INTRODUCTION

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Lung transplantation has become an accepted treatment option for selected patients with end-stage parenchymal or vascular lung disorders. Between 1982 and 1998, more than 10,400 thoracic procedures, combining heart-lung and single and double lung transplantations, have been reported worldwide. Although the growth in the number of lung transplantations appears to level off or even to decrease since 1993, the number of thoracic transplant centers still continues to grow (1, 2).

Short- and medium-term results of lung transplantation are improving because of improvements in surgical techniques and postoperative care and undoubtedly accumulating medical experience (3). Reported 1- and 3-yr survival rates as great as 80 and 65%, respectively, are encouraging (3). Unfortunately, the prospects for long-term survival are not so favorable. Chronic transplant dysfunction has emerged as the major complication after heart-lung or lung transplantation. Already in 1984, a clinical syndrome of progressive dyspnea and increasing airway obstruction had been described after heart-lung transplantation (4). Nowadays, this clinical syndrome, better known as bronchiolitis obliterans syndrome (BOS), affects nearly half of the long-term survivors of lung and heart-lung transplantation, with a median onset between 417 and 689 d after transplantation (5). The presence of BOS is associated with increased morbidity, and it is the major cause of mortality after 1 yr post-transplantation (8).

In 1992, a technology assessment (TA) study of the lung transplant program in our hospital was initiated. Until this moment, this TA continues to provide information on several aspects of the program, including health-related quality of life (HRQOL) effects. Apart from survival and prevalence of BOS, HRQOL is an important outcome measure (9). It has even been stated that for some patients with certain diagnoses, especially emphysema, the only benefit to be gained from lung transplantation is an improved HRQOL (10).

In the present study, the relationship between BOS and the HRQOL of Dutch lung transplant recipients was investigated. The present study focused on changes in physical, psychological, and social functioning in both a BOS and a non-BOS group, up to 49 mo after transplantation. Both a cross-sectional analysis, to compare HRQOL in patients with and without BOS, and a longitudinal analysis was performed, to study changes in HRQOL over time in patients developing BOS.

	METHODS

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Patients and Design

Between November 1990 and June 1998, 116 primary thoracic transplant procedures have been performed at the Groningen Lung Transplant Program: 93 bilateral lung transplantations, 22 single lung transplantations, and one heart-lung transplantation. The indications and patient characteristics are stated in Table 1. Two methods were employed to study the relationship between HRQOL and BOS. First, a cross-sectional comparison was made between patients with and without BOS. The number of patients who completed the questionnaires varied from 72 at 4 mo post-transplantation to 27 at 49 mo after transplant. Second, a longitudinal analysis was performed to study changes of HRQOL in the same group of patients over time.

Immunosuppression

All recipients were treated with conventional triple maintenance immunosuppression, consisting of cyclosporine, azathioprine, and prednisolone, after induction therapy of antithymocyte globulin. Cyclosporine administration was aimed at a trough level of 400 ng/ml at the start, as determined by high-performance liquid chromatography, and tapered in 3 wk to 150 ng/ml. Azathioprine (initially 2.5 mg/kg/d) was titrated to a leukocyte count between 4,000 and 7,000 cells/µl. Intraoperatively, a bolus of methylprednisolone (500 mg) was given at reperfusion of each lung, followed by three doses of 125 mg on the first postoperative day. Subsequently, prednisolone was given at a once-daily dosage of 15 mg. Acute rejection was treated with 1 g of methylprednisolone daily on 3 consecutive days, or with antithymocyte globulin in resistant cases. When BOS was diagnosed a 3-d course of methylprednisolone (500 to 1,000 mg/d) was given in the majority of the patients, or antithymocyte globulins in selected cases. During the last 2 yr, most patients with BOS were converted from cyclosporine to tacrolimus, or from azathioprine to mycophenolate mofetil if the renal function had deteriorated or if the stage of BOS progressed despite the use of tacrolimus.

Follow-up of Patients

All patients were seen at our outpatient clinic once every week for as long as 4 mo, and once every 2 wk until 7 mo after transplantation. Between 7 and 13 mo after transplantation, visits were made with intervals of 4 wk, and between 13 and 24 mo with intervals of 6 wk. Two years post-transplantation, visits were scheduled every 3 mo. If deemed necessary, patients were seen even more frequently. Spirometry was performed on all outpatient visits and twice a week when patients were hospitalized.

