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Juri Boguniewicz
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Samantha Bacon
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Tuhina Joseph
- Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jodi Smith
- Division of Nephrology, Department of Pediatrics, Seattle Children's Hospital, University of Washington Medical School, Seattle, Washington, USA
| | - Monica I Ardura
- Division of Infectious Diseases and Host Defense, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA
| | - Yin Su
- Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Gabriela M Maron
- Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Jose Ferrolino
- Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Betsy C Herold
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA
| |
Collapse
|
|
4
|
Ishikawa S, Tasaki M, Saito K, Nakagawa Y, Ikeda M, Takahashi K, Tomita Y. Acquisition of Antibody Against Cytomegalovirus After Kidney Transplantation in Seronegative Recipients. Transplant Proc 2023:S0041-1345(23)00126-4. [PMID: 37061354 DOI: 10.1016/j.transproceed.2023.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 03/13/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is one of the most important infectious diseases affecting recipients of kidney transplantation (KTx). However, the timing of seroconversion for CMV infection in seronegative recipients remains unclear. We evaluated CMV infections in CMV-seronegative recipients and the time to acquire antibodies against CMV. METHODS We conducted a retrospective study of 228 recipients who underwent KTx between March 1988 and February 2018 at the Niigata University Hospital. The anti-CMV IgG antibody profile before and after transplantation was analyzed. Oral acyclovir or valganciclovir was used as prophylactic therapy for at least 6 months after transplantation. Cytomegalovirus infection was defined as CMV viremia detected using the CMV pp65 antigenemia assay. RESULTS In this study, 50 cases (21.9%) were CMV-seronegative recipients. Over a median follow-up period of 126.7 months, 68% (34/50) of CMV-seronegative recipients experienced CMV viremia or overt disease symptoms as the first episode of CMV infection. The median duration from transplant to CMV infection was 69.0 days (range, 22-7426). All the recipients who experienced CMV infections acquired seroconversion. The median duration from KTx to seroconversion was 7.2 months (range, 2.8-252.3). Almost all CMV-seronegative recipients could acquire anti-CMV IgG antibodies within 2.5 years. In seronegative recipients whose donors were seronegative, no CMV viremia was found, and none developed anti-CMV IgG antibodies. CONCLUSIONS In the clinical practice of CMV-seronegative recipients, we should consider that physicians must closely monitor the occurrence of CMV infection up until 2.5 years after KTx.
Collapse
Affiliation(s)
- Shoko Ishikawa
- Division of Urology, Department of Regenerative & Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Masayuki Tasaki
- Division of Urology, Department of Regenerative & Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
| | - Kazuhide Saito
- Division of Urology, Department of Regenerative & Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yuki Nakagawa
- Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Masahiro Ikeda
- Division of Urology, Department of Regenerative & Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kota Takahashi
- Division of Urology, Department of Regenerative & Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yoshihiko Tomita
- Division of Urology, Department of Regenerative & Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| |
Collapse
|
|
5
|
Abstract
Solid organ transplantation is a life-saving treatment for people with end-stage organ disease. Immune-mediated transplant rejection is a common complication that decreases allograft survival. Although immunosuppression is required to prevent rejection, it also increases the risk of infection. Some infections, such as cytomegalovirus and BK virus, can promote inflammatory gene expression that can further tip the balance toward rejection. BK virus and other infections can induce damage that resembles the clinical pathology of rejection, and this complicates accurate diagnosis. Moreover, T cells specific for viral infection can lead to rejection through heterologous immunity to donor antigen directly mediated by antiviral cells. Thus, viral infections and allograft rejection interact in multiple ways that are important to maintain immunologic homeostasis in solid organ transplant recipients. Better insight into this dynamic interplay will help promote long-term transplant survival.
Collapse
Affiliation(s)
- Lauren E Higdon
- Department of Medicine/Nephrology, Stanford University, Palo Alto, CA
| | - Jane C Tan
- Department of Medicine/Nephrology, Stanford University, Palo Alto, CA
| | - Jonathan S Maltzman
- Department of Medicine/Nephrology, Stanford University, Palo Alto, CA
- Geriatric Research Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA
| |
Collapse
|
|
6
|
Daloul R, Schnelle K, Von Stein L, Logan A, Singh P, Yenebere P, Pesavento T, Washburn K. Kidney transplant from hepatitis C viremic donors into aviremic recipients and risk for post-transplant BK and CMV infection. Transpl Infect Dis 2022; 24:e13887. [PMID: 35752929 DOI: 10.1111/tid.13887] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/06/2022] [Accepted: 04/16/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND kidney transplantation from HCV-viremic donors to uninfected recipients is associated with excellent short-term outcomes. However, HCV viremia might be associated with an increased risk for post-transplant viral complications. METHODS We designed a retrospective study of HCV-negative kidney-only transplant recipients between 2018 and 2020. Recipients were grouped into group 1; HCV-negative donors, and group 2; HCV-viremic donors. Patients were matched 1:1 using propensity score. Primary objectives were to compare the incidence of CMV viremia ≥ 200 ml/IU, and BK viremia ≥1000 copies/ml between the groups. Secondary outcomes included group comparison of CMV disease, BK viremia ≥10,000 copies/ml, and one year patient and allograft survival. RESULTS The study included 634 patients in group 1, and 71 patients in group 2. 65 pairs of patients were matched. Incidence of CMV viremia (33.3% vs 40.0%, p = 0.4675), and BK viremia (15.9% vs 27.7%, P = 0.1353) did not differ significantly between groups in the matched cohort. Incidence of CMV disease (81.0% Vs 76.9%; p = 1.000), and BK viremia ≥10,000 copies/ml (9.5% vs 16.9%, p = 0.2987) were comparable between groups. There was no difference in the one-year patient or allograft survival between groups. CONCLUSION kidney transplant from HCV-viremic donors is not associated with increased risk for BK or CMV viremia. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Reem Daloul
- Division of Nephrology, Kidney and Pancreas Transplant Program, Allegheny General Hospital
| | - Kendra Schnelle
- Department of Pharmacy, The Ohio State University Wexner Medical Center
| | - Lauren Von Stein
- Department of Pharmacy, The Ohio State University Wexner Medical Center
| | - April Logan
- Division of Transplantation, Department of Surgery, The Ohio State University College of Medicine
| | - Priyamvada Singh
- Division of Nephrology, Department of Internal Medicine, The Ohio State University College of Medicine
| | - Priya Yenebere
- Division of Nephrology, Department of Internal Medicine, The Ohio State University College of Medicine
| | - Todd Pesavento
- Division of Nephrology, Department of Internal Medicine, The Ohio State University College of Medicine
| | - Kenneth Washburn
- Division of Transplantation, Department of Surgery, The Ohio State University College of Medicine
| |
Collapse
|
|
7
|
Ong DSY, Chong GLM, Chemaly RF, Cremer OL. Comparative clinical manifestations and immune effects of cytomegalovirus infections following distinct types of immunosuppression. Clin Microbiol Infect 2022; 28:1335-1344. [PMID: 35709902 DOI: 10.1016/j.cmi.2022.05.034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is a well-recognized complication of solid organ and hematopoietic cell transplantation. However, CMV infection also occurs in patients with human immunodeficiency virus (HIV) infection, previously immunocompetent intensive care unit (ICU) patients, and individuals on immunosuppressive medications for various underlying diseases. OBJECTIVES This review describes the comparative effects of CMV infection in distinct types of acquired immunosuppression. SOURCES Selected peer-reviewed publications on CMV infections published until December 2021. CONTENT CMV infection affects various organ systems through direct cytolytic mechanisms, but may also exert indirect effects by promoting pro-inflammatory and immunosuppressive responses. This has been well studied in transplant recipients, for whom antiviral prophylaxis and pre-emptive therapy have now become standard practice. These strategies not only prevent direct CMV disease manifestations, but also mitigate various immunopathological processes to reduce graft-versus-host disease, graft rejection, and the occurrence of secondary bacterial and fungal infections. The efficacy of neither prophylactic nor pre-emptive treatment of CMV infection has been demonstrated for patients with critical illness- or medication-induced immunosuppression. Many observational studies have shown an independent association between CMV reactivation and a prolonged duration of mechanical ventilation or increased mortality in the ICU. Furthermore, data suggest that CMV reactivation may increase pulmonary inflammation and prolong the duration of mechanical ventilation. IMPLICATIONS A large number of observational and experimental studies suggest attributable morbidity and mortality related to CMV infection, not only in transplant recipients and patients with HIV infection but also in patients with critically illness- or medication-induced immunosuppression. Adequately powered randomized controlled trials investigating the efficacy of prophylaxis or pre-emptive treatment of CMV infection in these patients are lacking, with a notable exception for transplant recipients.
Collapse
Affiliation(s)
- David S Y Ong
- Department of Medical Microbiology and Infection Control, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
| | - Ga-Lai M Chong
- Erasmus University Medical Center, Department of Medical Microbiology & Infectious Diseases, Rotterdam, the Netherlands
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Olaf L Cremer
- Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| |
Collapse
|
|
8
|
Erol Ç, Akdur A, Arslan H, Haberal M. Cytomegalovirus Viremia in Solid-Organ Transplant Patients in the First Year After Transplantation. EXP CLIN TRANSPLANT 2022; 20:125-128. [PMID: 35384821 DOI: 10.6002/ect.mesot2021.p54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Cytomegalovirus infection is an important problem for transplantation. Although effective antivirals for prophylaxis or preemptive therapy have reduced the severity and consequences of infection, cytomegalovirus viremia and cytomegalovirusrelated disease are still matters for patients and for graft survival. The aim of our study was to determine the frequency of cytomegalovirus infections during the first year after transplant. MATERIALS AND METHODS In this study, we analyzed the data of 252 liver and kidney transplant patients who had procedures between May 2016 and May 2020. Demographic and laboratory data of patients were recorded retrospectively and analyzed with the SPSS version 25 statistical program. RESULTS Our study included 35 liver (14%) and 217 kidney transplant recipients. The ratio of male to female was 3.8, and the median age was 41 years (range, 18-71 years). In our study group, there were 32 patients (12.7%) with cytomegalovirus DNAemia, 13 patients (5%) with cytomegalovirus syndrome, and 6 patients (2.4%) with cytomegalovirus endorgan diseases. Four patients were diagnosed with gastrointestinal disease with histopathology, and 2 patients were diagnosed with cytomegalovirus pneumonia with bronchoscopy and radiology. The mortality rate was 0.8% in the first year. CONCLUSIONS Cytomegalovirus reactivations in the first year after transplant play a critical role on graft survival in solid-organ transplant. Regular follow-up of cytomegalovirus DNAemia is crucial for modifying prophylactic and preemptive antiviral regimens.
