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1
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Solera JT, Ferreira VH, Cervera C, Hosseini-Moghaddam SM, Gill J, Shalhoub S, Zaltzman J, Kumar D, Humar A. Cell-mediated Immunity to Guide Primary Prophylaxis for CMV Infection in Organ Transplant Recipients: A Multicenter Single-arm Prospective Study. Transplantation 2025; 109:527-535. [PMID: 39160648 DOI: 10.1097/tp.0000000000005173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/21/2024]
Abstract
BACKGROUND There are few interventional studies using CMV cell-mediated immunity (CMI) to guide antiviral prophylaxis. We assessed the Quantiferon-CMV (QTF-CMV) assay to guide CMV prophylaxis duration in high-risk organ transplant recipients. METHODS A single-arm, multicenter, prospective interventional study including high-risk kidney, pancreas, liver, and heart transplant recipients who were either donor CMV-seropositive, recipient-seronegative (D + /R - ) or recipient-seropositive with antithymocyte globulin (R + /ATG) induction. CMI testing was performed using the QTF-CMV assay at months 3, 4, 5, and 6 posttransplant. Prophylaxis was discontinued for a positive CMI but continued for a negative result up to a maximum of 6 mo. The primary endpoint was CMV viremia ≥1000 IU/mL up to 1 y posttransplant. RESULTS One hundred eight patients were included, comprising kidney (n = 89), kidney-pancreas (n = 7), liver (n = 10), and heart (n = 2) transplants. Eighty-nine patients (82.4%) completed the study protocol (n = 39 D + /R - and n = 50 R + /ATG). In the D + /R - group, only 1 of 39 patients (2.6%) had a positive QTF-CMV result. In the R + /ATG group, 33 of 50 patients (66%) had a positive QTF-CMV result before 6 mo, allowing for early discontinuation of prophylaxis (28 at month 3, 4 at month 4, and 1 at month 5). During the follow-up, CMV viremia ≥1000 IU/mL occurred in only 4 of 33 patients (12.1%) who discontinued prophylaxis early compared with 6 of 17 patients (35.3%) with negative QTF-CMV results and continued prophylaxis (hazard ratio 0.31; 95% confidence interval, 0.09-1.09; P = 0.07). No R + patient developed CMV disease. CONCLUSIONS QTF-CMV-guided prophylaxis appears useful in R + patients who may benefit from a tailored duration of prophylaxis. This strategy does not appear to be useful in D + /R - patients.
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Affiliation(s)
- Javier T Solera
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
| | - Victor H Ferreira
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
| | - Carlos Cervera
- Division of Infectious Diseases, University of Alberta, Edmonton, AB, Canada
| | | | - John Gill
- Division of Nephrology, University of British Columbia, Vancouver, BC, Canada
| | - Sarah Shalhoub
- Division of Infectious Diseases, London Health Sciences Center, London, ON, Canada
| | - Jeff Zaltzman
- Division of Nephrology, Saint Michaels Hospital, Toronto, ON, Canada
| | - Deepali Kumar
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
| | - Atul Humar
- Ajmera Transplant Center, University Health Network, Toronto, ON, Canada
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2
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Chung MC, Chen CH, Chang SS, Lee CY, Tian YC, Wu MY, Wang HH, Yu CC, Chen TW, Kao CC, Hsu CY, Chiang YJ, Wu MJ, Chen YT, Wu MS. Prevention and management of cytomegalovirus infection and disease in kidney transplant: A consensus statement of the Transplantation Society of Taiwan. J Formos Med Assoc 2025; 124:104-111. [PMID: 38777672 DOI: 10.1016/j.jfma.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/24/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Kidney transplant recipients have an increased risk of cytomegalovirus (CMV) infection and disease. A strategy for mitigating the risk of CMV infection in kidney transplant recipients has not yet been established in Taiwan. The Transplantation Society of Taiwan aimed to develop a consensus by expert opinion on the prevention and management of CMV infection. Based on the results of Consensus Conference, we suggested low-dose valganciclovir prophylaxis (450 mg once daily) for kidney transplant recipients. The prophylaxis duration was ≥6 months for high-risk (D+/R-) patients and 3 months for moderate-risk (R+) patients. Even for low-risk (D-/R-) patients, prophylaxis for at least 3 months is recommended because of the high seroprevalence of CMV in Taiwan. CMV prophylaxis was suggested after anti-thymocyte globulin treatment but not after methylprednisolone pulse therapy. Routine surveillance after prophylaxis, secondary prophylaxis after CMV disease treatment, and mTOR inhibitors for primary CMV prophylaxis were not recommended. Letermovir and marabavir are emerging CMV agents used for prophylaxis and refractory CMV disease. CMV immunoglobulins have been used to treat refractory CMV disease in Taiwan. We hope this consensus will help professionals manage patients with CMV in Taiwan to improve the quality of care.
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Affiliation(s)
- Mu-Chi Chung
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Cheng-Hsu Chen
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Ph.D. Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; Department of Life Science, Tunghai University, Taichung, Taiwan
| | - Shen-Shin Chang
- Division of Transplantation, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Yuan Lee
- Department of Surgery, National Taiwan University Hospital, Taiwan
| | - Ya-Chung Tian
- Kidney Research Center and Department of Nephrology Linkou Chang Aging Memorial Hospital, Taiwan
| | - Mei-Yi Wu
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - Hsu-Han Wang
- Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chia-Cheng Yu
- Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Teng-Wei Chen
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Chang Kao
- Division of Urology, Department of Surgery, Tri-service General Hospital, National Defense Medical, Taiwan
| | - Chih-Yang Hsu
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Taiwan
| | - Yang-Jen Chiang
- Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Ju Wu
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yen-Ta Chen
- Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Descourouez JL, Kleiboeker H, Saddler CM, Smith JA, Rice JP, Mandelbrot DA, Odorico JS, Jorgenson MR. The UW Experience: Feasibility of De Novo Letermovir for Primary Prophylaxis After Abdominal Solid Organ Transplant. Ann Pharmacother 2025:10600280241307383. [PMID: 39815618 DOI: 10.1177/10600280241307383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Letermovir is approved for primary prophylaxis of cytomegalovirus (CMV) in high-risk kidney transplant recipients. However, many experts suggest the drug be reserved as a second-line agent when valganciclovir is not tolerated or fails. OBJECTIVE The purpose of this study was to describe the feasibility of a de novo letermovir prophylactic approach for CMV high-risk and seropositive abdominal solid organ transplant patients. METHODS Retrospective review of abdominal transplant recipients who required CMV prophylaxis between June 6, 2023, and June 6, 2024. The purpose was to evaluate feasibility of universal letermovir prophylaxis and prophylaxis success. RESULTS 278 patients required CMV prophylaxis and 207 obtained letermovir (74% success). Mean time from transplant to drug approval was 10.5 ± 27 days. Mean out of pocket patient cost was $10.19 ± $36.06 per 28-day supply of letermovir and $55.69 ± $311.48 per 30-day supply of valganciclovir (P = 0.0419). For patients who obtained letermovir, 107 (52%) required prior authorization; 32 (16%) required insurance appeal after denial of prior authorization. Forty-two patients (20%) used Merck copay assistance program while 23 (11%) used the Merck Access patient assistance program to obtain drug. There were no episodes of prophylaxis failure due to breakthrough replication necessitating termination. CONCLUSION AND RELEVANCE De novo use of letermovir for CMV primary prophylaxis after abdominal transplant was found to be feasible with a high rate of success in obtaining the drug in a timely manner posttransplant and without significant out-of-pocket cost to the patient.
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Affiliation(s)
- Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, UW Health, Madison WI, USA
| | - Hanna Kleiboeker
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, UW Health, Madison WI, USA
| | - Christopher M Saddler
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Jeannina A Smith
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - John P Rice
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Didier A Mandelbrot
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Jon S Odorico
- Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospitals and Clinics, Madison, WI, USA
| | - Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, UW Health, Madison WI, USA
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Vernooij RW, Michael M, Colombijn JM, Owers DS, Webster AC, Strippoli GF, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2025; 1:CD005133. [PMID: 39807668 PMCID: PMC11729901 DOI: 10.1002/14651858.cd005133.pub4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
BACKGROUND Cytomegalovirus (CMV) is a significant cause of morbidity and death in solid organ transplant recipients. Pre-emptive treatment of patients with CMV viraemia using antiviral agents has been suggested as an alternative to routine prophylaxis to prevent CMV disease. This is an update of a Cochrane review first published in 2006 and updated in 2013. OBJECTIVES To determine the benefits and harms of pre-emptive treatment of CMV viraemia to prevent CMV disease and death (any cause) and the indirect effects of CMV infection (acute rejection, graft loss, opportunistic infections) in solid organ transplant recipients. SEARCH METHODS The Cochrane Kidney and Transplant Register of Studies was searched up to 17 December 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs comparing pre-emptive treatment with placebo, no specific treatment, or antiviral prophylaxis in solid organ transplant recipients. DATA COLLECTION AND ANALYSIS Two authors independently assessed the eligibility of the identified studies, assessed the risk of bias, and extracted all data. Results were expressed as risk ratio (RR) and 95% confidence intervals (CI) for dichotomous outcomes. Statistical analyses were performed using a random-effects model. The certainty of evidence was assessed per outcome using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS In this update, we have included seven new studies, bringing the total number of included studies to 22 (1883 participants). Of these, seven investigated pre-emptive treatment versus placebo or standard care, 12 looked at pre-emptive treatment versus antiviral prophylaxis, one study investigated oral versus intravenous pre-emptive treatment, one investigated pre-emptive valganciclovir versus pre-emptive ganciclovir, and one investigated letermovir 40 mg twice/day versus 80 mg once/day. Studies were conducted in Australia, Brazil, the Czech Republic, Germany, Italy, Japan, Norway, Spain, South Korea, and the USA. Organ transplant recipients included kidney, liver, heart, lung, and kidney-pancreas. Thirteen studies were single-centre studies, six were multicentre, and three were unknown. The number of participants ranged from 12 to 296. Overall, selection bias was unclear (55%); performance, detection and attrition bias were high (91%, 63% and 95%, respectively), and reporting bias was low (55%). Compared with placebo or standard care, pre-emptive treatment probably reduces the risk of CMV disease (7 studies, 315 participants: RR 0.29, 95% CI 0.11 to 0.80; I2 = 54%; moderate-certainty evidence) but may result in little or no difference in death (any cause) (3 studies, 176 participants: RR 1.23, 95% CI 0.35 to 4.30; I2 = 0%; low-certainty evidence). Pre-emptive treatment may result in little or no difference in CMV organ involvement, CMV-associated symptoms, acute rejection, graft loss, other infections or leucopenia. Compared to prophylaxis, pre-emptive treatment may make little or no difference to the risk of developing CMV disease (11 studies, 1322 participants: RR 0.97, 95% CI 0.47 to 2.01; I2 = 54%; low-certainty evidence) and probably makes little or no difference to death (any cause) (9 studies, 1098 participants: RR 0.95, 95% CI 0.60 to 1.52; I2 = 0%; moderate-certainty evidence). Pre-emptive treatment may increase the risk of CMV infection (8 studies, 867 participants: RR 1.97, 95% CI 1.48 to 2.61; I2 = 66%; low-certainty evidence). The risk of leucopenia (7 studies, 869 participants: RR 0.57, 95% CI 0.38 to 0.87; I2 = 33%; moderate-certainty evidence) and neutropenia (5 studies, 859 participants: RR 0.63, 95% CI 0.44 to 0.90; I2 = 0% moderate certainty evidence) probably decreases with pre-emptive therapy. There may be little or no difference in the risks of acute rejection, graft loss, and infections other than CMV. Single studies were identified for comparisons between different pre-emptive treatments: 1) oral ganciclovir versus IV ganciclovir; 2) valganciclovir versus ganciclovir; 3) 40 mg twice/day versus 80 mg once/day. No differences between these treatment modalities in terms of CMV disease, death (any cause), or adverse events were identified. AUTHORS' CONCLUSIONS In this review, we have included seven new studies, yet the available evidence is overall of low certainty and the conclusions remain similar to the previous version of this review. Pre-emptive treatment probably reduces the risk of CMV disease compared with placebo or standard care. There were no clear differences between pre-emptive treatment and prophylaxis to prevent CMV disease or reduce the risk of death (any cause). The risk of CMV infection may be higher for patients receiving pre-emptive therapy, but the risk of adverse events, such as leucopenia, is probably lower.
