Outcomes of lung transplantation in adults with bronchiectasis

Bronchiectasis is an abnormal dilation of the bronchi and bronchioles that results in chronic cough, sputum production and recurrent infections. Bronchiectasis can lead to progressive loss of lung function, resulting in chronic morbidity and premature mortality [1]. Bronchiectasis not due to cystic fibrosis (often referred to as non-cystic fibrosis bronchiectasis; thereafter BR) has diverse causes, though post-infectious and idiopathic bronchiectasis are the most common [2, 3].

BR has been identified as a cause of increasing morbidity and mortality in the U.S. and Europe [4‐6]. As Bronchiectasis is increasingly encountered (or recognised) there is a greater need to understand the benefits and risks of lung transplantation for this indication. Lung transplantation is an intensive therapeutic intervention that can be performed for the treatment of end-stage BR [7, 8]. However, the recent guidelines from the British Thoracic Society (BTS) specifically note scarce data on the results of lung transplantation for bronchiectasis [2]. This knowledge gap results in uncertainty for clinicians in managing patients with more severe bronchiectasis.

A number of studies have assessed the association between pathogenic microorganisms and prognosis in adult BR. Persistent Pseudomonas aeruginosa infection is seen in approximately 30-40% of BR patients and it is linked with a poorer quality of life and increased mortality [9, 10]. Furthermore, it predicts a more severe disease phenotype with increased hospitalisation rates and is associated with poorer lung function and accelerated functional decline in BR patients [9‐12]. In some settings, Pseudomonas infection post-transplantation has been linked with increased rates of allograft dysfunction/obliterative bronchiolitis [13]. In contrast, information regarding the prognostic effects of pre-transplantation Pseudomonas status on both early and long-term outcomes of lung transplantation for BR remains limited.

In view of the above, we aimed to assess the survival outcomes of patients transplanted for BR at our centre. Additionally, we aimed to investigate a range of pre-transplant factors including pre-transplantation microbiology and their relationship to post-transplantation outcomes.

Our primary outcome of interest was post-transplant survival in those transplanted for BR. Other aims were to describe the demographic profiles of patients transplanted and the post-transplant outcomes in patients with BR as compared to other lung transplant indications

The total number of lung transplantation procedures performed for all indications at data capture (1990-2013) was 752, with 42 lung transplantations performed for BR (6% of the total lung transplant population). There were 39 patients that underwent BSLTx from cadaveric donors, one patient had single lung transplantation (SLTx) and two patients had heart-lung transplantation. Lung transplantation commenced at this institution in 1987 with the first transplantation for BR performed in 1990. The assessment protocol has evolved in this time period and hence full datasets are not available for all parameters.

There were 25 patients transplanted for BR between 1990 and 2000 from a total of 260 lung transplants performed (9.6%). Significantly fewer were transplanted between 2001 and 2011; 17 from a total of 429 (4.0%; Chi-square test, p<0.001). Thus, lung transplantation for BR was less frequent in the second 10-year time cohort compared to the first 10 years of transplantation. All recipients were adults (age >17 years), with a mean age at transplantation of 47.1 years (range; 22.6-62 years). There were 13 female patients (31%) and 29 male patients (69%) transplanted. For the control cohort (all sequential single lung transplants performed for any other indication) the mean age was 42 years with 42% female and 58% male (the majority of these other indications were cystic fibrosis and COPD without bronchiectasis).

Despite exciting new therapeutic pipelines in BR, a rising mortality rate and increasing hospitalisation rates for BR suggests there are significant unmet medical needs [6, 9]. Lung transplantation is one option for managing severe end stage BR. Lung transplantation for BR accounts for 6% of all lung transplantations performed at our centre, a distribution similar to that of the International Society for Heart Lung Transplantation (ISHLT) registry [21, 22]. We noted excellent post-transplant outcomes with greater than 50% survival at 5 years. Our outcomes were comparable to lung transplant outcomes for other indications at our centre. Our approach has predominantly been with BSLTx, which has been argued as the procedure of choice for this group of patients [21, 22]. Notably BR has been calculated to have a better cost effectiveness outcome following lung transplantation as compared to COPD, the commonest indication for lung transplantation [23]. The combined UK transplant experience also suggested that BR has one of the best post-transplant outcomes [24].

In view of this, the low rates of lung transplantation for BR need to be considered. They may be due to a number of factors including concerns about the risk benefit ratio of lung transplantation in BR. The prevalence of BR peaks in older patients who may be perceived beyond the optimal window for lung transplantation. Furthermore the lack of a validated prognostic scoring systems for BR in contrast to those for COPD may prevent timely referral for lung transplantation [25]. The role of either of the recently published indices, Bronchiectasis severity index (BSI) [4] or FACED score [14] in guiding transplant referrals remains to be defined. We noted that the majority of patients were classified as severe bronchiectasis using BSI but not with FACED. Further studies are needed to define the role of these scores in helping prompt referral for transplant assessment. These latter scores underrepresent those with severe disease until the age is beyond 70 years due to the weighting of the scores.

