Bronchiolitis Obliterans Syndrome (BOS) is a debilitating disease with limited treatment options that threatens both the quality of life and long-term survival of lung transplantation (LTx) recipients.1 The syndrome has been associated with restrictions in physical mobility and decreased energy.2 According to data from the registry of the International Society for Heart and Lung Transplantation (ISHLT) BOS affects at least 50% of lung recipients who survive beyond 5 years and is the leading cause of death for recipients who survive beyond 1 year post-transplant.3 Expected survival before and after transplantation has been shown to depend on prognostic variables of candidates for LTx such as functional exercise (walking) capacity.4,5 Only two studies6,7 have so far reported on the evolution of functional exercise capacity (FEC) in long-term LTx survivors. Gerbase and colleagues’ study is the only one to date that compared long-term evolution of FEC (6-minute walking distance) after LTx between BOS and NON-BOS patients.7 They observed that the distance covered during the 6-minute walking test (6MWD) remained fairly stable over time in patients who developed BOS.7 Based on these observations they concluded that the development of moderate to severe BOS did not seem to prevent lung recipients from walking independently and pursuing an autonomous life.7 In contrast with these findings Rutherford and colleagues observed in 10-year LTx survivors (including a significant fraction of patients with BOS; 46% with BOS Grade 1 and 36% with BOS Grade ≥2) significant reductions in the physical functioning domain of the SF-36 in comparison with both normative and chronic illness data.6 Based on these conflicting data and after contrasting clinical impressions in our own center we decided to formally study the evolution of FEC in LTx survivors with BOS diagnosis. In order to avoid the influence of possible confounding factors (age, gender, pre-LTx diagnosis, year of LTx and LTx characteristics) we individually matched BOS and non-BOS patients in a retrospective longitudinal case–control study design. Furthermore, only data from patients with complete follow-up were considered for analysis to avoid survival bias. We aimed to compare the evolution of functional exercise capacity, as well as symptoms of dyspnea and pulmonary function in surviving LTx recipients with and without BOS diagnosis.

All 24 LTx recipients (50% females; 57±11 years) diagnosed with BOS Grade ≥2 who were transplanted after June 1999 and who were still alive in August 2012 were selected for participation in the study (5.9% of LTx survivors in our center). Patients from the NON-BOS group were individually matched according to age, gender, pre-transplant diagnosis, year of transplantation and LTx characteristics which resulted in comparable baseline characteristics with regard to these variables (Table 1). Groups were also comparable regarding height, pulmonary function, 6MWD and symptoms at the pre-LTx measurement (Tables 1 and 2). The most common pre-transplant diagnosis was chronic obstructive pulmonary disease (42%), followed by interstitial lung disease (25%) and cystic fibrosis (17%). Approximately two-third of the performed surgical procedures were bilateral-LTx (Table 1). We assessed also other variables of interest to control for potential confounding: a similar proportion of patients from both groups performed a pre-transplantation rehabilitation program (29% vs. 38%, p=0.540; Table 1) and around 40% of candidates in both groups needed oxygen supplementation during the 6MWD pre-LTx (2.1±0.9 l vs. 2.6±0.2 l, p=0.432) in the NON-BOS and BOS group, respectively. Results of measurements performed at four time-points: (1) pre-LTx; (2) post-LTx; (3) peak FEV1; and (4) recent value, are summarized and illustrated in Table 2 and Fig. 1. Measurements pre-LTx were performed 170±192 days and 123±111 days before transplantation in the NON-BOS and BOS group, respectively (p>0.05). The peak FEV1 value was achieved 1026±736 days (2.8±2.0 years) and 479±384 days (1.3±1.1 years) after transplantation in the NON-BOS and BOS group, respectively (p=0.002). In the cases, BOS diagnosis was established on average 1305±932 days (3.6±2.6 years) after LTx. Final measurements were performed 2466±1242 days after LTx in the BOS group and after 2258±1128 days in the NON-BOS group (6.5±3.2 years after LTx on average for both groups; p>0.05).

