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Survival Impact of Lung Transplantation for Chronic
Obstructive Pulmonary Disease
S. Lahzami1, P.O. Bridevaux2, P.M. Soccal2,4, J. Wellinger3, J.H. Robert4, H.B. Ris3 and
J.D. Aubert1,5.
1Service de Pneumologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
2Service de Pneumologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland
3Service de Chirurgie Thoracique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
4Clinique de Chirurgie Thoracique, Hôpitaux Universitaires de Genève, Geneva, Switzerland
5Centre de Transplantation d’Organes, Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland
Corresponding author:
John-David Aubert, MD
Service de Pneumologie et Centre de Transplantation d’Organes
Centre Hospitalier Universitaire Vaudois
Rue du Bugnon 46
CH-1011 Lausanne, Switzerland
Phone : +41 21 314 13 76
Fax : +41 21 314 13 95
E-mail : John-David.Aubert@chuv.ch
Running Title: Survival after lung transplantation for COPD
Word count : 2968
Funding source:
This work was not supported by any research grant or funding.
. Published on December 8, 2009 as doi: 10.1183/09031936.00087809ERJ Express
Copyright 2009 by the European Respiratory Society.
ABSTRACT
Chronic Obstructive Pulmonary Disease (COPD) is the primary indication for lung transplantation
(LTx), but survival benefit is still debated. We analysed the survival impact of LTx in COPD with a
new approach using the BODE index.
We retrospectively reviewed 54 consecutive LTx performed for COPD. Pre-transplant BODE score
was calculated for each patient and a predicted survival was derived from the survival functions of
the original BODE index validation cohort. Predicted and observed post-transplant survival was
then compared.
In the subgroups with a BODE ≥7 and BODE <7, a majority of patients (66 and 69% respectively)
lived longer after LTx than predicted by their individual BODE index. The median survival was
significantly improved in the entire cohort and in the subgroup with a BODE ≥7. Four years after
LTx, a survival benefit was apparent only in patients with a pre-transplant BODE score ≥7.
In conclusion, while a majority of COPD patients had an individual survival benefit from LTx
regardless of their pre-transplant BODE score, a global survival benefit was seen only in patients
with the more severe disease. This supports the use of the BODE index as a selection criteria for
LTx candidates.
Abstract word count: 193
Keywords: BODE index, chronic obstructive pulmonary disease, lung transplantation,
patient selection, survival analysis
INTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality
around the world, making it one of the major challenges for the health-care community. The
primary management remains medical treatment, including smoking cessation, bronchodilators,
oxygen administration, adequate diet and pulmonary rehabilitation. However, these are often
insufficient in patients with advanced disease. For selected patients, surgical options include
bullectomy, lung volume reduction surgery and lung transplantation (LTx) [1]. LTx for COPD has
been first reported in 1970, but used on a larger scale only since the late 1980s, coinciding with
improvement of surgical technique and immunosuppressive therapy. COPD is presently the main
indication for LTx, accounting for more than one third of the procedures [2].
Although lung transplantation for COPD improves lung function [3], exercise capacity [4] and
quality of life [5], the controversy remains regarding survival benefit. Studies conducted so far,
whether showing a survival benefit [6-8] or not [9,10], have compared the survival of patients who
underwent transplantation with patients remaining on the waiting list. Despite having used different
approaches to take into account differences between patients on waiting list and those who
underwent the procedure, bias cannot be excluded.
In COPD patients, several univariate survival prognostic factors have been identified [11,12].
However, the pathophysiology of COPD is complex and none of these factors alone is an accurate
predictor of the survival of COPD patients. In 2004, Celli and co-workers identified from a large
multicenter cohort of COPD patients, a combination of four variables which showed a strong
association with survival in COPD: body-mass index (B), airflow obstruction (O), dyspnea (D) and
exercise capacity (E) [13]. These variables were used to create the BODE index, a multidimensional
scoring system that was shown to be a better predictor of survival than the spirometric staging
system developed by the American Thoracic Society (ATS) [14]. The BODE index assigns a score
from 0 to 10, with the higher score indicating more severe disease and predicting a poorer outcome.
