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Increased risk of PTLD in lung transplant recipients with cystic fibrosis
JCF-01471; No of Pages 8
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Increased risk of PTLD in lung transplant recipients with cystic fibrosis☆,☆☆ Erin M. Lowery a,b,⁎, William Adams b , Shellee A. Grim a , Nina M. Clark a , Leah Edwards c , Jennifer E. Layden a,b a
Department of Internal Medicine at Loyola University Medical Center, Maywood, IL, United States b Health Sciences Division, Loyola University Chicago, Maywood, IL, United States c United Network for Organ Sharing, United States Received 16 January 2017; revised 27 March 2017; accepted 28 March 2017 Available online xxxx
Abstract Background: Post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased risk of PTLD although the literature is limited to single center cohorts. Our primary aim is to examine PTLD in an adult lung transplant population by utilizing the International Society for Heart and Lung Transplantation Registry. Methods: We studied 30,598 adult recipients of lung transplants performed between 1999 and 2011. The primary outcome was development of and time to PTLD. In addition to indication for transplant, other predictors examined included Epstein–Barr virus (EBV) and cytomegalovirus (CMV) serostatus, gender, and age. Outcomes were assessed with univariable and multivariable Cox proportional hazard models to obtain hazard ratios (HR). Results: 17% of the cohort had a diagnosis of CF. PTLD developed in 2% of CF recipients compared to 1% for non-CF recipients (p b 0.001). Compared to non-CF recipients, CF recipients had higher prevalence of EBV and CMV seronegativity and higher prevalences of high risk EBV and CMV mismatch (D +/R −). There is a significant association between CF and the development of PTLD [HR 1.66 (95% CI 1.30–2.12)]. Stratified multivariable analysis controlling for age revealed EBV negative non-CF recipients have an almost 2 fold increased risk of developing PTLD, whereas EBV negative CF recipients had an almost 6.5 fold increased risk. Conclusions: CF recipients have a higher risk for PTLD compared to non-CF recipients. Further studies are needed to account for additional risk factors and management in this population post-transplant. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Post transplant lymphoproliferative disorder; Cystic fibrosis; Ebstein–Barr virus
Abbreviations: PTLD, Post-transplant lymphoproliferative disorder; CF, Cystic fibrosis; ISHLT, International Society of Heart and Lung Transplantation; EBV, Epstein–Barr virus; CMV, Cytomegalovirus; HR, Hazard ratios; CI, Confidence intervals. ☆ Dr. Lowery has no conflicts of interest. Mr. Adams has no conflicts of interest. Dr. Grim has no conflicts of interest. Dr. Clark has no conflicts of interest. Dr. Edwards has no conflicts of interest. Dr. Layden has no conflicts of interest. ☆☆ Sources of support: International Society of Heart and Lung Transplant Early Career Registry Award Presented April 2013, Montreal, Canada as an oral presentation at the international meeting of the International Society of Heart and Lung Transplantation: E.M. Lowery, S. Grim, E. Mahoney, R.B. Love, N. Clark, J.E. Layden. Increased Incidence of PTLD in Adult Lung Transplant recipients with cystic fibrosis: analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Trans April 2013 32(4):s145. ⁎ Corresponding author at: Loyola University Medical Center, Department of Internal Medicine, Division of Pulmonary/Critical, Care, 2160 S. First Ave, CTRE Building 115, Room 316, Maywood, IL 60153, United States. E-mail address: [email protected] (E.M. Lowery).
http://dx.doi.org/10.1016/j.jcf.2017.03.013 1569-1993/© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
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E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
1. Introduction Post-transplant lymphoproliferative disorder (PTLD), a spectrum of abnormal lymphoid proliferation occurring after transplant, is a devastating cause of morbidity and mortality following lung transplantation [1]. This potentially life-threatening complication of transplantation represents a heterogeneous group of disorders that vary in clinical manifestations, morphology, and response to treatment. Previously implicated risk factors for PTLD after lung transplant include Epstein–Barr virus (EBV) seronegativity at the time of transplant, cytomegalovirus (CMV) seronegativity at the time of transplant, young patient age, and intensity of immunosuppression [2,3]. The reported prevalence of PTLD in adult lung transplant recipients is 2–5%, [2,4–8] and is even higher in pediatric lung transplant recipients at 13–14%, [9,10] substantially higher than the reported 0.6–2% prevalence of PTLD in other solid organ transplant recipients [3,11–13]. Lung transplant recipients with cystic fibrosis (CF) may have an increased incidence of PTLD as reported by three single center investigations [9,14,15]. Jaksch et al. described their single center experience with 1157 patients in which 3.6% of CF patients and 1.2% of non-CF patients developed PTLD, concluding that CF as an underlying disease was found to be an independent risk factor for developing PTLD [15]. Saueressig et al. examined a cohort of 93 lung transplant recipients with CF in which they observed 8.6% developed PTLD [14]. Cohen et al. examined the incidence in a pediatric population and found that 9.2% of patients with CF developed PTLD following lung transplantation [9]. In the latter 2 studies, however, direct comparisons to non-CF populations were not attempted and limit the findings. Risk factors identified in the CF population in these two investigations included negative serostatus for EBV and human herpes viruses 1–3, 6 and 8 in recipients [14], and episodes of acute rejection in the first 3 months following transplantation [9]. Given the limited number of patients in these cohort studies, assessment of additional risk factors in the CF population was difficult and may not have captured all possible factors. Negative EBV serostatus in a recipient at the time of transplantation is a well-described risk factor for the development of PTLD, particularly if the allograft is from an EBV positive donor [11,16,17], The prevalence of EBV seronegativity and its risk for development of PTLD in patients with CF has not been well documented. It is expected, however, that CF populations have higher rates of EBV seronegativity due to lower mean age at the time of transplantation. This may in part explain the reported higher rate of PTLD. The objective of this study was to examine the impact of CF status and other previously studied risk factors on the development of PTLD post lung transplantation. Using an international data registry, we compared the rates of PTLD in lung transplant recipients with and without CF, and identified risk factors associated with the development of PTLD. 2. Methods 2.1. Study population and design We analyzed registry data provided by the International Society of Heart and Lung Transplantation (ISHLT), an international data
repository that collects longitudinal information on the worldwide thoracic organ transplant experience. Information on donor-recipient pairs is captured at the time of transplant, and recipients' data are reported for the duration of the recipient's life. We retrospectively examined all adolescents and adults (aged ≥ 12 years) who received their initial lung transplant between 1999 and 2010, with follow-up data through September 2011. Excluded from the analysis were re-transplant events, those with no recorded indication for lung transplant, those with no follow-up data, and those younger than 12 years of age. This study was approved by the Loyola University Chicago institutional review board LU203828. 2.2. Primary end points and co-variables The primary end point of interest was the development of and time to PTLD post-transplantation, with the primary independent variable of interest being CF status. At each follow-up time period, every 12 months, diagnosis of PTLD is recorded as yes/no. Because the date of diagnosis is not reported, time to PTLD was estimated as median point between the date of the annual follow-up report when the patient was PTLD negative and the date of the annual follow-up report at which PTLD positive status was first recorded. Those without reported PTLD were considered PTLD free for the duration of their follow-up. As confounders or effect modifiers, we considered donor, recipient, and transplant specific variables based on clinical relevance and results from prior studies. 