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Ann Thorac Surg 2007;84:1129-1135
© 2007 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Postlung Transplant Survival is Equivalent Regardless of Cytomegalovirus Match Status

^a Lung Transplant Program and International Center for Health Outcomes and Innovation Research (InCHOIR), Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York
^b Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York

Accepted for publication May 11, 2007.

^_* Address correspondence to Dr Sonett, Division of Cardiothoracic Surgery, New York-Presbyterian Hospital/Columbia, PH Room 104, 14th Floor, 622 W 168th St, New York, NY 10032 (Email: js2106{at}columbia.edu).

Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.

	Abstract

Top Abstract Introduction Material and Methods Results Comment Discussion Acknowledgments References

 
Background: The purpose of this study was to assess (1) the relationship between donor–recipient cytomegalovirus (CMV) serologic status and posttransplant survival in the current era and (2) temporal changes in posttransplant survival by CMV matching status.

Methods: De-identified data were obtained from the United Network for Organ Sharing. Based on pretransplant CMV serologic status (+ or –) of recipients (R) and donors (D), posttransplant survival was compared among three groups: D+R–, D±R+, and D–R–. Primary analysis focused on transplants performed January 1, 2000 to December 31, 2004, in recipients 18 years of age or older. To assess temporal trends in survival among groups, all lung transplants occurring between January 1, 1990, and December 31, 2004, were considered and divided into three periods based on transplant year: 1990 through 1994, 1995 through 1999, and 2000 through 2004. The primary outcome measure was survival, reported as rate of death per 100 patient-years. Kaplan–Meier analysis with log-rank test was used for time-to-event analysis.

Results: During the current era (2000 through 2004), D+R– (n = 951), D±R+ (n = 2,676), and D–R– (n = 772) exhibited no differences in survival (p = 0.561), with rates of death per 100 patient-years of 16.6 (95% confidence interval, 14.9 to 18.5), 15.0 (95% confidence interval, 14.0 to 16.0), and 14.7 (95% confidence interval, 13.0 to 16.6), respectively. However, survival was significantly different for groups in the earlier eras of 1990 through 1994 (p < 0.001) and 1995 through 1999 (p < 0.001). During the three periods, survival improved significantly in D+R– (p < 0.001) and D±R+ (p < 0.001), but survival in D–R– (p = 0.351) did not change significantly with time.

Conclusions: In the current era, survival after lung transplantation is statistically equivalent regardless of CMV match status. Although in previous eras survival was worse among the D±R+ and D+R– groups, in this era of aggressive CMV prophylaxis, CMV mismatch should not be sufficient grounds to decline a lung allograft offer.

	Introduction

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Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality in solid organ transplant recipients, particularly after lung transplantation [1]. After early experience with lung transplantation, many centers adopted a policy of CMV seromatching of recipients and donors to avoid transplantation of lungs from CMV-positive (CMV+) donors to CMV-negative (CMV–) recipients (CMV mismatching). However, because of the scarcity of organs and the conflicting findings of more recent studies exploring this relationship between CMV serologic status and outcomes [2–10], this practice has not been universally applied.

The primary objectives of this study were to assess (1) the relationship between donor–recipient CMV serologic status and survival in the current era and (2) temporal changes in survival by CMV serologic status. We hypothesized that, although CMV recipient–donor mismatch in previous eras may have been associated with worse posttransplant survival, with the advent of more effective and aggressive CMV prophylaxis strategies, CMV mismatching in the current era is no longer associated with worse posttransplant survival.

Although numerous studies have explored the effect of CMV serologic status on outcomes, these studies suffered from a number of limitations. First, these studies were largely single-center studies and therefore limited in size. Furthermore, these studies were completed before the implementation of more effective and aggressive CMV prophylaxis strategies or did not consider temporal changes in CMV prophylaxis strategies. This study differed from previous studies because, by analyzing the United Network for Organ Sharing (UNOS) database, it examined the national experience with lung transplantation during a 15-year period. Moreover, by dividing the analysis period into discrete time intervals, it considers possible advances in management strategies with time. Finally, this study examined the association between CMV match status and posttransplant morbidity, including bronchiolitis obliterans, infection, and rejection.

