Chronic obstructive pulmonary disease (COPD) is a very prevalent pathology, and it is associated with high morbidity, mortality and a great burden for health systems.1,2 Approximately 400 million people around the world are affected by COPD,3 constituting the fourth cause of death.

Lung transplantation is the only therapeutic alternative in very severe patients who have progressive deterioration despite receiving a correct treatment. According to the international pulmonary transplant registry data, COPD is the most frequent indication of lung transplantation in the world with a median survival of 6 years after transplantation.4 There is some controversy over whether the transplant provides a significant increase in survival5–7 in COPD, although it has been demonstrated a marked improvement in lung function, gas exchange, stress tolerance and quality of life of patients with this pathology.8 Much of the success of the transplant will reside in an adequate selection of the donor and recipient.9

Since it has been recognized that COPD is a heterogeneous disease characterized by chronic airflow obstruction in which exacerbations and comorbidities can contribute to its severity, an attempt to group patients with similar characteristics that could be associated to a differential clinical outcome has been done by using the term clinical phenotype.10 The approach to the patient based on clinical phenotypes allows them to be classified into subgroups with prognostic value and to determine the most convenient therapy, potentially obtaining better results.11,12 In this way, we have moved from an approach based on the severity of the obstruction to a more personalized approach. After a review of the literature we have not found any scientific work that describes the prevalence of the different COPD phenotypes in patients who are referred for transplantation, nor their potential impact on future evolution if they become transplanted.

Based on the above we have developed this work, where we hypothesize that the distribution of the phenotypes of the patients evaluated for transplantation is not homogeneous and that these clinical phenotypes can influence post-transplant evolution in terms of complications and survival.

Of the 502 patients analyzed, 196 (39%) had a diagnosis of COPD. After excluding 23 patients diagnosed with emphysema due to alpha-1-antitrypsin deficiency, we defined a final cohort of 173 patients. The flow chart of these patients can be seen in Fig. 1.

Fig. 1.

Flowchart of study population.

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The main characteristics of the patients evaluated for transplantation are shown in Table 1. The patients studied were mainly men (79.2%), with a mean age of 59.7 years (Standard deviation [SD] 6.1), and a very severe obstruction (forced expiratory volume in the first second [FEV1] average of 27.5% [SD 9.9]), patients have 1.2 (SD 1.9) exacerbations on average in the previous year, a BODE of 6.6 (SD 1.6) and around half of the patients were treated with triple therapy.

Complications and post-transplant evolution

With a mean follow-up of 1365 (SD 580) days, we observed a higher non-significant incidence of acute rejection, chronic rejection and mortality in patients with exacerbator phenotype compared to the rest (Table 4). When analyzing survival curves based on their phenotype at the time of transplantation (Fig. 2), we observe that, once transplanted, the survival of patients with COPD turned out to be higher in patients with ACO phenotype (1432 days [SD 507.5]) followed by non-exacerbating patients (1317.8 days [SD 544.7]), and the exacerbating phenotype had the shortest post-transplant survival time (1115.1 days [SD 587]); although these differences did not reach statistical significance (p log Rank=0.16).

Table 4.

Complications and evolution of transplanted patients according to their COPD clinical phenotype. (ACO: asthma COPD overlap).

	Total	Non exacerbator n(%)	Exacerbator n(%)	ACO n(%)	p
Acute rejection	5 (11.6)	2 (6)	2 (16)	1 (50)	0.113
Chronic rejection	2 (4.6)	1 (3.2)	1 (10)	0 (0)	0.64
Dead	14 (29.8)	8 (24.4)	6 (50)	0 (0)	0.159

Fig. 2.

Comparison of post-transplant survival according to the clinical COPD phenotype.

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The most COPD-phenotype evaluated for lung transplantation is the exacerbator, which is also the most likely to be discarded to be transplanted and, of those who are transplanted it is the one with the worst clinical evolution. Although this is not the first study that makes an assessment of patients with COPD referred for pulmonary transplant evaluation,15 it is the first one to date that has studied the prevalence of different COPD phenotypes among patients assessed and submitted for lung transplantation.