2.3. Statistical analyses Analyses and figures were generated using SAS/STAT version 9.4 (SAS Institute Inc., Cary, NC). Data were assessed for outliers and erroneous data entry. For nominal comparisons, Pearson chi-square tests were used to assess differences between those with CF and those without CF, and the independent t-test was used for continuous comparisons; when necessary, a Satterthwaite correction was applied to correct for heterogeneity [18]. Additionally, the linearity of age with the natural logarithm of CF status and with the natural logarithm of PTLD status was also assessed using a Hosmer and Lemeshow goodness of fit test [19]. Univariable and multivariable Cox proportional hazards models were used to analyze time to PTLD as a function of patient demographics and comorbidities. For each model, the proportional hazards assumption was evaluated graphically using martingale residuals as described by Lin et al. [20] Kaplan–Meier survival curves were generated to graphically depict cumulative PTLD-free probability curves. Statistical significance was considered if p b 0.05. Several relevant variables had a significant proportion of missing data, particularly the EBV status of recipients and donors and induction immunosuppression. While recipient EBV serostatus was widely available from 1999 through 2011, donor EBV serostatus was largely unavailable from 1999 through 2003. Therefore, models comprising recipient EBV data included all transplant years whereas models comprising EBV mismatch information included only transplant years with available donor
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
data (2004–2011). Regarding analyses focused on the effect of induction immunosuppression, the data for alemtuzumab were unavailable before 2003 while data for the other induction immunosuppression agents were available for all transplant years. To assess the sensitivity and impact of missing data, we attempted multiple iterations of the multivariable analyses. For example, to examine the effect of EBV serostatus we ran analyses using only recipient EBV status as well as analyses incorporating both donor and recipient serostatus. We also ran sensitivity analyses that set all missing data to either negative or positive to further assess the issue of missing data and we did not detect any changes in our conclusions. 3. Results 3.1. Study cohort We examined 30,598 lung transplant recipients receiving their first lung transplant between the years 1999–2010. Forty-nine were excluded as no primary pulmonary diagnosis was recorded, 60 had no follow-up data, and 314 were excluded for age b 12. Therefore, the cohort included 30,175 lung transplant recipients. 17% (5218) had a diagnosis of CF and 83% (24,957) had a pulmonary diagnosis other than CF as an indication for lung
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transplantation. Clinical characteristics of the study cohort by CF status are described in Table 1a. PTLD occurred in 2% (89) of the CF population compared to 1% (241) in the non-CF group, p b 0.001. Table 1b displays the characteristics of the recipients who developed PTLD. CF recipients more often received bilateral lung transplant, were significantly younger than non-CF recipients (mean age 24 vs 55, p b 0.001) and were more often EBV and CMV seronegative. As expected, the CF recipients were younger than the non-CF recipients with PTLD (p b 0.001). In fact, a test for the linearity of age with cystic fibrosis status revealed a significant non-linear relationship. As recipient age increases, the probability of CF quickly diminishes to zero (likely due to the competing risk of early mortality in the CF population; p b .001). Among those with PTLD, CMV recipient seronegativity was also higher in the CF group, 68% compared to 46% in the non-CF group (p = 0.001). EBV seronegative recipients were also much higher in the CF group, 78% compared to the Non-CF group, 42% (p b 0.001). 3.2. Risk for PTLD Table 2 displays the univariable Cox regression HR for time to PTLD development. At any given time, the hazard risk of developing PTLD were approximately 66% higher in the
Table 1a Overall study demographics.
PTLD Mean months to PTLD or last follow-up (SD) Double lung transplant Transplant Year 1999–2004 2005–2011 Mean age (SD) Recipient Donor Gender (Male) Recipient Donor Cytomegalovirus (CMV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Epstein–Barr Virus (EBV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Induction medications Interleukin-2 receptor (IL-2Ra) Antithymocyte globulin Muromonab-CD3 (OKT3) Alemtuzumab Maintenance medications during initial transplant hospitalization Tacrolimus Cyclosporine Mycophenolate mofetil Azathioprine Tacrolimus or Cyclosporine or Both Mycophenolate mofetil or Azathioprine or both
Non-CF n = 24,957 (83%)
CF n = 5218 (17%)
Total N = 30,175 (100%)
p
241/24957 (1.0%) 36.29 (35.27) 14,493/24949 (58%)
89/5218 (1.7%) 39.26 (36.79) 5131/5216 (98%)
330/30175 (1.1%) 36.80 (35.56) 19,624/30165 (65%)
b .001 b .001 b .001 .04
8928/24957 (36%) 16,029/24957 (64%)
1944/3338 (37%) 3274/5218 (63%)
10,872/30175 (36%) 19,303/30175 (64%)
53.52 (10.93) 36.83 (14.87)
28.44 (9.63) 33.72 (14.66)
49.18 (14.31) 36.29 (14.88)
b .001 b .001
13,981/24957 (56%) 14,292/24888 (57%)
2650/5217 (51%) 2656/5205 (51%)
16,631/30174 (55%) 16,948/30093 (56%)
b .001 b .001
5442/13523 (40%) 9086/15031 (60%) 3144/13420 (23%)
1486/2324 (64%) 1575/2732 (58%) 810/2299 (35%)
6928/15847 (44%) 10,661/17763 (60%) 3954/15719 (25%)
b .001 .01 b .001
3584/13432 (27%) 5816/6260 (93%) 1413/6101 (23%)
795/2317 (34%) 885/960 (92%) 289/935 (31%)
4379/15749 (28%) 6701/7220 (93%) 1702/7036 (24%)
b .001 .42 b .001
5158/16916 (31%) 1813/16916 (11%) 117/16916 (0.7%) 690/12201 (5.7%)
929/3115 (30%) 364/3115 (12%) 14/3115 (0.4%) 81/2220 (3.6%)
6087/20031 (30%) 2177/20031 (11%) 131/20031 (0.7%) 771/14421 (5.3%)
.46 .11 .12 b .001
10,586/16358 (65%) 5156/16358 (32%) 9186/16629 (55%) 5991/16629 (36%) 16,300/16916 (96%) 15,464/16916 (91%)
1922/2972 (65%) 991/2972 (33%) 1674/3077 (54%) 1171/3077 (38%) 3056/3115 (98%) 2883/3115 (93%)
12,508/19330 (65%) 6147/19330 (32%) 10,860/19706 (55%) 7162/19706 (36%) 19,356/20031 (97%) 18,347/20031 (92%)
.96 .049 .39 .03 b .001 .04
Note: PTLD = Post-transplant lymphoproliferative disorder. CF = Cystic fibrosis. Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
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E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
Table 1b Overall study demographics among patients with PTLD.
Mean months to PTLD (SD) Double lung transplant Transplant Year 1999–2004 2005–2011 Mean age (SD) Recipient Donor Gender (Male) Recipient Donor Cytomegalovirus (CMV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Epstein–Barr Virus (EBV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Induction medications Interleukin-2 receptor antagonist (IL-2Ra) Antithymocyte globulin Muromonab-CD3 (OKT3) Alemtuzumab Maintenance medications during initial transplant hospitalization Tacrolimus Cyclosporine Mycophenolate mofetil Azathioprine Tacrolimus or Cyclosporine or Both Mycophenolate mofetil or Azathioprine or Both
Non-CF n = 241 (73%)
CF n = 89 (27%)
Total N = 330 (100%)
p
24.42 (28.38) 125/241 (52%)
20.51 (26.90) 89/89 (100%)
23.37 (28.00) 214/330 (64%)
.26 b .001 .86
130/241 (54%) 111/241 (46%)
47/89 (53%) 42/89 (47%)
177/330 (54%) 153/330 (46%)
55.21 (11.42) 31.95 (13.75)
24.08 (7.78) 27.47 (13.68)
46.82 (17.40) 30.74 (13.85)
b .001 .01
148/241 (61%) 165/241 (69%)
40/89 (45%) 44/89 (49%)
188/330 (57%) 209/330 (63%)
.01 .001
107/231 (46%) 134/240 (56%) 57/231 (25%)
57/84 (68%) 48/89 (54%) 29/84 (35%)
164/315 (52%) 182/329 (55%) 86/315 (27%)
.001 .76 .08
92/219 (42%) 66/80 (83%) 34/79 (43%)
64/82 (78%) 24/25 (96%) 20/24 (83%)
156/301 (52%) 90/105 (86%) 54/103 (52%)
b .001 .11 .001
51/238 (21%) 49/238 (21%) 8/238 (3.4%) 12/141 (8.5%)
33/88 (38%) 12/88 (14%) 3/88 (3.4%) 1/51 (2.0%)
84/326 (26%) 61/326 (19%) 11/326 (3.4%) 13/192 (6.8%)
.003 .15 .99 .19
140/234 (60%) 91/234 (39%) 109/236 (46%) 101/236 (43%) 235/238 (99%) 212/238 (89%)
50/85 (59%) 35/85 (41%) 42/85 (49%) 37/85 (44%) 88/88 (100%) 82/88 (93%)
190/319 (60%) 126/319 (40%) 151/321 (47%) 138/321 (43%) 323/326 (99%) 294/326 (90%)
.87 .71 .61 .91 .57 .27
Note: PTLD = Post-transplant lymphoproliferative disorder. CF = Cystic fibrosis.