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Affiliation(s)
- Robin Wm Vernooij
- Department of Nephrology and Hypertension and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Mini Michael
- Division of Pediatric Nephrology, Department of Pediatrics, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA
| | - Julia Mt Colombijn
- Department of Nephrology and Hypertension and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Daniel S Owers
- Department of Critical Care, The Canberra Hospital, Garran, Australia
| | - Angela C Webster
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- Department of Transplant and Renal Medicine, Westmead Hospital, Westmead, Australia
| | - Giovanni Fm Strippoli
- Department of Precision and Regenerative Medicine and Ionian Area (Dimepre-J), University of Bari, Bari, Italy
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Elisabeth M Hodson
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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5
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Alizadeh Z, Mazloum-Ardakani M, Zhu Y, Seidi F. Enhanced Electrochemical Detection of Valganciclovir Using a Hierarchically Structured Lisianthus Flower-Inspired Bimetallic Ni-Ce Organic Framework. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2025; 41:66-78. [PMID: 39731573 DOI: 10.1021/acs.langmuir.4c02451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2024]
Abstract
This study reports the development of an innovative electrochemical sensor based on organometallic framework nanostructures for detecting valganciclovir (VLCV). VLCV is employed in the treatment of cytomegalovirus retinitis in AIDS patients. Rational design of nanoarchitectures for electroactive materials is a crucial approach for boosting their electrocatalytic performance. Herein, Lisianthus flower-inspired Ni-Ce-metal-organic framework (MOF), Ni-MOF, and rod-inspired Ce-MOF were synthesized by the solvothermal method. An electrochemical sensor for VLCV was developed by employing a multilayer approach using Lisianthus flower-inspired Ni-Ce metal-organic framework/multiwall carbon nanotubes (Ni-Ce-MOF/MWCNTs) modification on a glassy carbon electrode (GCE). Incorporating a bimetallic Ni-Ce-MOF into a conventional conductive material, such as MWCNTs, significantly increases the specific surface area and improves the conductivity and catalytic properties of the MWCNTs. Relative to the rod-inspired Ce-MOF and Ni-MOF, the electrocatalytic performance of the Lisianthus flower-inspired Ni-Ce-MOF coated on MWCNTs surpasses that of the rod-inspired Ce-MOF, showcasing enhanced performance in VLCV oxidation. This superiority arises from their enhanced electrical conductivity and enlarged surface area. The Lisianthus flower-inspired Ni-Ce-MOF/MWCNTs/GCE demonstrated extensive linear ranges (ranging from 4.0 to 3800.0 nM), a lower detection limit (1.4 nM), remarkable selectivity, and sustained stability over an extended period in the context of VLCV sensing. The real samples underwent analysis through using both electrochemical and UV-vis spectrophotometry methods, and the findings from both methods exhibited no substantial difference, validating the sensor's remarkable practical performance. These results suggest that Lisianthus flower-inspired Ni-Ce-MOF/MWCNTs/GCE electrocatalysts provide a promising sensing platform for analyzing biological samples.
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Affiliation(s)
- Zahra Alizadeh
- Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-741, Islamic Republic of Iran
| | - Mohammad Mazloum-Ardakani
- Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-741, Islamic Republic of Iran
| | - Yangzhi Zhu
- Terasaki Institute for Biomedical Innovation, Los Angeles, California 91367, United States
| | - Farzad Seidi
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources and International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing 210037, China
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6
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Haddad S, Dee K, Chiang AD, Feller F, Ding T, Ayers GD, Potts M, LaRue RW. Relationship Between Body Weight and Leukopenia in Non-Kidney Solid Organ Transplant Recipients With Normal Renal Function Who Are Receiving Valganciclovir for CMV Prophylaxis. Transpl Infect Dis 2024:e14418. [PMID: 39692604 DOI: 10.1111/tid.14418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/07/2024] [Accepted: 11/22/2024] [Indexed: 12/19/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) disease causes significant morbidity among solid organ transplant (SOT) recipients. To prevent CMV disease, eligible recipients are frequently started on valganciclovir (VGC) prophylaxis post-transplant. Leukopenia has been documented as a primary adverse events of the drug (1). This study's primary aim was to determine whether a patient's weight at the start of VGC prophylaxis was associated with the development of leukopenia. METHODS This was a single center, retrospective cohort study that included adults > 18 years of age, who had received an organ transplant (heart, liver, or lung) at an academic transplant center from January 1, 2018 through December 31, 2022. A creatinine clearance of > 60 mL/min was required. RESULTS All 294 included patients received 900 mg/day of VGC for CMV prophylaxis, without dose adjustment. Fifty-two percent of the patients developed leukopenia while receiving VGC prophylaxis. The mean weight at initiation of VGC was higher in patients who did not develop leukopenia (97.9 kg) compared to those who did (90.7 kg; p = 0.0112). It was found that with each 1 kg increase in body weight, the likelihood of developing leukopenia decreased by 1.7% (p = 0.004, odds ratio = 0.983, 95% confidence interval [CI], 0.972-0.994). Patients with a baseline body-mass index (BMI) > 25 had a longer median freedom time from leukopenia after initiation of VGC as compared to the group with baseline BMI < 25 (log-rank p = 0.035). CONCLUSION These data suggest that in SOT recipients with normal renal function, receiving a fixed dose of VGC resulted in a significant, inverse relationship between body weight and the development of leukopenia.
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Affiliation(s)
- Sara Haddad
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kevin Dee
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Augusto Dulanto Chiang
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Fionna Feller
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Tan Ding
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Gregory D Ayers
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Marissa Potts
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard W LaRue
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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7
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García-Masedo Fernández S, Laporta R, García Fadul C, Aguilar Pérez M, Anel Pedroche J, Sanabrias Fernández de Sevilla R, Royuela A, Sánchez Romero I, Ussetti Gil MP. CMV Infection Risk Factors and Viral Dynamics After Valganciclovir Prophylaxis: 10 Years of Experience in Lung Transplant Recipients. Microorganisms 2024; 12:2360. [PMID: 39597748 PMCID: PMC11596771 DOI: 10.3390/microorganisms12112360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
(1) The prevention of cytomegalovirus (CMV) in lung transplant recipients (LTx) is based on the administration of VGC for a period of 6-12 months, but there is little information on the premature discontinuation of the drug. Our objective was to evaluate the reasons for early cessation of VGC and the dynamics of CMV replication after discontinuation. (2) We carried out a retrospective study of LTx on VGC prophylaxis according to guidelines, with an outpatient follow-up period of >90 days. The detection of any level of CMV-DNA in the plasma (Cobas, Roche Diagnostics®) during a period of 18 months after the discontinuation of VGC was considered positive. (3) We included 312 patients (64% male, mean age 53.50 ± 12.27; 71% D+R+, 15% D-R+, and 14% D+R-) in our study. The prescribed prophylaxis was completed by 179 patients (57.05%). The mean duration of prophylaxis was 7.17 ± 1.08 months. The recorded reasons for VGC discontinuation in 133 patients (43%) were myelotoxicity (n = 55), impaired renal function (n = 32), and gastrointestinal disturbances (n = 11). The reason for discontinuation was not recorded for 29 patients. CMV-DNA was detected in 79% (n = 246) of cases, and D+R+ and D+R- recipients showed a high risk of detection (p < 0.001). The median times to onset of CMV-DNA detection were 35 days in D+R-, 73 days in D+R+, and 96 days in D-R+ (p < 0.001). (4) Adverse effects of VGC are frequent in LTx. CMV-DNA detection is very common after the discontinuation of VGC and is related to the CMV donor and recipient serostatus.
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Affiliation(s)
| | - Rosalía Laporta
- Pneumology Department, Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain (M.P.U.G.)
| | - Christian García Fadul
- Pneumology Department, Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain (M.P.U.G.)
| | - Myriam Aguilar Pérez
- Pneumology Department, Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain (M.P.U.G.)
| | - Jorge Anel Pedroche
- Microbiology Department, Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain
| | | | - Ana Royuela
- Clinical Biostatistics Unit, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain
| | - Isabel Sánchez Romero
- Microbiology Department, Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain
| | - María Piedad Ussetti Gil
- Pneumology Department, Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Spain (M.P.U.G.)
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8
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Zamora D, Dasgupta S, Stevens-Ayers T, Edmison B, Winston DJ, Razonable RR, Mehta AK, Lyon GM, Boeckh M, Singh N, Koelle DM, Limaye AP. Cytomegalovirus immunity in high-risk liver transplant recipients following preemptive antiviral therapy versus prophylaxis. JCI Insight 2024; 9:e180115. [PMID: 39099206 PMCID: PMC11457861 DOI: 10.1172/jci.insight.180115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 07/18/2024] [Indexed: 08/06/2024] Open
Abstract
CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.