Real-life studies16 conducted in Central European population of patients seen in outpatient clinics establish that, unlike this work, where the exacerbator phenotype prevails, the majority of patients with COPD (63%) had a non-exacerbating phenotype, representing 30% exacerbator phenotype and 9.5% ACO. Specific studies from Spain show a lower prevalence of the exacerbator phenotype (around 20%) and a higher prevalence of the ACO phenotype (15.9%).17 Among the reasons that would justify this difference would be that the population referred for transplant, object of this study, is a more selected population, mostly in a terminal respiratory failure status and more fragile, being these patients the most susceptible to exacerbations and hospital admissions. Perhaps, the lack of differences in the baseline clinical and therapeutic characteristics of the patients assessed, unlike other published works,18 represents the uniformity in the extreme clinical severity of these patients, derived after having exhausted the different therapeutic possibilities.

International guidelines recommend referral for transplant evaluation to those patients where the disease is progressive despite maximum treatment that includes rehabilitation, has a BODE between 5 and 6, pCO2>50mmHg and/or pO2<60mmMg or FEV1<25%. On the other hand, they recommend accepting for transplantation and put the patient on the waiting list when one of the following criteria is met: BODE≥7, FEV1 between 15 and 20%, three or more severe exacerbations in the last year, an exacerbation with acute hypercapnia or the presence of pulmonary hypertension.9,19 Since this cohort presented an average BODE of 6.6 reflects an adequate reference to be assessed as potential transplant candidates.

Although the patients with exacerbator phenotype are the most referred, the final transplant rate is 12%, indicating that the vast majority of them were discarded for this procedure. Different studies have shown that these patients have a higher prevalence of cardiovascular pathology and other comorbidities such as depression, insomnia or anemia, compared to non-exacerbating phenotypes and ACO.20 We hypothesize that greater fragility21 and the presence of comorbidities could be reasons that have caused these patients to be finally ruled out. Another possibility is that they would have referred after a recent severe exacerbation without enough recovering after an adequate rehabilitation program. It has been described that hospitalizations induces a greater musculoskeletal weakness and worse functional situation22 related to different factors such as prolonged inactivity during it or systemic steroid treatments that are not uncommon to be used with doses above the recommended.23

Another finding of this work is that we have observed that the phenotype of the patient at the time of transplantation could influence survival and the development of subsequent complications. Thus, we have observed a tendency to higher post-transplant mortality in the exacerbator phenotype compared to the ACO and the non-exacerbator that would have superior survival. These results, although they did not acquire statistical differences, could be reflecting a greater degree of fragility of these patients. This situation could challenge the indications of the international guidelines, recommending to list the patient when they had 3 serious exacerbations,9 indicating that it may not take so long to do so, since the results could be worse. However we would like to highlight that this study was not designed or powered to look for survival, so this finding must be interpreted with caution and just as a potential hypothesis generator and in order to confirm it, it should be under a multicenter bigger study.

This work has a series of limitations that should be highlighted. The first is that the exacerbator phenotype is grouped as a single phenotype and no differentiation was made between chronic bronchitis and emphysema as recommended by some guidelines.10 The fact that the variable related to the presence of chronic bronchitis was not included in the protocol conditions this limitation. The low prescription of roflumilast and macrolide in these patients makes us hypothesize that emphysema predominated in the majority, although this fact has not been confirmed. Another limitation of the study is related to the definition of ACO employed. In this sense there has been a lot of controversy in recent years,24 and, while initially the diagnosis required some major and minor criteria (which included a history of asthma, lung function, bronchodilator test or atopy data), currently the most used criterion is the presence of a chronic obstruction not reversible to air flow in a non-smoking patient and with a history of asthma before the age of 40 years.10,14,25 On the other hand, we decided to exclude patients with alpha 1 antitrypsin deficiency, since they present a series of slightly different clinical characteristics, as they use to be younger patients, with a greater degree of emphysema and with a different post-transplant evolution.14,26,27 When analyzing the results of post-transplant survival, it should be taken into account that it was not the main objective of this work, that the results were based on an univariate model and factors like mechanical ventilation, ischemia time, LAS index at the time of inclusion, etc., that could condition it were not studied. Finally, this is a study conducted in a single center, this determines the number of patients studied and transplanted in the study and on the other hand we cannot infer that these results are replicated in other cohorts. In this sense it would be interesting to compare these results with those presented in other transplant programs.

In summary, we can conclude based on our work that the COPD phenotype most valued for transplantation is the exacerbator, a phenotype that in approximately half of the cases does not complete the pre-transplant study and, among those who completed it, an important part do not get to transplant.

The authors declare that they have no conflicts of interest.