	Material and Methods

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Data Collection
Use of these data are consistent with the regulations of our university’s institutional review board and the UNOS Data Use Agreement. The Standard Transplant Analysis and Research Dataset was provided by UNOS (data source number 021606-4). It contains information collected from the UNetsm forms, including the Transplant Candidate Registration form, the Transplant Recipient Registration form, and the Transplant Recipient Follow-up form. These data are the basis of the UNOS Thoracic Registry.

Study Population
All recipients age 18 years and older undergoing lung transplantation between January 1, 1990, and December 31, 2004, were included in the study population. Patients were followed from the date of transplantation to February 27, 2006, which was the last day of follow-up data provided by UNOS. Mean patient follow-up period was 3.32 ± 3.07 years.

Primary analysis focused on lung transplants performed January 1, 2000, to December 31, 2004 (current era). This 5-year period was used for primary analysis because 2000 was the first complete year that UNOS collected data regarding use of ganciclovir or valganciclovir for CMV prophylaxis. Patients were categorized into three groups according to donor–recipient CMV serologic status: donor CMV+Recipient CMV– (D+R–), donor CMV+ or CMV–Recipient CMV+ (D±R+), and donor CMV–Recipient CMV– (D–R–). If CMV recipient or donor serologic status was omitted, patients (n = 1,513; 12.37%) were excluded from the analysis.

Outcome Measures
The primary outcome measure was survival reported as median posttransplant survival and rate of death (RD) per 100 patient-years with 95% confidence intervals (CI). Kaplan–Meier analysis with Cox proportional hazards regression (HR) was used for time-to-event analysis. Outcome of interest was death (n = 6,213, 53.7%) or retransplant (n = 331, 2.9%), whichever came first. Patients lost to follow-up (n = 280, 2.4%) or alive at last known follow-up (4,742, 41.0%) were censored at the date of last known follow-up.

Other outcomes of interest included severe rejection–free survival (FS), severe infection–FS, and bronchiolitis obliterans (BO)–FS. Severe rejection was defined as the need for hospitalization as a result of rejection. Severe infection was defined as the need for hospitalization as a result of infection. Bronchiolitis obliterans was defined as bronchiolitis obliterans grade 1 or higher. Ganciclovir or valganciclovir prophylaxis (GVP) indicates posttransplant use of ganciclovir or valganciclovir for CMV prophylaxis. These secondary analyses were limited to the current era.

Data Analysis
Continuous variables were reported as means ± standard deviation and compared using the Student’s t test. To compare categorical variables, the ² test was used. The conventional probability value of 0.05 or less was used to determine level of statistical significance. All reported probability values are two-sided. Kaplan–Meier analysis with log-rank test was used for time-to-event analysis for actuarial survival, as well as severe rejection–FS, severe infection–FS, and BO-FS. Cox proportional HR was also performed (backward, remove p > 0.15) to assess the simultaneous effect of multiple variables on survival after lung transplant including donor age younger than 50, recipient age younger than 60, cause of end-stage lung disease (ESLD: pulmonary hypertension, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease), type of transplant (single versus double), and ischemic time less than 4 hours. Median time to event was the day of follow-up when 50% of uncensored patients experienced the event of interest. Patients lost to follow-up were censored at the time of last known follow-up. To assess temporal trends in survival, patients were divided into three eras based on year of transplant: ERA1 (1990 through 1994), ERA2 (1995 through 1999), and ERA3 (2000 through 2004). All data were analyzed using a statistical software package, Stata 9 (Stata Corp, College Station, TX).

	Results

Top Abstract Introduction Material and Methods Results Comment Discussion Acknowledgments References

 
Study Population
Primary analysis focused on 5,068 lung transplantations performed 2000 through 2004, including 10,780.4 years at risk with a median survival of 5.01 years; 50.1% of donors (n = 1,178) and 65.9% of recipients (n = 1,448) were CMV positive (CMV+). Demographic and clinical characteristics of the study patients are summarized in Table 1.