Collapse
Affiliation(s)
- Çiğdem Erol
- From the Department of Infectious Diseases, Başkent University Medical School, Ankara, Turkey
| | | | | | | |
Collapse
|
|
9
|
Chen TH, Ou SM, Tarng DC. Associations of high anti-CMV IgG titer with renal function decline and allograft rejection in kidney transplant patients. J Chin Med Assoc 2022; 85:183-189. [PMID: 34882099 DOI: 10.1097/jcma.0000000000000678] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND An anti-cytomegalovirus (CMV) immunoglobulin G (IgG) antibody is produced after primary CMV infection and generally persists after the primary infection. However, it is not well-known about the relationship between anti-CMV IgG titer and outcomes in kidney transplant recipients. We, therefore, aimed to explore the role of anti-CMV IgG titer on the risks of CMV disease development, allograft rejection, renal function decline, and mortality. METHODS In a hospital-based study, we identified 179 CMV-seropositive kidney transplant recipients between January 2013 and December 2017. These patients were divided into low and high anti-CMV IgG titer groups, respectively. The cutoff level of anti-CMV IgG titer was determined by receiver operating characteristic curve analysis. The outcomes evaluated included CMV disease, decrease of ≥15% in estimated glomerular filtration rate (eGFR), biopsy-proven allograft rejection, and all-cause mortality. RESULTS The high anti-CMV IgG titer group (≥846.2 AU/mL) exhibited a higher risk of CMV disease (adjusted hazard ratio [aHR], 3.77; 95% CI, 1.47-9.68; p = 0.006), eGFR decline ≥15% (aHR, 2.00; 95% CI, 1.19-3.35; p = 0.009), and renal allograft rejection (aHR, 2.95; 95% CI, 1.11-7.87; p = 0.030) than the low titer group (<846.2 AU/mL). CONCLUSION In kidney transplant recipients, a high anti-CMV IgG titer was associated with higher risks for developing CMV disease, undergoing allograft rejection, and eGFR decline.
Collapse
Affiliation(s)
- Tz-Heng Chen
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital Yuli Branch, Hualien, Taiwan, ROC
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shuo-Ming Ou
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Der-Cherng Tarng
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department and Institute of Physiology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| |
Collapse
|
|
10
|
Daniel L, Tassery M, Lateur C, Thierry A, Herbelin A, Gombert JM, Barbarin A. Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component. Front Immunol 2021; 12:674016. [PMID: 34367138 PMCID: PMC8334557 DOI: 10.3389/fimmu.2021.674016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 06/30/2021] [Indexed: 12/21/2022] Open
Abstract
Immunosenescence is a physiological process that is associated with changes in the immune system, particularly among CD8 T-cells. Recent studies have hypothesized that senescent CD8 T-cells are produced with chronologic age by chronic stimulation, leading to the acquisition of hallmarks of innate-like T-cells. While conventional CD8 T-cells are quite well characterized, CD8 T-cells sharing features of NK cells and memory CD8 T-cells, are a newly described immune cell population. They can be distinguished from conventional CD8 T-cells by their combined expression of panKIR/NKG2A and Eomesodermin (E), a unique phenotype closely associated with IFN-γ production in response to innate stimulation. Here, we first provided new evidence in favor of the innate character of panKIR/NKG2A(+) E(+) CD8 T-cells in normal subjects, documenting their position at an intermediate level in the innateness gradient in terms of both innate IFN-γ production and diminished mitochondrial mass. We also revealed that CD8 E(+) panKIR/NKG2A(+) T-cells, hereafter referred to as Innate E(+) CD8 T-cells, exhibit increased senescent (CD27(-) CD28(-)) phenotype, compared to their conventional memory counterparts. Surprisingly, this phenomenon was not dependent on age. Given that inflammation related to chronic viral infection is known to induce NK-like marker expression and a senescence phenotype among CD8 T-cells, we hypothesized that innate E(+) CD8 T-cells will be preferentially associated with exacerbated cellular senescence in response to chronic alloantigen exposure or CMV infection. Accordingly, in a pilot cohort of stable kidney allotransplant recipients, we observed an increased frequency of the Innate E(+) CD8 T-cell subset, together with an exacerbated senescent phenotype. Importantly, this phenotype cannot be explained by age alone, in clear contrast to their conventional memory counterparts. The senescent phenotype in CD8 T-cells was further increased in cytomegalovirus (CMV) positive serology transplant recipients, suggesting that transplantation and CMV, rather than aging by itself, may promote an exacerbated senescent phenotype of innate CD8 T-cells. In conclusion, we proposed that kidney transplantation, via the setting of inflammatory stimuli of alloantigen exposure and CMV infection, may exogenously age the CD8 T-cell compartment, especially its innate component. The physiopathological consequences of this change in the immune system remain to be elucidated.
Collapse
Affiliation(s)
- Lauren Daniel
- Inserm U1082, Poitiers, France.,Université de Poitiers, Poitiers, France
| | - Marion Tassery
- Service de Néphrologie, Hémodialyse et Transplantation, CHU de Poitiers, Poitiers, France
| | - Clara Lateur
- Service d'Immunologie et Inflammation, CHU de Poitiers, Poitiers, France
| | - Antoine Thierry
- Inserm U1082, Poitiers, France.,Université de Poitiers, Poitiers, France.,Service de Néphrologie, Hémodialyse et Transplantation, CHU de Poitiers, Poitiers, France
| | - André Herbelin
- Inserm U1082, Poitiers, France.,Université de Poitiers, Poitiers, France
| | - Jean-Marc Gombert
- Inserm U1082, Poitiers, France.,Université de Poitiers, Poitiers, France.,Service d'Immunologie et Inflammation, CHU de Poitiers, Poitiers, France
| | - Alice Barbarin
- Inserm U1082, Poitiers, France.,CHU de Poitiers, Poitiers, France
| |
Collapse
|
|
11
|
Fragkou PC, Moschopoulos CD, Karofylakis E, Kelesidis T, Tsiodras S. Update in Viral Infections in the Intensive Care Unit. Front Med (Lausanne) 2021; 8:575580. [PMID: 33708775 PMCID: PMC7940368 DOI: 10.3389/fmed.2021.575580] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 02/02/2021] [Indexed: 12/15/2022] Open
Abstract
The advent of highly sensitive molecular diagnostic techniques has improved our ability to detect viral pathogens leading to severe and often fatal infections that require admission to the Intensive Care Unit (ICU). Viral infections in the ICU have pleomorphic clinical presentations including pneumonia, acute respiratory distress syndrome, respiratory failure, central or peripheral nervous system manifestations, and viral-induced shock. Besides de novo infections, certain viruses fall into latency and can be reactivated in both immunosuppressed and immunocompetent critically ill patients. Depending on the viral strain, transmission occurs either directly through contact with infectious materials and large droplets, or indirectly through suspended air particles (airborne transmission of droplet nuclei). Many viruses can efficiently spread within hospital environment leading to in-hospital outbreaks, sometimes with high rates of mortality and morbidity, thus infection control measures are of paramount importance. Despite the advances in detecting viral pathogens, limited progress has been made in antiviral treatments, contributing to unexpectedly high rates of unfavorable outcomes. Herein, we review the most updated data on epidemiology, common clinical features, diagnosis, pathogenesis, treatment and prevention of severe community- and hospital-acquired viral infections in the ICU settings.
Collapse
Affiliation(s)
- Paraskevi C. Fragkou
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece
| | - Charalampos D. Moschopoulos
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece
| | - Emmanouil Karofylakis
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece
| | - Theodoros Kelesidis
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Sotirios Tsiodras
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece
| |
Collapse
|
|
12
|
Boutolleau D, Coutance G, Désiré E, Bouglé A, Bréchot N, Leprince P, Varnous S. Association between cytomegalovirus infection and allograft rejection in a large contemporary cohort of heart transplant recipients. Transpl Infect Dis 2021; 23:e13569. [PMID: 33452851 DOI: 10.1111/tid.13569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection remains a common complication after heart transplantation (HTx). The association between CMV infection and allograft rejection is debated in the era of efficient prophylactic antiviral therapies. METHODS This single-center cohort study utilized a highly phenotyped database of HTx recipients (2012-2016). The primary endpoint was the analysis of the association between CMV infection (CMV load ≥ 500 IU/mL whole blood) and the risk of allograft rejection (cellular rejection ≥ 1R1B, antibody-mediated rejection ≥ pAMR1). Secondary endpoints included the analysis of a higher CMV load threshold (≥10 000 IU/mL) and different risk periods after PCR positivity. A mixed-effect logistic regression model with a random intercept was applied. Results were adjusted for important risk factors of rejection. RESULTS Overall, 384 patients were included and 6388 CMV loads and 3,494 endomyocardial biopsies were analyzed. CMV infections ≥ 500 IU/mL were diagnosed on 1223 (19.2%) blood samples from 284 (72.1%) patients and allograft rejections on 246 biopsies (7%) from 149 patients (38.8%). We did not find any association between CMV infection ≥ 500 IU/mL and rejection (univariable: OR 0.94, 95% CI [0.61, 1.45], P = .78, multivariable: OR 0.86, 95% CI [0.55, 1.33], P = .85). These results were consistent when analyzing a higher CMV load threshold and different periods of risk, reinforced by internal validation procedures and a posteriori calculation of the power (primary endpoint: power = 0.82, 95% CI [0.79-0.84]) and reproducible across different clinical scenarios. CONCLUSIONS CMV infection was not associated with an increased risk of rejection in a contemporary cohort of HTx recipients.