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Affiliation(s)
- Danniel Zamora
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Sayan Dasgupta
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Terry Stevens-Ayers
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Bradley Edmison
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Drew J. Winston
- Division of Infectious Diseases, UCLA Medical Center, Los Angeles, California, USA
| | - Raymund R. Razonable
- Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Aneesh K. Mehta
- Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA
| | - G. Marshall Lyon
- Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Michael Boeckh
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Nina Singh
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Transplant Infectious Diseases, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
| | - David M. Koelle
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Global Health and
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
- Benaroya Research Institute, Seattle, Washington, USA
| | - Ajit P. Limaye
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
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9
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Yilmaz ZB, Memisoglu F, Akbulut S. Management of cytomegalovirus infection after liver transplantation. World J Transplant 2024; 14:93209. [PMID: 39295968 PMCID: PMC11317856 DOI: 10.5500/wjt.v14.i3.93209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/05/2024] [Accepted: 05/27/2024] [Indexed: 07/31/2024] Open
Abstract
Cytomegalovirus (CMV) infection is one of the primary causes of morbidity and mortality following liver transplantation (LT). Based on current worldwide guidelines, the most effective strategies for avoiding post-transplant CMV infection are antiviral prophylaxis and pre-emptive treatment. CMV- IgG serology is the established technique for pretransplant screening of both donors and recipients. The clinical presentation of CMV infection and disease exhibits variability, prompting clinicians to consistently consider this possibility, particularly within the first year post-transplantation or subsequent to heightened immunosuppression. At annual symposia to discuss CMV prevention and how treatment outcomes can be improved, evidence on the incorporation of immune functional tests into clinical practice is presented, and the results of studies with new antiviral treatments are evaluated. Although there are ongoing studies on the use of letermovir and maribavir in solid organ transplantation, a consensus reflected in the guidelines has not been formed. Determining the most appropriate strategy at the individual level appears to be the key to enhancing outcomes. Although prevention strategies reduce the risk of CMV disease, the disease can still occur in up to 50% of high-risk patients. A balance between the risk of infection and disease development and the use of immunosuppressants must be considered when talking about the proper management of CMV in solid organ transplant recipients. The objective of this study was to establish a comprehensive framework for the management of CMV in patients who have had LT.
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Affiliation(s)
- Zeynep Burcin Yilmaz
- Infectious Diseases and Clinical Microbiology, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
| | - Funda Memisoglu
- Infectious Diseases and Clinical Microbiology, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
| | - Sami Akbulut
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
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10
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Khilnani GC, Tiwari P, Mittal S, Kulkarni AP, Chaudhry D, Zirpe KG, Todi SK, Mohan A, Hegde A, Jagiasi BG, Krishna B, Rodrigues C, Govil D, Pal D, Divatia JV, Sengar M, Gupta M, Desai M, Rungta N, Prayag PS, Bhattacharya PK, Samavedam S, Dixit SB, Sharma S, Bandopadhyay S, Kola VR, Deswal V, Mehta Y, Singh YP, Myatra SN. Guidelines for Antibiotics Prescription in Critically Ill Patients. Indian J Crit Care Med 2024; 28:S104-S216. [PMID: 39234229 PMCID: PMC11369928 DOI: 10.5005/jp-journals-10071-24677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/20/2024] [Indexed: 09/06/2024] Open
Abstract
How to cite this article: Khilnani GC, Tiwari P, Mittal S, Kulkarni AP, Chaudhry D, Zirpe KG, et al. Guidelines for Antibiotics Prescription in Critically Ill Patients. Indian J Crit Care Med 2024;28(S2):S104-S216.
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Affiliation(s)
- Gopi C Khilnani
- Department of Pulmonary, Critical Care and Sleep Medicine, PSRI Hospital, New Delhi, India
| | - Pawan Tiwari
- Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
| | - Saurabh Mittal
- Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
| | - Atul P Kulkarni
- Division of Critical Care Medicine, Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Dhruva Chaudhry
- Department of Pulmonary and Critical Care Medicine, University of Health Sciences, Rohtak, Haryana, India
| | - Kapil G Zirpe
- Department of Neuro Trauma Unit, Grant Medical Foundation, Pune, Maharashtra, India
| | - Subhash K Todi
- Department of Critical Care, AMRI Hospital, Kolkata, West Bengal, India
| | - Anant Mohan
- Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
| | - Ashit Hegde
- Department of Medicine & Critical Care, P D Hinduja National Hospital, Mumbai, India
| | - Bharat G Jagiasi
- Department of Critical Care, Kokilaben Dhirubhai Ambani Hospital, Navi Mumbai, Maharashtra, India
| | - Bhuvana Krishna
- Department of Critical Care Medicine, St John's Medical College and Hospital, Bengaluru, India
| | - Camila Rodrigues
- Department of Microbiology, P D Hinduja National Hospital, Mumbai, India
| | - Deepak Govil
- Department of Critical Care and Anesthesia, Medanta – The Medicity, GuruGram, Haryana, India
| | - Divya Pal
- Department of Critical Care and Anesthesia, Medanta – The Medicity, GuruGram, Haryana, India
| | - Jigeeshu V Divatia
- Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Manju Sengar
- Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Mansi Gupta
- Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mukesh Desai
- Department of Immunology, Pediatric Hematology and Oncology Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Narendra Rungta
- Department of Critical Care & Anaesthesiology, Rajasthan Hospital, Jaipur, India
| | - Parikshit S Prayag
- Department of Transplant Infectious Diseases, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
| | - Pradip K Bhattacharya
- Department of Critical Care Medicine, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
| | - Srinivas Samavedam
- Department of Critical Care, Ramdev Rao Hospital, Hyderabad, Telangana, India
| | - Subhal B Dixit
- Department of Critical Care, Sanjeevan and MJM Hospital, Pune, Maharashtra, India
| | - Sudivya Sharma
- Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Susruta Bandopadhyay
- Department of Critical Care, AMRI Hospitals Salt Lake, Kolkata, West Bengal, India
| | - Venkat R Kola
- Department of Critical Care Medicine, Yashoda Hospitals, Hyderabad, Telangana, India
| | - Vikas Deswal
- Consultant, Infectious Diseases, Medanta - The Medicity, Gurugram, Haryana, India
| | - Yatin Mehta
- Department of Critical Care and Anesthesia, Medanta – The Medicity, GuruGram, Haryana, India
| | - Yogendra P Singh
- Department of Critical Care, Max Super Speciality Hospital, Patparganj, New Delhi, India
| | - Sheila N Myatra
- Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
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11
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Fernández-García OA, Hernandez C, Robbins M, Kabbani D, Doucette K, Cervera C. Cytomegalovirus surveillance after antiviral prophylaxis in CMV mismatched transplant patients: Does recurrent cytomegalovirus DNAemia impact patient survival? Transpl Infect Dis 2024; 26:e14292. [PMID: 38728099 DOI: 10.1111/tid.14292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/03/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) mismatched, donor IgG-positive/recipient IgG-negative, solid organ transplant recipients (SOTRs) are at high risk of CMV invasive disease. Post-prophylaxis disease is an issue in this population. Some programs employ surveillance after prophylaxis (SAP) to limit the incidence of post-prophylaxis disease. METHODS This was a single-center retrospective cohort study that included all CMV mismatched SOTRs from 2003 to 2017. Patients underwent SAP with weekly CMV plasma viral load for 12 weeks. The subjects were classified into three post-prophylaxis DNAemia patterns: no DNAemia, one episode of DNAemia, and multiple episodes of DNAemia. We calculated the cumulative incidence of each DNAemia pattern. We also determined 5-year mortality based on DNAemia pattern stratified by organ transplant type. RESULTS Post-prophylaxis recurrent DNAemia occurred in 63% of lung recipients and 32% of non-lung recipients (p = .003). Tissue invasive CMV disease was diagnosed in 3% of the population and CMV syndrome was diagnosed in 33%. Recurrent DNAemia was not associated with 5-year mortality. CONCLUSION In this cohort, undergoing SAP tissue invasive disease was uncommon and CMV DNAemia recurrence did not have an impact on long-term mortality.
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Affiliation(s)
- Oscar A Fernández-García
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Cristina Hernandez
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Mark Robbins
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Dima Kabbani
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Karen Doucette
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, Edmonton, Alberta, Canada
| | - Carlos Cervera
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, Edmonton, Alberta, Canada
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12
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Gao C, Dong X, Zhang J, Mao L, Guo C, Qin X, Zou Z. Recommendations for the selection of nucleoside analogues as antihuman herpesvirus drugs: a real-world analysis of reported cases from the FDA adverse event reporting system. Expert Opin Drug Saf 2024:1-15. [PMID: 38943630 DOI: 10.1080/14740338.2024.2374919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 05/22/2024] [Indexed: 07/01/2024]
Abstract
OBJECTIVE The aim of this study is to provide guidance for refining medication protocols, developing alternative strategies, and enhancing protection against herpesvirus infections in personalized clinical settings. METHODS Adverse drug events (ADEs) data for anti-herpesvirus from the first quarter of 2004 to the fourth quarter of 2022 were collected from the FDA Adverse Event Reporting System (FAERS). Disproportionality analysis was performed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN) methods for data mining. RESULTS A total of 18,591, 24,206, 6,150, and 419 reports of ADEs associated with acyclovir (ACV), valacyclovir (VACV), ganciclovir (GCV), and famciclovir (FCV) were screened and extracted from the FAERS. In this study, the report summarized the high frequency and strong correlation of ADEs for the four drugs at the Preferred Term (PT) level. Additionally, the analysis also identified the relationship between ADEs and factors such as age, gender, and severity of outcome at the System Organ Class (SOC) level. CONCLUSION The safety reports for the four-nucleoside analogue anti-herpesvirus drugs are diverse and interconnected. Dosing for patients with herpesvirus infections should be tailored to their specific conditions and the potential risk of disease.
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Affiliation(s)
- Caixia Gao
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, P.R. China
| | - Xiaomei Dong
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, P.R. China
| | - Jun Zhang
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, P.R. China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Lejiao Mao
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, P.R. China
| | - Changxin Guo
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xia Qin
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Zhen Zou
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, P.R. China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, People's Republic of China
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13
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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.
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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
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14
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Vernooij RW, Michael M, Ladhani M, Webster AC, Strippoli GF, Craig JC, Hodson EM. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2024; 5:CD003774. [PMID: 38700045 PMCID: PMC11066972 DOI: 10.1002/14651858.cd003774.pub5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
BACKGROUND The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.
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Affiliation(s)
- Robin Wm Vernooij
- Department of Nephrology and Hypertension and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Mini Michael
- Division of Pediatric Nephrology, Baylor College of Medicine, Houston, TX, USA
| | - Maleeka Ladhani
- Nephrology, Lyell McEwin Hospital, Elizabeth Vale, Australia
| | - Angela C Webster
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- Centre for Transplant and Renal Medicine, Westmead Millennium Institute, The University of Sydney at Westmead, Westmead, Australia
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Elisabeth M Hodson
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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15
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Kleiboeker H, Descourouez JL, Schulz LT, Mandelbrot DA, Odorico JS, Saddler CM, Smith JA, Jorgenson MR. Resource Use and Financial Impact of Oral Step-Down Therapy for Resistant Cytomegalovirus in Solid Organ Transplant Recipients. Transplant Proc 2024; 56:434-439. [PMID: 38355369 DOI: 10.1016/j.transproceed.2024.01.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 01/16/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT. METHODS This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC. RESULTS Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV. CONCLUSION AND RELEVANCE In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings.