Thus, the BODE index offers an opportunity to evaluate the natural history of COPD patients
enrolled in a lung transplantation program, by using criteria that are free of the selection bias
introduced by the decisions of the transplantation team. This was recently emphasized by the
introduction of a BODE score ≥7 as a new recommended transplant criteria for COPD patients [15].
The primary goal of our study was to analyse the survival impact of lung transplantation in end-
stage COPD patients, by comparing the effective post-transplant survival with the survival
predicted by the BODE index as measured during pre-transplant clinical evaluation. The results
were then applied to refine the selection criteria of LTx candidates.
MATERIAL AND METHODS
Study subjects
We retrospectively reviewed all consecutive subjects who underwent single (SLT) or bilateral LTx
(BLT) for COPD at Lausanne and Geneva University Hospitals, Switzerland, from the start of the
program in 1993 until the end of 2007, with a follow-up until the 30th June 2009. The diagnosis of
COPD had been verified by a global assessment in every patient before listing, simultaneously with
assessment of suitability for LTx and potential cardiovascular, infectious or psychiatric contra-
indications to the procedure. Subjects with COPD related to alpha-1 antitrypsin deficiency were
excluded from the study.
Data collection
Demographic and clinical characteristics collected during the pre-transplant assessment period were
recorded from the patient’s chart, as well as the time to LTx and the type of procedure. The date of
death, when appropriate, was collected through centre-specific database.
BODE index calculation
The pre-transplant BODE index score was calculated for each patient as described by Celli et al.
[13], using data obtained during the pre-transplant assessment: body mass index in kilograms per
square meter, post-bronchodilator FEV1 as percentage of the predicted value, score on the modified
Medical Research Council (MMRC) dyspnea scale and 6-min walking distance (6MWD).
Spirometry measurements and equations used to determine the predicted normal values for FEV1
were according to the Official Statement of the European Respiratory Society for Standardized
Lung Function Testing [16]. MMRC was collected or retrospectively evaluated from patient’s chart
when necessary. Six-minute walk tests without encouragement were performed. Missing 6MWD (3
subjects) were derived from maximum oxygen consumption value (VO2 max) measured during the
pre-transplant assessment, using the equations developed by Cahalin and al. in transplant candidates
with end-stage lung disease [17]. A zero meter 6MWD was assigned to the 2 patients who were not
able to perform the 6-min walk test or the VO2 max test because of their respiratory condition.
Data analysis
We used the baseline survival function derived from the original BODE index cohort and provided
by the authors [13]. The 95% confidence interval (CI) of the hazard ratio was used to calculate
lower boundary, intermediate and upper boundary of life expectancy for each BODE level. The
predicted survival with lower and upper estimates of each patient was then individually calculated
as derived from their BODE score, and compared to their effective post transplant survival. Patients
who were still alive at the end of the follow-up but had not yet achieved the upper boundary of their
predicted survival were excluded from the analysis, as the survival impact of LTx could not be
evaluated. The survival effect of the procedure on the entire cohort was then assessed by comparing
the predicted survivals with the effective survival, and by determining the number of patients who
individually benefited from the procedure. The same analysis was repeated in the subgroups with a
pre-transplant BODE score <7 and ≥7. The survival after SLT versus BLT, and the difference
between transplant periods were also analysed.
Statistical analysis
Student’s T-test and chi-square test were used when appropriate to compare patient’s
characteristics. The survival effect of LTx on the entire cohort and on BODE score subgroups were
assessed by a Wilcoxon signed ranks test. Kaplan-Meier survival estimates were used to describe
the post-transplant survival of the entire cohort and log rank test was used to compare the survival
between types and periods of transplant, and between pre-transplant BODE subgroups. Statistical
analyses were performed with SPSS 17.0 for Windows (SPSS Inc. Chicago, IL, USA).
