Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis

doi:10.1016/j.healun.2010.04.022

The Journal of Heart and Lung Transplantation

Volume 29, Issue 9, September 2010, Pages 1014-1020

https://doi.org/10.1016/j.healun.2010.04.022 Get rights and content

Background

Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown.

Methods

Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis.

Results

Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions (< 900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n = 15) or gastrointestinal symptoms (n = 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p = 0.01), single-lung transplant (p = 0.03), chronic obstructive pulmonary disease (p = 0.05), reduced-dose valganciclovir (p = 0.001), and less than 6 months of prophylaxis (p = 0.005). By multivariate analysis, advanced age (p = 0.01) and reduced-dose valganciclovir (p = 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease.

Conclusions

Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease.

Section snippets

Methods

This study was approved by the University of Pittsburgh's Institutional Review Board.

D+/R– lung transplant recipients and valganciclovir prophylaxis

From January 2003 to July 2008, 120 CMV R– patients received D+ lungs, accounting for 25% of 483 lung transplants. The study excluded 11 patients because they died within 1 month of transplant (n = 9) and lack of valganciclovir prophylaxis (n = 1) or alemtuzumab induction (n = 1). The remaining 109 D+/R– recipients resembled the entire lung transplant cohort in demographics, baseline characteristics, types of transplant, and immunosuppression (Table 1).

The 109 patients received valganciclovir

Discussion

In this large study in which valganciclovir was used as the sole preventive agent among D+/R− lung transplant recipients, the incidence of CMV disease was lower than would be anticipated in the absence of preventive therapy. Nevertheless, the efficacy of valganciclovir prophylaxis was limited by the extent and severity of CMV disease, emergence of drug resistance, and toxicity.

CMV developed in 30 of the 109 patients (27%) despite receiving valganciclovir for a median of 6.8 months, and 5 (5%)

Disclosure statement

Dr Nguyen and Dr Clancy are funded by a National Institutes of Health Mycology Research Unit Program Project Award (5P01AI061537-02).

Dr Nguyen has received research funding from Pfizer, Enzon Pharmaceutical, and Merck. Dr Kwak and Dr Silveria have received research funding from Pfizer. Dr Clancy has received research funding from Pfizer, Astellas, Merck, and Ortho-McNeil. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the