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Affiliation(s)
- Hanna Kleiboeker
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.
| | - Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
| | - Lucas T Schulz
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
| | - Didier A Mandelbrot
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jon S Odorico
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Christopher M Saddler
- Department of Medicine, Division of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jeannina A Smith
- Department of Medicine, Division of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
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16
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Huh K, Lee SO, Kim J, Lee SJ, Choe PG, Kang JM, Yang J, Sung H, Kim SH, Moon C, Seok H, Shi HJ, Wi YM, Jeong SJ, Park WB, Kim YJ, Kim J, Ahn HJ, Kim NJ, Peck KR, Kim MS, Kim SI. Prevention of Cytomegalovirus Infection in Solid Organ Transplant Recipients: Guidelines by the Korean Society of Infectious Diseases and the Korean Society for Transplantation. Infect Chemother 2024; 56:101-121. [PMID: 38527780 PMCID: PMC10990892 DOI: 10.3947/ic.2024.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 03/27/2024] Open
Abstract
Cytomegalovirus (CMV) is the most important opportunistic viral pathogen in solid organ transplant (SOT) recipients. The Korean guideline for the prevention of CMV infection in SOT recipients was developed jointly by the Korean Society for Infectious Diseases and the Korean Society of Transplantation. CMV serostatus of both donors and recipients should be screened before transplantation to best assess the risk of CMV infection after SOT. Seronegative recipients receiving organs from seropositive donors face the highest risk, followed by seropositive recipients. Either antiviral prophylaxis or preemptive therapy can be used to prevent CMV infection. While both strategies have been demonstrated to prevent CMV infection post-transplant, each has its own advantages and disadvantages. CMV serostatus, transplant organ, other risk factors, and practical issues should be considered for the selection of preventive measures. There is no universal viral load threshold to guide treatment in preemptive therapy. Each institution should define and validate its own threshold. Valganciclovir is the favored agent for both prophylaxis and preemptive therapy. The evaluation of CMV-specific cell-mediated immunity and the monitoring of viral load kinetics are gaining interest, but there was insufficient evidence to issue recommendations. Specific considerations on pediatric transplant recipients are included.
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Affiliation(s)
- Kyungmin Huh
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang-Oh Lee
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - Jungok Kim
- Division of Infectious Diseases, Department of Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Su Jin Lee
- Division of Infectious Diseases, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Pyoeng Gyun Choe
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Ji-Man Kang
- Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jaeseok Yang
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Heungsup Sung
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Si-Ho Kim
- Division of Infectious Diseases, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Chisook Moon
- Division of Infectious Diseases, Department of Internal Medicine, Inje University Busan Paik Hospital, College of Medicine, Busan, Korea
| | - Hyeri Seok
- Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University Medicine, Ansan, Korea
| | - Hye Jin Shi
- Division of Infectious Diseases, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Yu Mi Wi
- Division of Infectious Diseases, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Su Jin Jeong
- Division of Infectious Diseases, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Wan Beom Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Youn Jeong Kim
- Division of Infectious Diseases, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyung Joon Ahn
- Department of Surgery, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Nam Joong Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Ran Peck
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Il Kim
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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17
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Magda G. Opportunistic Infections Post-Lung Transplantation: Viral, Fungal, and Mycobacterial. Infect Dis Clin North Am 2024; 38:121-147. [PMID: 38280760 DOI: 10.1016/j.idc.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2024]
Abstract
Opportunistic infections are a leading cause of lung transplant recipient morbidity and mortality. Risk factors for infection include continuous exposure of the lung allograft to the external environment, high levels of immunosuppression, impaired mucociliary clearance and decreased cough reflex, and impact of the native lung microbiome in single lung transplant recipients. Infection risk is mitigated through careful pretransplant screening of recipients and donors, implementation of antimicrobial prophylaxis strategies, and routine surveillance posttransplant. This review describes common viral, fungal, and mycobacterial infectious after lung transplant and provides recommendations on prevention and treatment.
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Affiliation(s)
- Gabriela Magda
- Columbia University Lung Transplant Program, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, Columbia University Vagelos College of Physicians and Surgeons, 622 West 168th Street PH-14, New York, NY 10032, USA.
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18
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Raymonda MH, Rodríguez-Sánchez I, Schafer XL, Smorodintsev-Schiller L, Harris IS, Munger J. Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation. mBio 2024; 15:e0303123. [PMID: 38117060 PMCID: PMC10790783 DOI: 10.1128/mbio.03031-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 11/14/2023] [Indexed: 12/21/2023] Open
Abstract
IMPORTANCE Viruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral UL38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as UL38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that UL38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of UL38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.
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Affiliation(s)
- Matthew H. Raymonda
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Irene Rodríguez-Sánchez
- Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA
| | - Xenia L. Schafer
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Leonid Smorodintsev-Schiller
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, USA
| | - Isaac S. Harris
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, USA
| | - Joshua Munger
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA
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19
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Wong DD, Ho SA, Domazetovska A, Yong MK, Rawlinson WD. Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation. Curr Opin Infect Dis 2023; 36:505-513. [PMID: 37729654 DOI: 10.1097/qco.0000000000000965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
PURPOSE OF REVIEW This review describes current knowledge of ganciclovir (GCV) and valganciclovir (ValGCV) pharmacokinetic/pharmacodynamic characteristics, highlighting the likely contribution from host genetic factors to interpatient variability. The evidence and challenges surrounding optimization of drug dosing through therapeutic drug monitoring (TDM) are examined, with recommendations made. RECENT FINDINGS Pharmacokinetic studies of current dosing guidelines have shown high interindividual and intraindividual variability of GCV concentrations. This is sometimes associated with a slow decline in cytomegalovirus (CMV) viral load in some transplant recipients. A high incidence of GCV-associated myelosuppression has limited the use of this drug in the transplant setting. Patient groups identified to benefit from GCV TDM include pediatric patients, cystic fibrosis with lung transplantation, obese with kidney transplantation, and patients with fluctuating renal function or on hemodialysis. The emergence of refractory resistant CMV, particularly in immune compromised patients, highlights the importance of appropriate dosing of these antivirals. Host genetic factors need to be considered where recently, two host genes were shown to account for interpatient variation during ganciclovir therapy. Therapeutic Drug Monitoring has been shown to improve target antiviral-level attainment. The use of TDM may guide concentration-based dose adjustment, potentially improving virological and clinical outcomes. However, evidence supporting the use of TDM in clinical practice remains limited and further study is needed in the transplant cohort. SUMMARY Further studies examining novel biomarkers are needed to guide target concentrations in prophylaxis and treatment. The use of TDM in transplant recipients is likely to improve the clinical efficacy of current antivirals and optimize outcomes in transplant recipients.
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Affiliation(s)
- Diana D Wong
- National Measurement Institute, Lindfield, Sydney, New South Wales
| | - Su Ann Ho
- Peter MacCallum Cancer Centre
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria
| | - Ana Domazetovska
- Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, New South Wales
| | - Michelle K Yong
- Peter MacCallum Cancer Centre
- Department Infectious Diseases, Royal Melbourne Hospital
- National Centre for Infections in Cancer, Parkville
| | - William D Rawlinson
- Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, New South Wales
- Schools of Biomedical Sciences, Biotechnology and Biomolecular Sciences, Clinical Sciences, University of NSW, Sydney New South Wales, Australia
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20
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Hinman B, Cox J, Umoru G, Kamble R, Musick W. Extended duration letermovir in allogeneic hematopoietic stem cell transplant. Transpl Immunol 2023; 81:101936. [PMID: 37770000 DOI: 10.1016/j.trim.2023.101936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 09/17/2023] [Accepted: 09/24/2023] [Indexed: 10/03/2023]
Abstract
OBJECTIVES Despite the use of antiviral prophylaxis in recipients of allogeneic hematopoietic cell transplants (HCT), cytomegalovirus (CMV) is a common clinically significant infection and is associated with significant morbidity and mortality in this patient population. Based on current approval, letermovir is initiated within 28 days following allogeneic HCT for CMV seropositive recipients and continued through 100 days post-transplant. However, it is unknown whether patients who receive extended duration CMV prophylaxis with letermovir would result in less CMV reactivation and reactivation compared to those who do not. This study aimed to evaluate the efficacy of letermovir prophylaxis in CMV seropositive patients when continued for greater than 100 days post-allogeneic stem cell transplant. METHODS A single-center retrospective chart review was conducted on recipients of allogeneic HCT from November 2017 to July 2021. Patients were eligible for inclusion if they were at least 18 years of age, received an allogeneic HCT, CMV seropositive, and initiated letermovir between days 0-28 post-transplant. The primary endpoint of this study is to compare rates of CMV reactivation in patients who stopped letermovir prophylaxis at 100 days post-transplant (standard duration group) versus those who continued letermovir prophylaxis past day 100 (extended duration group). RESULTS A total of 87 patients met the eligibility criteria for inclusion. The median duration of letermovir prophylaxis was 78 days in the standard duration group versus and 132 days in the extended duration group. There were more CMV reactivations in the standard duration group versus the extended duration group, 28% versus 19% respectively. CMV pneumonitis was observed in one of the patients in the standard duration group. All-cause mortality at day 200 post-transplant was similar between the two groups. CONCLUSION The results of this study suggest that extended duration letermovir prophylaxis may be associated with less CMV reactivation compared to the standard duration of prophylaxis.
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Affiliation(s)
- Breanna Hinman
- Houston Methodist Hospital, 6565 Fannin St., Houston, TX 77054, USA.
| | - James Cox
- Houston Methodist Hospital, 6565 Fannin St., Houston, TX 77054, USA.
| | - Godsfavour Umoru
- Houston Methodist Hospital, 6565 Fannin St., Houston, TX 77054, USA.
| | - Rammurti Kamble
- Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, 6565 Fannin St., Houston, TX 77054, USA.
| | - Will Musick
- Houston Methodist Hospital, 6565 Fannin St., Houston, TX 77054, USA.