Fig. 1.

Clinical evolution of patients who developed bronchiolitis obliterans (BOS group) and patients who did not develop bronchiolitis obliterans (NON-BOS group) after lung transplantation. LTx=date of lung transplantation. Symbols reflect measurements taken at 4 different time-points: 1st circle: before LTx (pre-LTx); 2nd circle: immediately after hospital discharge following LTx (post-LTx); 3rd circle: at the follow-up visit when the highest forced expiratory volume in one second (FEV1) was measured (peak FEV1); and 4th circle: at the most recent visit (recent value); *statistically significant difference between groups (p<0.05).

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Both groups presented a progressive improvement in FEV1 and FVC in the first months after LTx before achieving similar peak pulmonary function values (FEV1 101±31% predicted vs. 101±25% predicted, p=0.96; FVC 102±29% predicted vs. 101±19% predicted, p=0.80; in the NON-BOS and BOS group, respectively; Fig. 1A and Table 2). After achieving peak FEV1 the BOS group experienced a faster deterioration of pulmonary function as illustrated by significant differences in the evolution of pulmonary function variables (FVC and FEV1) over time between groups (p<0.001 and p=0.001 for group*time interaction of FEV1 and FVC respectively; Table 2). In addition, results of GLM analysis indicate differences between groups at the most recent assessment for both FEV1 (p<0.001; Fig. 1A) and FVC (p=0.013; Table 2). No differences were found in the evolution of TLCO between groups and also not at the most recent assessment (p=0.97; Fig. 1B).

In contrast to the pulmonary function variables and in accordance with previous findings the 6MWD immediately post-LTx was not increased (Table 2). It did only increase in the months following hospital discharge after LTx. The highest 6MWD (% predicted) was achieved close to the peak FEV1 measurement and was similar between groups (76±15% predicted in NON-BOS vs. 74±20% predicted in BOS, p=0.65). Evolution of 6MWD showed a significantly larger decline in BOS patients (group*time interaction: p=0.029; Table 2). Results of GLM analysis further revealed a significant difference in 6MWD between groups at the most recent assessment (p=0.039; Fig. 1C).

No differences between groups were observed in dyspnea symptoms at the peak FEV1 time point (p=0.54; Table 2). The further evolution of dyspnea scores was different between groups (group*time interaction: p=0.024; Table 2). Comparisons with unpaired t-tests revealed a statistically significant difference in dyspnea symptoms between groups at the most recent assessment (p=0.011; Fig. 1D). Evolution of Borg leg fatigue scores was not significantly different between groups (group*time interaction p=0.310; Table 2).

In patients with BOS both changes in dyspnea symptoms and changes in oxygen desaturation during 6MWD (calculated as differences between assessments performed at peak FEV1 assessment and values recorded at the most recent assessment) were significantly correlated with changes in 6MWD (m) (r=−0.447, p=0.048 and r=0.469, p=0.042, respectively) whereas this was not the case in NON-BOS patients (Fig. 2A and B). Changes in leg fatigue symptoms were not significantly correlated with changes in 6MWD (r=−0.194, p=0.219).

Fig. 2.

Panel (A) changes in reported dyspnea symptom scores (Borg CR-10) plotted against changes in six-minute walking distance (6MWD) in meters; panel (B) changes in peripheral oxygen saturation (SpO2) plotted against changes in six-minute walking distance (6MWD) in meters. Δ=differences between values collected at the follow-up visit when the highest forced expiratory volume in one second (FEV1) was measured (peak FEV1) and values collected at the most recent assessment.

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In this retrospective, longitudinal case–control study the functional evolution of LTx recipients with and without BOS diagnosis were compared. Reductions in functional exercise capacity, which were correlated with worsening dyspnea symptoms on exertion, were observed in patients after BOS diagnosis compared with matched patients who did not develop BOS. To our knowledge this is the first longitudinal case–control study showing that patients with BOS after LTx develop significant reductions in FEC and worsening of symptoms.