Definition of BOS

Patients were defined as having BOS according to the criteria of the International Society for Heart Lung Transplantation (11), either on functional data, if there was a sustained and significant decline in FEV₁ to less than 80% of a previously established baseline value, or on the presence of obliterative bronchiolitis in biopsies, even if the lung function had not deteriorated.

HRQL Assessment

Since December 1992, HRQOL questionnaires were sent to lung transplant recipients 18 yr and older at 4 mo, 7 mo, and then every 6 mo, until 49 mo after transplantation. The questionnaires consisted of a combination of generic and domain-specific health status measures. As a generic health state measure we used the Nottingham Health Profile (NHP, part I), which has been validated in several populations of patients and healthy volunteers (12). Domain-specific health status measures consisted of the State-Trait Anxiety Inventory (STAI) (13), the Self-rating Depression Scale-Zung (Zung) (14), and the Index of Well-Being (IWB) (15), to assess, respectively, anxiety, depressive symptoms, and well-being. Possible scores range from 0 to 100 for NHP, 25 to 100 for Zung, 20 to 80 for STAI, and 15 to 2 for IWB, with the best possible health status represented on the left and the worst possible health status on the right

Statistical Methods

All data analyses were performed using software (SPSS 7.5; SPSS, Inc., Chicago, IL). Freedom from the bronchiolitis obliterans syndrome was determined by Kaplan-Meier estimates. The Kolmogorov-Smirnov test was used to compare the distribution of the patient's responses to each HRQL measure with the standard normal distribution. In analyzing the cross-sectional data, differences between the NHP scores in the BOS group and the non-BOS group were tested with the Mann-Whitney U test. In assessing the differences between the STAI, Zung, and IWB scores in both groups, Student's t test was used.

In analyzing the longitudinal data, the changes in STAI, Zung, and IWB scores after developing BOS were tested with the use of repeated measures of variance, whereas Friedman's test was used to test changes in NHP scores. Post-hoc comparisons were made using the paired t test or Wilcoxon's test, respectively. All test results with chance probabilities < 0.05 were considered statistically significant.

	RESULTS

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Patient Characteristics

No significant differences regarding sex, age, type of transplant, and underlying diseases could be found between all recipients (with or without BOS in cross-sectional analyses, or those developing BOS) (Table 1).

Freedom from the Bronchiolitis Obliterans Syndrome

The actuarial freedom from BOS (mean ± SEM) in our population was 68 ± 5%, 64 ± 5%, 56 ± 5%, and 46 ± 6% at, respectively, 1, 2, 3, and 5 yr post-transplantation.

Cross-sectional Analysis of Difference in HRQOL between Patients with and without BOS

Patients with BOS reported statistically significantly more restrictions on the dimension physical mobility of the Nottingham Health Profile at 7, 19, 25, and 31 mo post-transplantation compared with patients without BOS (Table 2). Also, statistically significantly more restrictions were noted on the dimension energy of the NHP at 7, 13, 19, and 25 mo after transplantation. Other time points did not reveal statistically significant differences in mobility and energy. No difference at any point in time could be found for the dimensions pain, sleep, social isolation, or emotional reaction of the NHP between transplanted patients with or without BOS (data not shown).

Compared with recipients without BOS, patients with BOS also reported statistically significantly more depressive symptoms and feelings of anxiety at 13 and 25 mo after transplantation (Table 3). Scores on the Index of Well-Being in the latter group were significantly reduced at 13, 19, and 25 mo post-transplantation, compared with patients without BOS.

Transplanted patients without BOS did not differ from a normal healthy population on all measures, with the exception of the Zung, as much as 49 mo after transplantation (Tables 2 and 3). All transplanted patients, with or without BOS, reported higher depression scores.

Longitudinal Analysis of Association between BOS and HRQOL

From a total of 52 patients with BOS in our population, 22 filled out the questionnaires before and at two time points after the development of BOS. The measurement of HRQOL before development of BOS (T0) took place at a median of 7 mo (range 1 to 38 mo) after transplantation. BOS was established at a median of 5 mo after T0 (5 to 42 mo post-transplant), followed by the first measurement of HRQOL (T1) after a median of 2 mo after BOS (range, 7 to 44 mo post-transplant). The second measurement of HRQOL after BOS (T2) occurred at a median of 7 mo (range, 13 to 50 mo post-transplant) after T1. Thirty patients could not be included in the longitudinal analysis for the following reasons: 10 patients died before T2, seven patients only recently developed BOS, three patients had developed BOS before the start of the study, five patients developed BOS before the first measurement of HRQOL after transplantation, i.e., within 4 mo, two patients were younger than 18 yr of age, and three patients were unwilling to cooperate.