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21
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Chang CT, Chen HH, Chuang CC, Chang SH, Hsiao NW. Ganciclovir as a potential treatment for glioma: a systematic review and meta-analysis. J Neurooncol 2023; 165:399-411. [PMID: 38066255 DOI: 10.1007/s11060-023-04503-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 11/05/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND Glioma is a challenging malignant tumor with a low survival rate and no effective treatment. Recently, ganciclovir, an antiviral drug, combined with gene therapy and its own antiviral ability, has been proposed as a potential treatment for glioma. However, there are differences in the results of various clinical trials. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy of ganciclovir in treating glioma. METHODS We searched databases such as PubMed, EMBASE, and Cochrane Library before March 30, 2023. The search terms included glioma, ganciclovir, valganciclovir and treatment. Calculated 1, 2 and 4-year survival rate by risk difference (RD), and overall survival (OS) by odds ratio (OR). RESULTS Five randomized controlled trials (RCTs) with a total of 606 high-grade glioma patients were included. The results showed that ganciclovir can improve 2-yeaer (RD = 0.179, 95% CI 0.012-0.346, P = 0.036) and 4-year survival rate (RD = 0.185, 95% CI 0.069-0.3, P = 0.002) and OS (OR 2.393, 95% CI 1.212-4.728, P = 0.012) compared with the control group. CONCLUSIONS This meta-analysis showed that ganciclovir significantly improved the prognosis of glioma patients. Therefore, we suggest that more cases of ganciclovir as a glioma treatment can be conducted, or a large clinical trial can be designed.
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Affiliation(s)
- Chun-Tao Chang
- Department of Biology, National Changhua University of Education, No. 1, Jinde Rd, Changhua City, Changhua County, 500207, Taiwan
| | - Hsing-Hui Chen
- Department of Industrial Education and Technology, National Changhua University of Education, No. 1, Jinde Rd, Changhua City, Changhua County, 500207, Taiwan
| | - Chun-Chao Chuang
- Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd, South Dist., Taichung City, 402306, Taiwan
| | - Shao-Hsun Chang
- Department of Industrial Education and Technology, National Changhua University of Education, No. 1, Jinde Rd, Changhua City, Changhua County, 500207, Taiwan
| | - Nai-Wan Hsiao
- Department of Biology, National Changhua University of Education, No. 1, Jinde Rd, Changhua City, Changhua County, 500207, Taiwan.
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22
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Souan L, Jazar HA, Nashwan S, Sughayer MA. QuantiFERON-CMV and monitor predict cytomegalovirus, mortality, and graft-versus-host disease in transplant recipients. J Med Virol 2023; 95:e29250. [PMID: 38009250 DOI: 10.1002/jmv.29250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 11/03/2023] [Accepted: 11/10/2023] [Indexed: 11/28/2023]
Abstract
Cytomegalovirus (CMV) is the most prevalent infection in recipients of hematopoietic stem cell transplant (HSCT). QuantiFERON-CMV (QF-CMV) and QuantiFERON-Monitor (QFM) assays were used to test whether immune-competent adult allogeneic HSCT recipients with CMV-specific T cells can control CMV infection or reactivation. Our data demonstrated a significant correlation between CMV infection measured by CMV-antigenemia test and QF-CMV results, graft versus host disease (GvHD), and mortality rates. The QF-CMV test revealed that CMV-specific T cells with higher interferon-γ (IFN-γ) release were correlated with lower CMV infection rates. There was a significant negative association between QF-CMV results, GvHD, and mortality rates. Data showed that a one-unit rise in IFN-γ was linked with a 12.7% reduction in GvHD and a 20.7% reduction in the mortality odds ratio. In addition, a negative correlation was found between QF-M results and CMV infection, with the QFM test predicting protection against CMV infection by 1.9%. This is one of the few studies establishing the QF-CMV test's predictive value for GvHD and mortality, its use to monitor HSCT patients for pre-emptive therapy, and the use of the QFM test to predict CMV infection and mortality in HSCT patients. Thus, these assays could be utilized to optimize preventive and pre-emptive therapy procedures to reduce transplant recipient adverse effects and posttransplant therapy costs.
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Affiliation(s)
- Lina Souan
- Department of Pathology & Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Husam Abu Jazar
- Bone Marrow and Stem Cell Transplantation Program, King Hussein Cancer Center, Amman, Jordan
| | - Sura Nashwan
- Department of Pathology & Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Maher A Sughayer
- Department of Pathology & Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
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23
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Romao EA, Yamamoto AY, Gaspar GG, Garcia TMP, Muglia VA, Nardin MEP, Molina CAF, de Figueiredo VCTP, Moyses-Neto M. Significant Increase in Cytomegalovirus (CMV) Infection in Solid Organ Transplants Associated With Increased Use of Thymoglobulin as Induction Therapy? Transplant Proc 2023; 55:2035-2040. [PMID: 37778934 DOI: 10.1016/j.transproceed.2023.08.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/06/2023] [Accepted: 08/04/2023] [Indexed: 10/03/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection remains one of the most common viral pathogens affecting solid organ transplants (SOT). In 10 years of following the outcome of transplants, we noticed an increased incidence of CMV infection, along with increased use of rabbit anti-thymocyte globulin (rATG). The study aims to assess the incidence of active CMV infection and disease, response to treatment, and recurrence in a cohort of SOT. Furthermore, we look for correlating the CMV incidence with the type of induction therapy: r-ATG or interleukin 2 receptor-blocking antibody (basiliximab). METHODS This was a single-center, retrospective 10-year study in patients submitted to kidney, kidney-liver, and kidney-pancreas transplants who used a preemptive therapy protocol for CMV. RESULTS Among the 476 enrolled transplant recipients, 306 (64.2 %) had at least one episode of CMV infection (replication), and 71/306 patients (23.2 %) presented CMV-related disease. The most frequent clinical conditions associated with CMV disease were gastrointestinal. Among the 476 transplant patients, 333 received immunosuppressive induction with rATG (69.9 %); 140 (29.4 %) received induction with interleukin 2 receptor-blocking antibody (basiliximab). The initial maintenance immunosuppressive therapy in the patients who presented CMV infection was primarily performed with prednisone, tacrolimus, and sodium mycophenolate (91.7 %). The induction with rATG increased from 35.2%-94.6% in 10 years. The incidence of CMV infection was 20.7 % in the first year of observation and gradually increased to 87.3 % in the last year. CONCLUSIONS The data suggest that the increase in the use of rATG in recent years could be responsible for the very expressive increase in the incidence of CMV infection/disease.
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Affiliation(s)
- Elen Almeida Romao
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Aparecida Yulie Yamamoto
- Clinical Virology Laboratory, Hospital das Clinicas, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Gilberto Gambero Gaspar
- Division Of Infectious Disease, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Tania Marisa Pisi Garcia
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Valmir Aparecido Muglia
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Maria Estela Papini Nardin
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | | | | | - Miguel Moyses-Neto
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
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24
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Carlier FM, Evrard P, Dumonceaux M. Cytomegalovirus nephritis in a lung transplant recipient: A case report. JHLT OPEN 2023; 1:100003. [PMID: 40144580 PMCID: PMC11935480 DOI: 10.1016/j.jhlto.2023.100003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Introduction Cytomegalovirus (CMV) infections are frequent in solid organ transplant recipients and associated with increased allograft dysfunction. Clinical story We report the case of a 58-year-old lung transplant recipient (CMV mismatched) who presented with severe acute kidney injury (AKI) without any other organ involvement. Urinalysis showed moderate proteinuria, leukocyturia, and hematuria suggestive of interstitial nephritis, while renal/urinary tract ultrasound was normal. Anamnesis excluded iatrogenic AKI causes including contrast- and non-steroidal anti-inflammatory drugs-induced AKI, while dedicated blood tests excluded other AKI causes such as vasculitis, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection, thrombotic microangiopathy, tacrolimus overdosage, rhabdomyolysis. Urine and serum CMV polymerase chain reaction (PCR) were strongly positive, while urine BK virus was negative. A renal biopsy could not be performed due to anticoagulation and logistic reasons. Diagnosis Based on the existing literature, we made a presumptive diagnosis of CMV nephritis and initiated intravenous antiviral therapy with ganciclovir. Within a few weeks, renal function improved but did not fully recover. Conclusion CMV nephritis is very rare in nonkidney solid organ transplant recipient but should be investigated in case of acute kidney injury as it may lead to chronic renal impairment.
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Affiliation(s)
- François M. Carlier
- Lung Transplant Centre, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
- Department of Pneumology, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
| | - Patrick Evrard
- Lung Transplant Centre, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
- Intensive Care Unit, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
| | - Michel Dumonceaux
- Lung Transplant Centre, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
- Department of Pneumology, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
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25
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Miller W, January S, Klaus J, Neuner E, Pande A, Krekel T. Safety and efficacy of weight-based ganciclovir dosing strategies in overweight/obese patients. Transpl Infect Dis 2023; 25:e14134. [PMID: 37615196 DOI: 10.1111/tid.14134] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/18/2023] [Accepted: 08/14/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND The management of cytomegalovirus (CMV) is particularly challenging as both CMV and its usual first-line treatment, ganciclovir, are associated with neutropenia. Ganciclovir dosing is weight-based, most commonly utilizing total body weight (TBW). The subsequent high doses of ganciclovir in overweight/obese patients may increase the risk of toxicity. Utilizing adjusted body weight (AdjBW) dosing may help mitigate this risk. Therefore, the objective of this study was to evaluate the difference in toxicity and efficacy between TBW and AdjBW ganciclovir dosing strategies in overweight/obese patients. METHODS This retrospective study conducted safety and efficacy analyses of ganciclovir courses (≥72 h) used as CMV treatment. The primary safety outcome was the incidence of neutropenia (absolute neutrophil count <1000 cells/μL), and the primary efficacy outcome was a 2-log decrease in CMV polymerase chain reaction within 4 weeks following ganciclovir initiation. In both analyses, courses were excluded in which ganciclovir was dosed outside of specified renal dosing parameters for >20% of the course. RESULTS Among the 253 courses in the safety cohort, there was no difference in the incidence of neutropenia (17.4% vs. 13.5%, p = .50) in AdjBW compared to TBW dosing. In the 62 courses evaluating efficacy, there was no statistical difference between AdjBW and TBW dosing (60.0% vs. 45.2%, p = .28). No subgroups were identified in which AdjBW dosing was advantageous. CONCLUSION Utilization of AdjBW ganciclovir dosing did not result in decreased neutropenia or treatment efficacy as compared to TBW dosing. Further studies with larger patient populations would be beneficial to confirm these findings.