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Adult, CMV-seronegative first-time lung-only recipients were identified through the Scientific Registry of Transplant Recipients between May 2005 and December 2019. We used adjusted multivariable Cox regression to assess the relationship of donor CMV status and death. Interaction between recipient age and donor CMV was assessed via likelihood ratio testing of nested Cox models and by the relative excess risk due to interaction (RERI) and attributable proportion (AP) of joint effects.
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Among CMV-seronegative LTRs, donor CMV-seropositive status confers higher risk of posttransplant mortality, which is amplified in older recipients. Future studies should define optimal strategies for CMV prevention and management in older D+/R− LTRs.
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Transmission of latent human cytomegalovirus (HCMV) via organ transplantation with post-transplant viral reactivation is extremely prevalent and results in substantial adverse impact on outcomes. Therapies targeting the latent reservoir within the allograft to mitigate viral transmission would represent a major advance. Here, we delivered an immunotoxin (F49A-FTP) that targets and kills latent HCMV aiming at reducing the HCMV reservoir from donor lungs using ex-vivo lung perfusion (EVLP).
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Citation Excerpt :
Patients receiving standard duration prophylaxis had higher peak viral loads, perhaps because of a less effective immune response unable to control viral replication.35 Although our findings demonstrate a clear benefit to extending prophylaxis to 11 months in mismatch patients, most still developed CMV infection following prophylaxis discontinuation even at this later timepoint post-transplant.36 Amongst R+ patients, systemic infection was much less common and typically milder.37,38
The Quantiferon-Cytomegalovirus (QF-CMV) assay was introduced to predict CMV infection and inform prophylaxis duration in our lung transplant recipients (LTR) from 2012. The aims of this retrospective cohort study were to review our QF-CMV experience, understand factors associated with positive results and further explore its predictive utility.
LTR with QF-CMV testing performed at 5 months post-transplant were included. Patients receiving QF-directed prophylaxis (5 or 11 months) were compared to those receiving our prior standard of care (5 months). Outcomes were CMV infection >1,000 IU/mL in blood and/or bronchoalveolar lavage fluid. Factors associated with positive QF-CMV results were identified. Patients were compared based on serostatus, QF-CMV results and prophylaxis duration.
Our cohort included 263 LTR (59 D+/R-, 204 R+). QF-directed prophylaxis was used in 195 of 263 (74%) and was associated with reduced CMV infection (84/195, 43% vs 41/68, 60%, p < .001). Patients receiving extended prophylaxis experienced less CMV if negative and/or indeterminate (43% vs 70%, p < .01) or positive (10% vs 51%, p < .01). Only 5 of 59 (8%) D+/R- patients were QF-CMV positive compared to 155 of 204 (76%) R+ patients (adjusted OR 0.03, 0.01-0.07, p < .001). After controlling for prophylaxis duration, only D+/R- serostatus remained independently associated with CMV infection (adjusted HR 4.90, 95% CI 2.68-9.00, p < .0001).
QF-CMV results were strongly correlated with serostatus, with D+/R- patients unlikely to test positive while receiving prophylaxis. Extended prophylaxis was associated with delayed onset, reduced frequency and severity of CMV infection across all subgroups. After accounting for serostatus, the incremental predictive value of QF-CMV in this cohort was limited.
Global estimate of phenotypic and genotypic ganciclovir resistance in cytomegalovirus infections among HIV and organ transplant patients; A systematic review and meta-analysis
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Being one of the most causes of organ rejection in transplant patients, several studies have reported that CMV could exert deteriorate impacts on the efficacy of approximately 30% of haematopoietic stem cells and liver transplantation cases around the world [105,106]. The discovery of ganciclovir, a first antivirus drug for CMV treatment, has brought a promising perspective for transplant and HIV positive patients; however, it did not take long until the GCV resistant population appeared due to the mutations in UL54 and UL97, making the condition more difficult for susceptible patients [68,107–109]. Mounting body of molecular investigations have studied the nature of these mutations.
Human cytomegalovirus (CMV), an opportunistic pathogen belonging to Herpesviridae family, is considered as one of the major causes of morbidity and mortality among wide variety of patients, particularly in transplant recipients and HIV positive patients. As this virus can be resistant to treatment, frequency of CMV in patients who receive organ transplantation and people suffering from AIDS was studied between 1980 and 2019. Medline (via PubMed), Embase, Web of Science, and the Iranian Database were reviewed, and Comprehensive Meta-Analysis (V2.0, Biostat) software analyzed all data. Finally, we used Cochran's Q-statistic to encounter heterogeneity between different studies. Meta-analyses indicated, GCV resistance was 14.1% (95% CI 11.2–17.7); however, in patients suffering from AIDS and organ transplantation were 19.5% (95% CI 14.7–25.4) and 11.4% (95% CI 8.1–15.8), respectively. There were increasing rates in the prevalence of GCV resistance in CMV among transplant recipients, and HIV positive patients. Therefore, evaluation of these refractory infections is beneficial.
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Original clinical scienceCytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis

Background

Methods

Results

Conclusions

Section snippets

Methods

D+/R– lung transplant recipients and valganciclovir prophylaxis

Discussion

Disclosure statement

Chest

Chest

Am J Transplant

J Heart Lung Transplant

Chest

J Heart Lung Transplant

J Heart Lung Transplant

Transplant Proc

Am J Transplant

Am J Transplant

Am J Transplant

J Heart Lung Transplant

Am J Transplant

Am J Transplant

Am J Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Blood

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

Am Rev Respir Dis

Infectious complications of lung transplantation

Transpl Infect Dis

Use of cytomegalovirus immune globulin and ganciclovir for the prevention of cytomegalovirus disease in lung transplantation

Transpl Infect Dis

Cytomegalovirus infection and survival in lung transplant recipients

J Heart Lung Transplant

Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients

Am Rev Respir Dis

Original clinical science
Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis