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Ann Thorac Surg 2005;79:950-957
© 2005 The Society of Thoracic Surgeons

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Original article: General thoracic

Impact of Recipient Age and Procedure Type on Survival After Lung Transplantation for Pulmonary Fibrosis

^a Department of Thoracic and Cardiovascular Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
^b United Network of Organ Sharing (UNOS), Richmond, Virginia
^c Southwest Pulmonary Associates, Dallas, Texas
^d University of Western Ontario, London, Ontario, Canada

Accepted for publication August 26, 2004.

^* Address reprint requests to Dr Meyer, Department of Thoracic and Cardiovascular Surgery, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-8879 (E-mail: dan.meyer{at}utsouthwestern.edu).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Appendix. Potential Risk Factors... References

 
BACKGROUND: The decision to perform single-lung (SLT) or bilateral sequential lung (BSLT) transplantation in patients with pulmonary fibrosis is controversial. Some centers use recipient age (<50 years) as a criterion to select BSLT over SLT, but the rationale for this approach is not well established.

METHODS: Eight hundred twenty-one patients (636 SLT, 185 BSLT), aged 30 to 69 years, who were recipients of transplants for pulmonary fibrosis in the United States between 1994 and 2000 were reported to the United Network for Organ Sharing. Survival was compared by procedure type within three age groups (30 to 49 years, 50 to 59 years, and 60 to 69 years) using the Kaplan-Meier method. Multivariate logistic regression analysis was used to calculate risk-adjusted mortality within 1-month after transplantation, and proportional hazards regression was used to calculate risk-adjusted mortality after 1 month.

RESULTS: Early (1-month) and late (3-year) survival in recipients aged 30 to 49 years was significantly better with SLT than BSLT (early, 90.9% versus 77.1%; late, 63.8% versus 46.2%, respectively; p = 0.02). Survival was also significantly better with SLT than BSLT at these time points in those patients aged 50 to 59 years (early, 89.5% versus 81.7%; late, 53.6% versus 46.7%, respectively; p = 0.03). When posttransplant survival was reanalyzed contingent on survival to 1 month, no significant difference in survival by procedure type (SLT versus BSLT) was detected for any age group. Multivariate analysis of survival, adjusted for other known risk factors, as well as propensity analysis, yielded similar results.

CONCLUSIONS: Patients younger than 60 years of age who were recipients of transplants for pulmonary fibrosis appear to have better survival with SLT than with BSLT. Although the basis for this observation is unclear, events occurring in the early period (first month) after transplantation may play a role. Further studies will be needed, but these data do not appear to support the preferential use of BSLT for younger patients with pulmonary fibrosis.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Appendix. Potential Risk Factors... References

 
The decision whether to perform single-lung transplant (SLT) or bilateral sequential lung transplant (BLST) in patients with advanced pulmonary fibrosis (PF) is controversial. In 1983, the first successful lung transplant was performed as an SLT procedure in a patient with PF [1]. However, as more experience was gained with double-lung transplantation, and later BSLT [2], transplantation of both lungs began to be favored for younger (<50 years) patients with PF. Although BSLT may represent a better option from an operative and perioperative perspective in the subgroup of PF patients with elevated pulmonary artery (PA) pressures, the routine adoption of this practice for all younger PF patients would have a negative impact on the availability of donor lungs.

In a review of data from the International Society for Heart and Lung Transplantation database, the use of BSLT in younger patients with emphysema has been shown to offer a survival advantage [3]. However, similar analysis has not been reported for patients with PF, the second most common indication for lung transplantation. An enhanced understanding of the long-term results of SLT versus BSLT may suggest ways to optimize both long-term patient survival and allocation of these scarce donor organs. The purpose of this study was to compare outcome of SLT and BSLT in patients undergoing transplantation for end-stage PF.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Appendix. Potential Risk Factors... References

 
Patient Population
Between April 1, 1994, and December 31, 2000, there were 843 primary lung transplants (from cadaveric donors) performed in the United States for patients diagnosed with PF, as reported to the United Network for Organ Sharing. Owing to the small number of patients younger than 30 years of age (n = 15) and older than 70 years of age (n = 7), the analysis was limited to patients between 30 and 69 years of age at the time of transplantation. This resulted in a study population of 821 lung transplant recipients: 636 SLT and 185 BSLT. Patients were analyzed within clinically relevant subgroups, ages 30 to 49 years, 50 to 59 years, and 60 to 69 years. Patients diagnosed with PF were not classified into separate diagnostic categories on the basis of histologic or radiographic criteria [4]. Patients with end-stage sarcoid lung disease were not included. Similarly, patients with less common variants of PF such as bleomycin toxicity, radiation pneumonitis, and post–adult respiratory distress syndrome PF were classified by the United Network for Organ Sharing as "Pulmonary Fibrosis, other" and were not included in the current analysis. The clinical factors influencing the operative decision of SLT or BSLT were not available in the United Network for Organ Sharing database.