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Affiliation(s)
- William Miller
- Department of Pharmacy, Deaconess Hospital, Evansville, Indiana, USA
| | - Spenser January
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
| | - Jeff Klaus
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
| | - Elizabeth Neuner
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
| | - Anupam Pande
- Division of Infectious Disease, Washington University in St Louis School of Medicine, Saint Louis, Missouri, USA
| | - Tamara Krekel
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, Missouri, USA
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26
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Hock RA, Yousaf M, Allen JC, Heh E, Raynor M, Padilla O, Peralta DP. A Rare Case of Herpes Simplex Virus and Cytomegalovirus Dual Infection Inducing Unremitting Ulcerative Colitis. Cureus 2023; 15:e45166. [PMID: 37842466 PMCID: PMC10570757 DOI: 10.7759/cureus.45166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2023] [Indexed: 10/17/2023] Open
Abstract
Ulcerative colitis (UC) is a subtype of inflammatory bowel disease that results in inflammation and ulceration in the lining of the large intestine. Patients with UC are frequently prescribed immunosuppressive medications to treat their symptoms, resulting in an increased risk of reactivation of many latent viruses, including herpes simplex virus (HSV) and cytomegalovirus (CMV). However, it is rare for a patient to present with simultaneous reactivation of both viruses. Here, we document the presentation, hospital course, and clinical findings of a UC patient with HSV and CMV dual infection. We also describe treatment strategies and prophylactic measures for managing a dual infection. This is seen through initiating valganciclovir in the outpatient setting following the diagnosis.
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Affiliation(s)
- Rivers A Hock
- Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA
| | - Mohammad Yousaf
- Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA
| | - Jesse C Allen
- Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA
| | - Ethan Heh
- Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA
| | - Mark Raynor
- Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA
| | - Osvaldo Padilla
- Pathology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, USA
| | - Diego P Peralta
- Infectious Diseases, Texas Tech University Health Sciences Center, El Paso, USA
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Limaye AP, Budde K, Humar A, Vincenti F, Kuypers DRJ, Carroll RP, Stauffer N, Murata Y, Strizki JM, Teal VL, Gilbert CL, Haber BA. Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA 2023; 330:33-42. [PMID: 37279999 PMCID: PMC10245286 DOI: 10.1001/jama.2023.9106] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/19/2023] [Indexed: 06/08/2023]
Abstract
Importance Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression. Objective To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor. Design, Setting, and Participants Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022). Interventions Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos. Main Outcomes and Measures The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome. Results Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%). Conclusion and Relevance Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication. Trial Registration ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.
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Affiliation(s)
- Ajit P. Limaye
- Division of Allergy & Infectious Diseases, Departments of Medicine & Laboratory Medicine and Pathology, University of Washington Medicine, Seattle
| | | | - Atul Humar
- Ajmera Transplant Center, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Flavio Vincenti
- Division of Nephrology, University of California, San Francisco School of Medicine, San Francisco
| | - Dirk R. J. Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Renal Transplantation, UZ Leuven, Leuven, Belgium
| | - Robert P. Carroll
- Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia
- Department of Health Sciences, University of South Australia, Adelaide, South Australia, Australia
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Raglow Z, Kaul DR. A New Antiviral Option for Cytomegalovirus Prevention After Kidney Transplant. JAMA 2023; 330:27-29. [PMID: 37279971 DOI: 10.1001/jama.2023.9100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Affiliation(s)
- Zoe Raglow
- Division of Infectious Disease, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor
| | - Daniel R Kaul
- Division of Infectious Disease, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor
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Oloruntoba-Sanders O, Tanna SD. Evaluation and management of post-transplant infections for the hepatologist. Clin Liver Dis (Hoboken) 2023; 21:173-177. [PMID: 37361254 PMCID: PMC10287139 DOI: 10.1097/cld.0000000000000056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/25/2023] [Indexed: 06/28/2023] Open
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Raymonda MH, Rodríguez-Sánchez I, Schafer XL, Smorodintsev-Schiller L, Harris IS, Munger J. Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose limitation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.17.541212. [PMID: 37292722 PMCID: PMC10245705 DOI: 10.1101/2023.05.17.541212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Human cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV UL38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally-induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the UL38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of UL38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through UL38's inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Further, expression of UL38 or the inactivation of TSC2 results in anabolic rigidity in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.
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Affiliation(s)
- Matthew H. Raymonda
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Irene Rodríguez-Sánchez
- Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA
| | - Xenia L. Schafer
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Leonid Smorodintsev-Schiller
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, USA
| | - Isaac S. Harris
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, USA
| | - Joshua Munger
- Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA
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Marfil S, Märtson AG, Toren-Wielema M, Leer-Buter C, Schölvinck EH, Alffenaar JWC, Touw DJ, Sturkenboom MGG. Subtherapeutic Exposure of Ganciclovir in Children Despite Appropriate Dosing: A Short Communication. Ther Drug Monit 2023; 45:269-272. [PMID: 36920505 PMCID: PMC10013166 DOI: 10.1097/ftd.0000000000001050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 09/10/2022] [Indexed: 02/05/2023]
Abstract
ABSTRACT Therapeutic drug monitoring (TDM) results for ganciclovir in 12 different treatment episodes showed large intraindividual and interindividual variabilities in the trough concentration and area under the 24-hour concentration-time curve (AUC24). Despite adequate valganciclovir dosing, subtherapeutic concentrations were found in 30% of the treatment episodes. A decrease in viral load was observed regardless of subtherapeutic exposure. These findings show the need for target concentration evaluation and assessment of the applicability of ganciclovir TDM in children.
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Affiliation(s)
- Sjanene Marfil
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;
| | - Anne-Grete Märtson
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;
- University of Liverpool, Antimicrobial Pharmacodynamics and Therapeutics, Liverpool, United Kingdom;
| | - Marlous Toren-Wielema
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;
| | - Coretta Leer-Buter
- University of Groningen, University Medical Center Groningen, Groningen, Department of Medical Microbiology and Infection Prevention;
| | - Elisabeth H. Schölvinck
- University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Infectious Diseases, Groningen, the Netherlands;
| | - Jan-Willem C. Alffenaar
- Sydney Institute of Infectious Diseases, the University of Sydney, Westmead;
- The University of Sydney, Sydney Pharmacy School, Faculty of Medicine and Health, Camperdown; and
- Department of Pharmacy, Westmead Hospital, Westmead, Australia
| | - Daan J. Touw
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;
| | - Marieke G. G. Sturkenboom
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;
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Opportunistic Infections Post-Lung Transplantation: Viral, Fungal, and Mycobacterial. Clin Chest Med 2023; 44:159-177. [PMID: 36774162 DOI: 10.1016/j.ccm.2022.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Opportunistic infections are a leading cause of lung transplant recipient morbidity and mortality. Risk factors for infection include continuous exposure of the lung allograft to the external environment, high levels of immunosuppression, impaired mucociliary clearance and decreased cough reflex, and impact of the native lung microbiome in single lung transplant recipients. Infection risk is mitigated through careful pretransplant screening of recipients and donors, implementation of antimicrobial prophylaxis strategies, and routine surveillance posttransplant. This review describes common viral, fungal, and mycobacterial infectious after lung transplant and provides recommendations on prevention and treatment.
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Vyas A, Raval AD, Kamat S, LaPlante K, Tang Y, Chemaly RF. Real-World Outcomes Associated With Letermovir Use for Cytomegalovirus Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: A Systematic Review and Meta-analysis of Observational Studies. Open Forum Infect Dis 2023; 10:ofac687. [PMID: 36726548 PMCID: PMC9879759 DOI: 10.1093/ofid/ofac687] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Background A systematic review and meta-analysis of real-world observational studies was conducted to summarize the impact of letermovir cytomegalovirus (CMV) primary prophylaxis (PP) among adult allogeneic hematopoietic cell transplant (allo-HCT) recipients. Methods Systematic searches in Medline/PubMed, Embase, and conferences (from database inception to October 2021) were conducted to identify studies for inclusion. Random-effects models were used to derive pooled estimates on the relative effectiveness of letermovir PP compared to controls. Results Forty-eight unique studies (N = 7104 patients) were included, most of which were comparative, single-center, and conducted in the United States. Letermovir PP was associated with statistically significant reduction in odds of CMV reactivation (pooled odds ratio [pOR], 0.13 and 0.24; P < .05), clinically significant CMV infection (pOR, 0.09 and 0.19; P < .05), and CMV disease (pOR, 0.31 and 0.35; P < .05) by day +100 and day +200 after allo-HCT, respectively. Letermovir PP was associated with significantly lower odds of all-cause (pOR, 0.73; P < .01) and nonrelapse mortality (pOR, 0.65; P = .01) beyond day 200 after allo-HCT. Conclusions Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.
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Affiliation(s)
- Ami Vyas
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Amit D Raval
- Center for Observational and Real-World Evidence, Merck & Co., Inc., Rahway, New Jersey, USA
| | - Shweta Kamat
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Kerry LaPlante
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Yuexin Tang
- Center for Observational and Real-World Evidence, Merck & Co., Inc., Rahway, New Jersey, USA
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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34
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Balani SS, Sadiq S, Jensen CJ, Kizilbash SJ. Prevention and management of CMV infection in pediatric solid organ transplant recipients. Front Pediatr 2023; 11:1098434. [PMID: 36891229 PMCID: PMC9986459 DOI: 10.3389/fped.2023.1098434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/31/2023] [Indexed: 02/22/2023] Open
Abstract
Human cytomegalovirus (CMV) remains one of the most common opportunistic infections following solid organ transplantation in children. CMV causes morbidity and mortality through direct tissue-invasive disease and indirect immunomodulatory effects. In recent years, several new agents have emerged for the prevention and treatment of CMV disease in solid organ transplant recipients. However, pediatric data remain scarce, and many of the treatments are extrapolated from the adult literature. Controversies exist about the type and duration of prophylactic therapies and the optimal dosing of antiviral agents. This review provides an up-to-date overview of treatment modalities used to prevent and treat CMV disease in solid organ transplant (SOT) recipients.
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Affiliation(s)
- Shanthi S Balani
- Division of Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
| | - Sanober Sadiq
- Division of Nephrology, Department of Pediatrics, University of California, San Francisco, CA, United States
| | - Chelsey J Jensen
- Department of Solid Organ Transplant, University of Minnesota, Minneapolis, MN, United States
| | - Sarah J Kizilbash
- Division of Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
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35
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Magid M, Byrns J, Gommer J, Yang Z, Lee H, Harris M. Early versus delayed initiation of cytomegalovirus prophylaxis after liver transplant. Pharmacotherapy 2022; 42:634-640. [DOI: 10.1002/phar.2714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 11/08/2022]
Affiliation(s)
- Mackenzie Magid
- Department of Pharmacy Duke University Hospital Durham North Carolina USA
| | - Jennifer Byrns
- Department of Pharmacy Duke University Hospital Durham North Carolina USA
| | - Jennifer Gommer
- Department of Pharmacy Duke University Hospital Durham North Carolina USA
| | - Zidanyue Yang
- Department of Biostatistics and Bioinformatics Duke University School of Medicine Durham North Carolina USA
| | - Hui‐Jie Lee
- Department of Biostatistics and Bioinformatics Duke University School of Medicine Durham North Carolina USA
| | - Matt Harris
- Department of Pharmacy Duke University Hospital Durham North Carolina USA
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36
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Saner FH, Hoyer DP, Hartmann M, Nowak KM, Bezinover D. The Edge of Unknown: Postoperative Critical Care in Liver Transplantation. J Clin Med 2022; 11:jcm11144036. [PMID: 35887797 PMCID: PMC9322367 DOI: 10.3390/jcm11144036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 02/04/2023] Open
Abstract
Perioperative care of patients undergoing liver transplantation (LT) is very complex. Metabolic derangements, hypothermia, coagulopathy and thromboses, severe infections, and graft dysfunction can affect outcomes. In this manuscript, we discuss several perioperative problems that can be encountered in LT recipients. The authors present the most up-to-date information regarding predicting and treating hemodynamic instability, coagulation monitoring and management, postoperative ventilation strategies and early extubation, management of infections, and ESLD-related pulmonary complications. In addition, early post-transplant allograft dysfunction will be discussed.