RESULTS
A total of 54 patients with COPD unrelated to alpha-1 antitrypsin deficiency underwent LTx from
June 1993 until the end of 2007. No COPD patients listed for transplantation died during the
waiting period. Twenty-six procedures (48%) were performed at Geneva University Hospitals and
28 (52%) in Lausanne, using a similar surgical and medical approach. Thirty-five patients (65%)
underwent BLT whereas 19 (35%) had SLT. At the end of the follow-up, 29 patients (54%) were
still alive. Six of these patients had not yet achieved the upper boundary of their predicted survival
according to their pre-transplant BODE index, and were excluded from survival analysis. The
patient’s flow chart with life status at the end of the follow-up is shown on Figure 1.
The cohort included a patient with a low BODE score of 2, where the estimated half-life could not
be calculated according to the data from the BODE original survival function [13]. Instead, the half-
life was conservatively estimated according to the survival curve of the cohort of COPD patients
described by Martinez et al [18]. One patient was retransplanted during the studied period and his
survival time was calculated from the first LTx to death. Baseline characteristics of the transplanted
patients are shown in Table 1. Excluded patients did not differ significantly from the cohort used for
survival analysis with respect to baseline characteristics. The mean follow-up was 5.7±4.5 (SD)
years.
The comparison between observed post-transplant survival and expected survival according to pre-
transplant BODE index is shown in Table 2. For the whole cohort, the median survival was
significantly improved after LTx. This survival benefit was seen in the subgroup with a BODE
score ≥7, but not in the subgroup with a BODE score <7, although a trend toward better survival
with LTx was present. An individual survival benefit was seen in two third of the lung recipients,
regardless of their BODE score subgroup. The detailed survival loss or gain for each patient is
shown in Figure 2. It appears that a majority of patients lived much longer than expected while
others, mainly in the BODE score <7, experienced a potential survival loss.
A sensitivity analysis on the effect of the exclusion of 6 patients from the survival analysis was
performed. A pessimistic, intermediate, and optimistic survival were assigned to each of these
excluded patients, using respectively the quartile 1, median and quartile 3 of the survival observed
in the other patients who reached at least the same post-transplant survival. These 6 patients were
then included in the analysis. In the entire cohort (n=48+6), the median post-transplant survival
(pessimistic: 5.4 years; intermediate: 6.3 years; optimistic: 6.3 years) was significantly higher than
the expected survival (lower boundary: 2.8 years; intermediate: 3.5 years; upper boundary: 4.2
years) in all scenarii. In the BODE ≥ 7 subgroup (n=35+2), the significant survival benefit of LTx
was strengthened when compared to the lower boundary and intermediate expected survivals, and
there was a trend towards benefit when compared to the upper boundary of predicted survival. The
BODE < 7 subgroup (n=13+4) had a significant survival benefit from LTx only when compared to
the lower boundary of the expected survival.
We found no significant survival difference between SLT and BLT subgroups, which had no
between groups pre-transplant differences. The period of transplant (1993-1999 versus 2000-2007)
was not associated with a survival difference.
The Kaplan-Meier post-LTx survival was not different between pre-transplant BODE score
subgroups (Figure 3). This allowed us to compare the predicted survival at each step of the BODE
index with the effective Kaplan-Meier post-transplant survival of the entire cohort (Table 3). This
theoretical analysis showed that 4 years after LTx, the survival benefit is limited to patients with a
pre-transplant BODE score ≥7.
DISCUSSION
This study showed a significant survival benefit of LTx in our cohort of COPD patients, with a
median survival time significantly higher than expected before transplant. Considering that almost
half of the patients were still alive at the end of the follow-up (see Figure 1), these results are
particularly relevant, as the importance of the survival benefit may have been underestimated due to a
limited follow-up period. Moreover, a majority of patients had an individual benefit from the
intervention in terms of survival.
These results support two previous studies that have shown a global survival benefit after 260 [6]
and 369 days [7], as well as a recent complex statistical simulation on the United Network for
Organ Sharing database which showed a survival benefit in a majority of transplanted patients [8].
Two other studies did not demonstrate a survival benefit after 48 [9] and 24 months [10] of follow-
up, but the follow-up time of the latter was too short to allow meaningful comparisons.