Survival and Statistical Analyses
Survival was compared between the procedure types within each age group (30 to 49 years, 50 to 59 years, 60 to 69 years) using the Kaplan-Meier method. The statistical difference between Kaplan-Meier survival curves was assessed using the log rank test. A multivariate logistic regression analysis was also undertaken to calculate risk-adjusted mortality within 1 month after transplantation, and proportional hazards regression was used to calculate risk-adjusted mortality after 1 month. Standard known risk factors for mortality, such as cytomegalovirus status, ventilator dependence, PA pressures, graft ischemic time, and donor age, were among the variables included in the analysis. Continuous characteristics were compared using a Student's t test or Kruskal-Wallis test; categorical characteristics were compared using the ² statistic or Fisher's exact test. Missing data were imputed. A very simple imputation scheme was used: if a variable was missing it was replaced by the mean value for that procedure type. A complete list of candidate variables included in the analysis is provided in the Appendix.

In addition to the standard multivariate analysis, further testing was performed to take into consideration the nonrandomness of procedure type. By using a propensity analysis [5], differences in patient characteristics between SLT and BSLT recipients were modeled in such a way as to provide a more reliable assessment of the impact of procedure type. The first step in the propensity analysis involved the development of a model to estimate the probability of a patient receiving a BSLT. Although multiple variables were considered for the propensity model (see Appendix), the factors used in this model were recipient age, PA mean pressure, ischemia time, center volume, donor age, year of transplant, steroid use, and prior thoracotomy. After this, propensity scores were analyzed by three possible techniques—matching, stratification, and regression adjustment. The first technique matched cases (BSLT) and controls (SLT) by the propensity score and then compared outcomes. The second method grouped the patients into distinct percentile bands (strata) on the basis of the propensity scores. The final technique included both operative procedure and propensity score as outcome predictors in a regression model. These techniques are described in greater detail later, but serve to adjust for the increased likelihood of BSLT in certain settings.

	Results

Top Abstract Introduction Patients and Methods Results Comment Appendix. Potential Risk Factors... References

 
Donor and recipient characteristics were similar among the three age groups (30 to 49 years, 50 to 59 years, and 60 to 69 years; Table 1). However, when clinical characteristics were compared by procedure type, a number of significant differences emerged (Table 2). The BSLT recipients were younger than patients undergoing SLT (49.3 ± 8.7 years versus 54.9 ± 7.9 years). Graft ischemic time, which is measured as the time from recovery to implantation of the second lung in BSLT, was, as expected, longer in the BSLT group (BSLT versus SLT, 5.5 ± 1.9 hours versus 3.9 ± 1.5 hours). Recipient PA systolic, diastolic, and mean pressures were also greater in the BSLT as compared with the SLT patients (PA systolic, 45.1 ± 20.9 mm Hg versus 38.4 ± 13.9 mm Hg; PA diastolic, 20.2 ± 11.1 mm Hg versus 16.7 ± 8.0 mm Hg; and PA mean, 29.0 ± 13.1 mm Hg versus 24.4 ± 9.9 mm Hg). Transplant center volume per year was also greater in those patients undergoing BSLT compared with SLT (24.8 ± 15.1 versus 19.6 ± 11.9).

View larger version (15K): [in this window] [in a new window]   Fig 1. (A) Posttransplant survival stratified by procedure type for age group 30 to 49 years. (B) Posttransplant survival stratified by procedure type for age group 30 to 49 years, contingent on survival to 3 months.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Appendix. Potential Risk Factors... References

 
Pulmonary fibrosis encompasses many types of lung diseases. Once the diagnosis is established, the treatment follows an algorithm including the use of corticosteroids, antimetabolites, and other immunosuppressive therapies [7, 8]. Only when these methods fail does lung transplantation become a consideration. Data from the United Network for Organ Sharing has consistently demonstrated that patients with PF undergoing lung transplantation have a poorer survival than their counterparts with chronic obstructive pulmonary disease or cystic fibrosis. For lung transplantations performed between 1994 and 1997, 5-year survival was 39.4% in the PF patients, compared with 46.0% and 49.9% in those receiving transplantations for chronic obstructive pulmonary disease and cystic fibrosis, respectively [9]. It has been established that the PF patient population on the waiting list is more susceptible to death than other patients awaiting lung transplantation [10]. To account for this difference, the waiting time for PF patients is adjusted by an additional 90 days for the purposes of lung allocation. It is not surprising, therefore, that the mortality seen in this "sicker" group is heavily weighted toward the early postoperative period.