Our findings are not in agreement with previous observations of stable 6MWD during long-term follow-up in patients developing BOS.7 These different observations might be explained by several factors. First, in the current study all included subjects (n=48) had a complete follow-up after transplantation up to the final assessment. This is in contrast to the study of Gerbase and colleagues in which only 25 of the 58 included patients completed follow-up measurements.7 Patients who dropped out might have been more severely impaired in terms of pulmonary function or functional exercise capacity. This ‘healthy survivor effect’ might have caused the impression of stable 6MWD in the long-term follow-up. By restricting our sample to patients with complete follow-up, we prevented survival bias to influence our results. The larger number of subjects who completed follow-up further increased our ability to detect statistically significant differences between groups. The attainment of about 70–75% of predicted normal FEC at the attainment of peak FEV1 observed in our study is in line with previous findings reporting persisting limitations in exercise capacity after transplantation despite a normal pulmonary function.15–17 In agreement with data from Belloni et al. we observed an initial general increase in FEV1 over time, as well as a concurrent decline of FEV1 and FVC in the BOS group following peak pulmonary function.18 Further support for the validity of our findings (reductions in FEC and increasing symptoms of dyspnea with worsening expiratory flow limitation in the patients who develop BOS) comes from comparisons of our data with observations made in patients with chronic expiratory flow limitation. In patients with COPD, the degree of expiratory flow limitation has consistently been shown to be related to the degree of impairments in functional exercise capacity, and symptoms of dyspnea.19–22 Based on the magnitude of increase in airflow obstruction observed in our BOS cohort (decrease in FEV1 from normal values at peak FEV1 to an average of 44% of predicted normal values after developing BOS) increases in symptoms and reductions in exercise capacity should be expected. The magnitude of observed changes seems physiologically plausible when comparing with data available in patients with chronic expiratory flow limitation.22 It had previously been hypothesized that maintenance of walking capacity in BOS patients might have be achieved by encouraging patients to maintain an active lifestyle. Based on previous data in patients after LTx it seems, however, unlikely that these patients (especially those who develop increasing symptoms of dyspnea due to worsening expiratory flow limitation) will maintain sufficiently physically active.7 Previous studies in LTx recipients with normal pulmonary function revealed that patients remained inactive in comparison to sedentary healthy controls.16,23 Reduced participation in daily activity despite of normal pulmonary function in this patients was strongly associated with remaining impairments in exercise capacity.16,23 The additional dyspnea symptoms developing in BOS patients are likely contributing to further inactivity in this already sedentary group of patients. Again in patients with chronic airflow obstruction it has previously been demonstrated that reductions in participation in physical activity are related to increases in symptoms of dyspnea.22

In patients with normal pulmonary function after LTx peripheral muscle dysfunction contributes importantly to exercise limitation and leg fatigue is usually the main symptom reported by patients to limit exercise, rather than dyspnea.17,24,25 This is in sharp contrast to the situation before LTx where respiratory factors importantly contribute to exercise limitation and dyspnea is usually reported as the main symptom limiting exercise.26 These trends were also observed in the evolution of symptoms in our groups over time (Table 2). While both groups report higher dyspnea scores than leg fatigue scores pre-LTx, they score higher on symptoms of leg fatigue than dyspnea after LTx at the end of a walking test. Again, in patients who develop BOS this trend is reversed at the most recent assessment. Dyspnea symptoms at this point were significantly higher than in NON-BOS patients (Table 2) and were even exceeding their scores before transplantation (Fig. 1D and Table 2). Evolution of weight and BMI were similar between BOS and NON-BOS patients during the follow-up and can therefore be excluded as possible confounding factors for the evolution of FEC in the two groups. The exertional oxygen desaturation that was observed in BOS-patients might also have contributed to the decline in walking capacity (Table 2 and Fig. 2B).

The authors declare no conflict of interests.