Methodologically, we used the pre-transplant BODE index to predict a theoretical survival at time
of LTx. In contrast, the five studies published so far compared, either directly or with a statistical
model, the survival of transplanted patients with patients staying on waiting list. This way of
comparing survival is susceptible to potential bias against LTx. Indeed, the starting assumption is
that all patients on the waiting list need a lung transplant at the time of listing. However,
considering the usual duration of the waiting time (often beyond 2 years) [6,19], transplant centres
may register their patients early [20], which would improve the survival rate of the waiting list
population. Furthermore, if patients on the waiting list are good candidates for transplantation at the
time of listing, progression of the disease and ageing during waiting time make them potentially
worse candidates, as older recipients have a significantly worse survival rate [2]. In contrast, high-
risk patients have an increased probability of dying while on the waiting list, compared with low-
risk patients who can survive long enough on the waiting list to undergo LTx. This could bias the
results in favour of LTx. The likely different type of care received by patients on the waiting list
compared to those not considered or denied for lung transplantation is another major potential bias.
By assigning a BODE score-based predicted survival time, post-LTx survival can be compared with
the predicted “natural” survival of the same patients, thus avoiding such risk of bias.
Our cohort’s post-LTx survival rates, 77% at 1 year, 71% at 2 years and 65% at 4 years, are in
accordance with previous studies in COPD patients [2, 21-23]. The short mean waiting time (6±4
months) and the absence of death on waiting list in our cohort may differ from other transplantation
centres. However, our centres apply standard surgical and medical procedures, and the model used
in this study is independent of any waiting list consideration. Our findings are therefore applicable
to other lung transplantation centres.
Survival benefit is not the sole criteria to consider when evaluating the benefit of LTx in COPD
patients, as LTx leads to a dramatic improvement of quality of life [5]. However, owing to the
chronic shortage of lung donors, it is well accepted that LTx for COPD patients should be limited to
a subset of those having the worst survival probability without intervention.
The presence of a FEV1 < 25% of predicted value, a PaCO2 ≥ 55 mmHg (7.3 kPa), or pulmonary
arterial hypertension with progressive deterioration has been used for many years as standard
guidelines for the selection of COPD lung transplant candidates [24]. Nathan et al. [25] were the
first to recommend the additional use of BODE index, and proposed a BODE score ≥ 7 as a new
transplant criteria. In 2006, the International Society of Heart and Lung Transplantation formalized
the use of BODE score in the guidelines for the selection of lung transplant candidates [15], by
adding a BODE index score ≥7 for transplantation and ≥5 for referral.
We found that the post-transplant mortality risk did not depend on the pre-operative BODE index.
Based on our cohort’s observed survival, the theoretical comparison with the survival predicted by
each score of the BODE index showed a significant benefit at 4 years only with a pre-transplant
BODE score ≥7. Moreover, in our cohort, we found that LTx improved the median survival only in
the subgroup with a BODE score ≥7. In the subgroup with a BODE score <7, the mortality related
to the intervention is higher than the long term expected benefit. Thus, these patients should not be
transplanted at this stage of the disease or the indication should at least be carefully re-examined.
Our results highlight the need for BODE index to become part of all pre-transplant assessments in
COPD patients and provide support to the official recommendation to use a cut-off BODE score of
7 as transplant criteria.
Our cohort's baseline BODE scores repartition was significantly higher than in the original BODE
index validation cohort [13] (Fig 4), reflecting the severity of COPD. The BODE index has not
been specifically validated in a population listed for transplantation such as our cohort, but several
factors suggest that this does not contraindicate its use. Not only did all our patients meet the
inclusion criteria of Celli and co-worker’s study [13], but almost 50% of the BODE index
validation cohort had BODE scores ≥5 and therefore could have been referred for LTx as presently
recommended [15]. More importantly, the BODE index has already proved its ability to predict
mortality in severe COPD patients included in the National Emphysema Treatment Trial study [18].
These patients were likely to be selected and followed as closely as patients listed for LTx.