CF group than in the non-CF group (HR = 1.66, 95% CI 1.30–2.12; p b 0.001). Recipients with EBV primary mismatch had the highest risk of developing PTLD at any given time with HR 3.47 (95% CI 2.35–5.10), p b 0.001. Fig. 1 depicts the Kaplan–Meier curve for development of PTLD according to CF status. Multivariable Cox regression analyses are described in Table 3. Four models were calculated by stratifying for both CF and non-CF recipients, which was necessary because of significant interactions between the CF status, age, and EBV serostatus. In the CF population, increasing age was associated with a decreased risk of PTLD, HR 0.94 per year of age (95% CI 0.91–0.96; p b 0.001), whereas age was not significantly associated with the development of PTLD in the non-CF group (p = 0.21). Recipient EBV seronegative status was significantly associated with PTLD development in both the CF and non-CF populations (both p b 0.001), though the magnitude of the effect varied. More specifically, in the non-CF population the HR was 1.92 (95% CI 1.47–2.51), but in the CF population the risk of PTLD at any given time in EBV seronegative recipients was over 3 times higher with HR 6.4 (95% CI 3.79–10). EBV status was considered two different ways due to significant missing data as described in the Methods section.
In Table 3, models 1 and 3 considered EBV seronegative recipients, whereas in Models 2 and 4 we used EBV donor positive/recipient seronegative constituting the high-risk combination. In this analysis, the same association for age was found, in that increasing age was protective in the CF population (p = 0.01), but not significant in the non-CF population (p = 0.55). Regarding the risk of developing PTLD in the high risk group of EBV mismatch, the non-CF recipients had an over 2-fold increased risk of developing PTLD at any given time (HR 2.49; 95% CI 1.60–3.90), and the CF population had an almost 10-fold increased risk of developing PTLD (HR 9.85; 95% CI 3.35–29.01). We additionally ran the same multivariable analyses but included use of induction immunosuppression medications. When doing so, induction immunosuppression was not significantly associated with PTLD, and the same associations held true for age and EBV serostatus (data not shown). We also ran models incorporating lung transplant era (1999–2004; 2005–2011), though transplant era did not significantly change the risk of developing PTLD and did not change the associations presented above for age and EBV status. Fig. 2A and B depict the cumulative PTLD-free curves for these cohorts, stratified by CF status, and show the impact of EBV recipient serostatus.
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 2 Univariable Cox regression hazards for time to post-transplant lymphoproliferative disorder (PTLD). HR Double lung transplant (Ref = Single lung transplant) Cystic fibrosis (Ref = Non-CF) Transplant year 1999–2004 (Ref = 2005–2011) Age Recipient Donor Gender (Ref = Female) Recipient Donor Cytomegalovirus serostatus Recipient negative (Ref = CMV IgG positive) Donor negative (Ref = CMV IgG positive) High risk (D+/R− versus all other combinations) Epstein–Barr Virus serostatus Recipient EBV IgG negative (Ref = EBV IgG Positive) Donor Negative (Ref = EBV IgG positive) High Risk (D+/R− versus all other combinations) Induction Medications (Ref = No induction medication) Interleukin-2 receptor antagonist (IL-2Ra) Antithymocyte globulin Muromonab-CD3 (OKT3) Alemtuzumab Initial maintenance medications Cyclosporine (Ref = Tacrolimus) Azathioprine (Ref = Mycophenolate mofetil)
95% CI
.54 b .001 .03
0.99 0.98–0.99 0.98 0.97–0.99
.01 b .001
1.14 0.92–1.42 1.30 1.04–1.63
.24 .02
1.42 1.14–1.78 1.14 0.92–1.42 1.19 0.93–1.53
.002 .23 .17
2.74 2.18–3.43
b.001
2.03 1.18–3.51 3.47 2.35–5.10
.01 b .001
0.78 1.68 4.86 1.31
.054 b.001 b .001 .35
0.61–1.004 1.27–2.21 2.66–8.87 0.74–2.30
1.23 0.98–1.55 1.16 0.92–1.47
.07 .20
Note: HR = Hazard ratio. CI = confidence interval for the estimate.
4. Discussion This is the first study designed to evaluate PTLD following lung transplant in cystic fibrosis recipients utilizing a large
Fig. 1. Cumulative PTLD-free curves by cystic-fibrosis status.
Table 3 Multivariable Cox regression models for time to post-transplant lymphoproliferative disorder (PTLD), stratified by cystic fibrosis status.
p
1.07 0.86–1.35 1.66 1.30–2.12 1.30 1.03–1.63
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HR (95% CI) Non-cystic fibrosis Model 1 Age Recipient EBV IgG negative (ref: EBV IgG positive) Model 2 Age High risk EBV (versus all other combinations) Cystic fibrosis Model 3 Age Recipient EBV IgG negative (ref: EBV IgG positive) Model 4 Age High risk EBV (versus all other combinations)
p
1.01 (0.99–1.02) .21 1.92 (1.47–2.51) b.001
0.99 (0.98–1.01) .55 2.49 (1.60–3.90) b.001 0.94 (0.91–0.96) b.001 6.40 (3.79–10.82) b.001
0.93 (0.88–0.99) .01 9.85 (3.35–29.01) b.001
Note: HR = Hazard ratio. CI = confidence interval for the estimate. High risk EBV is defined as donor positive and recipient negative. For both strata, the interaction of age and EBV IgG Negative was not significant. For the cystic fibrosis stratum, the interaction of age and High Risk EBV status was not significant.
international transplant database. There are three major findings. First, there is a higher risk of PTLD in the CF population following lung transplantation compared to lung transplant recipients with other pulmonary diagnoses. There also is a higher occurrence of recipient EBV and CMV seronegativity in the CF population at the time of transplantation compared to the non-CF population. Not surprisingly then, there is also a higher rate of EBV and CMV primary mismatch in this population. Third, in addition to CF status, age and EBV serostatus remained significantly associated with PTLD post lung transplantation in multivariable analyses. However, the association varied across CF status. For the CF population, increasing age was protective for the development of PTLD, while there was no significant association observed in the non-CF population. For both CF and non-CF, EBV recipient seronegativity as well as EBV mismatch were both highly associated with PTLD, but with varied levels of risk. The highest rates of PTLD occurred in lung transplant recipients who had CF and were EBV seronegative. In this investigation we found a relatively low prevalence of PTLD in both the CF and non-CF populations compared to previously reported studies [2,4–10]. The occurrence we observed in lung transplant recipients is more aligned with reported prevalence of PTLD in other solid organ transplants [3,11–13]. This difference may be due to inconsistencies in reporting and definitions used for PTLD. The international data registry is not designed to specifically look at PTLD, and thus may not capture all PTLD cases. Studies specifically designed to assess for PTLD may identify higher rates due to better case ascertainment and reporting. Despite this difference, the same association with EBV, and risk for EBV seronegative and EBV mismatch recipients to develop PTLD was observed. This is the first study, however, to examine the association of EBV
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
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E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
Fig. 2. A. Cumulative PTLD-free curves by EBV IgG status for non-cystic fibrosis subjects. B. Cumulative PTLD-free curves by EBV IgG status for cystic fibrosis subjects.