Collapse
Affiliation(s)
- David Boutolleau
- Virology Department, Sorbonne Université, INSERM UMR U1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Team 3 THERAVIR, and Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, National Reference Centre for Herpesviruses, Paris, France
| | - Guillaume Coutance
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, Paris, France
| | - Eva Désiré
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, Paris, France
| | - Adrien Bouglé
- Department of Anesthesiology and Critical Care Medicine, Sorbonne Université, UMR INSERM 1166, IHU ICAN, Assistance Publique-Hôpitaux de Paris (AP-HP), Cardiology Institute, Pitié-Salpêtrière Hospital, Paris, France
| | - Nicolas Bréchot
- Department of Medical Intensive Care Unit, Cardiology Institute, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, Paris, France.,INSERM, UMRS 1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France
| | - Pascal Leprince
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, Paris, France
| | - Shaida Varnous
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, Paris, France
| |
Collapse
|
|
13
|
Bischof N, Wehmeier C, Dickenmann M, Hirt-Minkowski P, Amico P, Steiger J, Naegele K, Hirsch HH, Schaub S. Revisiting cytomegalovirus serostatus and replication as risk factors for inferior long-term outcomes in the current era of renal transplantation. Nephrol Dial Transplant 2020; 35:346-356. [PMID: 31943075 DOI: 10.1093/ndt/gfz268] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/15/2019] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) serostatus and CMV replication are considered as risk factors for inferior graft and patient survival after renal transplantation, but long-term outcome data are limited. The aim of this retrospective single-centre study was to investigate the impact of CMV serostatus and CMV replication/disease on long-term outcomes in a well-defined cohort managed by a standardized CMV prevention/treatment protocol. METHODS We investigated 599 consecutive kidney transplantations having a CMV prevention protocol consisting of either prophylaxis (D+/R- and R+ with ATG induction) or screening/deferred therapy (R+ without ATG induction). Patients were grouped according to CMV serostatus [high risk (D+/R-): n = 122; intermediate risk (R+): n = 306; low risk (D-/R-): n = 171] and occurrence of CMV replication/disease (no CMV replication: n = 419; asymptomatic CMV replication: n = 110; CMV syndrome: n = 39; tissue-invasive CMV disease: n = 31). The median follow-up time was 6.5 years. RESULTS Graft and patient survival were not different among the three CMV serostatus groups as well as the four CMV replication/disease groups (P ≥ 0.44). Eighty-seven patients died, 17 due to infections (21%), but none was attributable to CMV. The overall hospitalization incidence for CMV-related infection was 3% (17/599 patients). The incidence of clinical and (sub)clinical rejection was similar among the groups (P ≥ 0.17). In a multivariate Cox proportional hazard model, neither CMV serostatus, nor CMV replication, nor CMV disease were independent predictors for patient death or graft failure, respectively. CONCLUSIONS This retrospective single-centre study suggests that the negative impact of CMV infection on long-term patient and allograft survival as well as on allograft rejection can be largely eliminated with current diagnostic/therapeutic management.
Collapse
Affiliation(s)
- Nicole Bischof
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Caroline Wehmeier
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Michael Dickenmann
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patricia Hirt-Minkowski
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patrizia Amico
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Klaudia Naegele
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Hans H Hirsch
- Clinic for Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.,Transplantation and Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.,HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| |
Collapse
|
|
14
|
Zhu W, Liu S. The role of human cytomegalovirus in atherosclerosis: a systematic review. Acta Biochim Biophys Sin (Shanghai) 2020; 52:339-353. [PMID: 32253424 DOI: 10.1093/abbs/gmaa005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/05/2019] [Accepted: 01/20/2020] [Indexed: 12/11/2022] Open
Abstract
Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is closely associated with the development of atherosclerosis. HCMV infection may accelerate graft atherosclerosis and the development of transplant vasculopathy in organ transplantation. However, our current understanding of HCMV-associated atherosclerosis remains limited and is mainly based on clinical observations. The underlying mechanism of the involvement of HCMV infection in atherogenesis remains unclear. Here, we summarized current knowledge regarding the multiple influences of HCMV on a diverse range of infected cells, including vascular endothelial cells, vascular smooth muscle cells, monocytes, macrophages, and T cells. In addition, we described potential HCMV-induced molecular mechanisms, such as oxidative stress, endoplasmic reticulum stress, autophagy, lipid metabolism, and miRNA regulation, which are involved in the development of HCMV-associated atherogenesis. Gaining an improved understanding of these mechanisms will facilitate the development of novel and effective therapeutic strategies for the treatment of HCMV-related cardiovascular disease.
Collapse
Affiliation(s)
- Wenbo Zhu
- Clinical Research Institute, First Affiliated Hospital, University of South China, Hengyang 421001, China
| | - Shuangquan Liu
- Clinical Laboratory, First Affiliated Hospital, University of South China, Hengyang 421001, China
| |
Collapse
|
|
15
|
|
|
16
|
Vanichanan J, Udomkarnjananun S, Avihingsanon Y, Jutivorakool K. Common viral infections in kidney transplant recipients. Kidney Res Clin Pract 2018; 37:323-337. [PMID: 30619688 PMCID: PMC6312768 DOI: 10.23876/j.krcp.18.0063] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/22/2018] [Accepted: 10/07/2018] [Indexed: 12/15/2022] Open
Abstract
Infectious complications have been considered as a major cause of morbidity and mortality after kidney transplantation, especially in the Asian population. Therefore, prevention, early detection, and prompt treatment of such infections are crucial in kidney transplant recipients. Among all infectious complications, viruses are considered to be the most common agents because of their abundance, infectivity, and latency ability. Herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, hepatitis B virus, BK polyomavirus, and adenovirus are well-known etiologic agents of viral infections in kidney transplant patients worldwide because of their wide range of distribution. As DNA viruses, they are able to reactivate after affected patients receive immunosuppressive agents. These DNA viruses can cause systemic diseases or allograft dysfunction, especially in the first six months after transplantation. Pretransplant evaluation and immunization as well as appropriate prophylaxis and preemptive approaches after transplant have been established in the guidelines and are used effectively to reduce the incidence of these viral infections. This review will describe the etiology, diagnosis, prevention, and treatment of viral infections that commonly affect kidney transplant recipients.
Collapse
Affiliation(s)
- Jakapat Vanichanan
- Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Renal Immunology and Therapeutic Apheresis Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Yingyos Avihingsanon
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Renal Immunology and Therapeutic Apheresis Research Unit, Chulalongkorn University, Bangkok, Thailand.,Excellence Center of Immunology and Immune-mediated Diseases, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kamonwan Jutivorakool
- Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| |
Collapse
|
|
17
|
Abstract
Cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7 are ubiquitous β-herpesviruses that can cause opportunistic infection and disease in kidney transplant recipients. Active CMV infection and disease are associated with acute allograft failure and death, and HHV-6 and HHV-7 replication are associated with CMV disease. CMV prevention strategies are used commonly after kidney transplantation, and include prophylaxis with antiviral medications and preemptive treatment upon the detection of asymptomatic viral replication in blood. Both approaches decrease CMV disease and allograft rejection, but CMV prophylaxis is preferred for high-risk patients because it is easy to administer and may be more effective in real-world settings. CMV disease commonly occurs even with current preventive strategies, whereas HHV-6 and HHV-7 diseases are rare. The clinical manifestations of CMV, HHV-6, and HHV-7 are nonspecific, and laboratory confirmation is essential to establishing diagnoses. Although nucleic acid testing has supplanted other diagnostic modalities given its high sensitivity and specificity, histopathologic examination sometimes is necessary to identify disease definitively. Ganciclovir and valganciclovir are the treatments of choice for CMV and HHV-6, and foscarnet can be used to treat HHV-7. Treatment duration should be informed by the initial severity of disease, and subsequent clinical and virologic responses.
Collapse
|
|
18
|
Han SH. Immunological Prediction of Cytomegalovirus (CMV) Replication Risk in Solid Organ Transplantation Recipients: Approaches for Regulating the Targeted Anti-CMV Prevention Strategies. Infect Chemother 2017; 49:161-175. [PMID: 29027383 PMCID: PMC5620383 DOI: 10.3947/ic.2017.49.3.161] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The current cytomegalovirus (CMV) prevention strategies in solid organ transplantation (SOT) recipients have contributed towards overcoming the detrimental effects caused by CMV lytic infection, and improving the long-term success rate of graft survival. Although the quantification of CMV in peripheral blood is the standard method, and an excellent end-point for diagnosing CMV replication and modulating the anti-CMV prevention strategies in SOT recipients, a novel biomarker mimicking the CMV control mechanism is required. CMV-specific immune monitoring can be employed as a basic tool predicting CMV infection or disease after SOT, since uncontrolled CMV replication mostly originates from the impairment of immune responses against CMV under immunosuppressive conditions in SOT recipients. Several studies conducted during the past few decades have indicated the possibility of measuring the CMV-specific cell-mediated immune response in clinical situations. Among several analytical assays, the most advancing standardized tool is the QuantiFERON®-CMV assay. The T-Track® CMV kit that uses the standardized enzyme-linked immunospot assay is also widely employed. In addition to these assays, immunophenotyping and intracellular cytokine analysis using flow cytometry (with fluorescence-labeled monoclonal antibodies or peptide-major histocompatibility complex multimers) needs to be adequately standardized and validated for potential clinical applications.
