Lung transplantation is an established treatment for end stage pulmonary disease [10]. The number of clinical lung transplantation is limited by the shortage of organs, which have resulted in a constant searching for new ways to increase the number of organs [11,12,13,14], while survival after lung transplantation mainly limited by CLAD. Survival after lung transplantation has improved significantly over the last decade, however, CLAD, predominantly manifesting as BOS, remains the primary cause of morbidity and mortality after LTx. Although the risk of developing BOS within the first year is low, cumulative incidence of BOS quickly increases within the first five years [9, 15, 16].
The risk factors for BOS are still not fully understood [17]. Anti-human leukocyte antigen (HLA) donor-specific antibodies (DSA) have been associated with early and high-grade BOS and death after LTx in some studies but is still controversial [18, 19]. Treatments to remove antibodies or limit antibody-mediated damage using plasmapheresis have been shown to have some effect when DSA are first detected. However, the impact of this treatment on clinical outcome following LTx remains unclear [20]. Bacterial and viral infection has also been identified as a possible trigger of BOS after LTx [21, 22]. Although BOS was generally thought to be irreversible, recent evidence suggests that some patients with BOS may respond to azithromycin with an improvement of their FEV1 with more than 10% [22]. In addition, another form of chronic rejection, restrictive allograft syndrome (RAS), has recently been described, which does not fit the BOS definition but is instead characterized by restrictive functional changes involving peripheral lung pathology, leading to the introduction of the more encompassing term CLAD [5, 23].
The overall cumulative incidence of BOS grade ≥ 2 among our 278 recipients was 15% after 5 years, 26% after 10-years, 30% after 15-years, and 32% after 20 years post-transplant. The incidence of BOS was highest among the group referred to as “other”. This group describes a heterogenic group of patients who underwent LTx due to bronchiectasis, sarcoidosis, bronchioalveolary cancer, silicosis, BOS, and graft-vs-host disease (GVHD) that might reflect the high incidence of BOS. The group’s heterogenic appearance makes it difficult to draw any conclusions. Besides the group “other,” the highest incidence of BOS was seen among PF recipients followed by CF, COPD, PH, and AAT1 recipients in the described descending order. It has been shown that BOS and PF respectively exhibit similar disease characteristics with overlapping pathophysiology such as epithelial cell injury and increase in production/deposition of ECM [24]. This patient group is of great interest as the identification of biomarkers in PF could contribute to finding new means of earlier finding BOS [25]. The highest mortality was seen among COPD recipients followed by PH, AAT1, PF, and CF recipients in the described descending order, indicating that CF and PF recipients have a better chance of survival despite developing BOS compared to the other major indications such as COPD and PH. However, it should also be acknowledged that patient outcome among LTx-recipients in Sweden might differ in comparison to other countries such as the US due to a significantly higher incidence of COPD/CF vs. interstitial lung disease, in combination with Sweden having younger recipients [26]. As well as reports from the ISHLT showing almost double the incidence of interstitial lung disease in LTx in comparison to Sweden.
When we compared the different patient groups (pairs of two) of major indications between each other, the group referred to as “other” had significantly higher risk of developing BOS (grade ≥ 2) compared to COPD, AAT1, and PH recipients, keeping in mind that this group of recipients reflects a heterogeneous group of patients where some of the recipients underwent LTx due to BOS and GVHD and where the recipients probably already at the time of transplantation have an immunologic response that might lead to the development of BOS in the pulmonary graft.
Recipients with CF had a significantly higher risk of developing BOS compared to AAT1 recipients, but AAT1 had a significantly higher mortality rate, indicating that CF recipients might withstand the development of BOS better than AAT1 recipients. This finding could have a positive effect on the clinical implication of favoring CF recipients in LTx. Previously the overall survival benefit of LTx in CF has been reported as controversial due to associated risk factors such as CF-related arthropathy as well as associated chronic infections with bacterial/fungal agents like B.cepacia, P.Auriginosa and Aspergillus that can be serious and life-threatening [27]. Interestingly, recipients with CF had a significantly higher risk of developing BOS compared to PH recipients, however, CF and PH recipients had the same mortality, indicating that CF and PH recipients developing BOS have the same chance of survival despite BOS. It has been shown that PH patients undergo extensive remodeling of the pulmonary arterial walls as part of their pathophysiology, leading to permanent changes of the intima [28]. However, PH is also seen post-LTx among different recipients as bronchiolitis obliterans is often associated with immune-mediated arterio- and venopathy leading to pre- and post-capillary PH [29]. It could be theorized that patients with PH prior to LTx might better withstand this phenomenon, indicating why PH recipients don’t show inferior survival to CF despite BOS. The clinical implication of understanding the development of BOS in this disease state could be of immense potential. This hypothesis was however not investigated in this study with the need of further data.
Recipients with CF and COPD had the same incidence of BOS, but COPD recipients had a significantly higher mortality, indicating that CF recipients might withstand the development of BOS better than COPD recipients. COPD recipients are often older than CF patients at the time of transplant, and the COPD patients often have comorbidities such as heart and vascular disease that might in part explain these results. We did an expanded analysis to investigate the impact of age on the development of BOS and the risk of death. We concluded that age had no impact on the development of BOS, but recipients 50 years or older had a 9% higher mortality 5 years post-transplant and a 16% increased risk after 10 years post-transplant compared to recipients younger than 50 years (p < 0. 05).
Interestingly, when we compared DLTx to SLTx in the entire cohort we found that DLTx and SLTx recipients had equal risk of developing BOS grade ≥ 2. However, recipients receiving DLTx had a significantly better chance of surviving. These results further support a clinical program favoring DLTx instead of SLTx. We tried to analyze the pattern of DLTx and SLTx among major indications such as COPD, but unfortunately the groups were not big enough to reach statistical evaluation. Our findings indicate that DLTx and SLTx had the same risk of developing BOS, but DLTx had a better chance of survival. We suspect that these results might reflect the fact that during the last 10–15 years, we have initiated early treatment for viral and bacterial infection, used more aggressive therapy at the first sign of rejection, and favored DLTx over SLTx. The frequency of SLTx reached its peak in 2002 at our clinic and has significantly declined since then in favor of DLTx. However, our results did not support these hypotheses as no difference was found between the risk of BOS or mortality in different time periods. In Fig. 5 we show the results for the two different time periods 1990–2002 and 2003–2014.
Limitations
There have been significant changes in the care of transplant patients over the last 25 years, which affects outcome variables such as survival depending on year of transplantation. Recipient inclusion criteria have broadened over the years and now preoperative ECMO support or ventilator support are no longer contraindications for LTx, representing a complex recipient clientele. Several confounding factors have been linked to long-term survival in LTx that could be playing a role here. Such variables are recipient/donor age and total lung capacity in addition to recipient kidney function, O2 requirement and allograft ischemic time. In the present study patients diagnosed as BOS grade 1 did not, in the majority, of the cases get a specific treatment or an alternation in the present regime even though the patient was diagnosed with BOS. It is possible to diagnose BOS through spirometry, where according to ISHLT a drop in FEV1 more than 20% from baseline is associated with BOS grade ≥ 1. Though possible confounders that might affect post-operative pulmonary function besides BOS are recurring infections or a decline in FEV1 affected by the natural aging-process or other comorbidities. It should also be acknowledged that the definition of FEV1 < 80% from best baseline for BOS is debatable in comparison to current CLAD criteria, such as phenotyping into BOS vs. RAS. To differentiate those who really have a rejection (BOS) or not, we have in this analysis calculated BOS as BOS grade 2 or more. This can of course be cautious to follow.