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Affiliation(s)
- Fuat H. Saner
- Department of General-, Visceral- and Transplant Surgery, Medical Center University Duisburg-Essen, 45147 Essen, Germany; (D.P.H.); (K.M.N.)
- Correspondence: ; Fax: +49-201-723-1145
| | - Dieter P. Hoyer
- Department of General-, Visceral- and Transplant Surgery, Medical Center University Duisburg-Essen, 45147 Essen, Germany; (D.P.H.); (K.M.N.)
| | - Matthias Hartmann
- Department of Anaesthesia and Critical Care, Medical Center University Duisburg-Essen, 45147 Essen, Germany;
| | - Knut M. Nowak
- Department of General-, Visceral- and Transplant Surgery, Medical Center University Duisburg-Essen, 45147 Essen, Germany; (D.P.H.); (K.M.N.)
| | - Dmitri Bezinover
- Department of Anesthesiology and Perioperative Medicine, Penn State Hershey Medical Center, Penn State College of Medicine, Hershey, PA 17033, USA;
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37
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Grossi PA, Kamar N, Saliba F, Baldanti F, Aguado JM, Gottlieb J, Banas B, Potena L. Cytomegalovirus Management in Solid Organ Transplant Recipients: A Pre-COVID-19 Survey From the Working Group of the European Society for Organ Transplantation. Transpl Int 2022; 35:10332. [PMID: 35812158 PMCID: PMC9257585 DOI: 10.3389/ti.2022.10332] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 05/20/2022] [Indexed: 11/13/2022]
Abstract
Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July–31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients’ needs, and respondents’ expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R− SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10–10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population.
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Affiliation(s)
- Paolo Antonio Grossi
- Department of Medicine and Surgery, University of Insubria, ASST-Sette Laghi, Varese, Italy
- *Correspondence: Paolo Antonio Grossi,
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, Toulouse, France
| | - Faouzi Saliba
- AP-HP Hôpital Paul Brousse, Center Hépato-Biliaire, Université Paris-Saclay, INSERM Unit N°1193, Villejuif, France
| | - Fausto Baldanti
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Molecular Virology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Jose M. Aguado
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Jens Gottlieb
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Luciano Potena
- Heart Failure and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Utility of Cytomegalovirus Cell-Mediated Immunity Assays in Solid Organ Transplantation. J Clin Microbiol 2022; 60:e0171621. [PMID: 35543099 DOI: 10.1128/jcm.01716-21] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cytomegalovirus (CMV) is one of the most important viral complications after solid organ transplantation (SOT). Current preventive and management strategies rely primarily on serologic and viral load testing and remain suboptimal. To address these issues, multiple techniques to measure CMV-specific cell-mediated immunity (CMI) have been developed and evaluated in clinical studies over the past two decades. These assays show significant promise for the personalization of CMV management. For example, CMI assays can be used to help determine the optimal duration of antiviral prophylaxis or whether antiviral therapy is indicated in patients with low levels of CMV reactivation. However, despite numerous studies showing potential utility, these assays are not yet in widespread routine clinical use. Barriers to adoption include variations in test complexity, standardization, and thresholds for positivity and insufficient interventional clinical trials. Here, we provide an updated assessment of commonly available tests and the clinical utility of CMV-specific CMI testing in SOT recipients.
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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.
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Affiliation(s)
- Çiğdem Erol
- From the Department of Infectious Diseases, Başkent University Medical School, Ankara, Turkey
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40
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Ruenroengbun N, Sapankaew T, Chaiyakittisopon K, Phoompoung P, Ngamprasertchai T. Efficacy and Safety of Antiviral Agents in Preventing Allograft Rejection Following CMV Prophylaxis in High-Risk Kidney Transplantation: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. Front Cell Infect Microbiol 2022; 12:865735. [PMID: 35433502 PMCID: PMC9010655 DOI: 10.3389/fcimb.2022.865735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/07/2022] [Indexed: 11/15/2022] Open
Abstract
Many antiviral agents have been studied in clinical trials for allograft rejection prevention following cytomegalovirus (CMV) prophylaxis in high-risk kidney transplant patients. However, data on the most effective and safest treatment are lacking. We conducted a systematic review and network meta-analysis to rank CMV prophylaxis agents for allograft rejection prevention following CMV prophylaxis in high-risk kidney transplant patients according to their efficacy and safety. We conducted searches on the MEDLINE, Embase, SCOPUS, and CENTRAL databases, as well as the reference lists of selected studies up to December 2021, for published and peer-reviewed randomized controlled trials assessing the efficacy of CMV prophylaxis agents in high-risk kidney transplant patients. Thirteen studies were independently selected by three reviewers and included post-kidney transplant patients indicated for CMV prophylaxis who had been randomized to receive prophylactic antiviral agents or standard of care. The reviewers independently extracted data from the included studies, and direct and network meta-analyses were applied to assess the study outcomes. The probability of efficacy and safety was evaluated, and the drugs were assigned a numerical ranking. We evaluated the risk of bias using the Cochrane Risk of Bias 2.0 tool. The primary outcome was an incidence of biopsy-proven acute rejection, whereas the secondary outcome was a composite of major adverse drug reactions. Each outcome referred to the definition provided in the original studies. Valganciclovir, valacyclovir, and ganciclovir were identified to significantly decrease the incidence of biopsy-proven acute rejection with pooled risk differences (RDs) of −20.53% (95% confidence interval [CI] = −36.09% to −4.98%), −19.3% (95% CI = −32.7% to −5.93%), and −10.4% (95% CI = −19.7% to −0.12%), respectively. The overall major adverse drug reaction was 5.7% without a significant difference when compared with placebo. Valganciclovir had the best combined efficacy and safety among the examined antiviral agents and was the most effective and safest antiviral agent overall for allograft rejection prevention following CMV prophylaxis. Valacyclovir was the optimal alternative antiviral agent for patients who were unable to tolerate intravenous ganciclovir or access oral valganciclovir as financial problem. However, compliance and dose-related toxicities should be closely monitored.
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Affiliation(s)
- Narisa Ruenroengbun
- Department of Pharmaceutics (Clinical Pharmacy), Faculty of Pharmacy, Slipakorn University, Nakornprathom, Thailand
| | - Tunlanut Sapankaew
- Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Kamolpat Chaiyakittisopon
- Department of Community Pharmacy and Administrations, Faculty of Pharmacy, Slipakorn University, Nakornprathom, Thailand
| | - Pakpoom Phoompoung
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Thundon Ngamprasertchai
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
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Abstract
Recipients of solid organ and hematopoietic stem cell transplantation undergo substantial immune suppression, placing them at risk for opportunistic viral infection. Few randomized controlled trials have been dedicated to the treatment of viral infections in children, and current practices are extrapolated from data generated from adult patients. Here we discuss the prevention and treatment of viral infections using available antiviral drugs, as well as novel agents that may provide benefit to pediatric patients in the future.
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Affiliation(s)
- William R Otto
- Division of Infectious Diseases, Department of Pediatrics, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104-4399, USA
| | - Abby Green
- Division of Infectious Diseases, Department of Pediatrics, Washington University, 425 S. Euclid Avenue, McDonnell Pediatric Research Building, #5105, St Louis, MO 63106, USA.
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42
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Bigley TM, Yang L, Kang LI, Saenz JB, Victorino F, Yokoyama WM. Disruption of thymic central tolerance by infection with murine roseolovirus induces autoimmune gastritis. J Exp Med 2022; 219:213039. [PMID: 35226043 PMCID: PMC8932538 DOI: 10.1084/jem.20211403] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 11/29/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Infections with herpesviruses, including human roseoloviruses, have been proposed to cause autoimmune disease, but defining a causal relationship and mechanism has been difficult due to the ubiquitous nature of infection and development of autoimmunity long after acute infection. Murine roseolovirus (MRV) is highly related to human roseoloviruses. Herein we show that neonatal MRV infection induced autoimmune gastritis (AIG) in adult mice in the absence of ongoing infection. MRV-induced AIG was dependent on replication during the neonatal period and was CD4+ T cell and IL-17 dependent. Moreover, neonatal MRV infection was associated with development of a wide array of autoantibodies in adult mice. Finally, neonatal MRV infection reduced medullary thymic epithelial cell numbers, thymic dendritic cell numbers, and thymic expression of AIRE and tissue-restricted antigens, in addition to increasing thymocyte apoptosis at the stage of negative selection. These findings strongly suggest that infection with a roseolovirus early in life results in disruption of central tolerance and development of autoimmune disease.
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Affiliation(s)
- Tarin M. Bigley
- Department of Pediatrics, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO
| | - Liping Yang
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO
| | - Liang-I Kang
- Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO
| | - Jose B. Saenz
- Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO
| | - Francisco Victorino
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO
| | - Wayne M. Yokoyama
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO
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43
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Märtson AG, Sturkenboom MGG, Knoester M, van der Werf TS, Alffenaar JWC, Hope W. Standard ganciclovir dosing results in slow decline of cytomegalovirus viral loads. J Antimicrob Chemother 2022; 77:466-473. [PMID: 35107143 PMCID: PMC8809194 DOI: 10.1093/jac/dkab419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 10/14/2021] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) can cause severe disease, including rejection in transplant recipients. Ganciclovir and its oral prodrug valganciclovir have been used as first-line therapy for CMV disease in transplant recipients. The exposure targets of ganciclovir are not exactly known, and toxicity and resistance have interfered with ganciclovir therapy. OBJECTIVES To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ganciclovir in transplant recipients. METHODS We used patient data from a previous observational study on ganciclovir therapeutic drug monitoring (TDM) in prophylaxis and therapy. The ganciclovir concentrations and CMV viral loads were determined during routine clinical care. The PK/PD population modelling and simulations were done with non-parametric methodology using the Pmetrics program. RESULTS Eighty-five patients were included in the PK modelling. The final PK model was a two-compartment model with first-order absorption and elimination. A subset of 17 patients on CMV therapy were included in the PD modelling. A median of 4 (range 2-8) viral loads were obtained per patient. A simulation of 10 000 patients showed that an approximately 1 log10 reduction of CMV viral load will be observed after 12.5 days at the current recommended dose. CONCLUSIONS The developed linked PK/PD population model and subsequent PD simulations showed slow decline of CMV viral load and it appears that dosing of (val)ganciclovir in this study might have been inadequate to achieve fast reduction of viral load. It is clear that further studies are needed to specify the PD effects of ganciclovir by performing systematic measurements of both ganciclovir concentrations and CMV viral loads.