Interestingly, the optimal surgical procedure for patients with PF has yet to be conclusively determined. For septic lung disease, BSLT is the standard operative approach. For end-stage chronic obstructive pulmonary disease, both SLT and BSLT have been performed. In the younger population, a survival advantage had been reported in those patients with end-stage emphysema receiving BSLT when compared with SLT [3]. The current study demonstrated that patients younger than 60 years of age who underwent transplantation for PF appear to have a tendency toward a better survival with SLT than with BSLT. Although the basis for this observation is unknown, it may be related to a tendency toward more surgical problems and graft failure in the early posttransplant period in the BSLT patients when compared with the SLT patients. From a strictly technical standpoint, the surgical procedure in patients with PF is often more difficult because of the limited amount of space present in the contracted pleural cavity of the PF patients. Typically, the diaphragm is pushed cephalad and fibrosis in the hilum may be present, further complicating the dissection. These factors may contribute to the lower mortality observed in PF patients who receive SLT.

Previous smaller reports have not identified a survival advantage of BSLT versus SLT in patients with PF. Meyers and associates [2], in an experience with 45 patients with PF, found no difference in survival with SLT versus BSLT. Age of the recipient did not differ significantly between the SLT and BSLT groups and therefore was not assessed as a risk factor for mortality in patients with the diagnosis of PF. Similarly, Charman and colleagues [11] reviewed 653 patients accepted for lung transplantation at their institution. Of this group, 100 were patients with PF. This group found no significant long-term survival difference between SLT and BSLT in patients with PF, although they reported a higher mortality at 1 month in the BSLT group. Pulmonary hypertension was not examined as a risk factor in this report. The authors did note that their analysis did not assess quality of life, which may be an important consideration in these patients.

The coexistence of pulmonary hypertension may define a subset of patients who are at increased mortality risk. The United Network for Organ Sharing data presented here support the concept that survival decreases with increasing levels of pulmonary hypertension (Table 4). Many centers have a bias toward transplanting both lungs in PF patients with pulmonary hypertension. This practice is difficult to support on the basis of the data presented here, in which propensity analysis failed to show any advantage of BSLT over SLT within the subgroup of patients with pulmonary hypertension. As well, Huerd and colleagues [12] found that secondary PA hypertension had no negative effect on outcome after SLT. A study by Gammie and associates [13] found no significant difference in outcome in patients with pulmonary hypertension who underwent SLT or BSLT.

In the current study, propensity analyses were performed to better assess the impact of some of these risk factors, especially PA hypertension, in PF patients. The techniques used to analyze the propensity scores included matching, stratification, and regression adjustment. The first technique matches cases (BSLT) and controls (SLT) on the propensity score. One of the primary drawbacks to this method is that many of the observations may have propensity scores that do not permit them to be matched to an observation in the other group. In our analyses, there were many BSLT recipients with relatively high propensity scores (meaning that they would be predicted to have received a BSLT) but there were fewer SLT patients with high propensity scores. Therefore, some of the BSLT patients would have gone unmatched in the final sample. With so few BSLT individuals in the cohort, two other techniques were explored instead: stratification and regression adjustment. Both of these analyses confirmed the results of the multivariate analysis: there is no advantage of BSLT over SLT in patients with PF.

Study Limitations
The limitations of large prospective database reviews are well known. The voluntary nature, participation by multiple institutions, and the lack of standardized immunosuppressive regimens make analysis of survival data difficult. The patient cohort from 1994 to 2000 was selected to capture an adequate period of follow-up in an era when more standardized immunosuppressive management had evolved. Although all patients included carried a diagnosis of PF, it is recognized that this entity encompasses a wide range of pathophysiologic processes, each with a different natural history. Information on the specific pathologic subsets was not available in this database. Efforts to obtain a more homogeneous patient population were made by excluding the groups described in the methods section.