serostatus across CF/non-CF status. EBV negative serostatus, and EBV mismatch carried a much greater risk in the CF population compared to the non-CF population. The reason for this difference is unclear. In a recent review of infections in CF patients undergoing lung transplant, the question of a genetic predisposition to lymphoma in the setting of immunosuppression following transplant was raised [21]. Supporting this theory is an investigation utilizing patient registry data from the Cystic Fibrosis Foundation where Maisonneuve et al. observed an increase in lymphoid leukemia in non-transplant cystic fibrosis patients compared to what would be expected in the general population [22]. Further investigation into the mechanisms and interactions of EBV, CF transmembrane receptor mutations and the increased risk of lymphoid leukemia and PTLD in CF patients are necessary. In this investigation we found a higher prevalence of EBV and CMV seronegativity in CF recipients. This may be related to the significant differences in the ages of the two populations. Infection with EBV affects 90% of the world's population, with immunity to EBV present in the majority of adults [23]. In this study, both CF and non-CF transplant recipients had lower seroimmunity to EBV. There may be reporting errors if the EBV serostatus inputted into the registry is that from initiation of the lung transplant evaluation, as opposed to the EBV serostatus at the actual time of the transplant, with spontaneous seroconversion in the interim interval. If this is true, one would expect this to drive the HR to the null, which is not what was observed. One common hypothesis for negative viral serologies in CF patients is that young people with CF are shielded from viral exposures from other children and thus are persistently seronegative, but this has not been firmly established. The decrease in CMV seropositivity also seen in the CF population in this investigation would support this theory. 80% of all PTLD arises from B-cell proliferation induced by EBV [24].
EBV seronegativity is a well-known risk factor for subsequent development of PTLD [17,25,26]. EBV vaccine studies have been pursued and while some candidate vaccines are immunogenic in healthy volunteers and even in children with chronic kidney disease, they have thus far been ineffective in protecting against EBV infection [27–30]. Also striking in this investigation among the patients who developed PTLD, 78% of the CF recipients were EBV recipient seronegative, whereas only 42% of non-CF recipients were EBV seronegative. Perhaps a greater percentage of non-CF recipients develop non-EBV-related PTLD, a hypothesis which would need additional data and further investigation. Data from this study, as well as others, raises the issues of prevention and surveillance for PTLD, especially in light of the significant morbidity and mortality attributed to this posttransplant complication. This investigation found that younger, EBV seronegative CF recipients are at the highest risk for PTLD. We calculated conditional probabilities of PTLD at 12 and 24 months post-transplant and noted that a hypothetical adolescent non-CF patient may have a 6.2% and 8.9% probability of PTLD respectively, whereas a CF patient would have a 12.8% and 13.7% probability, respectively (data not shown). Since developing a predictive model was not the main aim of our investigation, pursuit of this would be a relevant investigation, as a predictive model may help lung transplant centers guide surveillance efforts for PTLD. Surveillance of these high risk patients by monitoring for clinical signs and symptoms of EBV as well as following EBV viral loads is recommended, particularly in the first year following transplant [31–33]. Adult lung transplant recipients whose immunosuppression was adjusted guided by EBV viral load had a low incidence of developing PTLD [34]. Prophylaxis for PTLD is more controversial. A large multicenter retrospective investigation of anti-CMV immunoglobulin prophylaxis in kidney
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
transplant recipients showed a reduced incidence of early PTLD [35]. This effect was also seen in a single center cohort of lung transplant recipients [15]. Treatment with valganciclovir reduced EBV primary infection and viremia in EBV seronegative pediatric renal recipients [36]. Several investigations have looked at treatment of increasing EBV viral loads with rituximab with some successful results in preventing PTLD [37]. Despite these investigations, prevention and surveillance for PTLD are still areas of great uncertainty that need further study. The strength of this study is the use of a multi-center, large database to compare rates of PTLD post transplantation. There are, however, limitations. Data on EBV serostatus were not collected by the registry until 2006 in the U.S. and 2011 internationally. The rate of missing data, especially for pertinent variables such as immunosuppression and rejection limits a comprehensive assessment of risk factors. We did run sub-analyses for serologic status numerous ways and found consistent results regardless of the method used. Further, we ran sub-analyses including immunosuppression regimens which failed to find any strong association between induction/ maintenance regimens and PTLD in multivariable models. However, such analyses have to be viewed with caution given the amount of missing data. Single center studies performed at high volume centers, such as that performed by Kumarasinghe et al. and Shyu et al., are able to more accurately assess information such as induction/maintenance regimens, rejection episodes and histopathology outcome data in PTLD and as such, Shyu et al. did not observe an association between type of induction immunosuppression and development of PTLD [38,39]. As registry data accumulates over time, a more accurate collection of this particular information may allow for further studies specifically accounting for both induction and maintenance therapy to properly assess the risk of varied agents on the development of PTLD. In conclusion, this analysis is the largest to date on PTLD in lung transplant recipients, and the only investigation to utilize a large international database. CF recipients were found to have a higher risk for PTLD compared to non-CF recipients. Recipient EBV seronegative status and EBV mismatch are associated with PTLD in both populations. Increasing age, however, is protective against PTLD, but only in the CF population. Further studies are needed to account for other potential risk factors, especially the role of immunosuppression and rejection treatment. Such studies will help identify individuals at greatest risk for this important post-transplant complication. Author contributions EL had access to the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. EL was involved in the conceptualization of the study, analyzed the results and wrote the first draft of the manuscript. EL, SG, LE, WA, NC, JL were involved in the statistical analysis of the data and study design. JL, WA, NC, EL were involved in the conceptualization of the study, provided intellectual input and made substantial contributions to the manuscript.
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Acknowledgments International Society of Heart and Lung Transplant which supported this work with an Early Career Registry Award. References [1] Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Dobbels F, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report2012. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2012; 31:1073–86. [2] Glotz D, Chapman JR, Dharnidharka VR, Hanto DW, Castro MC, Hirsch HH, et al. The Seville expert workshop for progress in posttransplant lymphoproliferative disorders. Transplantation 2012;94:784–93. [3] Mynarek M, Schober T, Behrends U, Maecker-Kolhoff B. Posttransplant lymphoproliferative disease after pediatric solid organ transplantation. Clinical & developmental immunology 2013;2013:814973. [4] Ramalingam P, Rybicki L, Smith MD, Abrahams NA, Tubbs RR, Pettay J, et al. Posttransplant lymphoproliferative disorders in lung transplant patients: the Cleveland Clinic experience. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2002;15:647–56. [5] Reams BD, McAdams HP, Howell DN, Steele MP, Davis RD, Palmer SM. Posttransplant lymphoproliferative disorder: incidence, presentation, and response to treatment in lung transplant recipients. Chest 2003;124: 1242–9. [6] Kremer BE, Reshef R, Misleh JG, Christie JD, Ahya VN, Blumenthal NP, et al. Post-transplant lymphoproliferative disorder after lung transplantation: a review of 35 cases. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2012;31:296–304. [7] Wudhikarn K, Holman CJ, Linan M, Blaes AH, Dunitz JM, Hertz ME, et al. Post-transplant lymphoproliferative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota. Clinical transplantation 2011;25:705–13. [8] Wigle DA, Chaparro C, Humar A, Hutcheon MA, Chan CK, Keshavjee S. Epstein-Barr virus serology and posttransplant lymphoproliferative disease in lung transplantation. Transplantation 2001;72:1783–6. [9] Cohen AH, Sweet SC, Mendeloff E, Mallory Jr GB, Huddleston CB, Kraus M, et al. High incidence of posttransplant lymphoproliferative disease in pediatric patients with cystic fibrosis. American journal of respiratory and critical care medicine 2000;161:1252–5. [10] Elidemir O, Kancherla BS, Schecter MG, McKenzie ED, Morales DL, Heinle JS, et al. Post-transplant lymphoproliferative disease in pediatric lung transplant recipients: recent advances in monitoring. Pediatric transplantation 2009;13:606–10. [11] Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI. Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. Current oncology reports 2010;12: 383–94. [12] Ibrahim HA, Naresh KN. Posttransplant lymphoproliferative disorders. Advances in hematology 2012;2012:230173. [13] Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2004;4:222–30. [14] Saueressig MG, Boussaud V, Amrein C, Guillemain R, Souilamas J, Souilamas R. Risk factors for post-transplant lymphoproliferative disease in patients with cystic fibrosis. Clinical transplantation 2011; 25:E430–6. [15] Jaksch P, Wiedemann D, Kocher A, Murakozy G, Augustin V, Klepetko W. Effect of cytomegalovirus immunoglobulin on the incidence of lymphoproliferative disease after lung transplantation: single-center experience with 1157 patients. Transplantation 2013;95:766–72.
