Skip to main content
PMC home page
PLOS ONE logoLink to PLOS ONE
. 2021 Apr 7;16(4):e0249758. doi: 10.1371/journal.pone.0249758

The influence of the native lung on early outcomes and survival after single lung transplantation

Francisco Javier Gonzalez 1, Enriqueta Alvarez 1, Paula Moreno 1, David Poveda 1, Eloisa Ruiz 1, Alba Maria Fernandez 1, Angel Salvatierra 1, Antonio Alvarez 1,*
Editor: Robert Jeenchen Chen2
PMCID: PMC8026083  PMID: 33826650

Abstract

Objective

To determine whether problems arising in the native lung may influence the short-term outcomes and survival after single lung transplantation (SLT), and therefore should be taken into consideration when selecting the transplant procedure.

Patients and methods

Retrospective review of 258 lung transplants performed between June 2012 and June 2019. Among them, 161 SLT were selected for the analysis. Complications in the native lung were recorded and distributed into two groups: early and late complications (within 30 days or after 30 days post-transplant). Donor and recipient preoperative factors, 30-day mortality and survival were analysed and compared between groups by univariable and multivariable analyses, and adjusting for transplant indication.

Results

There were 161 patients (126M/35F; 57±7 years) transplanted for emphysema (COPD) (n = 72), pulmonary fibrosis (IPF) (n = 77), or other indications (n = 12). Forty-nine patients (30%) presented complications in the native lung. Thirty-day mortality did not differ between patients with or without early complications (6% vs. 12% respectively; p = 0.56). Twelve patients died due to a native lung complication (7.4% of patients; 24% of all deaths). Survival (1,3,5 years) without vs. with late complications: COPD (89%, 86%, 80% vs. 86%, 71%, 51%; p = 0.04); IPF (83%, 77%, 72% vs. 93%, 68%, 58%; p = 0.65). Among 30-day survivors: COPD (94%, 91%, 84% vs. 86%, 71%, 51%; p = 0.01); IPF (93%, 86%, 81% vs. 93%, 68%, 58%; p = 0.19). Native lung complications were associated to longer ICU stay (10±17 vs. 33±96 days; p<0.001), longer postoperative intubation (41±85 vs. 99±318 hours; p = 0.006), and longer hospital stay (30±24 vs. 45±34 days; p = 0.03). The presence of late native lung problems predicted survival in COPD patients (OR: 2.55; p = 0.07).

Conclusion

The native lung is a source of morbidity in the short-term and mortality in the long-term after lung transplantation. This should be taken into consideration when choosing the transplant procedure, especially in COPD patients.

Introduction

Lung transplantation is a well established, and lifesaving treatment for end-stage pulmonary diseases, especially in whom all medical treatment has failed. After more than 40 years of worldwide clinical experience, both single (SLT) and bilateral lung transplants (BLT) are widely accepted, and its selection rely on clinical features, such as age, pulmonary arterial pressure or infectious status [1].

In the first lung transplant era, SLT was the procedure of choice. Nonetheless, in the last decade, this trend has been inverted, and BLT is the most frequently performed after demonstrating better survival, among other several advantages in comparison with SLT [2, 3].

Despite all this, the topic remains controversial, and some authors still recommend performing SLT in older patients with specific diseases such as pulmonary fibrosis [4], especially given the limited organ availability and the unacceptable mortality rate while on the waiting list [5].

The longer survival of BLT has been related to a better postoperative lung function and less chronic lung allograft dysfunction (CLAD) compared with unilateral procedures [6, 7]. However, there is little evidence demonstrating that the native lung could be the cause of a worst survival after a SLT.

Therefore, the aim of this study is to determine whether the native lung after SLT could be the source of morbidity and mortality that might explain, at least in part, the longer survival of BLT.

Patients and methods

Study design

This is an observational analytic retrospective case-control study to determine the influence of native lung complications on early outcomes and survival after SLT for IPF or COPD. The primary end-points were 30-day mortality and survival. For this purpose, the medical records of 258 patients transplanted between June 2012 and June 2019 at our Institution were retrospectively reviewed from the pulmonary transplantation database. Among them, 161 SLT were selected for the analysis. Complications in the native lung were recorded and distributed into two groups: early and late complications (within 30 days or after 30 days post-transplant).

Lung transplantation procedure

Lungs were retrieved from brain death donors using our standard protocol of cardiopulmonary harvesting [8]. Either a right or left SLT was performed in all cases through a standard posterolateral thoracotomy or through an anterior thoracotomy. The surgical procedure and the postoperative standard of care for lung transplant recipients were performed as previously reported by our group [9].

Data collection

Recipient preoperative data included: age, gender, steroid therapy, preoperative ventilation, native lung perfusion, indication for lung transplantation (COPD, IPF, or other indication) and comorbidities (airway colonizations, bullae, granulomas, lung hyperinflation, bronchiectasis).

Surgical and early postoperative data included: side of lung transplant, use of intraoperative extracorporeal life support (ECLS) (cardiopulmonary bypass or extracorporeal membrane oxygenation—ECMO), ischemic time, duration of mechanical ventilation, ICU stay, need of intraoperative or postoperative lung volume reduction surgery, and 30-day mortality.

Late postoperative data included: late native complications, overall mortality, and survival.

Data were analysed and compared between groups (early and late complications) by univariable and multivariable analyses, adjusting for transplant indication (COPD or IPF).

Definitions

Recipients were considered on preoperative steroid therapy when receiving steroids at doses above 15mg/kg for 30 days just before transplantation.

Statistical analysis

Univariable analysis

We compared complicated vs. non-complicated recipients by either Pearson’s χ2 or Fisher’s exact test for categorical variables, and either unpaired t-test or Mann-Whitney U-test for quantitative variables. These comparisons were performed in the overall series, and in each subgroup of patients transplanted either for COPD or IPF.

Given the large sample size of the study population, we assumed homogeneous variances and normal distribution in most of the analyses. We used parametric tests when more than 30 cases for each group were compared and non-parametric tests when less than 30 cases for each group were compared. Pre-tests for normality were not performed.

Survival was analysed and compared using the Kaplan–Meier method and log-rank test.

Multivariable analysis

To determine independent predictors of mortality, those variables exhibiting p values below 0.1 in the univariable analyses entered into a multivariable Cox-regression analysis (forward stepwise likelihood ratio). Those variables with p values below 0.05 in the final model were judged to be independent predictors of mortality.

Continuous variables are expressed as means ± standard deviation. Categorical variables are expressed as counts and proportions with 95% confidence intervals (95% CI). Differences with p values <0.05 were considered significant. The statistical analysis was performed using SPSS (SPSS 20.0 for Mac: SPSS, Inc., Chicago, IL, USA).

The data set from which the analysis was performed is available in S1 File. This file contains fully anonymized data before accession to the analysis, and includes the date range (month and year) during which patients’ medical records were accessed. The data file belongs to the Lung Transplant Unit, Hospital Universitario Reina Sofía, Cordoba, Spain.

Ethical statement

The present study followed the World Medical Association Declaration of Helsinki-Ethical Principles for Medical Research involving human subjects. All patients had signed the Informed Consent at the time of inclusion in waiting list to undergo the procedure and to use their medical records for research.

Our Institutional Review Board approved this study and waived the need for additional specific informed consent for the purposes of the present study.

None of the transplant donors was from a vulnerable population and all donors or next of kin provided written informed consent that was freely given. A blank example of the form used to obtain consent from donors is included (S2 File).

Presumed consent was introduced in Spain by law in 1979. The law establishes that absence of explicit refusal automatically makes the patient a potential donor, but requires that a patient’s possible refusal to donate should be sought by checking their belongings and consulting proxy decision makers. Since most patients have not registered as donors and do not carry donor cards, Spanish transplant coordinators usually have to establish the patient’s wishes through discussion with the family. In practice, organ procurement is not undertaken if the family refuses the donation. Therefore, even though we have a presumed consent policy, we do not apply it in practice. We always approach the relatives, explaining to them the patient’s health conditions and we try to find out whether the individual wanted to be an organ donor or not. If the relatives oppose to deceased organ donation, we do not go on with it.

The Spanish Real Decreto 2070–1999 forbids any person from obtaining any kind of financial compensation for human organs and frames organ donation as a voluntary and altruistic act. Therefore, obtaining reimbursements or financial compensations for organ donation in Spain is illegal [10].

Results

Overall patient series

From June 2012 to June 2019, 258 lung transplants were performed at our Institution. Among them, 161 were single lung transplants (study group): 126 (78%) males, 35 (22%) females. The mean age was 57±7 [33–68] years old.

Indications for SLT were COPD in 72 patients, IPF in 77 patients, and other indications in 12 cases.

The overall rate of native complications was 30% (49 patients). Fifteen patients developed early complications (9%), and 41 patients developed late complications (25%).

Native lung complications analysis

Complications in the native lung within 30 days post-transplant (early complications) included atelectasis requiring bronchoscopic toilette of bronchial secretions, pneumothorax requiring pleural drainage, pneumonia, pleural effusion and air leaks following lung volume reduction surgery in the native lung following SLT for COPD (Table 1).

Table 1. Summary of complications in the native lung in patients after single lung transplantation.

Complication Early Late
n(%) n(%)
Atelectasis 3 (2) 4 (2)
Pneumothorax 4 (2.5) 2 (1)
Pneumonia 2 (1) 8 (5)
Pleural effusion 3 (2)
Air leaksa 3 (2)
Hyperinflation 15 (9)
Carcinoma 11 (7)
Fibrosis progression 1 (0.6)
Open in a new tab

aAfter lung volume reduction surgery in the native lung.

Late complications were more frequently related to progression of COPD changes in the native lung (lung hyperinflation leading to mediastinal shift and subsequent dysfunction of the implanted lung, secondary to parenchymal compression), and to the development of neoplasms (up to 11 COPD patients developed bronchogenic carcinoma in the native lung) (Table 1).

Mortality

Overall mortality was 22 (30%) for COPD and 27 (35%) for IPF patients. 30-day mortality was higher for IPF patients than for COPD patients: 15 (19%) vs. 6 (8%) respectively (p = 0.04). Interestingly, patients without native lung complications presented higher 30-day mortality than those with some native lung complication: 16 (15%) vs. 1 (2%) respectively (p = 0.008). These differences persisted, but not significantly, when analysing 30-day mortality by transplant indication (Fig 1).

Fig 1. 30-day mortality.

Fig 1

Open in a new tab

A) 30-day mortality of COPD vs. IPF patients after single lung transplantation. B) 30-day mortality in patients with or without native lung complications (overall study group). C) 30-day mortality in COPD patients with or without native lung complications. D) 30-day mortality in IPF patients with or without native lung complications.

Among 22 deaths in COPD recipients, 5 were related to native lung complications (23% of COPD deaths). Among 27 deaths in IPF patients, 7 were related to native lung complications (26% of IPF deaths). Overall, 12 deaths were due to native lung complications (7.4% of all patients, and 24,4% of all deaths). Native-related causes of death were lung cancer in 5 COPD patients, pneumonia in 6 IPF patients and fibrosis progression in another IPF patient.

Comparative analysis between recipients with and without native lung complications

Patients with native lung complications required prolonged postoperative ventilation, and longer ICU and hospital stay. Some preoperative conditions were associated to native lung complications, such as the presence of airway colonizations, bullae, lung hyperinflation and the need of volume reduction surgery (Table 2). Interestingly, 30-day mortality was more frequent in patients without native lung complications, indicating that the causes of early mortality post-transplantation are unrelated to the native lung (Table 2).