View larger version (19K): [in this window] [in a new window]   Fig 1. Kaplan–Meier survival analysis after lung transplantation by cytomegalovirus (CMV) serologic status. (D+ = donor CMV+; Dx = donor CMV+ or –; R– = recipient CMV–; R+ = recipient CMV+.)

View larger version (20K): [in this window] [in a new window]   Fig 2. Kaplan–Meier survival functions for posttransplant survival within each of the three eras stratified by cytomegalovirus (CMV) match status. (A) Group 2 (D+R–); (B) group 2 (DxR+); (C) group 3 (D–R–). 4-year incremental time periods for the 1991 to 2004 era. (D+ = donor CMV+; Dx = donor CMV+ or –; R– = recipient CMV–; R+ = recipient CMV+.)

Posttransplant Morbidity in the Current Era: Bronchiolitis Obliterans, Infection, and Rejection
Severe infection–FS was significantly different (p = 0.032) across groups, with D+R– (with median time to event = 698 days) < D±R+ (739 days) < D–R– (869 days; Fig 3). Conversely, severe rejection–FS did not differ significantly (p = 0.46) across the three groups. Likewise, BO-FS was not significantly different (p = 0.57) across the three groups; however, when stratified by GVP, recipients who received prophylaxis in the D±R+ (p < 0.001) and D+R– (p = 0.055) groups had significantly better BO-FS, whereas BO-FS in the D–R– group (p = .547) was not different on the basis of GVP status (Fig 4).

View larger version (19K): [in this window] [in a new window]   Fig 3. Kaplan–Meier survival functions for posttransplant bronchiolitis obliterans, infection, and rejection–free survival in the current era. (A) Bronchiolitis obliterans; (B) infection; (C) rejection. (D+ = donor cytomegalovirus +; Dx = donor cytomegalovirus + or –; R– = recipient cytomegalovirus –; R+ = recipient cytomegalovirus +.)

View larger version (16K): [in this window] [in a new window]   Fig 4. Kaplan–Meier survival functions for posttransplant bronchiolitis obliterans stratified by cytomegalovirus (CMV) match status and CMV prophylaxis. (A) Group I (D+R–); (B) group II (DxR+); (C) group III (D–R–). (D+ = donor CMV+; Dx = donor CMV+ or –; R– = recipient CMV–; R+ = recipient CMV+.)

	Comment

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Given the critical scarcity of organs available for transplantation, achieving maximal benefit from this therapy is predicated on optimal use of the donor pool. To this end, the risks and benefits associated with matching characteristics of donors and recipients must be better understood. Although early experience suggested poor outcomes in cases of CMV recipient–donor mismatch, significant advances in CMV prophylaxis have been widely reported. For example, Zamora and associates [11] reported no CMV infections, CMV-related disease, or CMV-related mortality among 60 lung transplant patients actively taking valganciclovir compared with 15%, 20%, and 1.4% incidence, respectively, in 140 patients taking acyclovir.

Findings presented here demonstrate that in the current era of aggressive ganciclovir-based CMV prophylaxis, CMV mismatching is not associated with worse posttransplant survival (Fig 1). This change with time resulted from improvements in survival among the D+R– and D±R+ groups, although survival in the D–R– group remained unchanged during the three eras (Fig 2).

The lack of long-term data regarding CMV prophylaxis makes it impossible to attribute these findings solely to more effective CMV-prophylactic strategies. In fact, it is possible that other factors, including improved patient selection, advances in operative techniques, and other advances in posttransplant management, explain these observations. In multivariable Cox proportional hazards regression, D+R– and D±R+ were associated with worse survival before 2000; however, in the current era there was no demonstrable relationship between these characteristics and survival while controlling for other factors. There was also a statistically significant interaction between CMV status and the era of transplantation in these analyses. Moreover, the observed improvement in survival was limited to D+R– and D±R+ groups and coincided with the U.S. Food and Drug Administration’s approval of valganciclovir in March 2001 as well as increased use of CMV prophylaxis. Therefore, it seems that more effective and aggressive CMV prophylaxis contributed to the observation that, in the current era, survival after lung transplant is equivalent regardless of CMV match status.