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Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Increased risk of PTLD in lung transplant recipients with cystic fibrosis☆,☆☆ Erin M. Lowery a,b,⁎, William Adams b , Shellee A. Grim a , Nina M. Clark a , Leah Edwards c , Jennifer E. Layden a,b a
Department of Internal Medicine at Loyola University Medical Center, Maywood, IL, United States b Health Sciences Division, Loyola University Chicago, Maywood, IL, United States c United Network for Organ Sharing, United States Received 16 January 2017; revised 27 March 2017; accepted 28 March 2017 Available online xxxx
Abstract Background: Post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased risk of PTLD although the literature is limited to single center cohorts. Our primary aim is to examine PTLD in an adult lung transplant population by utilizing the International Society for Heart and Lung Transplantation Registry. Methods: We studied 30,598 adult recipients of lung transplants performed between 1999 and 2011. The primary outcome was development of and time to PTLD. In addition to indication for transplant, other predictors examined included Epstein–Barr virus (EBV) and cytomegalovirus (CMV) serostatus, gender, and age. Outcomes were assessed with univariable and multivariable Cox proportional hazard models to obtain hazard ratios (HR). Results: 17% of the cohort had a diagnosis of CF. PTLD developed in 2% of CF recipients compared to 1% for non-CF recipients (p b 0.001). Compared to non-CF recipients, CF recipients had higher prevalence of EBV and CMV seronegativity and higher prevalences of high risk EBV and CMV mismatch (D +/R −). There is a significant association between CF and the development of PTLD [HR 1.66 (95% CI 1.30–2.12)]. Stratified multivariable analysis controlling for age revealed EBV negative non-CF recipients have an almost 2 fold increased risk of developing PTLD, whereas EBV negative CF recipients had an almost 6.5 fold increased risk. Conclusions: CF recipients have a higher risk for PTLD compared to non-CF recipients. Further studies are needed to account for additional risk factors and management in this population post-transplant. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Post transplant lymphoproliferative disorder; Cystic fibrosis; Ebstein–Barr virus
Abbreviations: PTLD, Post-transplant lymphoproliferative disorder; CF, Cystic fibrosis; ISHLT, International Society of Heart and Lung Transplantation; EBV, Epstein–Barr virus; CMV, Cytomegalovirus; HR, Hazard ratios; CI, Confidence intervals. ☆ Dr. Lowery has no conflicts of interest. Mr. Adams has no conflicts of interest. Dr. Grim has no conflicts of interest. Dr. Clark has no conflicts of interest. Dr. Edwards has no conflicts of interest. Dr. Layden has no conflicts of interest. ☆☆ Sources of support: International Society of Heart and Lung Transplant Early Career Registry Award Presented April 2013, Montreal, Canada as an oral presentation at the international meeting of the International Society of Heart and Lung Transplantation: E.M. Lowery, S. Grim, E. Mahoney, R.B. Love, N. Clark, J.E. Layden. Increased Incidence of PTLD in Adult Lung Transplant recipients with cystic fibrosis: analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Trans April 2013 32(4):s145. ⁎ Corresponding author at: Loyola University Medical Center, Department of Internal Medicine, Division of Pulmonary/Critical, Care, 2160 S. First Ave, CTRE Building 115, Room 316, Maywood, IL 60153, United States. E-mail address: [email protected] (E.M. Lowery).
http://dx.doi.org/10.1016/j.jcf.2017.03.013 1569-1993/© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
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1. Introduction Post-transplant lymphoproliferative disorder (PTLD), a spectrum of abnormal lymphoid proliferation occurring after transplant, is a devastating cause of morbidity and mortality following lung transplantation [1]. This potentially life-threatening complication of transplantation represents a heterogeneous group of disorders that vary in clinical manifestations, morphology, and response to treatment. Previously implicated risk factors for PTLD after lung transplant include Epstein–Barr virus (EBV) seronegativity at the time of transplant, cytomegalovirus (CMV) seronegativity at the time of transplant, young patient age, and intensity of immunosuppression [2,3]. The reported prevalence of PTLD in adult lung transplant recipients is 2–5%, [2,4–8] and is even higher in pediatric lung transplant recipients at 13–14%, [9,10] substantially higher than the reported 0.6–2% prevalence of PTLD in other solid organ transplant recipients [3,11–13]. Lung transplant recipients with cystic fibrosis (CF) may have an increased incidence of PTLD as reported by three single center investigations [9,14,15]. Jaksch et al. described their single center experience with 1157 patients in which 3.6% of CF patients and 1.2% of non-CF patients developed PTLD, concluding that CF as an underlying disease was found to be an independent risk factor for developing PTLD [15]. Saueressig et al. examined a cohort of 93 lung transplant recipients with CF in which they observed 8.6% developed PTLD [14]. Cohen et al. examined the incidence in a pediatric population and found that 9.2% of patients with CF developed PTLD following lung transplantation [9]. In the latter 2 studies, however, direct comparisons to non-CF populations were not attempted and limit the findings. Risk factors identified in the CF population in these two investigations included negative serostatus for EBV and human herpes viruses 1–3, 6 and 8 in recipients [14], and episodes of acute rejection in the first 3 months following transplantation [9]. Given the limited number of patients in these cohort studies, assessment of additional risk factors in the CF population was difficult and may not have captured all possible factors. Negative EBV serostatus in a recipient at the time of transplantation is a well-described risk factor for the development of PTLD, particularly if the allograft is from an EBV positive donor [11,16,17], The prevalence of EBV seronegativity and its risk for development of PTLD in patients with CF has not been well documented. It is expected, however, that CF populations have higher rates of EBV seronegativity due to lower mean age at the time of transplantation. This may in part explain the reported higher rate of PTLD. The objective of this study was to examine the impact of CF status and other previously studied risk factors on the development of PTLD post lung transplantation. Using an international data registry, we compared the rates of PTLD in lung transplant recipients with and without CF, and identified risk factors associated with the development of PTLD. 2. Methods 2.1. Study population and design We analyzed registry data provided by the International Society of Heart and Lung Transplantation (ISHLT), an international data