Table 2. Comparative data between patients with and without native lung complications following single lung transplantation (overall group).

NATIVE LUNG COMPLICATIONS NO (n = 112) YES (n = 49) p
95% CI 95% CI
Recipient age (years) 57±7 58±7 0.86
Recipient gender: 0.48
    Male 80 (71) 38 (77)
    Female 32 (29) 11 (23)
Preop. Steroids 20 (19) 12–26 14 (28) 16–40 0.14
Ischemic time (min) 307±57 297–317 295±53 281–309 0.57
CPB / ECMO 14 (12) 6–18 2 (4) 0–8 0.05
ICU stay (days) 10±17 7–13 33±96 7–59 <0.001
Postop. Intubation (h) 41±85 26–56 99±318 54–144 0.006
Hospital stay (days) 30±24 26–34 45±34 36–54 0.03
PaO2/FiO2 24h postop. (mm Hg) 345±146 318–372 316±182 265–367 0.35
Comorbidities 39 (35) 26–44 24 (49) 35–63 0.04
Native lung perfusion (%) 52±9 51–53 48±13 45–51 0.29
Native lung side (left/right) 30/82 (26/74) 18-34/66-82 10/39 (20/80) 9-31/69-91 0.29
CLAD 4 (3) 0–6 5 (10) 2–18 0.12
Pre-transplant status
    Airway colonizations 4 (3) 0–6 15 (30) 18–42 <0.001
    Bullae 36 (32) 24–40 30 (61) 48–74 0.003
    Granulomas 7 (6) 2–10 7 (14) 5–23 0.13
    Hyperinflation 0 3 (6) 0–12 0.03
    Mechanical ventilation 2 (2) 0–4 0 0.44
    LVRS 0 3 (6) 0–12 0.03
30-day mortality 16 (14) 8–20 1 (2) 0–4 0.008
Open in a new tab

CPB: cardiopulmonary bypass; CLAD: chronic lung allograft dysfunction; ECMO: extracorporeal membrane oxygenation; LVRS: lung volume reduction surgery. Quantitative variables are expressed as mean ± standard deviation. Qualitative variables are expressed as counts and proportions within each column, in parenthesis.

Survival

Survival was not influenced by the presence of native lung complications in IPF patients, neither overall nor when comparing early vs. late complications (Fig 2). On the contrary, those patients transplanted for COPD exhibited worse survival when native lung complications arose. This is especially true when comparing survival between those COPD patients with early complications vs. late complications (89%, 86%, 80% vs. 86%, 71%, 51%; p = 0.04) (Fig 3).

Fig 2. Survival in IPF patients.

Fig 2

Open in a new tab

Post-transplant survival of IPF patients comparing those with or without native lung complications (left), and those with early or late native lung complications (right).

Fig 3. Survival in COPD patients.

Fig 3

Open in a new tab

Post-transplant survival of COPD patients comparing those with or without native lung complications (left), and those with early or late native lung complications (right).

In an additional analysis comparing survival among those patients surviving beyond 30 days post-transplant, we observed that long-term survival was significantly impaired in COPD patients developing late complications (neoplasms and lung hyperinflation) (94%, 91%, 84% vs. 86%, 71%, 51%; p = 0.01) (Fig 4), while differences in IPF patients remained not significant (Fig 5).

Fig 4. Survival in COPD patients conditional to survive 30 days.

Fig 4

Open in a new tab

Post-transplant survival, conditional to survive 30 days, of COPD patients comparing those with or without native lung complications (left), and those with early or late native lung complications (right).

Fig 5. Survival in IPF patients conditional to survive 30 days.

Fig 5

Open in a new tab

Post-transplant survival, conditional to survive 30 days, of IPF patients comparing those with or without native lung complications (left), and those with early or late native lung complications (right).

Multivariable analysis of survival

Factors predicting survival are depicted in Table 3. Interestingly, the presence of late native lung problems predicted survival in emphysema patients (OR: 2.55; p = 0.07).

Table 3. Factors predictive of survival in the overall group, stratified by indication of lung transplantation.

HR 95% CI p
OVERALL
CPB/ECMO 8.20 6.52–9.88 <0.001
Length of postop. ventilation (min.) 1.99 1.79–2.11 <0.001
Hospital stay (days) 1.02 1.01–1.03 0.008
Preop. airway colonizations (no/yes) 2.26 2.12–2.47 0.048
COPD
Native lung late complications (no/yes) 2.55 2.31–2.67 0.007
IPF
Length of postop. ventilation (min.) 1.99 1.82–2.07 0.035
Open in a new tab

CPB: cardiopulmonary bypass; ECMO: extracorporeal membrane oxygenation; HR: hazard ratio.

Discussion

Lung transplantation is the unique treatment that has demonstrated to improve quality of life and survival in patients with end-stage lung parenchymal and vascular diseases, in whom all medical therapy has failed [1].

This surgical therapy differs from the one in other solid organ transplants, as it offers the transplant team the possibility of selecting different transplant procedures: left SLT, right SLT or BLT.

Currently, SLT represents around 45% of the lung transplant options [2]. The main advantages of this procedure are a quicker and less aggressive surgery, decreased organ ischemic time, and a more efficient use of the scarce lung donor pool by performing twinning procedures (two recipients transplanted from the same donor), which decreases the mortality rate while on the waiting list [11]. On the other hand, a poorer survival among patients undergoing a SLT has been reported [2, 6, 7].

On the contrary, bilateral lung transplants have demonstrated a better long-term survival due to a greater postoperative pulmonary reserve and to a decreased incidence of CLAD [2–4].