As this study was a database review and therefore not randomized, selection bias may have played a role in skewing the results of the study in favor of SLT, as opposed to BSLT. Our data did show that patients undergoing BSLT had a lower preoperative forced expiratory volume in 1 second and higher recipient PA pressures preoperatively than those undergoing SLT. However, although the use of propensity score analysis may not completely correct for these potentially confounding variables, the technique does offer a valuable statistical tool to assess subgroups that would typically be too small on which to perform a stratified analysis.

Conclusions
The great disparity between the need and availability of donor organs places the responsibility of the transplant physicians to optimize the allocation of this scarce resource to their patients. In younger patients with PF, SLT appears to provide superior early and intermediate survival when compared with BSLT. In patients older than 60 years of age, SLT also appears to be the preferred procedure. Further studies will be needed to formulate recommendations regarding the preferred operative procedure for the more controversial subgroup of patients with secondary pulmonary hypertension, but data advocating the use of BSLT in this group are lacking. On the basis of these data, transplant centers should consider SLT as the primary surgical option for patients with PF. This strategy should not deter outcomes and would increase the number of available organs for patients with end-stage lung disease.

	Appendix. Potential Risk Factors Considered

Top Abstract Introduction Patients and Methods Results Comment Appendix. Potential Risk Factors... References

 

View larger version (14K): [in this window] [in a new window]   Fig 2. (A) Posttransplant survival stratified by procedure type for age group 50 to 59 years. (B) Posttransplant survival stratified by procedure type for age group 50 to 59 years, contingent on survival to 3 months.

View larger version (14K): [in this window] [in a new window]   Fig 3. (A) Posttransplant survival stratified by procedure type for age group 60 to 69 years. (B) Posttransplant survival stratified by procedure type for age group 60 to 69 years, contingent on survival to 3 months.

	References

Top Abstract Introduction Patients and Methods Results Comment Appendix. Potential Risk Factors... References

1. Cooper JD, Ginsberg RJ, Goldberg M, The Toronto Lung Transplantation Group Unilateral transplantation for pulmonary fibrosis N Engl J Med 1986;314:1140-1145.[Abstract]
2. Meyers BF, Lynch JP, Trulock EP, Guthrie T, Cooper JD, Patterson GA. Single versus bilateral lung transplantation for idiopathic pulmonary fibrosis: a ten-year institutional experience J Thorac Cardiovasc Surg 2000;120:99-107.[Abstract/Free Full Text]
3. Meyer DM, Bennett LE, Novick RJ, Hosenpud JD. Single versus bilateral sequential lung transplantation for end-stage emphysema: influence of recipient age on survival and secondary end-points J Heart Lung Transplant 2001;20:935-941.[Medline]
4. American Thoracic Society and European Respiratory Society American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias Am J Respir Crit Care Med 2002;165:277-304.[Free Full Text]
5. D'Agostino R. Tutorial in biostatistics: propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group Stat Med 1998;17:2265-2281.[Medline]
6. Hosmer Jr DW, Lemeshow S. Applied logistic regression, 2nd edJohn Wiley and Sons; 2000.
7. Michaelson JE, Aguayo SM, Roman J. Idiopathic pulmonary fibrosis: a practical approach for diagnosis and management Chest 2000;118:788-794.[Free Full Text]
8. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis N Engl J Med 2001;345:517-525.[Free Full Text]
9. Based on the United Network for Organ Sharing data as of March 2003. Available at http://www.optn.org/data/citing.asp..
10. Harari S, Simmonneau G, De Juli E, et al. Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation J Heart Lung Transplant 1997;16:460-463.[Medline]
11. Charman SC, Shaples LD, McNeil KD, Wallwork J. Assessment of survival benefit after lung transplantation by patient diagnosis J Heart Lung Transplant 2002;21:226-232.[Medline]
12. Huerd SS, Hodges TN, Grover FL, et al. Secondary pulmonary hypertension does not adversely affect outcome after single lung transplantation J Thorac Cardiovasc Surg 2000;119:458-465.[Abstract/Free Full Text]
13. Gammie JS, Keenan RJ, Pham SM, et al. Single- versus double-lung transplantation for pulmonary hypertension J Thorac Cardiovasc Surg 1998;115:397-403.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Dan M. Meyer Michael E. Jessen Richard J. Novick Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meyer, D. M. Articles by Novick, R. J. Search for Related Content PubMed PubMed Citation Articles by Meyer, D. M. Articles by Novick, R. J. Related Collections Lung - transplantation Related Article