Posttransplant Morbidity: Rejection, Infection, and Bronchiolitis Obliterans
This study found no demonstrable relationship between CMV mismatch status and severe rejection–FS or BO-FS. Likewise, BO-FS did not differ by CMV match status. However, BO-FS was improved in recipients in the D+R– and D±R+ groups receiving GVP. Given previous studies demonstrating that CMV may be a risk factor for BO in lung transplantation patients, [4, 12, 13], this finding suggests that GVP may protect against the development of BO in cases with seropositive recipients or donors. However, in this study, D+R– had a significantly worse severe infection–FS. The explanation for this is outside of the scope of this study, but it may result from increased risk of CMV-related infection owing to CMV mismatch status. Unfortunately, detailed information regarding type of infection was not available.

Limitations
Patient registries often suffer from variability in data entry. However, fields contained within this database were generally well populated with a 95% to 99% data entry rate for the majority of variables; moreover, both the percentage of recipients and donors with CMV by serology [14] and survival [15] was similar to data reported in other studies, supporting the validity of these findings. Although the UNOS reporting system provided definitions for such complications as BO and rejection in data guidelines, definitions may vary by center.

Time-to-event analysis for BO-FS, severe rejection–FS, and severe infection–FS assumes that the event of interest is the only possible outcome. Therefore, if death occurred before this outcome, the patients were censored. As part of future studies we will perform analysis of competing outcomes to assess factors predicting long-term survival; this analysis was omitted here because it was outside the scope of this study.

Conclusion and Implications
In the current era, there is no demonstrable difference in survival after lung transplantation among CMV-mismatched recipients compared with other serologic combinations. These findings suggest that in this era of aggressive CMV prophylaxis, CMV mismatch does not confer greater posttransplant morbidity or mortality. Although in previous eras survival was worse among the D±R+ and D–R+ groups, in the current era, CMV mismatch should not be sufficient grounds to decline a lung allograft offer. However, further studies are needed to further optimize CMV prophylaxis in lung transplant recipients.

	Discussion

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DR SCOTT J. SWANSON (New York, New York): Excellent paper. One question that comes to mind is that the slope of those graphs doesn’t really change. You have sort of improved the outcome early. So do you think treating CMV differently affects OB and long-term rejection or not?

DR STERNBERG: Interesting question. To rephrase your question, does treating CMV affect BOS, there are more than a few reports that it probably does, and there is a putative molecular mechanism given as well, because infection may upregulate TNF-alpha and TNF-alpha may also be pivotal in BOS. So there may be a molecular mechanism that may be involved as well. I think it probably does.

DR SWANSON: I realize all that, but you would expect the slope of the graph to change, then, and it didn’t.

DR STERNBERG: Later or earlier?

DR SWANSON: At any point.

DR STERNBERG: Possibly.

DR MALCOLM M. DECAMP (Boston, Massachusetts): I enjoyed that very much. I hope you have closed the door on the controversy of CMV matching of donor and recipient. Can you comment on your strategy about CMV prophylaxis? When do you start it? Do you use a preemptive strategy or a purely prophylactic strategy? How often do you check the CMV viral loads, and do you manage the negative–negative patients with any CMV prophylaxis in your medical center?

DR STERNBERG: Thank you for the question. We use a prophylactic strategy. For Group 3, negative–negative patients, they are treated with Valcyte for up to a year. For Groups 1 and 2 patients, they get IV ganciclovir bid for 2 weeks, and then they get IV ganciclovir q-daily up until 3 months, and then they get switched to the valganciclovir up until a year, if they tolerate it. If there is a higher risk transplant, we also give CMV immunoglobulin pretransplant. They do get screened for a quantitative PCR, and I believe it’s every week or two.

	Acknowledgments

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We thank UNOS for supplying these data and Katarina Anderson, PhD, for her assistance with our analysis. This work was supported in part by Health Resources and Services Administration contract 231-00-0115. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mark J. Russo Alan J. Moskowitz Annetine C. Gelijns Frank D’Ovidio Joshua R. Sonett Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Russo, M. J. Articles by Sonett, J. R. Search for Related Content PubMed PubMed Citation Articles by Russo, M. J. Articles by Sonett, J. R. Related Collections Lung - transplantation