Collapse
Affiliation(s)
- Sang Hoon Han
- Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
19
|
Bhat V, Joshi A, Sarode R, Chavan P. Cytomegalovirus infection in the bone marrow transplant patient. World J Transplant 2015; 5:287-291. [PMID: 26722656 PMCID: PMC4689939 DOI: 10.5500/wjt.v5.i4.287] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 09/09/2015] [Accepted: 11/17/2015] [Indexed: 02/05/2023] Open
Abstract
Cytomegalovirus (CMV) infection is an important contributor to the morbidity and mortality associated with bone marrow transplantation (BMT). Infection may lead to CMV disease involving multiple organs such as pneumonia, gastroenteritis, retinitis, central nervus system involvement and others. CMV seropositivity is an important risk factor and approximately half of BMT recipients will develop clinically significant infection most commonly in the first 100 d post-transplant. The commonly used tests to diagnose CMV infection in these patients include the pp65 antigenemia test and the CMV DNA polymerase chain reaction (PCR) assay. Because of its greater sensitivity and lesser turnaround time, the CMV PCR is nowadays the preferred test and serves as a main guide for pre-emptive therapy. Methods of CMV prevention include use of blood products from seronegative donors or leukodepleted products. Prophylaxis or pre-emptive therapy strategies for CMV prevention may be used post-transplant with the latter becoming more common. The commonly used antivirals for pre-emptive therapy and CMV disease management include intravenous gancyclovir and foscarnet. The role of intravenous immunoglobulin, although used commonly in CMV pneumonia is not clear.
Collapse
|
|
20
|
Lum EL, Schaenman JM, DeNicola M, Reddy UG, Shen JI, Pullarkat ST. A case report of CMV lymphadenitis in an adult kidney transplant recipient. Transplant Proc 2015; 47:141-5. [PMID: 25645793 DOI: 10.1016/j.transproceed.2014.09.105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 09/17/2014] [Indexed: 11/28/2022]
Abstract
Cytomegalovirus (CMV) infection following kidney transplantation is associated with increased morbidity and mortality. In this case report we describe a case of a 23-year-old woman with an unusual presentation of diffuse CMV lymphadenitis following kidney transplantation that did not respond to gangiclovir therapy. This case highlights the atypical presentation of CMV disease in a kidney transplant recipient, the importance of CMV hypergammaglobulin in the treatment of CMV infection post kidney transplantation, and the difficulties in transitioning care from pediatric to adult transplant programs.
Collapse
Affiliation(s)
- E L Lum
- UCLA David Geffen School of Medicine Department of Medicine, Division of Nephrology, Kidney Transplant, Los Angeles, Califonia, USA.
| | - J M Schaenman
- UCLA David Geffen School of Medicine Department of Medicine, Infectious Diseases, Los Angeles, Califonia, USA
| | - M DeNicola
- UCLA David Geffen School of Medicine Department of Pathology, Los Angeles, Califonia, USA
| | - U G Reddy
- UCLA David Geffen School of Medicine Department of Medicine, Division of Nephrology, Kidney Transplant, Los Angeles, Califonia, USA
| | - J I Shen
- UCLA Harbor Department of Medicine, Division of Nephrology, Los Angeles, Califonia, USA
| | - S T Pullarkat
- UCLA David Geffen School of Medicine Department of Pathology, Los Angeles, Califonia, USA
| |
Collapse
|
|
21
|
Reduced rate of cardiovascular death after cytomegalovirus prophylaxis in renal transplant recipients. Transplantation 2015; 99:1197-202. [PMID: 25606797 DOI: 10.1097/tp.0000000000000522] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND It is unknown how death with a functioning graft (DWFG) is affected in renal transplant recipients who receive prophylaxis for cytomegalovirus (CMV) infection. METHODS Data from 61,927 adult recipients of a deceased donor kidney transplant in 1990 to 2012 registered with the Collaborative Transplant Study were analyzed. RESULTS Cytomegalovirus prophylaxis was administered in 18%, 75%, 27% and 34% of R-/D- (recipient-negative, donor-negative), R-/D+, R+/D- and R+/D+ transplants, respectively. Only in R-/D+ transplants was CMV prophylaxis associated with significantly improved patient survival versus no prophylaxis (P<0.001). Unexpectedly, in the R-/D+ subgroup, DWFG because of infection was not significantly affected by use of CMV prophylaxis (P=0.16) but death from cardiovascular disease was significantly lower (P<0.001). Cox regression analysis confirmed that the primary impact of CMV prophylaxis on DWFG in R-/D+ transplants was because of reduced cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.51-0.85; P=0.002), an effect restricted to patients aged 40 years or older (hazard ratio, 0.61; 95% confidence interval, 0.46-0.81; P<0.001). CONCLUSION We conclude that CMV prophylaxis is associated with a significant benefit for risk of cardiovascular DWFG among R-/D+ kidney transplant patients aged ≥ 40 years. Cytomegalovirus prophylaxis appears particularly critical in this patient subpopulation.
Collapse
|
|
22
|
Florescu DF, Qiu F, Schmidt CM, Kalil AC. A Direct and Indirect Comparison Meta-Analysis on the Efficacy of Cytomegalovirus Preventive Strategies in Solid Organ Transplant. Clin Infect Dis 2014; 58:785-803. [DOI: 10.1093/cid/cit945] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
|
|
23
|
Roux A, Mourin G, Fastenackels S, Almeida JR, Iglesias MC, Boyd A, Gostick E, Larsen M, Price DA, Sacre K, Douek DC, Autran B, Picard C, Miranda SD, Sauce D, Stern M, Appay V. CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation. Clin Immunol 2013; 148:16-26. [PMID: 23644452 DOI: 10.1016/j.clim.2013.03.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Revised: 02/11/2013] [Accepted: 03/16/2013] [Indexed: 10/27/2022]
Abstract
Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection.
Collapse
Affiliation(s)
- Antoine Roux
- INSERM UMR S 945, Infections and Immunity, Université Pierre et Marie Curie-Paris6, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Heiske A, Roettger Y, Bacher M. Cytomegalovirus upregulates vascular endothelial growth factor and its second cellular kinase domain receptor in human fibroblasts. Viral Immunol 2012; 25:360-7. [PMID: 22985288 DOI: 10.1089/vim.2012.0028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Human cytomegalovirus (HCMV) activation and elevated levels of vascular endothelial growth factor (VEGF) have been found to be associated with transplant rejection. However, information is lacking about whether elevated levels of this multifunctional factor are directly due to viral activation, or if they derive from impurities within the culture supernatant of infected cell cultures. We used purified as well as unpurified viral stocks to infect human fibroblasts in vitro and applied PCR, Western blot, ELISA, and immunofluorescence staining to investigate the expression of VEGF and its receptors. Our data suggest that HCMV infection triggers an early and sustained induction of VEGF and kinase insert domain receptor (KDR) mRNAs, whereas transcript levels of FLT-1 remain unchanged by viral infection. Analysis of the extracellular VEGF and cellular KDR protein expression after infection with purified and unpurified HCMV strains AD169 and TOLEDO showed, in clear contrast to UV-inactivated virus preparations, an increased release of VEGF and KDR proteins. In addition, immunofluorescence revealed that HCMV infection was also accompanied by a profound increase in intracellular VEGF and KDR levels. These results confirm that active HCMV infection is required to induce VEGF and the most important VEGF receptor KDR, and that the upregulation of VEGF and KDR are a direct viral effect and not a secondary effect mediated by inflammatory cytokines within the supernatant. The HCMV-dependent upregulation of VEGF and KDR contributes to the theory that viral-induced immune mediators play a key role in transplant rejection.
Collapse
Affiliation(s)
- Andreas Heiske
- Institute of Virology, Philipps University Marburg, Marburg, Germany
| | | | | |
Collapse
|
|
25
|
Vymětalová J, Kubánek M, Gazdič T, Vrbská J, Málek I, Kautzner J. Comparison of universal prophylaxis and preemptive treatment with valganciclovir in management of cytomegalovirus infection in heart transplant recipients. COR ET VASA 2012. [DOI: 10.1016/j.crvasa.2012.01.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
26
|
Erdbruegger U, Scheffner I, Mengel M, Schwarz A, Verhagen W, Haller H, Gwinner W. Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant 2011; 27:435-43. [PMID: 21712490 DOI: 10.1093/ndt/gfr306] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Higher rates of acute rejection (AR) and reduced graft survival have been reported in patients with cytomegalovirus (CMV) infection, but an association between these factors remains controversial. METHODS In this study, serial protocol biopsies (PBs) and clinically indicated biopsies (IBs) from a large cohort of renal allograft recipients (n ¼ 594) were analyzed to examine the relation between CMV and AR. RESULTS Patients with CMV were more likely to receive IB (85 of the 153 patients; 56%) compared to patients without CMV (138 of 441 patients; 32%; P = 0.003). However, this did not translate into a greater number of patients with episodes of acute cellular rejection on histopathology in IBs. Analysis of PBs revealed a significantly higher number of episodes of rejection per patient with CMV infection (P = 0.04), but only in a subgroup of patients with triple immunosuppression. Long-term graft function post-transplantation was analyzed in four different subgroups according to CMV infection and/or AR. Differences in renal function were apparent within the first 6 weeks after transplantation and persisted during follow-up, with the best renal function in patients without AR or CMV, whereas patients with both AR and CMV had the worst (P < 0.012 at 1 year; P < 0.001 at 2 years). On average, the latter group had significantly older donors and more often delayed graft function. CONCLUSIONS Our data suggests that the link between CMV and AR is far less significant than previously thought. Outcome in patients with CMV may be more determined by coexisting conditions like high donor age and delayed graft function.
Collapse
Affiliation(s)
- Uta Erdbruegger
- Division of Nephrology and Hypertension, University of Virginia, Charlottesville, VA, USA.