As highlighted in recent BR guidelines very few studies have examined lung transplantation in detail. The survival in our series was similar to the survival figures previously reported by our institution for CF patients [16].

The most recent case series of 34 patients from Germany reported good outcomes for bronchiectasis with one-year Kaplan-Meier survival for patients with bronchiectasis being 85% and 5-year survival being 73%. These outcomes were comparable to the overall lung transplant cohort. Notably however the mean age group was much younger at 40 years. In those with pre-transplant Pseudomonas infection poorer outcomes and higher rates of BOS were reported from the Hannover group [26]. The UK wide experience spanning 5 centres with 123 BR patients listed for transplantation was noted in a study of all lung transplant indications published in 2009 [24]. Unfortunately, little in depth data beyond survival in BR were available but the study demonstrated only 54 BR patients listed survived on the waiting list to transplantation (48%). Of those transplanted the median waiting time on the list was nearly 1 year with a median post-transplantation survival of 3000 days. Notably the BR post-transplantation survival was the best of 5 major indications for lung transplantations. Despite this apparently good outcome it seems unlikely that the BR cohort were less sick than the other indications studied; along with interstitial lung disease, BR had the highest “on-list” pre-transplantation mortality rates (59/123 died on the waiting list). This correlates well with our observed high rates of respiratory failure and secondary pulmonary hypertension in our cohort.

The ISHLT registry data show that the major causes of mortality in the first year following lung transplantation for any indication are graft failure and infection. We noted a large range of pathogens with potential to complicate the early postoperative period. Our immediate pre-transplantation rate of Pseudomonas infection was 45%, which is broadly similar to a prior Spanish series of 17 patients where 64% of patients had Pseudomonas infection pre-transplantation [27]. These contrast with our experience in CF, where the majority of patients had Pseudomonas pre-transplantation [16].

BR transplant recipients could be predicted to suffer high rates of infection or, in the event of over-cautious immunosuppression, high rates of acute rejection. Firstly we observed an early septic death rate of 7%, which appears similar to that observed elsewhere for other non-septic lung transplantation [16]. Whilst there were high rates of multi-resistance in those with Pseudomonas infection, none were pan-resistant. Furthermore, the septic deaths were unrelated to Pseudomonas infection per se. The prior literature denotes that Pseudomonas infection is seen in those with more severe bronchiectasis, which has led other authors to conclude that it is a marker of more severe lung disease. It is plausible that a non-significant trend towards more deaths in the Pseudomonas group herein reflects more severe disease. Alternatively, as suggested by Rademacher and colleagues in the Hannover series, Pseudomonas may be driving poorer outcomes [26].

The previously noted UK wide BR transplant data set of 54 patients is likely to include many of the 37 BR patients transplanted at Papworth Hospital, reported in a case series in 2005 [28]. In this cohort, 32 were defined as “bronchiectasis alone” and the remaining 5 had an antibody deficiency that required immunoglobulin replacement therapy. In this latter case series the observed actuarial survival was similar in the 2 groups (81% at 12 months in the bronchiectasis group and 80% in the antibody deficiency group). The post-operative complication rates were acceptable with infection episodes per 100 patient-days for bronchiectasis alone being 0.90 vs. 0.53 and rejection episodes per 100 patient-days being 0.59 vs. 0.24. Whilst we did not quantify rejection rates in this manner, our rates of symptomatic or surveillance rejection were not detected.

Whilst this is the largest single centre study of lung transplantation in bronchiectasis to date limitations of our study should be acknowledged. These include missing data points: whilst there were 28 deaths we could only report data on 13 of these cases reflecting that many of the deaths occurred late transplant and occurred at the referring centre and not transplant centre. The newer definition of chronic lung allograft dysfunction (CLAD) [19] was not used in our study awaiting ISHLT guidelines on the implementation of CLAD. The study is limited by the sample size that are inherent in the single centre retrospective design. Furthermore there have been changes in both our peri transplant protocols reflecting novel immunosuppressants and anti-viral agents used over the study period. Additionally the majority of the transplants performed are sequential single lung transplants so we cannot define the differences between heart-lung transplantation and our preferred operative type. Larger multicentre studies, with multivariate analyses, that define pre-transplant characteristics that are associated with increased risks of early deaths would be helpful. Nevertheless our study highlights important findings that have not been reported before. Important areas to be considered for future studies will be an assessment of rejection rates and frequency of and prognostic implications of clonal Pseudomonas strains [29].

Transplantation for BR has excellent outcomes yet poor on-list survival [24]. In our experience the numbers of transplants for this indication may be declining for reasons unknown. Physicians should consider transplantation as an option in those with severe bronchiectasis.