Moreover, the use of the 95%CI of BODE index’s predicted survival is likely to have accounted for
most of the differences between patients which are not evaluated by the BODE index, such as age,
or presence of pulmonary hypertension or other comorbidities. Nevertheless, the possibility that,
due to a positive selection bias, BODE index might be less accurate to predict mortality in a cohort
listed for transplantation has to be considered when interpreting the results of our study.
The determination of BODE index scores from data collected during pre-transplant assessment is
another limitation that should be recognized. Consequently, the calculated theoretical survival was
not identical to the one at the time of LTx. However, considering the short waiting time (6±4
months), a significant worsening of patients conditions during this time is unlikely. The absence of
deaths during this period reinforces this hypothesis. In any case, it would result in an
underestimation of BODE index scores at the time of transplant and thus an overestimation of the
predicted survival time. Consequently, we would have found a higher survival benefit of LTx.
In summary, the results of this study showed a significant survival benefit of LTx in our cohort of
COPD patients. Importantly, not only the median survival was improved with LTx, but a significant
majority of patients had an individual survival benefit from this procedure. Although the latter was
independent from pre-transplant BODE score, the former was seen in the entire cohort and in the
subgroup with a BODE score ≥7, but not in the subset of patients with a BODE score <7. Moreover,
in a theoretical analysis, we found that 4 years after LTx a survival benefit can be expected only in
the patients with a pre-transplant BODE score ≥7. For those with low BODE scores, the risk of the
procedure outweighs the survival benefit. These results support the current recommendation to use
a BODE score ≥ 7 as transplant criteria for patients with COPD.
Acknowledgement
We are grateful to Professor BR Celli and colleagues who provided the original BODE index
validation cohort’s baseline survival function, Dr Wei Xuan for his statistical advices, and all
present and former members of the lung transplant units of Lausanne and Geneva University
Hospitals who have assisted in the care of these patients.
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TABLES
Table 1. Patients baseline characteristics
All BODE BODE
n=48 score <7 score ≥7
n=13 n=35
p value*
Sex, male, n (%) 30 (63) 8 (62) 22 (63) 0.93
Age at LTx, years
(mean ± SD) 55 ± 6 54 ± 5 56 ± 6 0.41
BMI, k
g
/m2 (mean ± SD) 22.4 ± 4.2 23.0 ± 4.1 22.2 ± 4.3 0.53
FEV1, % of predicted
value (mean ± SD) 23 ± 7 29 ± 8 22 ± 4 <0.001
MMRC dyspnea scale
Class 2, n 5 5 0
Class 3, n 28 8 20
Class 4, n 15 0 15
<0.001
6MWD, m (mean ± SD) 242 ± 121 358 ± 106 199 ± 97 <0.001
BODE index (mean ± SD) 7.2 ± 1.5 5.3 ± 1.2 7.9 ± 1.0 <0.001
Time on waiting list,
months (mean ± SD) 6 ± 4 5 ± 4 7 ± 4
0.09
Bilateral lung
transplantation, n (%) 30 (63) 8 (62) 22 (63) 0.93
Transplant period
1993-1999, n 22 7 15
2000- 2007, n 26 6 20
0.50
*comparisons between BODE score < 7 and BODE score ≥ 7 subgroups. LTx: lung transplantation; BMI:
body mass index, FEV1: forced expiratory volume in 1 s; MMRC: Modified Medical Research Council;
6MWD: 6-min walk distance.