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Tayebi-Khosroshahi H, Makhdami N, Heris HK, Habibzadeh A, Zadimani A, Badrogli N. Universal prophylaxis with gancyclovir preparation is not necessary in our kidney allograft recipients. Transplant Proc 2011; 43:547-550. [PMID: 21440757 DOI: 10.1016/j.transproceed.2011.01.042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is a common cause of morbidity, graft loss, and mortality among kidney recipients due to its direct and indirect influences on organs and systems. In this study, we evaluated CMV infection in transplant recipients in Iran. MATERIALS AND METHODS We performed a retrospective study of 104 renal allograft recipients and their donors transplanted between January 2005 and January 2010. We included all patients (recipients and donors) with least one valid laboratory result for CMV immunoglobulin (Ig)G and CMV IgM. We evaluated the occurrence of CMV disease in allograft recipients in at least the first 3 years after renal transplantation. RESULTS Fifty-seven renal allograft recipients (54.8%) were males and 47 (45.2%) were females. The overall mean (±standard error) age was 40.32±13.30 years. CMV IgG was positive in 95 cases (91.3%), negative in 9 (8.7%). Serologically, 76.9% patients were D+/R+ 14.4% D-/R+, and 8.7% D+R-. Due to the proccurrence of rejection rendering them high-risk patients for CMV infection about 15% of subjects were treated with anti thymocyte globulin (ATG) followed by prophylactic intravenous gancyclovir for 2 weeks, at doses based on allograft function. Confirmed CMV infection and CMV disease occurred in less than 5% of recipients in the first year after transplantation. About 6% of renal allograft recipients died due to infections during the first 3 years posttransplantation but CMV disease was not confirmed in these patients. CONCLUSION Due to the living donor-based renal transplantation program, the selection of low-risk patients (panel-reactive antibodies 30%), the low percent of D+/R- patients (8.7%) and the low use of ATG for induction therapy in the Iranian model, universal prophylaxis with gancyclovir is not routinely recommended for our cases.
Collapse
Affiliation(s)
- H Tayebi-Khosroshahi
- Kidney Transplant Center, Department of Internal Medicine, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | | | | | | | | |
Collapse
|
|
28
|
Berglund D, Bengtsson M, Biglarnia A, Berglund E, Yamamoto S, von Zur-Mühlen B, Lorant T, Tufveson G. Screening of mortality in transplant patients using an assay for immune function. Transpl Immunol 2011; 24:246-50. [PMID: 21232600 DOI: 10.1016/j.trim.2010.12.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Revised: 12/29/2010] [Accepted: 12/31/2010] [Indexed: 12/28/2022]
Abstract
BACKGROUND So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney+pancreas, kidney+islet cells, liver or liver+kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175ng/mL and patients with all ImmuKnow assays from 175ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. RESULTS The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175ng/mL and 251 patients had all their ImmuKnow assays from 175ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175ng/mL and above (p=0.0053, Fisher's exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p=0.66). CONCLUSIONS In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.
Collapse
Affiliation(s)
- David Berglund
- Department of Surgical Sciences, Section of Transplantation Surgery, Uppsala University, Sweden
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Dahiya D, Lee CF, Chan KM, Wu TJ, Chou HS, Cheng SS, Lee WC. A short-term preemptive treatment for cytomegalovirus infection in seropositive patients after liver transplantation. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:32-38. [PMID: 20499109 DOI: 10.1007/s00534-010-0286-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Accepted: 03/23/2010] [Indexed: 01/22/2023]
Abstract
BACKGROUND/PURPOSE Cytomegalovirus (CMV) infection remains a challenge following liver transplantation. Preemptive treatment is an effective strategy for CMV infection. However, how long preemptive treatment should be applied is not defined. METHODS Clinical records of preemptive treatment for CMV infection in patients who underwent liver transplantation were collected. CMV antigenemia (pp65) was monitored weekly during hospital stay and subsequently on follow up whenever indicated clinically. Antiviral treatment was administered based on positive antigenemia (>1 positive cell per 500,000 leukocytes) and discontinued when antigenemia became negative. RESULTS CMV infection was diagnosed in 58 (43.9%) of 132 liver transplantation patients. All 58 patients were seropositive for CMV before transplantation. CMV infection was first diagnosed at a median time of 20 days (interquartile range [IQR] 15.3-26) after transplantation. Twelve (20.7%) patients developed repeated infections. Only one of 58 patients (1.7%) was suspected to have invasive disease. The median (IQR) duration of antiviral treatment was 7 (7-12) days. Of these patients with CMV infection, 14 (24.1%) patients developed acute rejection peri-anti-CMV treatment and 36 (62.1%) developed other infectious complications. CONCLUSION Preemptive treatment is an effective way to halt the progression of asymptomatic CMV infection. A brief course of antiviral treatment is enough for seropositive patients with CMV infection after liver transplantation.
Collapse
Affiliation(s)
- Divya Dahiya
- Department of Liver and Transplantation Surgery, Chang-Gung Transplantation Institute, Chang-Gung Memorial Hospital, Chang-Gung University Medical School, Taoyuan, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Cytomegalovirus Prevention and Long-Term Recipient and Graft Survival in Pediatric Heart Transplant Recipients. Transplantation 2010; 90:1432-8. [DOI: 10.1097/tp.0b013e3181ffba7e] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
31
|
Höfer D, Aliabadi A, Ebner C, Hörmann C, Mahr S, Mascherbauer R, Pölzl G, Reiter A, Wasler A, Weber T, Zink M, Zuckermann A, Antretter H. [Evaluation of the potential organ donor with special regards to heart donation]. Wien Klin Wochenschr 2010; 122:441-51. [PMID: 20628904 PMCID: PMC7102121 DOI: 10.1007/s00508-010-1407-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2010] [Accepted: 06/10/2010] [Indexed: 05/26/2023]
Abstract
Angesichts der auch in Österreich vorherrschenden Knappheit an verfügbaren Organspendern für Herztransplantationen erscheint es dringlich notwendig, eine Optimierung von Spenderevaluierung und Management zu diskutieren. In der vorliegenden Arbeit werden allgemeine Spenderkriterien und herzspezifische Parameter detailliert diskutiert und im Zusammenhang mit der internationalen Literatur dargestellt. Es wird der "marginale" und im Gegensatz dazu der "optimale" Organspender definiert. Das Spendermanagement wird besprochen, wobei neben der hämodynamischen Optimierung auch auf zusätzliche intensivmedizinische Aspekte eingegangen wird. Erst die exakte Evaluierung erlaubt die individuelle Zuteilung des Organs zum passenden Empfänger und stellt somit insbesondere bei marginalen Spendern die Grundlage eines Therapieerfolgs dar.
Collapse
Affiliation(s)
- Daniel Höfer
- Universitätsklinik für Herzchirurgie, Medizinische Universität Innsbruck, Innsbruck, Austria.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Smith JM, Corey L, Bittner R, Finn LS, Healey PJ, Davis CL, McDonald RA. Subclinical viremia increases risk for chronic allograft injury in pediatric renal transplantation. J Am Soc Nephrol 2010; 21:1579-86. [PMID: 20616168 DOI: 10.1681/asn.2009111188] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The impact of subclinical viral infection on chronic allograft injury in the pediatric renal transplant population is not well defined. We prospectively assessed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNAemia by monthly PCR in 55 pediatric renal transplant recipients for the first 2 years after transplantation. Subclinical CMV and EBV infection occurred in 22 and 36%, respectively. Multivariable linear regression analysis suggested that both subclinical CMV and EBV infection independently associate with significant declines in GFR during the first 2 years after transplantation. CMV seronegativity associated with a significantly greater decline in GFR than seropositivity (P < 0.01). Subclinical CMV infection and subclinical EBV infection each associated with approximately fourfold greater odds of histologic evidence of chronic allograft injury (odds ratio 4.61 [95% confidence interval 1.18 to 18.07] and odds ratio 4.33 [95% confidence interval 1.34 to 14.00], respectively). An increase in viral load of CMV or EBV also associated with increased risk for moderate to severe chronic allograft injury. Taken together, these results demonstrate an association between subclinical CMV and EBV infections, which occur despite standard antiviral prophylaxis, and chronic allograft injury in pediatric renal transplant recipients.
Collapse
Affiliation(s)
- Jodi M Smith
- Department of Pediatrics, University of Washington, Seattle, Washington, USA.
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Probabilistic modeling of cytomegalovirus infection under consensus clinical management guidelines. Transplantation 2009; 87:570-7. [PMID: 19307796 DOI: 10.1097/tp.0b013e3181949e09] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) is the most common viral pathogen after renal transplantation and remains a major therapeutic challenge with important clinical and economic implications from both direct and indirect consequences of infection. METHODS This 5-year study modeled the relationship between CMV infection and biopsy-proven graft rejection, graft loss, or death after renal transplantation in an inception cohort using Canadian consensus guidelines for CMV management as a component of a detailed cost-analysis of viral infection. RESULTS Probabilities of CMV viremia and syndrome/disease among 270 sequential graft recipients were 0.27 and 0.09, respectively; 91% of cases occurred in the first 6 months. Probability of CMV infection as the first event was 0.29, with a probability of subsequent biopsy-proven acute rejection (BPAR) of 0.05 (mean: 62+/-26 days, range: 32-85 days), whereas the probability of BPAR as the first event was 0.18, with a probability of subsequent CMV infection of 0.38 (mean: 63+/-31, range: 27-119 days). Probability of freedom from both CMV infection and BPAR throughout the period of observation was 0.53. Time-dependent Cox analysis showed that neither donor/recipient CMV risk stratum nor CMV infection influenced the risks of BPAR (P=0.24; P=0.74) or of graft loss or death (P=0.26; P=0.34). In contrast, BPAR significantly increased the risk of both subsequent CMV infection (hazard ratio=1.77, P=0.03) and of graft loss or death (hazard ratio=8.31, P<0.0001). CONCLUSIONS Although current antiviral therapy seems to mitigate the reported deleterious effects of CMV infection on BPAR or graft survival, BPAR remains a significantly risk factor for both CMV infection and functional graft survival.