In general, almost all investigations aimed at comparing survival between unilateral and bilateral procedures have been focused on the lung grafts. However, little is known about the role of the native diseased lung as the cause of a worst survival after SLT.

In the present study, we were able to demonstrate that native lung complications adversely affected post-transplant survival, especially in COPD patients, but did not have an impact on 30-day mortality.

Pneumonia, pneumothorax, native lung hyperinflation and lung cancer are the most common complications observed in the native lung after SLT [12–14]. In one of the largest series published to date, these complications occurred in about 14% of all patients after SLT, with a significant reduction in post-transplant survival [14]. This high incidence of native lung complications questions the role of SLT in patients with COPD and IPF and has resulted in recent years in a worldwide shift from SLT to BLT, with better survival results [2].

In the present series, after analysing 161 patients, we observed complications arising in the native lung in 30% of the cases, with a higher incidence in the long-term period. Using smaller lung transplant populations, other authors have reported an incidence of native lung complications ranging from 14% to 50% [12–15].

Early native lung complications were observed in 9% of the cases. They were mainly atelectasis, pneumonia, pleural effusion, air leaks after LVRS, and pneumothorax, but none of them were itself the cause of 30-day mortality. These complications were strongly associated to longer post-transplant ventilation, ICU, and hospital stay. However, it is noteworthy that early mortality after SLT was not related to problems in the native lung, neither in COPD or IPF patients. So it seems clear that this early mortality after lung transplantation is related to problems in the transplanted lung (graft dysfunction, pneumonia, etc.), or to cardiac adverse events.

Within 30 days post-transplant, atelectasis in the native lung requiring bronchoscopy, was observed in 2% of the cases, and pneumonia in 1% of the cases. Both of these early complications are commonly related to mortality in patients undergoing general thoracic procedures [16]. In line with this observation, Venuta et al. [12] reported one case of atelectasis and one case of pneumonia among their 35 lung transplant recipients. None of these complications were the cause of death in their investigation, as did not in the present study. On the contrary, in our series, the rate of late pneumonia in the native lung leading to death is remarkably high, especially in fibrotic patients.

Three COPD patients (2%) underwent a lung volume reduction surgery in the native lung after completion of the lung transplant. All of them presented prolonged air leaks that added morbidity to the postoperative course, but none of these patients died from this complication and were successfully treated conservatively by maintaining an adequate drainage of the pleural space. Even though BLT is the better option to avoid this complication in the native lung, some authors postulated that LVRS after a SLT is an effective treatment strategy with an acceptable surgical risk, but patient selection remains of paramount importance [17].

Postoperative pneumothorax in the native lung was present in 2.5% of our series, similar to that reported by Venuta et al. [12], who treated successfully this complication by VATS. Our patients were successfully treated with pleural drainage in the majority of cases. Only 2 patients required VATS due to persistent air leaks. We strongly recommend indicating early surgery to solve this problem, considering that the subjacent native lung is a diseased organ and the air leak will unlikely resolve spontaneously.

In the long-term, we observed a higher rate of native lung complications reaching up to 25% of our patients. When analysing long-term survival, late native lung complications were strongly associated with a worst survival among COPD patients. On the contrary, IPF patients did not exhibit these differences in survival. Main complications in the non-transplanted lung were hyperinflation and lung cancer.

Hyperinflation was present in 15 COPD patients (9%), leading to a worsening of clinical and functional status. All of these patients presented preoperative bullous emphysema in the preoperative chest CT scan, which support the idea that this technique may be the most useful tool to decide the transplant procedure in order to prevent this complication. Other series have reported lower native hyperinflation rates ranging from 5% to 8% [13, 15], possibly due to the variability in the use of clinical, functional and radiological parameters to describe this complication, and because of the lack of objective parameters to assess hyperinflation and distinguish it from CLAD in the transplanted lung.

In the present series, lung cancer was the most devastating native lung complication, arising in 11 COPD patients (7%). It also impaired long-term survival, with a significant decline of survival in COPD patients presenting lung carcinoma of the native lung. In a previous analysis of the first 340 transplanted patients at our Institution, we identified 9 (2.6%) patients developing lung cancer after lung transplantation, with an interval from transplantation to lung cancer diagnosis of 53.3 ± 12 months and mean survival after cancer diagnosis of 49.3 ± 6.3 months [18].

In one of the first series on lung cancer after lung transplantation including patients from seven U.S. centres, Collins et al. reported an incidence of 2.5% of lung cancer in the native lung after SLT [19]. The group of Leuven recently reported an incidence of developing lung cancer of 9.8% in COPD or IPF patients undergoing SLT. At diagnosis, four patients had local disease (cT1N0M0 and cT2N0M0), whereas all others had loco-regionally advanced or metastatic disease. Five patients were surgically treated and all other patients were treated with chemotherapy with or without radiotherapy [20]. In our series, 5 lung cancer patients were in stages I/II and underwent surgical resection, whereas the remaining 6 cases underwent chemo/radiotherapy.

Other authors have also described lung cancer in the native lung after SLT with an incidence ranging from 0.4% to 8.9% [21–24]. The majority of patients presented with an advanced disease not amenable to surgical treatment. The prognosis of patients treated with chemotherapy and/or radiotherapy alone was poor, with an aggressive and frequently fatal course. Only 25% of patients survived despite treatment, the majority of these patients had early stage lung cancer and underwent curative resection.

These findings suggest that careful surveillance of any change in the native lung after SLT is of paramount importance for early detection of lung cancer.

In the present series, both early and late complications were statistically associated to the presence of bullae and severe air trapping in the COPD group, and to bronchiectasis and preoperative colonizations among the whole study group. These preoperative findings must be carefully assessed by the multidisciplinary team when indicating the type of lung transplant for each candidate.