No statistically significant difference could be found for depressive feelings (Zung) before and after development of BOS (Table 4). Scores on the STAI scale increased significantly after the development of BOS. This increase in reported feelings of anxiety occurred more or less simultaneously with the development of BOS; no further increase could be noted for the second measurement after BOS. Also, a significantly lower IWB was found after development of BOS, showing a more gradual deterioration.

Statistically significantly more restrictions were reported on the dimensions energy and physical mobility of the NHP after the development of BOS. Furthermore, the reported restriction in energy appeared to increase over time, as a statistically significant difference could be found between the first and second measurement after the development of BOS. No association could be found between the onset of BOS and any other dimension of the NHP.

	DISCUSSION

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Only two previous reports have mentioned a relationship between BOS and a reduced HRQOL, derived from observations in small patient groups (9, 16). The present study has shown that lung transplant patients with BOS experience a lower HRQOL than do recipients without this condition. The reduction in HRQOL associated with BOS is already apparent soon after transplantation, and it remains detectable for as long as 2.5 yr post-transplantation. However, not all domains of the NHP were affected. Particularly, patients with BOS reported statistically significantly more restrictions on the dimension physical mobility of this health profile. The explanation for this may be that a decrease in lung function, which is a hallmark for the diagnosis and staging of BOS (11), leads to an impairment in physical mobility. Indeed, a weak but statistically significant correlation between the percent predicted FEV₁ and the score on the dimension physical mobility of the NHP has been reported after heart-lung transplantation (17).

Studies on HRQOL after lung or heart-lung transplantation are limited in number. The results of most longitudinal (9, 16) and cross-sectional analyses (19) suggest that transplant recipients experience better HRQOL than do transplant candidates. Moreover, this improvement of HRQOL seems to be sustained, possibly as long as 3 yr after transplantation (9, 16). We can now add our series of recipients without BOS, ranging from 60 patients to 18 patients at, respectively, 7 mo to 49 mo post-transplantation. Patients without BOS reported scores similar to those of a normal population on all dimensions and measures of HRQOL used, except for the Zung scale. Although this represents a selected population, it indicates that lung transplant recipients may enjoy a normal HRQOL in the absence of BOS. If the results of the present study are compared with the HRQOL of lung transplant candidates, as reported previously by our group (9), it becomes readily apparent that lung transplantation, among others, confers at least a temporary normalization of HRQOL. This means that all patients who are to be transplanted may benefit from a lung transplantation initially, even if this benefit is not sustained when BOS occurs.

The number and severity of episodes of acute rejection have been identified as one of the most important risk factors for the development of BOS (3, 5, 8, 22); another risk factor may be cytomegalovirus pneumonitis (25, 26), although this remains disputed (3). Often, these complications of lung transplantation require hospitalization. Nonetheless, the results from our longitudal series show that a reduction in HRQOL becomes apparent only after a diagnosis of BOS, suggesting that these early complications do not influence HRQOL, or perhaps only slightly and not detectable by the measures used.

No effective treatment is currently available for BOS. In general, augmented immunosuppression is given, either with short-term courses of high doses of corticosteroids or antithymocytic globulins as was common in the past, or more recently, with conversion to the newer immunosuppressants such as tacrolimus or mycophenolate mofetil (27). It is tempting to speculate that the change in immunosuppression may contribute to a reduced HRQOL. Unfortunately, although we report on the largest series of patients with BOS and HRQOL, the number so far is not sufficiently large enough to perform subgroup analysis.

The limitation of a cross-sectional analysis is analysis of potentially different groups of subjects, whereas a longitudinal analysis may be handicapped by loss of subjects. As the results of both approaches in our study are indeed similar, we are confident that the BOS-associated reduction in HRQOL is not merely a fortuitous one.

In summary, patients with BOS reported a statistically significant lower HRQOL than did recipients without BOS. This effect becomes readily apparent after, but not before the development of this complication. Notwithstanding this observation, even patients who develop BOS may at least temporarily benefit from a lung transplantation with regard to HRQOL. Our study reemphasizes the need to focus efforts on prevention of BOS to enhance both survival and health-related quality of life.