Collapse
|
|
34
|
Lima R, Santos P, Malafronte P, Muller H, Caiaffa-Filho H, Sens Y. Oral Manifestation of Cytomegalovirus Associated With Herpes Simplex Virus in Renal Transplant Recipient. Transplant Proc 2008; 40:1378-81. [DOI: 10.1016/j.transproceed.2008.03.138] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2007] [Accepted: 03/06/2008] [Indexed: 10/21/2022]
|
|
35
|
Reischig T, Jindra P, Hes O, Svecová M, Klaboch J, Treska V. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant 2008; 8:69-77. [PMID: 17973956 DOI: 10.1111/j.1600-6143.2007.02031.x] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Both preemptive therapy and universal prophylaxis are used to prevent cytomegalovirus (CMV) disease after transplantation. Randomized trials comparing both strategies are sparse. Renal transplant recipients at risk for CMV (D+/R-, D+/R+, D-/R+) were randomized to 3-month prophylaxis with valacyclovir (2 g q.i.d., n = 34) or preemptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days, n = 36) for significant CMV DNAemia (>/=2000 copies/mL by quantitative PCR in whole blood) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. The 12-month incidence of CMV DNAemia was higher in the preemptive group (92% vs. 59%, p < 0.001) while the incidence of CMV disease was not different (6% vs. 9%, p = 0.567). The onset of CMV DNAemia was delayed in the valacyclovir group (37 +/- 22 vs. 187 +/- 110 days, p < 0.001). Significantly higher rate of biopsy-proven acute rejection during 12 months was observed in the preemptive group (36% vs. 15%, p = 0.034). The average CMV-associated costs per patient were $5525 and $2629 in preemptive therapy and valacyclovir, respectively (p < 0.001). However, assuming the cost of $60 per PCR test, there was no difference in overall costs. In conclusion, preemptive valganciclovir therapy and valacyclovir prophylaxis are equally effective in the prevention of CMV disease after renal transplantation.
Collapse
Affiliation(s)
- T Reischig
- Department of Internal Medicine I, Charles Medical School and Teaching Hospital, Pilsen, Czech Republic.
| | | | | | | | | | | |
Collapse
|
|
36
|
McDevitt LM. Etiology and impact of cytomegalovirus disease on solid organ transplant recipients. Am J Health Syst Pharm 2007; 63:S3-9. [PMID: 16990643 DOI: 10.2146/ajhp060377] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
PURPOSE The characteristics, etiology, natural history, and direct and indirect effects of CMV disease in solid organ transplant recipients are described. SUMMARY CMV is a common herpesvirus that may be present in the donor or recipient of a solid organ transplant. Even though it is rarely pathogenic in healthy patients, transplant recipients are at risk for CMV viremia and symptomatic disease due to their immune-suppressed status. In addition to symptoms directly attributed to active disease, CMV can have a variety of indirect effects. Indirect effects may include additional infectious complications, posttransplant lymphoproliferative disease, allograft rejection, allograft loss, or death. The three most prevalent risk factors for CMV infection are CMV seronegativity in a recipient of an organ from a CMV-seropositive donor, the type of organ transplanted, and the degree of immune suppression. CMV prophylaxis is effective at preventing disease, but may result in a delayed onset where CMV disease occurs once the prophylaxis is stopped. CONCLUSION Knowledge of risk factors for CMV infection and disease, the natural history in transplant recipients, and its direct and indirect effects will help clinicians make appropriate decisions regarding the use of preventive strategies.
Collapse
Affiliation(s)
- Lisa M McDevitt
- Massachusetts College of Pharmacy and Health Sciences, Boston, MA 21150, USA.
| |
Collapse
|
|
37
|
Ishibashi K, Tokumoto T, Tanabe K, Shirakawa H, Hashimoto K, Kushida N, Yanagida T, Inoue N, Yamaguchi O, Toma H, Suzutani T. Association of the Outcome of Renal Transplantation with Antibody Response to Cytomegalovirus Strain--Specific Glycoprotein H Epitopes. Clin Infect Dis 2007; 45:60-7. [PMID: 17554702 DOI: 10.1086/518571] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Accepted: 03/09/2007] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) is the most important pathogen affecting the outcome of renal transplantation. The combination of CMV-seronegative transplant recipients with CMV-seropositive transplant donors places recipients at the highest risk of CMV disease. In cases of congenital CMV infection, existing immunity only partially protected mothers from reinfection with a different genotypic strain. The effect of differences in infected CMV strains between CMV-seropositive transplant donors and CMV seropositive transplant recipients on the outcome of transplantation remains unclear. METHODS In this prospective multicenter study, the presence of antibodies against strain-specific glycoprotein H epitopes in 84 CMV-seropositive transplant donor/CMV-seropositive transplant recipient renal transplantation cases were determined, and their relationships to acute transplant rejection, CMV infection, degree of antigenemia, and CMV disease were evaluated. RESULTS Among the 84 donor/recipient pairs, 45 and 32 had matched and mismatched strain-specific glycoprotein H antibodies, respectively. Acute transplant rejection in the mismatched group was more frequent than it was in the matched group (63% vs. 22%; P=.005). CMV disease was also more frequently observed in the mismatched group (28% vs. 9%; P=.026). The mismatched group had a higher level of antigenemia (P=.019). CONCLUSIONS Our results illustrate more adverse events in the cases with a CMV-seropositive transplant donor and a CMV-seropositive transplant recipient in which the glycoprotein H antibodies are mismatched, suggesting that reinfection with a different CMV strain results in more complications.
Collapse
Affiliation(s)
- Kei Ishibashi
- Department of Microbiology, Fukushima Medical University, Fukushima, Japan.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Puliyanda DP, Stablein DM, Dharnidharka VR. Younger age and antibody induction increase the risk for infection in pediatric renal transplantation: a NAPRTCS report. Am J Transplant 2007; 7:662-6. [PMID: 17250558 DOI: 10.1111/j.1600-6143.2006.01675.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
UNLABELLED Infections now exceed rejection as a cause of hospitalization in the first 2 years post-renal transplantation. We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine risks for hospitalization for infection (HI), either bacterial (HBI) or viral (HVI). 3106 children transplanted between 1996 and 2002 with 2-year follow-up were analyzed. Univariate and multivariate logistic regression analyses identified factors for cause-specific hospitalization. RESULTS 23.4% experienced HBI, 23.9% HVI; 8.9% were hospitalized for both. Children 0-1 years age at transplant had higher rates of HI (64.2%), HBI (40.3%) and HVI (43.3%) compared to >12 years (31%, 17.5% and 18.9%, p < 0.0001). In comparison to no induction, patients receiving monoclonal or polyclonal antibody were more likely to have HI (>42% vs. 34.0%), HBI (>24% vs. 21%) or HVI (>29% vs. 21%, all p < 0.003) but had equivalent graft survival (p = NS). Higher rates of HI, HBI and HVI were also seen with prophylactic antimicrobial use and with >5 transfusions pretransplant. Since antibody induction in recent era was not associated with better graft or patient survival but was associated with more HI and HVI, the need for routine antibody induction in children needs to be reassessed.
Collapse
Affiliation(s)
- D P Puliyanda
- Pediatric Nephrology, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | | | | |
Collapse
|
|
39
|
Dharnidharka VR, Agodoa LY, Abbott KC. Risk factors for hospitalization for bacterial or viral infection in renal transplant recipients--an analysis of USRDS data. Am J Transplant 2007; 7:653-61. [PMID: 17250559 DOI: 10.1111/j.1600-6143.2006.01674.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We previously showed that children are more likely to develop viral infections post-kidney transplant while adults are more likely to develop bacterial infections. In this study we determined the overall risk factors for hospitalization with either a bacterial (HBI) or a viral infection (HVI). We analyzed data from 28 924 United States Renal Data System (USRDS) Medicare primary renal transplant recipients from January 1996 to July 2000, for adjusted hazard ratio (AHR) for HBI or HVI in the first 3 years posttransplant. For HVI, significantly higher AHR was seen with (a) recipient age <18 years (AHR 1.57, 95% CI = 1.02, 2.42), (b) donor CMV positive (AHR 1.72, 95% CI = 1.34, 2.19). For HBI, significantly higher AHR was seen with (i) delayed graft function (AHR 1.28, 95% CI = 1.076, 1.518), (ii) primary renal diagnosis chronic pyelonephritis (AHR 1.71, 95% CI = 1.18, 2.49); (iii) associated pretransplant diabetes (AHR 1.80, 95% CI = 1.53, 2.12); (iv) female gender AHR 1.63, 95% CI = 1.41, 1.88). Lower AHR for HVI was seen in CMV-positive recipients and for HBI with more recent year of transplant. Other covariates did not impact significantly in either HVI or HBI.
Collapse
Affiliation(s)
- V R Dharnidharka
- Division of Pediatric Nephrology, University of Florida College of Medicine, Gainesville, FL, USA.
| | | | | |
Collapse
|
|
40
|
Cooke ME, Potena L, Luikart H, Valantine HA. Peripheral Blood Leukocyte Counts in Cytomegalovirus Infected Heart Transplant Patients: Impact of Acute Disease Versus Subclinical Infection. Transplantation 2006; 82:1419-24. [PMID: 17164711 DOI: 10.1097/01.tp.0000242139.13197.7f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV)-associated leucopenia in heart transplant patients is poorly characterized. METHODS We conducted a retrospective analysis of timing, degree, and type of leukopenia in four groups of patients: cases (n=20); controls (n=20); subclinical early infection (n=21), and subclinical late infection (n=22). In the cases, white blood cells (WBC) count at diagnosis was compared to prediagnosis; and cases were compared to controls. Subclinical cases (early and late) were identified by measurement of CMV DNA in peripheral blood mononucleocytes, and WBC was compared to those of the cases and controls. RESULTS First, in human heart transplant recipients the total leukocyte count decreased prior to the time of diagnosis of CMV disease: cases: 5.4+/-2.1 x 10/microL vs. 3.7+/-2.1x10/muL (P<0.01); subclinical early: 8.1+/-4.1 x 10/microL vs. 6.9+/-1.6 x 10/microL (P<0.01). Second, the leukocyte populations most reduced during CMV disease are the neutrophils: 4.4 x 10/microL (78%) to 2.5 x 10/microL (69%) (P<0.05), and monocytes 0.6 x 10/microL (11%) to 0.3 x 10/microL (7.5%) (P<0.05). Third, the reduction in leukocyte count that occurs during CMV disease appears to be independent of immunosuppressive therapy (using cyclosporine A, mycophenolate mofetil, or azathioprine and prednisone). Finally, subclinical CMV infection in stable long-term heart transplant patients without disease is unassociated with a reduction in the leukocyte count. CONCLUSIONS Aside from implications for early diagnosis, CMV-associated decrease in monocytes is important because viral infections like Epstein-Barr virus cause monocytosis. The absence of leucopenia in subclinical late infections is a new important finding.