The present study has several limitations. First, the weaknesses and biases inherent to the retrospective nature of the study. Second, no donor factors were analysed, although the donor selection and retrieval procedure was performed homogenously throughout the period of study, some donor-related factors could have had an influence on the analysis, but not to the degree to invalidate the main results. Third, bilateral procedures were excluded because they were out of the focus of the analysis (the native lung), and therefore, comparisons between bilateral and unilateral procedures were not performed. Finally, minor complications following the transplant procedures could have been not reported in the clinical charts and therefore not taken into account for the analysis.

Conclusions

The present study demonstrates that the native lung is a source of morbidity in the short and long term for IPF patients, and appears to be associated to a reduction of long-term survival in COPD patients. The native lung behaviour after SLT should be taken into consideration when choosing the transplant procedure, especially in COPD patients.

Supporting information

S1 File. Complete dataset from which the analysis was performed.

(SAV)

Click here for additional data file. (63.3KB, sav)
S2 File. Model of informed consent for organ donation in Spain.

(PDF)

Click here for additional data file. (94.8KB, pdf)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

References

  • 1.Kotloff RM, Thabut G. Lung transplantation. Am J Respir Crit Care Med 2011; 184: 159–71. 10.1164/rccm.201101-0134CI [DOI] [PubMed] [Google Scholar]
  • 2.Chambers DC, Zuckermann A, Cherikh WS, Harhay MO, Hayes D Jr, Hsich E, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult lung transplantation report—2020; focus on deceased donor characteristics. J Heart Lung Transplant 2020; 39(10): 1016–27. 10.1016/j.healun.2020.07.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Yu H, Bian T, Yu Z, Wei Y, Xu J, Zhu J, et al. Bilateral lung transplantation provides better long-term survival and pulmonary function than single lung transplantation: a systematic review and meta-analysis. Transplantation 2019; 103 (12): 2634–44. 10.1097/TP.0000000000002841 [DOI] [PubMed] [Google Scholar]
  • 4.Lehmann S, Uhlemann M, Leontyev S, Seeburger J, Garbadec J, Merk DR, et al. Bilateral versus single lung transplant for idiopathic pulmonary fibrosis. Exp Clin Transplant 2014; 5: 443–7. [PubMed] [Google Scholar]
  • 5.Spratt JR, Tomic R, Brown RZ, Rudser K, Loor G, Hetz M, et al. Single versus bilateral lung transplantation for idiopathic pulmonary fibrosis in the lung allocation score era. J Surg Res 2019; 234: 84–95. 10.1016/j.jss.2018.08.054 [DOI] [PubMed] [Google Scholar]
  • 6.Subramanian MP, Meyers BF. Bilateral versus single lung transplantation: are two lungs better than one? J Thorac Dis 2018; 10: 4588–601. 10.21037/jtd.2018.06.56 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Fakhro M, Broberg E, Algotsson L, Hansson L, Koul B, Gustafsson R, et al. Double lung, unlike single lung transplantation might provide a protective effect on mortality and bronchiolitis obliterans syndrome. J Cardiothorac Surg 2017; 12: 100. 10.1186/s13019-017-0666-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Álvarez A, Moreno P, Espinosa D, Illana J, Santos F, Algar FJ, et al. Assessment of lungs for transplantation: a stepwise analysis of 476 donors. Eur J Cardiothorac Surg 2010; 37: 432–9. 10.1016/j.ejcts.2009.08.011 [DOI] [PubMed] [Google Scholar]
  • 9.Moreno P, Álvarez A, Santos F, Vaquero JM, Baamonde C, Redel J, et al. Extended recipients but not extended donors are associated with poor outcomes following lung transplantation. Eur J Cardiothorac Surg 2014; 45: 1040–7. 10.1093/ejcts/ezt501 [DOI] [PubMed] [Google Scholar]
  • 10.Rodriguez-Arias D, Wright L, Paredes D. Success factors and ethical challenges of the Spanish Model of organ donation. Lancet 2010; 376: 1109–12. 10.1016/S0140-6736(10)61342-6 [DOI] [PubMed] [Google Scholar]
  • 11.Padilla J, Calvo V, Teixidor J, Varela A, Carbajo M, Alvarez A. Pulmonary “twinning” transplantation procedure. Transplant Proc 2002; 34: 1287–9. 10.1016/s0041-1345(02)02747-1 [DOI] [PubMed] [Google Scholar]
  • 12.Venutta F, Boehler A, Rendina EA, De Giacomo T, Speich R, Schmid R, et al. Complications in the native lung after single lung transplantation. Eur J Cardiothorac Surg 1999; 16: 54–8. 10.1016/s1010-7940(99)00141-4 [DOI] [PubMed] [Google Scholar]
  • 13.King CS, Khandhar S, Burton N, Shlobin OA, Ahmad S, Lefrak E, et al. Native lung complications in single-lung transplant recipients and the role of pneumonectomy. J Heart Lung Transplant 2009; 28 (8): 851–6. 10.1016/j.healun.2009.04.023 [DOI] [PubMed] [Google Scholar]
  • 14.Chen QK, Jiang GN, Ding JA. Complications in the native lung after single lung transplantation. Chin J Organ Transplant 2013; 34: 235–8. [Google Scholar]
  • 15.McAdams HP, Erasmus JJ, Palmer SM. Complications (excluding hyperinflation) involving the native lung after single-lung transplantation: incidence, radiologic features, and clinical importance. Radiology 2001; 218: 233–41. 10.1148/radiology.218.1.r01ja45233 [DOI] [PubMed] [Google Scholar]
  • 16.Hoshikawa Y, Tochii D. Postoperative atelectasis and pneumonia after general thoracic surgery. Kyobu Geka 2017; 70 (8): 649–55. [PubMed] [Google Scholar]
  • 17.Wilson H, Carby M, Beddow E. Lung volume reduction surgery for native lung hyperinflation following single-lung transplantation for emphysema: which patients? Eur J Cardiothorac Surg 2012; 42: 410–3. 10.1093/ejcts/ezs086 [DOI] [PubMed] [Google Scholar]
  • 18.Espinosa D, Baamonde C, Illana J, Arango E, Carrasco G, Moreno P, et al. Lung cancer in patients with lung transplants. Transplant Proc 2012; 44 (7): 2118–9. 10.1016/j.transproceed.2012.07.067 [DOI] [PubMed] [Google Scholar]
  • 19.Collins J, Kazerooni EA, Lacomis J, McAdams HP, Leung AN, Shiau M, et al. Bronchogenic carcinoma after lung transplantation: frequency, clinical characteristics, and imaging findings. Radiology 2002; 224: 131–8. 10.1148/radiol.2241011189 [DOI] [PubMed] [Google Scholar]
  • 20.Yserbyt J, Verleden GM, Dupont LJ, Van Raemdonck DE, Dooms C. Bronchial carcinoma after lung transplantation: a single-center experience. J Heart Lung Transplant 2012; 31: 585–90. 10.1016/j.healun.2012.02.022 [DOI] [PubMed] [Google Scholar]
  • 21.Dickson RP, Davis RD, Rea JB, Palmer SM. High frequency of bronchogenic carcinoma after single-lung transplantation. J Heart Lung Transplant 2006; 25: 1297–301. 10.1016/j.healun.2006.09.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Schulman LL, Htun T, Staniloae C, McGregor CC, Austin JHM. Pulmonary nodules and masses after lung and heart-lung transplantation. J Thorac Imaging 2000; 15 (3): 173–9. 10.1097/00005382-200007000-00004 [DOI] [PubMed] [Google Scholar]
  • 23.Grewal AS, Padera RF, Boukedes S, Divo M, Rosas IO, Camp PC, et al. Prevalence and outcome of lung cancer in lung transplant recipients. Respir Med 2015; 109 (3): 427–33. 10.1016/j.rmed.2014.12.013 [DOI] [PubMed] [Google Scholar]
  • 24.Minai OA, Shah S, Mazzone P, Budev MM, Sahoo D, Murthy S, et al. Bronchogenic carcinoma after lung transplantation: characteristics and outcomes. J Thorac Oncol 2008; 3 (12): 1404–9. 10.1097/JTO.0b013e31818e1259 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Robert Jeenchen Chen