repository that collects longitudinal information on the worldwide thoracic organ transplant experience. Information on donor-recipient pairs is captured at the time of transplant, and recipients' data are reported for the duration of the recipient's life. We retrospectively examined all adolescents and adults (aged ≥ 12 years) who received their initial lung transplant between 1999 and 2010, with follow-up data through September 2011. Excluded from the analysis were re-transplant events, those with no recorded indication for lung transplant, those with no follow-up data, and those younger than 12 years of age. This study was approved by the Loyola University Chicago institutional review board LU203828. 2.2. Primary end points and co-variables The primary end point of interest was the development of and time to PTLD post-transplantation, with the primary independent variable of interest being CF status. At each follow-up time period, every 12 months, diagnosis of PTLD is recorded as yes/no. Because the date of diagnosis is not reported, time to PTLD was estimated as median point between the date of the annual follow-up report when the patient was PTLD negative and the date of the annual follow-up report at which PTLD positive status was first recorded. Those without reported PTLD were considered PTLD free for the duration of their follow-up. As confounders or effect modifiers, we considered donor, recipient, and transplant specific variables based on clinical relevance and results from prior studies. 2.3. Statistical analyses Analyses and figures were generated using SAS/STAT version 9.4 (SAS Institute Inc., Cary, NC). Data were assessed for outliers and erroneous data entry. For nominal comparisons, Pearson chi-square tests were used to assess differences between those with CF and those without CF, and the independent t-test was used for continuous comparisons; when necessary, a Satterthwaite correction was applied to correct for heterogeneity [18]. Additionally, the linearity of age with the natural logarithm of CF status and with the natural logarithm of PTLD status was also assessed using a Hosmer and Lemeshow goodness of fit test [19]. Univariable and multivariable Cox proportional hazards models were used to analyze time to PTLD as a function of patient demographics and comorbidities. For each model, the proportional hazards assumption was evaluated graphically using martingale residuals as described by Lin et al. [20] Kaplan–Meier survival curves were generated to graphically depict cumulative PTLD-free probability curves. Statistical significance was considered if p b 0.05. Several relevant variables had a significant proportion of missing data, particularly the EBV status of recipients and donors and induction immunosuppression. While recipient EBV serostatus was widely available from 1999 through 2011, donor EBV serostatus was largely unavailable from 1999 through 2003. Therefore, models comprising recipient EBV data included all transplant years whereas models comprising EBV mismatch information included only transplant years with available donor
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
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data (2004–2011). Regarding analyses focused on the effect of induction immunosuppression, the data for alemtuzumab were unavailable before 2003 while data for the other induction immunosuppression agents were available for all transplant years. To assess the sensitivity and impact of missing data, we attempted multiple iterations of the multivariable analyses. For example, to examine the effect of EBV serostatus we ran analyses using only recipient EBV status as well as analyses incorporating both donor and recipient serostatus. We also ran sensitivity analyses that set all missing data to either negative or positive to further assess the issue of missing data and we did not detect any changes in our conclusions. 3. Results 3.1. Study cohort We examined 30,598 lung transplant recipients receiving their first lung transplant between the years 1999–2010. Forty-nine were excluded as no primary pulmonary diagnosis was recorded, 60 had no follow-up data, and 314 were excluded for age b 12. Therefore, the cohort included 30,175 lung transplant recipients. 17% (5218) had a diagnosis of CF and 83% (24,957) had a pulmonary diagnosis other than CF as an indication for lung
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transplantation. Clinical characteristics of the study cohort by CF status are described in Table 1a. PTLD occurred in 2% (89) of the CF population compared to 1% (241) in the non-CF group, p b 0.001. Table 1b displays the characteristics of the recipients who developed PTLD. CF recipients more often received bilateral lung transplant, were significantly younger than non-CF recipients (mean age 24 vs 55, p b 0.001) and were more often EBV and CMV seronegative. As expected, the CF recipients were younger than the non-CF recipients with PTLD (p b 0.001). In fact, a test for the linearity of age with cystic fibrosis status revealed a significant non-linear relationship. As recipient age increases, the probability of CF quickly diminishes to zero (likely due to the competing risk of early mortality in the CF population; p b .001). Among those with PTLD, CMV recipient seronegativity was also higher in the CF group, 68% compared to 46% in the non-CF group (p = 0.001). EBV seronegative recipients were also much higher in the CF group, 78% compared to the Non-CF group, 42% (p b 0.001). 3.2. Risk for PTLD Table 2 displays the univariable Cox regression HR for time to PTLD development. At any given time, the hazard risk of developing PTLD were approximately 66% higher in the
Table 1a Overall study demographics.
PTLD Mean months to PTLD or last follow-up (SD) Double lung transplant Transplant Year 1999–2004 2005–2011 Mean age (SD) Recipient Donor Gender (Male) Recipient Donor Cytomegalovirus (CMV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Epstein–Barr Virus (EBV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Induction medications Interleukin-2 receptor (IL-2Ra) Antithymocyte globulin Muromonab-CD3 (OKT3) Alemtuzumab Maintenance medications during initial transplant hospitalization Tacrolimus Cyclosporine Mycophenolate mofetil Azathioprine Tacrolimus or Cyclosporine or Both Mycophenolate mofetil or Azathioprine or both
Non-CF n = 24,957 (83%)
CF n = 5218 (17%)
Total N = 30,175 (100%)
p
241/24957 (1.0%) 36.29 (35.27) 14,493/24949 (58%)
89/5218 (1.7%) 39.26 (36.79) 5131/5216 (98%)
330/30175 (1.1%) 36.80 (35.56) 19,624/30165 (65%)
b .001 b .001 b .001 .04
8928/24957 (36%) 16,029/24957 (64%)
1944/3338 (37%) 3274/5218 (63%)
10,872/30175 (36%) 19,303/30175 (64%)
53.52 (10.93) 36.83 (14.87)
28.44 (9.63) 33.72 (14.66)
49.18 (14.31) 36.29 (14.88)
b .001 b .001
13,981/24957 (56%) 14,292/24888 (57%)
2650/5217 (51%) 2656/5205 (51%)
16,631/30174 (55%) 16,948/30093 (56%)
b .001 b .001
5442/13523 (40%) 9086/15031 (60%) 3144/13420 (23%)
1486/2324 (64%) 1575/2732 (58%) 810/2299 (35%)
6928/15847 (44%) 10,661/17763 (60%) 3954/15719 (25%)
b .001 .01 b .001
3584/13432 (27%) 5816/6260 (93%) 1413/6101 (23%)
795/2317 (34%) 885/960 (92%) 289/935 (31%)
4379/15749 (28%) 6701/7220 (93%) 1702/7036 (24%)
b .001 .42 b .001
5158/16916 (31%) 1813/16916 (11%) 117/16916 (0.7%) 690/12201 (5.7%)
929/3115 (30%) 364/3115 (12%) 14/3115 (0.4%) 81/2220 (3.6%)
6087/20031 (30%) 2177/20031 (11%) 131/20031 (0.7%) 771/14421 (5.3%)
.46 .11 .12 b .001
10,586/16358 (65%) 5156/16358 (32%) 9186/16629 (55%) 5991/16629 (36%) 16,300/16916 (96%) 15,464/16916 (91%)
1922/2972 (65%) 991/2972 (33%) 1674/3077 (54%) 1171/3077 (38%) 3056/3115 (98%) 2883/3115 (93%)
12,508/19330 (65%) 6147/19330 (32%) 10,860/19706 (55%) 7162/19706 (36%) 19,356/20031 (97%) 18,347/20031 (92%)
.96 .049 .39 .03 b .001 .04
Note: PTLD = Post-transplant lymphoproliferative disorder. CF = Cystic fibrosis. Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
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Table 1b Overall study demographics among patients with PTLD.