Table 2. Observed post-transplant survival versus cohort’s expected survival at enrolment according to BODE index score
All Patients BODE score <7 BODE score ≥7
(n=48) (n=13) (n=35)
Expected survival at enrolment Expected survival at enrolment Expected survival at enrolment
Observed
post LTx
survival lower
boundary intermediate upper
boundary
Observed
post LTx
survival lower
boundary intermediate upper
boundary
Observed
post LTx
survival lower
boundary intermediate upper
boundary
Median survival,
yrs (interquartile
range)
5.4
(1.6-7.9)
2.8
(2.3-3.4)
3.5
(3.3-4.0)
4.2
(3.8-4.6)
7.7
(0.8-11.0)
3.4
(3.4-4.0)
4.6
(4.6-4.7)
4.0
(4.0-4.4)
5.0
(1.8-7.4)
2.3
(1.8-2.8)
3.3
(2.5-3.5)
3.8
(3.4-4.2)
p value* ─ 0.0002 0.002 0.06 ─ 0.08 0.15 0.31 ─ 0.0009 0.009 0.15
Death occurrence
before/after
predicted, n;
patients alive at
the end of follow-
up (n)
─ 15 / 10
(23)
16 / 9
(23)
17 / 8
(23) ─ 4 / 3
(6)
4 / 3
(6)
4 / 3
(6) ─ 11 / 7
(17)
12 / 6
(17)
13 / 5
(17)
Patients with
individual
survival benefit
─ 69% 67% 65% ─ 69% 69% 69% ─ 69% 66% 63%
* Observed vs expected survival (Wilcoxon signed rank test). LTx: lung transplantation
Table 3. Post- transplant observed Kaplan-Meier survival and expected survival according to BODE index score
Expected survival according to BODE score (95% CI)
Observed Kaplan-
Meier post transplant
survival (95% CI)
(n= 48)
BODE
score 4
BODE
score 5
BODE
score 6
BODE
score 7
BODE
score 8
BODE
score 9
BODE
score 10
1 year
0.77
(0.65 - 0.89)
0.97
(0.96-0.98)
0.96
(0.95-0.97)
0.95
(0.93-0.96)
0.93
(0.90-0.95)
0.91
(0.86-0.94)
0.88
(0.81-0.93)
0.85
(0.74-0.91)
2 years
0.71
(0.58 - 0.84)
0.89
(0.87-0.91)
0.86
(0.81-0.89)
0.82
(0.75-0.87)
0.76
(0.66-0.83)
0.70
(0.56-0.80)
0.61
(0.44-0.75)
0.52
(0.31-0.70)
3 years
0.67
(0.54 - 0.80)
0.81
(0.77-0.85)
0.76
(0.69-0.81)
0.69
(0.59-0.77)
0.61
(0.47-0.72)
0.52
(0.34-0.66)
0.41 *
(0.22-0.60)
0.31 *
(0.12-0.31)
4 years
0.65
(0.51 - 0.79)
0.66
(0.59-0.72)
0.57
(0.47-0.66)
0.47
(0.34-0.59)
0.37 *
(0.22-0.52)
0.26 *
(0.12-0.44)
0.17 *
(0.05-0.35)
0.09 *
(0.01-0.27)
10 years
0.39
(0.21 - 0.57)
ND ND ND ND ND ND ND
* Significant survival benefit (chi-square test). CI: confidence interval; ND: not determined
FIGURE LEGENDS
Figure 1: Patient’s flow-chart with life status at the end of the follow-up.
Figure 2: Individual survival impact of lung transplantation on each patient.
Individual survival loss or gain was obtained for each patient by comparing the
observed post-transplant survival with the 95% CI’s upper boundary of predicted
survival according to pre-transplant BODE score. Patients are separated in 2
subgroups based on their pre-transplant BODE score (BODE < 7 and BODE ≥ 7).
Patients still alive at the end of the follow-up are presented differently to highlight
their potentially longer survival gain.
Figure 3: Observed post-transplant survival: difference between pre-transplant
BODE score subgroups.
Figure 4: BODE index repartition: studied transplanted cohort versus original
BODE index validation cohort [13].
FIGURE 1.
Patients with LTx for COPD
n = 54
Status at the end of follow-up:
- 29 alive
- 25 deceased
Excluded Patients
n = 6
6 : insufficient follow-up
Patients used for survival analysis
n = 48
Status at the end of follow-up:
- 23 alive
- 25 deceased
21
FIGURE 2.
: deceased at the end of follow-up : alive at the end of follow-up
-8 -6 -4 -2 0 2 4 6 8 10 12
Time (years)
BODE ≥ 7
(n=35)
BODE < 7
(n= 13)
Survival loss Survival gain
FIGURE 3.
23
FIGURE 4.
0%
5%
10%
15%
20%
25%
30%
35%
012345678910
BODE index score
percentage
Transplanted study cohort BODE index validation cohort