3 Feb 2021

PONE-D-21-01459

THE INFLUENCE OF THE NATIVE LUNG ON EARLY OUTCOMES AND SURVIVAL AFTER SINGLE LUNG TRANSPLANTATION

PLOS ONE

Dear Dr. Alvarez,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please address the issues and revise accordingly.

Please submit your revised manuscript by Mar 19 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2) We note that your study involved tissue/organ transplantation. Please provide the following information regarding tissue/organ donors for transplantation cases analyzed in your study.

3) Please provide the source(s) of the transplanted tissue/organs used in the study, including the institution name and a non-identifying description of the donor(s).

4) Please state in your response letter and ethics statement whether the transplant cases for this study involved any vulnerable populations; for example, tissue/organs from prisoners, subjects with reduced mental capacity due to illness or age, or minors.

- If a vulnerable population was used, please describe the population, justify the decision to use tissue/organ donations from this group, and clearly describe what measures were taken in the informed consent procedure to assure protection of the vulnerable group and avoid coercion.

- If a vulnerable population was not used, please state in your ethics statement, “None of the transplant donors was from a vulnerable population and all donors or next of kin provided written informed consent that was freely given.

5)  In the Methods, please provide detailed information about the procedure by which informed consent was obtained from organ/tissue donors or their next of kin. In addition, please provide a blank example of the form used to obtain consent from donors, and an English translation if the original is in a different language.

6) Please indicate whether the donors were previously registered as organ donors. If tissues/organs were obtained from deceased donors or cadavers, please provide details as to the donors’ cause(s) of death.

7) Please provide the participant recruitment dates and the period during which transplant procedures were done (as month and year).

8) Please discuss whether medical costs were covered or other cash payments were provided to the family of the donor. If so, please specify the value of this support (in local currency and equivalent to U.S. dollars)."

9) In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records/samples were accessed; c) the source of the medical records/samples analyzed in this work (e.g. hospital, institution or medical center name).

10) In the Ethics Statement on the online submission form and the manuscript Methods , please clarify the context in which consent was obtained, and specify whether patients provided:

    a) Consent to use their medical records/samples used in research

    b) Consent to undergo the procedure

    c) Consent to take part in the study reported in this manuscript.

If the ethics committee waived the need for additional informed consent, please state this.

Thank you for your attention to these requests.

11) We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

12) Please amend your manuscript to include your abstract after the title page.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript entitled "THE INFLUENCE OF THE NATIVE LUNG ON EARLY OUTCOMES AND SURVIVAL

AFTER SINGLE LUNG TRANSPLANTATION" is well written and a potential topic of interest in the field of lung transplant. The research finding is not novel and there is no direct evidence how the native lung is a source of morbidity. As the author mentioned that this topic is a very controversial, However, due to the correct, appropriately and rigorous data analysis I will recommend this paper for acceptance, and the controversies related to this topic i will leave on the readers.