Mean months to PTLD (SD) Double lung transplant Transplant Year 1999–2004 2005–2011 Mean age (SD) Recipient Donor Gender (Male) Recipient Donor Cytomegalovirus (CMV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Epstein–Barr Virus (EBV IgG) serostatus Recipient negative Donor positive High risk (donor positive & recipient negative) Induction medications Interleukin-2 receptor antagonist (IL-2Ra) Antithymocyte globulin Muromonab-CD3 (OKT3) Alemtuzumab Maintenance medications during initial transplant hospitalization Tacrolimus Cyclosporine Mycophenolate mofetil Azathioprine Tacrolimus or Cyclosporine or Both Mycophenolate mofetil or Azathioprine or Both
Non-CF n = 241 (73%)
CF n = 89 (27%)
Total N = 330 (100%)
p
24.42 (28.38) 125/241 (52%)
20.51 (26.90) 89/89 (100%)
23.37 (28.00) 214/330 (64%)
.26 b .001 .86
130/241 (54%) 111/241 (46%)
47/89 (53%) 42/89 (47%)
177/330 (54%) 153/330 (46%)
55.21 (11.42) 31.95 (13.75)
24.08 (7.78) 27.47 (13.68)
46.82 (17.40) 30.74 (13.85)
b .001 .01
148/241 (61%) 165/241 (69%)
40/89 (45%) 44/89 (49%)
188/330 (57%) 209/330 (63%)
.01 .001
107/231 (46%) 134/240 (56%) 57/231 (25%)
57/84 (68%) 48/89 (54%) 29/84 (35%)
164/315 (52%) 182/329 (55%) 86/315 (27%)
.001 .76 .08
92/219 (42%) 66/80 (83%) 34/79 (43%)
64/82 (78%) 24/25 (96%) 20/24 (83%)
156/301 (52%) 90/105 (86%) 54/103 (52%)
b .001 .11 .001
51/238 (21%) 49/238 (21%) 8/238 (3.4%) 12/141 (8.5%)
33/88 (38%) 12/88 (14%) 3/88 (3.4%) 1/51 (2.0%)
84/326 (26%) 61/326 (19%) 11/326 (3.4%) 13/192 (6.8%)
.003 .15 .99 .19
140/234 (60%) 91/234 (39%) 109/236 (46%) 101/236 (43%) 235/238 (99%) 212/238 (89%)
50/85 (59%) 35/85 (41%) 42/85 (49%) 37/85 (44%) 88/88 (100%) 82/88 (93%)
190/319 (60%) 126/319 (40%) 151/321 (47%) 138/321 (43%) 323/326 (99%) 294/326 (90%)
.87 .71 .61 .91 .57 .27
Note: PTLD = Post-transplant lymphoproliferative disorder. CF = Cystic fibrosis.
CF group than in the non-CF group (HR = 1.66, 95% CI 1.30–2.12; p b 0.001). Recipients with EBV primary mismatch had the highest risk of developing PTLD at any given time with HR 3.47 (95% CI 2.35–5.10), p b 0.001. Fig. 1 depicts the Kaplan–Meier curve for development of PTLD according to CF status. Multivariable Cox regression analyses are described in Table 3. Four models were calculated by stratifying for both CF and non-CF recipients, which was necessary because of significant interactions between the CF status, age, and EBV serostatus. In the CF population, increasing age was associated with a decreased risk of PTLD, HR 0.94 per year of age (95% CI 0.91–0.96; p b 0.001), whereas age was not significantly associated with the development of PTLD in the non-CF group (p = 0.21). Recipient EBV seronegative status was significantly associated with PTLD development in both the CF and non-CF populations (both p b 0.001), though the magnitude of the effect varied. More specifically, in the non-CF population the HR was 1.92 (95% CI 1.47–2.51), but in the CF population the risk of PTLD at any given time in EBV seronegative recipients was over 3 times higher with HR 6.4 (95% CI 3.79–10). EBV status was considered two different ways due to significant missing data as described in the Methods section.
In Table 3, models 1 and 3 considered EBV seronegative recipients, whereas in Models 2 and 4 we used EBV donor positive/recipient seronegative constituting the high-risk combination. In this analysis, the same association for age was found, in that increasing age was protective in the CF population (p = 0.01), but not significant in the non-CF population (p = 0.55). Regarding the risk of developing PTLD in the high risk group of EBV mismatch, the non-CF recipients had an over 2-fold increased risk of developing PTLD at any given time (HR 2.49; 95% CI 1.60–3.90), and the CF population had an almost 10-fold increased risk of developing PTLD (HR 9.85; 95% CI 3.35–29.01). We additionally ran the same multivariable analyses but included use of induction immunosuppression medications. When doing so, induction immunosuppression was not significantly associated with PTLD, and the same associations held true for age and EBV serostatus (data not shown). We also ran models incorporating lung transplant era (1999–2004; 2005–2011), though transplant era did not significantly change the risk of developing PTLD and did not change the associations presented above for age and EBV status. Fig. 2A and B depict the cumulative PTLD-free curves for these cohorts, stratified by CF status, and show the impact of EBV recipient serostatus.
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 2 Univariable Cox regression hazards for time to post-transplant lymphoproliferative disorder (PTLD). HR Double lung transplant (Ref = Single lung transplant) Cystic fibrosis (Ref = Non-CF) Transplant year 1999–2004 (Ref = 2005–2011) Age Recipient Donor Gender (Ref = Female) Recipient Donor Cytomegalovirus serostatus Recipient negative (Ref = CMV IgG positive) Donor negative (Ref = CMV IgG positive) High risk (D+/R− versus all other combinations) Epstein–Barr Virus serostatus Recipient EBV IgG negative (Ref = EBV IgG Positive) Donor Negative (Ref = EBV IgG positive) High Risk (D+/R− versus all other combinations) Induction Medications (Ref = No induction medication) Interleukin-2 receptor antagonist (IL-2Ra) Antithymocyte globulin Muromonab-CD3 (OKT3) Alemtuzumab Initial maintenance medications Cyclosporine (Ref = Tacrolimus) Azathioprine (Ref = Mycophenolate mofetil)
95% CI
.54 b .001 .03
0.99 0.98–0.99 0.98 0.97–0.99
.01 b .001
1.14 0.92–1.42 1.30 1.04–1.63
.24 .02
1.42 1.14–1.78 1.14 0.92–1.42 1.19 0.93–1.53
.002 .23 .17
2.74 2.18–3.43
b.001
2.03 1.18–3.51 3.47 2.35–5.10
.01 b .001
0.78 1.68 4.86 1.31
.054 b.001 b .001 .35
0.61–1.004 1.27–2.21 2.66–8.87 0.74–2.30
1.23 0.98–1.55 1.16 0.92–1.47
.07 .20
Note: HR = Hazard ratio. CI = confidence interval for the estimate.
4. Discussion This is the first study designed to evaluate PTLD following lung transplant in cystic fibrosis recipients utilizing a large
Fig. 1. Cumulative PTLD-free curves by cystic-fibrosis status.