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Affiliation(s)
- Anne-Grete Märtson
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marieke G G Sturkenboom
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marjolein Knoester
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Tjip S van der Werf
- Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan-Willem C Alffenaar
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Westmead Hospital, Westmead, New South Wales, Australia.,Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Sydney, New South Wales, Australia
| | - William Hope
- Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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Märtson AG, Edwina AE, Kim HY, Knoester M, Touw DJ, Sturkenboom MGG, Alffenaar JWC. Therapeutic Drug Monitoring of Ganciclovir: Where Are We? Ther Drug Monit 2022; 44:138-147. [PMID: 34610621 PMCID: PMC8746890 DOI: 10.1097/ftd.0000000000000925] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/07/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps. METHODS For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened. RESULTS The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window. CONCLUSIONS Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted.
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Affiliation(s)
- Anne-Grete Märtson
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Angela E. Edwina
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Hannah Yejin Kim
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Department of Pharmacy, Westmead Hospital, Westmead, NSW, Australia
- Marie Bashir Institute of Infectious Diseases and Biosecurity, The University of Sydney, Camperdown, NSW, Australia
| | - Marjolein Knoester
- Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; and
| | - Daan J. Touw
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marieke G. G. Sturkenboom
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jan-Willem C. Alffenaar
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
- Department of Pharmacy, Westmead Hospital, Westmead, NSW, Australia
- Marie Bashir Institute of Infectious Diseases and Biosecurity, The University of Sydney, Camperdown, NSW, Australia
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45
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Payne AT, Lindner BK, Gilbert AJ, Kumar RN, Thomas BS, Timpone JG. Evaluation of cytomegalovirus "Blips" in high risk kidney/kidney-pancreas transplant recipients. Transpl Infect Dis 2022; 24:e13789. [PMID: 35014122 DOI: 10.1111/tid.13789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/13/2021] [Accepted: 12/27/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) is a significant cause of morbidity and mortality after solid organ transplantation. While guidelines suggest using highly sensitive QNAT assays for CMV detection, there is no defined viral load to guide initiation of preemptive therapy.1,2 This study evaluates the progression to quantifiable CMV (DNAemia) following a CMV "blip" in high risk (D+/R) kidney/kidney-pancreas (KP) transplant recipients. METHODS This is a single center, retrospective study. A CMV "blip" was defined as the first positive QNAT assay below the level of quantification (< 1.37×102 IU/mL or < 200 viral copies). Subsequent CMV QNAT assays were followed to assess the progression from blip to CMV DNAemia for 1 year following transplant. RESULTS 134 patients were included in the study. Fifty-three (39.6%) patients had their first positive CMV QNAT value below the level of quantification, a "CMV blip". Of these 53 patients, 69.8% (n = 37) progressed to DNAemia while 30.2% (n = 16) did not. The median time from transplant to the first CMV blip was 68 (46-97) days and most patients with viral blips (71.1%) were on prophylaxis. No differences in patient characteristics were found among those who progressed from blip to DNAemia and those who only had a blip. CONCLUSIONS In CMV high risk kidney/KP transplant recipients, CMV blips progressed to CMV DNAemia in the majority of cases. This progression typically occurred 2-3 weeks following the initial blip. CMV blips are common early post-transplant despite prophylaxis and likely represent an early marker of CMV infection. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Alexandra T Payne
- Georgetown University School of Medicine, Washington, DC, 20007, USA
| | - Brian K Lindner
- MedStar Georgetown University Hospital Department of Pharmacy, Washington, DC, 20007, USA
| | - Alexander J Gilbert
- MedStar Georgetown University Hospital Transplant Institute, Washington, DC, 20007, USA
| | - Rebecca N Kumar
- MedStar Georgetown University Hospital Division of Infectious Diseases and Tropical Medicine, Washington, DC, 20007, USA
| | - Beje S Thomas
- MedStar Georgetown University Hospital Transplant Institute, Washington, DC, 20007, USA
| | - Joseph G Timpone
- MedStar Georgetown University Hospital Division of Infectious Diseases and Tropical Medicine, Washington, DC, 20007, USA
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46
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Munting A, Manuel O. Viral infections in lung transplantation. J Thorac Dis 2022; 13:6673-6694. [PMID: 34992844 PMCID: PMC8662465 DOI: 10.21037/jtd-2021-24] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022]
Abstract
Viral infections account for up to 30% of all infectious complications in lung transplant recipients, remaining a significant cause of morbidity and even mortality. Impact of viral infections is not only due to the direct effects of viral replication, but also to immunologically-mediated lung injury that may lead to acute rejection and chronic lung allograft dysfunction. This has particularly been seen in infections caused by herpesviruses and respiratory viruses. The implementation of universal preventive measures against cytomegalovirus (CMV) and influenza (by means of antiviral prophylaxis and vaccination, respectively) and administration of early antiviral treatment have reduced the burden of these diseases and potentially their role in affecting allograft outcomes. New antivirals against CMV for prophylaxis and for treatment of antiviral-resistant CMV infection are currently being evaluated in transplant recipients, and may continue to improve the management of CMV in lung transplant recipients. However, new therapeutic and preventive strategies are highly needed for other viruses such as respiratory syncytial virus (RSV) or parainfluenza virus (PIV), including new antivirals and vaccines. This is particularly important in the advent of the COVID-19 pandemic, for which several unanswered questions remain, in particular on the best antiviral and immunomodulatory regimen for decreasing mortality specifically in lung transplant recipients. In conclusion, the appropriate management of viral complications after transplantation remain an essential step to continue improving survival and quality of life of lung transplant recipients.
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Affiliation(s)
- Aline Munting
- Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland
| | - Oriol Manuel
- Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland.,Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland
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Makharia G, Mohta S, Sridharan S, Gopalakrishnan R, Prasad N, Bansal S. Diarrhea in solid organ transplant recipients in the South Asian Region - Expert group opinion for diagnosis and management. INDIAN JOURNAL OF TRANSPLANTATION 2022; 16:23. [DOI: 10.4103/ijot.ijot_79_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Pickering H, Sen S, Arakawa-Hoyt J, Ishiyama K, Sun Y, Parmar R, Ahn RS, Sunga G, Llamas M, Hoffmann A, Deng M, Bunnapradist S, Schaenman JM, Gjertson DW, Rossetti M, Lanier LL, Reed EF. NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant. JCI Insight 2021; 6:153175. [PMID: 34609965 PMCID: PMC8663544 DOI: 10.1172/jci.insight.153175] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/29/2021] [Indexed: 01/08/2023] Open
Abstract
CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28–CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28–CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.
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Affiliation(s)
- Harry Pickering
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Subha Sen
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Janice Arakawa-Hoyt
- Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, California, USA
| | - Kenichi Ishiyama
- Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, California, USA
| | - Yumeng Sun
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Rajesh Parmar
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Richard S Ahn
- Microbiology, Immunology, and Molecular Genetics.,Institute for Quantitative and Computational Biosciences, and
| | - Gemalene Sunga
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Megan Llamas
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Alexander Hoffmann
- Institute for Quantitative and Computational Biosciences, and.,Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Mario Deng
- Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Suphamai Bunnapradist
- Division of Nephrology, David Geffen School of Medicine, Los Angeles, California, USA
| | - Joanna M Schaenman
- Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - David W Gjertson
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.,Biostatistics, University of California, Los Angeles, Los Angeles, California, USA
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Lewis L Lanier
- Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, California, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
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Singh N, Winston DJ, Razonable RR, Lyon GM, Silveira FP, Wagener MM, Limaye AP. Cost-effectiveness of Preemptive Therapy Versus Prophylaxis in a Randomized Clinical Trial for the Prevention of Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors. Clin Infect Dis 2021; 73:e2739-e2745. [PMID: 32712663 DOI: 10.1093/cid/ciaa1051] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND The relative costs of preemptive therapy (PET) or prophylaxis for the prevention of cytomegalovirus (CMV) disease in high-risk donor CMV-seropositive/recipient-seronegative (D+/R-) liver transplant recipients have not been assessed in the context of a randomized trial. METHODS A decision tree model was constructed based on the probability of outcomes in a randomized controlled trial that compared valganciclovir as PET or prophylaxis for 100 days in 205 D+/R- liver transplant recipients. Itemized costs for each site were obtained from a federal cost transparency database. Total costs included costs of implementation of the strategy and CMV disease treatment-related costs. Net cost per patient was estimated from the decision tree for each strategy. RESULTS PET was associated with a 10% lower absolute rate of CMV disease (9% vs 19%). The cost of treating a case of CMV disease in our patients was $88 190. Considering cost of implementation of strategy and treatment-related cost for CMV disease, the net cost-savings per patient associated with PET was $8707 compared to prophylaxis. PET remained cost-effective across a range of assumptions (varying costs of monitoring and treatment, and rates of disease). CONCLUSIONS PET is the dominant CMV prevention strategy in that it was associated with lower rates of CMV disease and lower overall costs compared to prophylaxis in D+/R- liver transplant recipients. Costs were driven primarily by more hospitalizations and higher CMV disease-associated costs due to delayed onset postprophylaxis disease in the prophylaxis group.
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Affiliation(s)
- Nina Singh
- University of Pittsburgh and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
| | - Drew J Winston
- University of California, Los Angeles Medical Center, Los Angeles, California, USA
| | | | | | - Fernanda P Silveira
- University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Marilyn M Wagener
- University of Pittsburgh and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
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50
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Association of HHV-6 With Outcomes in CMV-seronegative Liver Transplant Recipients With CMV-seropositive Donors Receiving Preemptive Antiviral Therapy. Transplantation 2021; 105:2427-2434. [PMID: 33587431 DOI: 10.1097/tp.0000000000003604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Risk factors, virological parameters, and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined. METHODS The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 d in the PET group were tested for HHV-6 viremia using a real-time quantitative polymerase chain reaction. Assessments included virological characteristics and relationship with CMV, risk factors, and impact of HHV-6 viremia with outcomes through 12 mo posttransplant. RESULTS HHV-6 viremia at any level developed in 42% (40 of 96). Older patient age (P = 0.03), longer hospitalization (P = 0.015), and ICU stay at transplantation (P = 0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (P = 0.004), higher HHV-6 area under the curve (P = 0.043), and higher peak HHV-6 viral load (P = 0.006) versus HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 mo (P = 0.045) posttransplant. CONCLUSIONS Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical illness in ICU at time of transplant and was independently associated with allograft rejection.
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