Collapse
Affiliation(s)
- Margaret E Cooke
- Heart Transplantation Unit, Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA 94305, USA
| | | | | | | |
Collapse
|
|
41
|
Engstrand M, Larsson E, Naghibi M, Tufveson G, Korsgren O, Johnsson C. Lymphocyte propagation from biopsies of kidney allografts. Transpl Immunol 2006; 16:215-9. [PMID: 17138056 DOI: 10.1016/j.trim.2006.09.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2006] [Revised: 08/22/2006] [Accepted: 09/08/2006] [Indexed: 10/24/2022]
Abstract
Morphological evaluation of transplant biopsies, usually using the Banff classification, is the most important tool to diagnose rejection after kidney transplantation. However, morphological analysis only scores the amount and localisation of infiltrating cells, and studies show that up to 30% of grafts with a stable function display infiltration of lymphocytes consistent with acute cellular rejection. Methods to study the functional properties of the infiltrating lymphocytes are therefore needed. We applied a tissue culture system on biopsies from transplanted human kidneys, allowing infiltrating cells to propagate out from the tissue. Cells were then counted and subtyped by flow cytometry. The results were correlated to morphology. In total, 92 biopsies from 69 patients were analysed. For 14 patients, serial biopsies were available. In grafts with cellular or combined cellular and vascular rejection, the number of ex vivo propagated mononuclear cells was higher than from non-rejecting grafts. A similar pattern was seen for CD3(+) T cells as well as for T cells expressing CD25 or MHC class II antigens. However, the proportion of CD25(+) or MHC class II(+) T lymphocytes was similar in all groups (no rejection, vascular rejection, borderline changes, cellular rejection, combined cellular and vascular rejection). In all groups the number of CD4(+) cells was higher than the number of CD8(+) cells. The results confirm previous experimental studies showing that graft-infiltrating cells are possible to culture in vitro and that lymphocyte propagation correlates to acute cellular rejection. Tissue culturing is easy to perform and evaluate and can be used to determine and analyse the cellular immune response to allografts and may thus be used as a complement to morphological analyses.
Collapse
Affiliation(s)
- Mats Engstrand
- Department of Clinical Immunology, Rudbeck Laboratory, University Hospital, Uppsala, Sweden
| | | | | | | | | | | |
Collapse
|
|
42
|
Potena L, Holweg CTJ, Chin C, Luikart H, Weisshaar D, Narasimhan B, Fearon WF, Lewis DB, Cooke JP, Mocarski ES, Valantine HA. Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection. Transplantation 2006; 82:398-405. [PMID: 16906040 DOI: 10.1097/01.tp.0000229039.87735.76] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Anticytomegalovirus (CMV) prophylaxis prevents the acute disease but its impact on subclinical infection and allograft outcome is unknown. We sought to determine whether CMV prophylaxis administered for three months after heart transplant would improve patient outcomes. METHODS This prospective cohort study of 66 heart transplant recipients compared aggressive CMV prophylaxis (n = 21, CMV hyperimmune globulin [CMVIG] plus four weeks of intravenous ganciclovir followed by two months of valganciclovir); with standard prophylaxis (n = 45, intravenous ganciclovir for four weeks). Prophylaxis was based on pretransplant donor (D) and recipient (R) CMV serology: R-/D+ received aggressive prophylaxis; R+ received standard prophylaxis. Outcome measures were: CMV infection assessed by DNA-polymerase chain reaction on peripheral blood polymorphonuclear leukocytes, acute rejection, and cardiac allograft vascular disease (CAV) assessed by intravascular ultrasound. All patients completed one year of follow-up. RESULTS.: CMV infection was subclinical in all but four patients (two in each group). Aggressively treated patients had a lower incidence of CMV infection (73 +/- 10% vs. 94 +/- 4%; P = 0.038), and an independent reduced relative risk for acute rejection graded > or =3A (relative risk [95% CI] = 0.55 [0.26-0.96]; P = 0.03), as compared with the standard prophylaxis group. Aggressively prophylaxed patients also showed a slower progression of CAV, in terms of coronary artery lumen loss (lumen volume change=-21 +/- 13% vs. -10+/-14%; P = 0.05); and vessel shrinkage (vessel volume change = -15 +/- 11% vs. -3 +/- 18%; P = 0.03). CONCLUSIONS Prolonged (val)ganciclovir plus CMVIG reduces viral levels, acute rejection, and allograft vascular disease, suggesting a role for chronic subclinical infection in the pathophysiology of the most common diseases affecting heart transplant recipients.
Collapse
Affiliation(s)
- Luciano Potena
- Division of Cardiovascular Medicine, Stanford University School of Medicine, CA, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Reischig T, Jindra P, Svecová M, Kormunda S, Opatrný K, Treska V. The impact of cytomegalovirus disease and asymptomatic infection on acute renal allograft rejection. J Clin Virol 2006; 36:146-51. [PMID: 16531113 DOI: 10.1016/j.jcv.2006.01.015] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2005] [Revised: 12/29/2005] [Accepted: 01/12/2006] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) disease is a risk factor for allograft rejection in renal transplant (RTx) recipients. However, the role of asymptomatic CMV infection remains controversial. OBJECTIVES To determine the impact of CMV disease and asymptomatic infection on biopsy-proven acute rejection (BPAR) during 12 months post-RTx. STUDY DESIGN A total of 106 consecutive RTx recipients at risk for CMV (donor and/or recipient CMV seropositive) were followed prospectively for 12 months post-RTx. CMV activity was monitored using nested PCR from whole blood. Three-month prophylaxis with valacyclovir or ganciclovir was given to 94 patients. BPAR episodes were classified according to the Banff 97 criteria. Multivariate Cox proportional hazards model was used to estimate the effect of CMV disease, asymptomatic infection, and other covariates on BPAR. RESULTS Asymptomatic CMV infection occurred in 23% of the patients and 10% developed CMV disease. The incidence of BPAR was 29%. CMV disease was an independent risk factor for BPAR (HR=3.0, P=0.014), while asymptomatic CMV infection was not (P=0.987). In addition to CMV disease, expanded criteria donor and donor age were independent predictors for BPAR. In univariate analysis, valacyclovir (HR=0.26, P=0.008) decreased the risk of BPAR. A similar trend was observed with ganciclovir (HR=0.42, P=0.058). Only valacyclovir remained significant in multivariate analysis (HR=0.18, P=0.044). CONCLUSIONS CMV disease, but not asymptomatic infection, is an independent risk factor for BPAR during the first 12 months post-RTx.
Collapse
Affiliation(s)
- Tomás Reischig
- Department of Internal Medicine I, Charles University School of Medicine and Teaching Hospital, Alej Svobody 80, 301 60 Pilsen, Czech Republic.
| | | | | | | | | | | |
Collapse
|
|
44
|
Chen JH, Mao YY, He Q, Wu JY, Lv R. The Impact of Pretransplant Cytomegalovirus Infection on Acute Renal Allograft Rejection. Transplant Proc 2005; 37:4203-7. [PMID: 16387078 DOI: 10.1016/j.transproceed.2005.11.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2004] [Indexed: 11/18/2022]
Abstract
BACKGROUND The role of cytomegalovirus (CMV) infection in renal allograft rejection remains controversial; moreover, there are few studies on pretransplant infections. This study sought to investigate whether pretransplant CMV infections had negative effects on acute rejection episodes (ARE) and to evaluate the effect of preemptive treatment. METHODS This retrospective single-center study of 416 transplant recipients from October 1, 2000 to September 1, 2003 had CMV infections diagnosed by CMV antigenemia tests. The incidences of ARE were compared between CMV-infected and noninfected groups. Risk factors for ARE were analyzed. Based on preemptive treatment, pretransplant CMV-infected recipients were divided into ganciclovir-treated and nontreated groups and the incidence of ARE was compared between the two groups. RESULTS One hundred eighty four recipients had CMV infections pretransplant; the infection rate was 44.2%. Fifty five recipients had ARE among the pretransplant CMV-positive group, which was significantly higher than that in the noninfected group (29.9% vs 19.5%, P = .014). But the rejection subgroups and renal function recovery had no significant differences. While the presence of pretransplant infection was an independent predictor of ARE (RR = 1.807), severity showed no significant impact on ARE. Among 184 pretransplant CMV infection recipients, the incidences of ARE were 14.3% and 18.0% in ganciclovir-treated versus nontreated patients, respectively (P = .650). CONCLUSIONS Pretransplant CMV-positive recipients were at greater risk of ARE. Pretransplant CMV infection was an independent risk factor for ARE. Preemptive antiviral treatment did not show protective effects against ARE related to CMV infection-mediated immunological injuries.
Collapse
Affiliation(s)
- J H Chen
- Kidney Disease Center, the First Affiliated Hospital of Medical College, Department of Nephrology, Medical College of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
| | | | | | | | | |
Collapse
|
|
45
|
Bordils A, Plumed JS, Ramos D, Beneyto I, Mascarós V, Molina JM, Cordoba J, García J, Crúz JM. Comparison of Quantitative PCR and Antigenemia in Cytomegalovirus Infection in Renal Transplant Recipients. Transplant Proc 2005; 37:3756-9. [PMID: 16386529 DOI: 10.1016/j.transproceed.2005.10.074] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
UNLABELLED Cytomegalovirus infection is a common complication of renal transplantation. Antigen pp65 levels serve as indicators of viral load, although the technique is difficult to perform and interpret. We sought to determine whether quantitative PCR had a higher sensitivity and predictive value in CMV infection. METHODS The study included 100 renal transplant recipients who were screened for IgM and IgG at the time of admission. On days 7, 15, 30, 45, 60, 75, 90, 120, 180, and 360, antigenemia tests were performed on blood (pp65) and urine, and a quantitative PCR on blood. Among 59 patients recruited between November 2003 and August 2004 the mean age was 54.5 +/- 12.9 years. Two patients did not reach 90 days follow-up (3%); four patients have not surpassed 90 days (7%); 22, 120 days (37%); and 31, 180 days (53%). Ninety-three percent of patients showed anti-IgG CMV-positive titers with all being IgM CMV-negative at baseline. The patients at risk for infection were given valgancyclovir as prophylaxis throughout the study. RESULTS At 474 visits, 8 samples (2.4%) were positive with urine; 5 (1.4%) with pp65, and 15 (4.7%) with PCR. Among the 15 positive samples, two (>100,000 and 3250 copies) revealed agreement of positive IgM and shellvial test on urine; two (15,100 and 5670 copies), antigen pp65 1+; one (17,400 copies) with pp65 2+ and shellvial urine; two (99,400 and 28,300 copies) with pp65 1+ and shellvial urine; and eight remaining determinations, 749, 2250, 686, 928, 2250, 26600, 777, and 2790 copies. The rest of the tests were negative. CONCLUSION The preliminary results of this study demonstrated that quantitative PCR was a useful rapid tool for diagnosing and monitoring CMV infections.