Reviewer #2: Most of LT are performed as the last therapeutic option in end stage degenerative lung disease as COPD-EMPHYSEMA and fibrotic lung disease , mainly IPF. The last decade was marked by a clear shift to BLT vs SLT due to surgical, prognostic (mortality/survival) causes. Although world statistics still present almost half of patients receiving SLT the BLT trend mainly in very active transplant centers is clear. Focusing on lung grafts as a source of lower survival in SLT is limited as the authors noticed. The native lung was analyzed by various groups before as to its impact on survival

The authors add a local retrospective study to the existing data and looked on the impact of the native lung status on survival following SLT

There ar 2 main flaws in the methodology as far as I understand:

1. one may not decide the impact on survival on patients following SLT using any parameter without comparing to BLT. As mentioned by the authors this lack of comparison is a limitation, in my opinion a fundamental one. You may noy recommend BLT for COPD patients instead of SLT without comparing relevant data from BOTH options

2. I am confused by comparing the survival and mortality data. All patients without native lung complications presented higher 30 days mortality than those with (even when divided between COPD and IPF although not significant).On the othe hand survival was worse in COPD patients with native lung complications (both early and late) but not in IPF patients. There is no clear explanation to this aparent discrepance both in text and figure legends.

Reviewer #3: The topic is of interest for the lung transplant community.

English language is the first main limitation of the manuscript. Many paragraphs are very hard to understand.

The design of the study is somehow confusing and should be clearly presented upfront. The reader is expecting to understand the object of your analysis, the outcome measures, and the methodology of your analysis.

The statistical methodology is also confusing and should be reviewed both for the descriptives and the regression analysis.

I also suggest to redraft your discussion and try to define the key results of the study. The discussion is very long and the take-home messages are not clearly presented. Please shorten your text and make it simple.

Overall, I think that you should consider revising the structure and presentation of your study. The topic is interesting and deserves the work and time of a revision.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Apr 7;16(4):e0249758. doi: 10.1371/journal.pone.0249758.r002

Author response to Decision Letter 0

3 Mar 2021

Dear Editor

We wish to thank you and the reviewers for your consideration and comments regarding our manuscript entitled:

THE INFLUENCE OF THE NATIVE LUNG ON EARLY OUTCOMES AND SURVIVAL AFTER SINGLE LUNG TRANSPLANTATION

(PONE-D-21-01459)

Some concerns have been raised in relation to the use of donors in the present study:

1. Regarding consent for donation: Presumed consent was introduced in Spain by law in 1979. The law establishes that absence of explicit refusal automatically makes the patient a potential donor, but requires that a patient’s possible refusal to donate should be sought by checking their belongings and consulting proxy decision makers. Since most patients have not registered as donors and do not carry donor cards, Spanish transplant coordinators usually have to establish the patient’s wishes through discussion with the family. In practice, organ procurement is not undertaken if the family refuses the donation. Therefore, even though we have a presumed consent policy, we do not apply it in practice. We always approach the relatives, explaining to them the patient’s health conditions and we try to find out whether the individual wanted to be an organ donor or not. If the relatives oppose to deceased organ donation, we do not go on with it.

2. Regarding reimbursements to donor relatives: In some parts of the USA, financial incentives are used as a strategy to increase organ donation— eg, reimbursement for funeral expenses to the family of the deceased individual—despite concerns that excessive sums can constitute a form of unethical inducement. The Spanish Real Decreto 2070–1999 forbids any person from obtaining any kind of financial compensation for human organs and frames organ donation as a voluntary and altruistic act. Therefore, obtaining reimbursements or financial compensations for organ donation in Spain is illegal (Rodriguez-Arias D, Wright L, Paredes D. Success factors and ethical challenges of the Spanish Model of organ donation. Lancet 2010; 376: 1109–12). In addition, the spanish activity on transplantation and donor procurement, follows strictly the regulations approved by the European Parliament: Directive of the European Parliament and of the Council on standards of quality and safety of human organs intended for transplantation: http://www.europarl.europa.eu/sides/getDoc.do?type=TA&reference=P7-TA-2010-0181&format=XML&language=EN Date: May 19, 2010 (accessed Feb 6, 2021).

3. The source of the transplanted organs used in the study, including the donor Institution name (variable: “donor_centre”), city (variable “donor_city”), donor cause of death (variable “donor_death”) and a non-identifying description of the donor including, age, gender, optimal vs. suboptimal, and oxygenation index, are included in the data set submitted as Supporting Information File. This file, not only contains the donor data, but also the complete data set from which the analysis was performed including recruitment dates and the period during which transplant procedures were done (as month and year).

4. None of the transplant donors was from a vulnerable population and all donors or next of kin provided written informed consent that was freely given. This sentence has been included in the Ethics Statement within the text.

In the revised submission, please find a rebuttal letter answering the reviewers’ comments and a detailed explanation of changes in the text.

We have also changed our Data Availability Statement by submitting the complete anonymized data set to replicate our study findings (Supporting Information File).

Thank you for you attention to our manuscript.

Best regards

Antonio Alvarez

RESPONSE TO REVIEWERS

We would like to thank the reviewers of PLOS ONE for taking the time to review our manuscript entitled THE INFLUENCE OF THE NATIVE LUNG ON EARLY OUTCOMES AND SURVIVAL AFTER SINGLE LUNG TRANSPLANTATION. We appreciate the valuable and detailed comments provided by the reviewers.

We have made some corrections and clarifications in the manuscript after going over the reviewer’s comments.

Reviewer #1: The manuscript entitled "THE INFLUENCE OF THE NATIVE LUNG ON EARLY OUTCOMES AND SURVIVALAFTER SINGLE LUNG TRANSPLANTATION" is well written and a potential topic of interest in the field of lung transplant. The research finding is not novel and there is no direct evidence how the native lung is a source of morbidity. As the author mentioned that this topic is a very controversial, however, due to the correct, appropriately and rigorous data analysis I will recommend this paper for acceptance, and the controversies related to this topic I will leave on the readers.

RESPONSE: We thank the reviewer for his/her comments to our manuscript.