Table 3 Multivariable Cox regression models for time to post-transplant lymphoproliferative disorder (PTLD), stratified by cystic fibrosis status.
p
1.07 0.86–1.35 1.66 1.30–2.12 1.30 1.03–1.63
5
HR (95% CI) Non-cystic fibrosis Model 1 Age Recipient EBV IgG negative (ref: EBV IgG positive) Model 2 Age High risk EBV (versus all other combinations) Cystic fibrosis Model 3 Age Recipient EBV IgG negative (ref: EBV IgG positive) Model 4 Age High risk EBV (versus all other combinations)
p
1.01 (0.99–1.02) .21 1.92 (1.47–2.51) b.001
0.99 (0.98–1.01) .55 2.49 (1.60–3.90) b.001 0.94 (0.91–0.96) b.001 6.40 (3.79–10.82) b.001
0.93 (0.88–0.99) .01 9.85 (3.35–29.01) b.001
Note: HR = Hazard ratio. CI = confidence interval for the estimate. High risk EBV is defined as donor positive and recipient negative. For both strata, the interaction of age and EBV IgG Negative was not significant. For the cystic fibrosis stratum, the interaction of age and High Risk EBV status was not significant.
international transplant database. There are three major findings. First, there is a higher risk of PTLD in the CF population following lung transplantation compared to lung transplant recipients with other pulmonary diagnoses. There also is a higher occurrence of recipient EBV and CMV seronegativity in the CF population at the time of transplantation compared to the non-CF population. Not surprisingly then, there is also a higher rate of EBV and CMV primary mismatch in this population. Third, in addition to CF status, age and EBV serostatus remained significantly associated with PTLD post lung transplantation in multivariable analyses. However, the association varied across CF status. For the CF population, increasing age was protective for the development of PTLD, while there was no significant association observed in the non-CF population. For both CF and non-CF, EBV recipient seronegativity as well as EBV mismatch were both highly associated with PTLD, but with varied levels of risk. The highest rates of PTLD occurred in lung transplant recipients who had CF and were EBV seronegative. In this investigation we found a relatively low prevalence of PTLD in both the CF and non-CF populations compared to previously reported studies [2,4–10]. The occurrence we observed in lung transplant recipients is more aligned with reported prevalence of PTLD in other solid organ transplants [3,11–13]. This difference may be due to inconsistencies in reporting and definitions used for PTLD. The international data registry is not designed to specifically look at PTLD, and thus may not capture all PTLD cases. Studies specifically designed to assess for PTLD may identify higher rates due to better case ascertainment and reporting. Despite this difference, the same association with EBV, and risk for EBV seronegative and EBV mismatch recipients to develop PTLD was observed. This is the first study, however, to examine the association of EBV
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
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Fig. 2. A. Cumulative PTLD-free curves by EBV IgG status for non-cystic fibrosis subjects. B. Cumulative PTLD-free curves by EBV IgG status for cystic fibrosis subjects.
serostatus across CF/non-CF status. EBV negative serostatus, and EBV mismatch carried a much greater risk in the CF population compared to the non-CF population. The reason for this difference is unclear. In a recent review of infections in CF patients undergoing lung transplant, the question of a genetic predisposition to lymphoma in the setting of immunosuppression following transplant was raised [21]. Supporting this theory is an investigation utilizing patient registry data from the Cystic Fibrosis Foundation where Maisonneuve et al. observed an increase in lymphoid leukemia in non-transplant cystic fibrosis patients compared to what would be expected in the general population [22]. Further investigation into the mechanisms and interactions of EBV, CF transmembrane receptor mutations and the increased risk of lymphoid leukemia and PTLD in CF patients are necessary. In this investigation we found a higher prevalence of EBV and CMV seronegativity in CF recipients. This may be related to the significant differences in the ages of the two populations. Infection with EBV affects 90% of the world's population, with immunity to EBV present in the majority of adults [23]. In this study, both CF and non-CF transplant recipients had lower seroimmunity to EBV. There may be reporting errors if the EBV serostatus inputted into the registry is that from initiation of the lung transplant evaluation, as opposed to the EBV serostatus at the actual time of the transplant, with spontaneous seroconversion in the interim interval. If this is true, one would expect this to drive the HR to the null, which is not what was observed. One common hypothesis for negative viral serologies in CF patients is that young people with CF are shielded from viral exposures from other children and thus are persistently seronegative, but this has not been firmly established. The decrease in CMV seropositivity also seen in the CF population in this investigation would support this theory. 80% of all PTLD arises from B-cell proliferation induced by EBV [24].
EBV seronegativity is a well-known risk factor for subsequent development of PTLD [17,25,26]. EBV vaccine studies have been pursued and while some candidate vaccines are immunogenic in healthy volunteers and even in children with chronic kidney disease, they have thus far been ineffective in protecting against EBV infection [27–30]. Also striking in this investigation among the patients who developed PTLD, 78% of the CF recipients were EBV recipient seronegative, whereas only 42% of non-CF recipients were EBV seronegative. Perhaps a greater percentage of non-CF recipients develop non-EBV-related PTLD, a hypothesis which would need additional data and further investigation. Data from this study, as well as others, raises the issues of prevention and surveillance for PTLD, especially in light of the significant morbidity and mortality attributed to this posttransplant complication. This investigation found that younger, EBV seronegative CF recipients are at the highest risk for PTLD. We calculated conditional probabilities of PTLD at 12 and 24 months post-transplant and noted that a hypothetical adolescent non-CF patient may have a 6.2% and 8.9% probability of PTLD respectively, whereas a CF patient would have a 12.8% and 13.7% probability, respectively (data not shown). Since developing a predictive model was not the main aim of our investigation, pursuit of this would be a relevant investigation, as a predictive model may help lung transplant centers guide surveillance efforts for PTLD. Surveillance of these high risk patients by monitoring for clinical signs and symptoms of EBV as well as following EBV viral loads is recommended, particularly in the first year following transplant [31–33]. Adult lung transplant recipients whose immunosuppression was adjusted guided by EBV viral load had a low incidence of developing PTLD [34]. Prophylaxis for PTLD is more controversial. A large multicenter retrospective investigation of anti-CMV immunoglobulin prophylaxis in kidney
Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013
E.M. Lowery et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
transplant recipients showed a reduced incidence of early PTLD [35]. This effect was also seen in a single center cohort of lung transplant recipients [15]. Treatment with valganciclovir reduced EBV primary infection and viremia in EBV seronegative pediatric renal recipients [36]. Several investigations have looked at treatment of increasing EBV viral loads with rituximab with some successful results in preventing PTLD [37]. Despite these investigations, prevention and surveillance for PTLD are still areas of great uncertainty that need further study. The strength of this study is the use of a multi-center, large database to compare rates of PTLD post transplantation. There are, however, limitations. Data on EBV serostatus were not collected by the registry until 2006 in the U.S. and 2011 internationally. The rate of missing data, especially for pertinent variables such as immunosuppression and rejection limits a comprehensive assessment of risk factors. We did run sub-analyses for serologic status numerous ways and found consistent results regardless of the method used. Further, we ran sub-analyses including immunosuppression regimens which failed to find any strong association between induction/ maintenance regimens and PTLD in multivariable models. However, such analyses have to be viewed with caution given the amount of missing data. Single center studies performed at high volume centers, such as that performed by Kumarasinghe et al. and Shyu et al., are able to more accurately assess information such as induction/maintenance regimens, rejection episodes and histopathology outcome data in PTLD and as such, Shyu et al. did not observe an association between type of induction immunosuppression and development of PTLD [38,39]. As registry data accumulates over time, a more accurate collection of this particular information may allow for further studies specifically accounting for both induction and maintenance therapy to properly assess the risk of varied agents on the development of PTLD. In conclusion, this analysis is the largest to date on PTLD in lung transplant recipients, and the only investigation to utilize a large international database. CF recipients were found to have a higher risk for PTLD compared to non-CF recipients. Recipient EBV seronegative status and EBV mismatch are associated with PTLD in both populations. Increasing age, however, is protective against PTLD, but only in the CF population. Further studies are needed to account for other potential risk factors, especially the role of immunosuppression and rejection treatment. Such studies will help identify individuals at greatest risk for this important post-transplant complication. Author contributions EL had access to the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. EL was involved in the conceptualization of the study, analyzed the results and wrote the first draft of the manuscript. EL, SG, LE, WA, NC, JL were involved in the statistical analysis of the data and study design. JL, WA, NC, EL were involved in the conceptualization of the study, provided intellectual input and made substantial contributions to the manuscript.
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Please cite this article as: Lowery EM, et al, Increased risk of PTLD in lung transplant recipients with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/ j.jcf.2017.03.013