Collapse
Affiliation(s)
- A Bordils
- Servicio de Nefrología, Valencia, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Kasman LM. CD13/aminopeptidase N and murine cytomegalovirus infection. Virology 2005; 334:1-9. [PMID: 15749117 PMCID: PMC7172656 DOI: 10.1016/j.virol.2005.01.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2004] [Revised: 10/11/2004] [Accepted: 01/26/2005] [Indexed: 11/19/2022]
Abstract
CD13/aminopeptidase N is a membrane-bound metalloproteinase implicated in human cytomegalovirus (HCMV) infection and pathogenesis. Anti-CD13 antibodies can neutralize HCMV infectivity, and HCMV viremia after bone marrow transplantation induces anti-CD13 autoantibodies which correlate with development of chronic graft vs. host disease. We examined whether murine CD13/APN was similarly implicated in murine cytomegalovirus (MCMV) disease. MCMV infection did induce anti-CD13 antibodies in mice in a strain-specific manner. ICR and 129S mice developed high titers of anti-CD13 antibodies and anti-MCMV antibodies after MCMV infection, whereas CBA and CBAxC57BL/6 f1 hybrid mice produced antibodies against MCMV only. Unlike HCMV, no evidence was found for a correlation between host cell CD13/APN expression and infection, or for the presence of CD13/APN on MCMV particles, although APN inhibitors decreased MCMV plaque formation. Reproduction of CD13/APN autoantibody production in the murine system should make it possible to determine if these antibodies contribute to CMV pathogenesis.
Collapse
Affiliation(s)
- Laura M Kasman
- Department of Microbiology and Immunology, Medical University of South Carolina, BSB-201, PO Box 250504, 173 Ashley Avenue, Charleston, SC 29425, USA.
| |
Collapse
|
|
47
|
Reischig T, Jindra P, Mares J, Cechura M, Svecová M, Hes O, Opatrný K, Treska V. Valacyclovir for Cytomegalovirus Prophylaxis Reduces the Risk of Acute Renal Allograft Rejection. Transplantation 2005; 79:317-24. [PMID: 15699762 DOI: 10.1097/01.tp.0000150024.01672.ca] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Both oral ganciclovir and valacyclovir decrease the incidence of cytomegalovirus (CMV) disease after renal transplantation. Moreover, valacyclovir has been shown to reduce the risk of acute rejection. Our study was designed to compare the efficacy and safety of oral ganciclovir and valacyclovir in the prophylaxis of CMV disease after renal transplantation. METHODS A total of 83 patients were prospectively randomized to 3-month treatment with oral ganciclovir (3 g/day, n=36, GAN) or oral valacyclovir (8 g/day, n=35, VAL). A control group (DEF, n=12) was managed by deferred therapy. RESULTS No differences were found in demography, immunosuppression, or donor/recipient CMV serology. The 12-month incidence of CMV disease was 67% in the DEF group compared with 6% in the GAN group and 3% in the VAL group (P<0.001 GAN or VAL vs. DEF; P=0.575 GAN vs. VAL). The biopsy-confirmed acute rejection rate at 12 months was 12% in the VAL group compared with 34% in the GAN group (P=0.030) and 58% in the DEF group (P<0.001). The difference between the GAN and DEF groups was not significant (P=0.087). The average CMV-associated costs per patient were $3,072, $2,906, and $4,906 in the GAN, VAL, and DEF groups, respectively. CONCLUSIONS Valacyclovir and oral ganciclovir are equally effective in the prevention of CMV disease after renal transplantation. Both regimens are cost-effective. Valacyclovir is associated with a significantly reduced risk of acute rejection compared with both ganciclovir prophylaxis and deferred therapy.
Collapse
Affiliation(s)
- Tomás Reischig
- Department of Internal Medicine I, Charles University Hospital, Pilsen, Czech Republic.
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Leis M, Marschall M, Stamminger T. Downregulation of the cellular adhesion molecule Thy-1 (CD90) by cytomegalovirus infection of human fibroblasts. J Gen Virol 2004; 85:1995-2000. [PMID: 15218185 DOI: 10.1099/vir.0.79818-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The deregulation of cellular adhesion molecules by human cytomegalovirus (HCMV) appears to be correlated with the development of vascular disease. In this study, it was investigated whether the expression of Thy-1 (CD90), a member of the immunoglobulin superfamily of adhesion molecules with constitutive expression on fibroblast cells, is modulated following infection with HCMV. It was observed that Thy-1 cell surface expression decreased significantly during the course of infection. Addition of neutralizing antibodies, as well as UV inactivation of virus, prevented Thy-1 downregulation. In contrast, inhibition of virus replication by cidofovir did not alter Thy-1 regulation by HCMV, indicating that immediate-early (IE) and/or early (E) gene products are responsible. Interestingly, after infection of fibroblasts with a recombinant GFP-expressing virus, infected as well as non-infected cells showed a reduced Thy-1 cell surface expression. From these findings, it is concluded that IE or E gene products of HCMV induce a so far unidentified soluble factor that mediates Thy-1 downregulation.
Collapse
Affiliation(s)
- Martina Leis
- Institut für Klinische und Molekulare Virologie, Schlossgarten 4, 91054 Erlangen, Germany
| | - Manfred Marschall
- Institut für Klinische und Molekulare Virologie, Schlossgarten 4, 91054 Erlangen, Germany
| | - Thomas Stamminger
- Institut für Klinische und Molekulare Virologie, Schlossgarten 4, 91054 Erlangen, Germany
| |
Collapse
|
|
49
|
Fitzgerald JT, Gallay B, Taranto SE, McVicar JP, Troppmann C, Chen X, McIntosh MJ, Perez RV. Pretransplant recipient cytomegalovirus seropositivity and hemodialysis are associated with decreased renal allograft and patient survival. Transplantation 2004; 77:1405-11. [PMID: 15167599 DOI: 10.1097/01.tp.0000122184.97674.20] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Pretransplant systemic inflammation has been associated with decreased renal allograft survival, and infectious agents such as cytomegalovirus (CMV) may play a role. We hypothesized that pretransplant CMV seropositivity is a risk factor for decreased patient and allograft survival after cadaveric renal transplantation and that other factors believed to modulate systemic inflammation, such as dialysis modality, might act synergistically with CMV to decrease patient and allograft survival. METHODS The United Network for Organ Sharing database was reviewed to identify all patients undergoing cadaveric renal transplantation in the United States from 1988 to 1997. Outcomes for CMV seropositive and seronegative recipients of organs from CMV seronegative donors were analyzed. Subgroup analysis was performed to identify any synergistic influence on outcome between CMV serostatus and known determinants of risk, including degree of human leukocyte antigen mismatch, pretransplant dialysis, and cold ischemia time. RESULTS Of 29,875 patients who underwent transplantation, 12,239 were CMV seronegative and 17,636 were CMV seropositive. Patient survival was decreased by pretransplant seropositivity (relative risk [RR] 1.11, P =0.001). In addition, this group demonstrated worse overall allograft survival (RR 1.05, P =0.029), although this adverse effect disappeared when patients who died with a functioning graft were censored. Decreased allograft survival was most pronounced in patients who were on hemodialysis before transplantation (RR 1.62, P =0.004). CONCLUSIONS Pretransplant CMV seropositivity is associated with decreased patient survival. Pretransplant CMV seropositivity and hemodialysis have a synergistic adverse effect on graft survival, independent of patient mortality. Additional studies are required to define mechanisms by which pretransplant CMV infection and dialysis modality may contribute to decreased allograft survival.
Collapse
Affiliation(s)
- Jason T Fitzgerald
- Department of Surgery, Division of Transplantation, University of California, Davis Medical Center, Sacramento, California 95817, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Opelz G, Döhler B, Ruhenstroth A. Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4:928-36. [PMID: 15147427 DOI: 10.1111/j.1600-6143.2004.00451.x] [Citation(s) in RCA: 147] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We investigated relationships between cytomegalovirus (CMV) seropairing and CMV prophylaxis on graft outcome in recipients of solid organ transplants. Transplants carried out from 1985 to 2002 and reported to the Collaborative Transplant Study were analyzed. In cadaver kidney recipients, CMV prophylaxis was significantly associated with improved graft survival only in the seronegative-recipient/seropositive-donor combination (at 3 years: 79.4% with prophylaxis vs. 73.5% without prophylaxis; RR 0.80, p < 0.0001). Among patients who had a functioning graft at 1 year, significantly fewer patients who received CMV prophylaxis received rejection treatment in the preceding year (26.3%), compared with patients who did not receive prophylaxis (32.4%) (p = 0.0001), suggesting an inhibitory effect of CMV prophylaxis on acute rejection. Significant improvements in graft survival after CMV prophylaxis were found also in CMV-negative recipients of CMV-positive heart, and lung or heart-lung transplants, but not liver transplants. The age of the recipient had a differential effect on graft and patient survival after CMV prophylaxis. Use of antilymphocyte antibodies or mycophenolate mofetil was not associated with an enhanced CMV effect on graft outcome. These results may contribute to a better understanding of the influence of pretransplant CMV serology on the effect of CMV prophylaxis.
Collapse
Affiliation(s)
- Gerhard Opelz
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany.
| | | | | |
Collapse
|