Reviewer #2: Most of LT are performed as the last therapeutic option in end stage degenerative lung disease as COPD-EMPHYSEMA and fibrotic lung disease, mainly IPF. The last decade was marked by a clear shift to BLT vs. SLT due to surgical, prognostic (mortality/survival) causes. Although world statistics still present almost half of patients receiving SLT the BLT trend mainly in very active transplant centers is clear. Focusing on lung grafts as a source of lower survival in SLT is limited as the authors noticed. The native lung was analyzed by various groups before as to its impact on survival

The authors add a local retrospective study to the existing data and looked on the impact of the native lung status on survival following SLT. There are 2 main flaws in the methodology as far as I understand:

1. One may not decide the impact on survival on patients following SLT using any parameter without comparing to BLT. As mentioned by the authors this lack of comparison is a limitation, in my opinion a fundamental one. You may not recommend BLT for COPD patients instead of SLT without comparing relevant data from BOTH options.

RESPONSE: We thank the comments of the reviewer. It is clear that we cannot recommend a bilateral procedure over a unilateral lung transplant on the basis of the analysis or single lung transplants alone. We agree with the reviewer that, for these purposes, the cohort of BLT should have been included in the study. However, the analysis of bilateral procedures was out of the focus of the present analysis. Our purpose has to know what happened with the native lung, irrespective of the behaviour of the lung graft, and whether the native complications could impact on early outcomes and survival. For this reason, according to the suggestions of the reviewer, we have eliminated recommendations of BLT for COPD instead of SLT because this statement is not supported by the data reported in our study.

2. I am confused by comparing the survival and mortality data. All patients without native lung complications presented higher 30 days mortality than those with (even when divided between COPD and IPF although not significant). On the other hand survival was worse in COPD patients with native lung complications (both early and late) but not in IPF patients. There is no clear explanation to this aparent discrepancy both in text and figure legends.

RESPONSE: We thank the reviewer comments. This is one of the major observations of our study: the fact that the native lung is not responsible of major complications leading to death in the early post-transplant period (30-days). Our analysis confirms that 30-day mortality after SLT occurs as a consequence of complications related to the lung graft (not the native), in addition to other well-known causes of early death (cardiac failure, infectious complications). On the contrary, long-term survival was adversely affected by complications in the native lungs, especially in COPD patients with lung cancer arising in the native lung. As shown in figure 1, only one case (IPF group) (2%) died due to native complications (native lung pneumonia), as opposed to 16 (15%) of early deaths that were unrelated to native lung problems. As only one case died in the early post-transplant period as a consequence of a native complication, differences of survival, especially for COPD, are related with late complications (rather than early complications), especially lung neoplasms in the native. This is more clearly demonstrated when analysing survival in the cohort of patients surviving 30 days post-transplant.

Reviewer #3: The topic is of interest for the lung transplant community.

English language is the first main limitation of the manuscript. Many paragraphs are very hard to understand.

RESPONSE: Thank you for your comments. An extensive review of English language has been done. English grammar, expressions, and syntax corrections have been made throughout the text. Some paragraphs have been shortened to make them more understandable.

The design of the study is somehow confusing and should be clearly presented upfront. The reader is expecting to understand the object of your analysis, the outcome measures, and the methodology of your analysis.

RESPONSE: Thank you for your comments. This is an observational analytic retrospective case-control study to determine the influence of native lung complications on early outcomes and survival after SLT for IPF or COPD. The primary end-points are 30-day mortality and survival. This clarification has been included in methods section (lines 86-96).

The statistical methodology is also confusing and should be reviewed both for the descriptives and the regression analysis.

RESPONSE: Thank you for your valuable comments. The description of the statistical methods was reviewed by our statistician without observing major flaws in the description. Nevertheless, changes have been included to better describe the statistics, according to the suggestions of the reviewer (lines 137-141). Also, we have included information regarding the availability of the data set used for the present analysis (lines 176-180).

I also suggest to redraft your discussion and try to define the key results of the study. The discussion is very long and the take-home messages are not clearly presented. Please shorten your text and make it simple.

RESPONSE: Thank you for you comments. We agree with the reviewer that the Discussion is too long. We have made extensive changes throughout the text to make it clearer. We believe that the main message is more clearly presented.

Overall, I think that you should consider revising the structure and presentation of your study. The topic is interesting and deserves the work and time of a revision.

RESPONSE: We wish to thank the reviewer for taking the time to review our manuscript.

Attachment

Submitted filename: Response Letter to Reviewers.docx

Click here for additional data file. (148.4KB, docx)

Decision Letter 1

Robert Jeenchen Chen

25 Mar 2021

THE INFLUENCE OF THE NATIVE LUNG ON EARLY OUTCOMES AND SURVIVAL AFTER SINGLE LUNG TRANSPLANTATION

PONE-D-21-01459R1

Dear Dr. Alvarez,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The author properly addressed the reviewers recommendation point by point, and I can recommend to accept the manuscript in its current form.

Reviewer #4: Dear Authors,

In the updated version of your manuscript investigating on short- and long-term mortality after lung transplantation in COPD and IPF patients, you exhaustively addressed all the reviewr comments.

Regards

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #4: No

Acceptance letter

Robert Jeenchen Chen

29 Mar 2021

PONE-D-21-01459R1

THE INFLUENCE OF THE NATIVE LUNG ON EARLY OUTCOMES AND SURVIVAL AFTER SINGLE LUNG TRANSPLANTATION

Dear Dr. Alvarez:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Robert Jeenchen Chen

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Complete dataset from which the analysis was performed.

    (SAV)

    Click here for additional data file. (63.3KB, sav)
    S2 File. Model of informed consent for organ donation in Spain.

    (PDF)

    Click here for additional data file. (94.8KB, pdf)
    Attachment

    Submitted filename: Response Letter to Reviewers.docx

    Click here for additional data file. (148.4KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES