Outcomes and survival following lung transplantation in non-cystic fibrosis bronchiectasis

Discussion

Lung transplantation is an accepted therapy for end-stage NCFB, but outcomes are not well-described in the USA due to low volume and single-centre reporting. This study shows that survival of patients undergoing lung transplantation for NCFB in the USA from institution of the LAS to September 2019 is similar to the survival of an age-, sex- and activation date-matched cohort of patients undergoing lung transplantation for other indications. This study also describes the most common causes of death in patients undergoing lung transplantation for NCFB.

Since this is a retrospective study of registry data, some of the specifics regarding lung transplantation are unavailable. For example, it has been shown that the microbiology of the airway before transplant can affect outcomes after lung transplantation. Mattner et al. [10] demonstrated in a German cohort that patients colonised with gram-negative rods prior to transplant had a higher risk of post-operative pneumonia. In the cohort from Birch et al. [11], the only patients who developed Pseudomonas aeruginosa colonisation at one year were those who were colonised with P. aeruginosa prior to their transplant. In the CF population, it has also been demonstrated in a small cohort that P. aeruginosa isolates after transplant match those isolated pre-transplant, suggesting a within-host source [12]. A study by Willner et al. [13] demonstrated that in patients transplanted for CF, recolonisation of the donor lungs with P. aeruginosa is not associated with bronchiolitis obliterans syndrome (BOS). However, de novo P. aeruginosa colonisation of the airway is associated with development of BOS [14]. All of the above demonstrates that the microbiome that develops in the transplanted lung can influence outcomes after transplant. Unfortunately, these pre-transplant microbiological data were not available for review, so we are unable to assess how differences in airway microbiology may have affected mortality.

Several centres have reported their own experience with lung transplantation in the NCFB population, but these studies have lower patient volumes, ranging in patient numbers from 20 to 54 patients. Rusanov et al. [15] published their experience from a single institution over 16 years in Israel comparing lung transplantation for NCFB to lung transplantation for CF lung disease. Their NCFB group of 33 patients had a median survival of 7.1 years post lung transplantation, compared to 8.4 years in the CF lung disease group, a difference that did not reach statistical significance. They also performed a Cox proportional hazard analysis to examine risk factors for mortality, finding that going on cardiopulmonary bypass during surgery was a risk factor for mortality in patients with NCFB. In general, they found that the outcomes for lung transplantation for NCFB and CF lung disease were similar.

Birch et al. [11] also published their experience performing lung transplantation for NCFB. They found that the median survival post-lung transplantation for their cohort of 42 patients was 9.3 years, which was comparable to survival in lung transplantation for other indications at their centre. Several abstracts have been presented recently, which also report single-centre experience with lung transplantation for NCFB. Kennedy et al. [16] found that the median survival at their institution in Australia was 38% at 5 years and noted that this was much worse than their survival for patients transplanted for CF lung disease. Dantas et al. [17] from Portugal found that the survival at their institution at 5 years was 79% and noted that this was better than the survival for other indications. It is unclear what accounts for this dramatic difference in outcomes. The largest study available is from Titman et al. [9], which evaluated outcomes of lung transplantation for all diseases in the UK from 1995 to 2006. Their bronchiectasis cohort was made up of 54 patients, and their median survival was 8.2 years.

Our data agree with what others have found. Survival for patients transplanted for NCFB tends to be comparable to survival for all other indications for lung transplantation. These patients are transplanted in low numbers, yet our study demonstrates that their survival is similar to other patients who undergo lung transplantation.

In many ways, experience from lung transplantation in the CF population is applied to the NCFB patient population. For example, listing criteria and expected outcomes are often extrapolated to the NCFB population from patients with CF [1]. The International Society for Heart and Lung Transplantation guidelines for lung transplant recipient selection either do not give guidance regarding recipients with NCFB [18] or NCFB is combined with CF lung disease, with the admission that data for NCFB are limited [19, 20].

In addition, we found an age discrepancy for transplanting the NCFB population. The average age of diagnosis for these patients is 57 years old [3], yet our study found that the average age of lung transplantation listing was actually 10 years younger, at 47 years old. This age discrepancy suggests a few important points. First, it suggests a selection bias for referred and transplanted subjects. It is possible that the lack of listing criteria specific to bronchiectasis leads to fewer patients being referred to transplant and a more stringent screening process. A more stringent screening process for transplantation may produce transplant candidates that are younger and have fewer comorbidities. Second, registry data show that patients with CF tend to have lung transplantation at a younger age. Sethi et al. [21] found in the UNOS registry that the average age of patients undergoing lung transplantation for CF was 31 years, much lower than the average of 47 years for the NCFB patient group. It is possible that younger patients with NCFB are more likely to meet criteria for lung transplantation listing developed for CF and thus are referred more often. Criteria that are more specific to NCFB may allow older patients to undergo transplantation.

There is evidence that the application of CF criteria for transplant is poorly applied to the NCFB population. For example, Hayes et al. [22] demonstrated that patients with advanced NCFB had significantly lower waitlist mortality compared to patients with CF lung disease. Given the differences in demographics and associated comorbidities, such as liver and pancreatic disease in the CF population, these patient groups may be too dissimilar to allow the same criteria to be used for consideration of lung transplant. It may be more appropriate to develop a separate set of criteria for listing patients with NCFB. New bronchiectasis severity scores, such as the Bronchiectasis Severity Index or the FACED [23, 24], may assist in the development of listing criteria for bronchiectasis specifically.

This study has several strengths. First, it is the largest study to evaluate outcomes of lung transplantation in NCFB. There have been several studies reporting single-centre experience in this area, but the patient numbers are small. This study presents survival data on a patient cohort more than twice the size of the largest studies published elsewhere. Second, the data came from multiple centres, which avoid the bias of a single institution's practices and outcomes.

This study does have limitations. It is retrospective in nature. Given the extensive screening process that is used in lung transplantation, the data may be subject to a selection bias. As discussed above, the lack of established guidelines for when to perform lung transplantation for NCFB may make physicians shy away from selecting these patients for lung transplantation. Comparatively, this may mean that younger and otherwise healthier patients undergo lung transplantation for NCFB compared to the patients who undergo lung transplantation for other indications. We sought to avoid this selection bias by comparing survival against age-, sex- and activation date-matched controls.

Another weakness of this study is that it covers a long time period, during which many advances have been made in immunosuppression, surgical techniques and lung allocation. The outcomes presented here are an average over that time and may not reflect the expected outcomes of a patient undergoing lung transplantation for NCFB today. The survival data presented are from the LAS period and are more recent. These survival data are probably more reflective of the outcomes that can be expected today for lung transplantation for NFCB.