Survival benefit of induction immunosuppression in cystic fibrosis lung transplant recipients

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Original Article

Survival bene

fit of induction immunosuppression in cystic

fibrosis lung transplant recipients

,

☆☆

,

Stephen Kirkby

a,b,e,

, Bryan A. Whitson

c

, Allison M. Wehr

d

, Amy M. Lehman

d

,

Robert S. Higgins

c

, Don Hayes Jr.

a,b,e

aDepartment of Pediatrics, The Ohio State University, Columbus, OH, USA bDepartment of Internal Medicine, The Ohio State University, Columbus, OH, USA

cDepartment of Surgery, The Ohio State University, Columbus, OH, USA dCenter for Biostatistics, The Ohio State University, Columbus, OH, USA

e

Nationwide Children's Hospital, Columbus, OH, USA

Received 27 November 2013; received in revised form 13 May 2014; accepted 13 May 2014 Available online 16 June 2014

Abstract

Background: Despite resistant microbes, induction immunosuppression is used in patients with cysticfibrosis (CF) undergoing lung transplantation (LTx).

Methods: To evaluate the effect of induction immunosuppression on survival, the United Network for Organ Sharing (UNOS) was queried restricting analysis to transplant patients 6–55 years old from 2001 to 2012, who received induction agents (INDUCED) or did not (NONE). Results: A total of 1721 CF patients who underwent LTx were included in the analysis; of these 791 (46%) were INDUCED. Of the INDUCED patients, 65% received basiliximab, 10% alemtuzumab, and 25% thymoglobulin/anti-lymphocyte globulin/anti-thymocyte globulin. Mean age was 28.0 years (SD = 9.7) and 28.5 (SD = 9.5) for the INDUCED and NONE groups, respectively. The median survival in the INDUCED group was 93.8 months (95% CI: 73.8, --) compared to 61.8 months (95% CI: 55.8–73.8) for the NONE group (log rank p-value b0.001).

Conclusions: Antibody-based induction immunosuppression had a survival benefit in CF patients undergoing LTx. © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Keywords: Cysticfibrosis; Induction; Immunosuppression; Lung transplantation; Survival

1. Introduction

Cystic fibrosis (CF) is the most common fatal genetic disease in Caucasians and is associated with chronic airway infection,

profound airway and systemic inflammation, bronchiectasis, and progressively worsening obstructive lung physiology. Chronic lung disease is the leading cause of death[1]. Lung transplan-tation (LTx) is a therapeutic option for patients with CF and

advanced pulmonary disease[2]. The importance of LTx as a

treatment in this patient population is highlighted by the fact that CF is the third most common indication for LTx among adults, and is the most common indication for children older than age six

[3,4]. In addition to improved quality of life, there is a survival benefit for LTx in adult patients with CF[5].

Chronic infection in CF airways raises numerous concerns in the selection of these patients for LTx. The presence of drug-resistant organisms such as Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus (MRSA), other ☆ No funding was required to complete this work.

☆☆ The authors have no conflicts of interest with any companies or organizations whose products or services are discussed in this article.

★ The manuscript represents original work that is not being considered or has been accepted for publication elsewhere. The data was presented at the 2013 North American Cystic Fibrosis Conference (Salt Lake City, Utah; USA).

⁎ Corresponding author at: The Ohio State University, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205,USA. Tel.: + 1 614 722 3425; fax: + 1 614 722 3426.

E-mail address:stephen.kirkby@nationwidechildrens.org(S. Kirkby).

http://dx.doi.org/10.1016/j.jcf.2014.05.010

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gram negative bacteria including Burkholderia cepacia com-plex, fungal pathogens, and non-tuberculosis mycobacterium species, would appear to complicate transplantation of solid organs and place patients at significant risk for overwhelming infection. However, multiple studies have reported successful outcomes in CF despite these challenging infections and current established guidelines for LTx do not list specific airway pathogens as absolute contraindications[6–11].

Induction immunosuppression for LTx diminishes the early recipient immune response and may decrease the incidence of acute allograft rejection and bronchiolitis obliterans syndrome

[12]. Another benefit of induction is the ability to delay the use of calcineurin inhibitors in the immediate post-transplant period. The major potential complication of induction strategy is an increased risk of infection, which is the major cause of death in the early post-transplant period. The currently available induction agents include: the IL-2 receptor (CD25) monoclonal antibody Basiliximab, antithymocyte globulin which is a non-specific anti-lymphocyte antibody, and the anti-CD52 antibody alemtuzumab

[12]. There is no clear consensus on the use and benefits of

induction immunosuppression. Thus, the choice of whether or not to give induction and the use of specific induction agents varies from center to center. There is evidence that the use of induction for LTx has increased over the last decade, and now a majority of patients are receiving some form of induction. The IL-2 receptor antagonists are the most commonly used agents[3].

While a comprehensive analysis of United Network for Organ Sharing (UNOS) registry data has demonstrated evidence that induction immunosuppression has a positive effect on both graft and overall survival in lung transplant recipients as a group, the

specific effects of induction in CF remains unclear [13]. As

patients with CF and chronic infection may theoretically be at increased risk, we sought to evaluate the effect of contemporary induction immunosuppression with the primary endpoint being survival using national registry data.

2. Methods

2.1. Data collection/database

We retrospectively evaluated the outcome of CF lung transplant recipients whose data were registered in the Organ Procurement and Transplant Network (OPTN) Standard

Trans-plant Analysis and Research (STAR) Database [14]. With the

National Organ Transplant Act of 1984, the OPTN was established by the Congress of the United States. UNOS is a private, nonprofit organization that administers the OPTN under a federal contract. The STAR database is administrated through UNOS/OPTN as overseen by the United States Department of Health and Human Services. The UNOS/OPTN STAR database maintains data elements reflecting donor characteristics (e.g., donor mechanism of death, donor age, donor gender), pre-transplant recipient characteristics (e.g., indication for transplan-tation, recipient age, recipient gender), and post-transplant recipient characteristics and outcomes (i.e., length of stay, recipient survival, development of postoperative complication) for solid organ transplants from 1987 to present. Data is entered at

the time of a patient's listing, and again at their time of transplantation. The data are extracted by the individual centers and submitted as aggregate data to the OPTN United States Scientific Registry of Transplant Recipients (SRTR) which then collates and manages the data per the above referenced contract. This retrospective review was approved by The Ohio State University Wexner Medical Center Institutional Review Board with a waiver of the need for individual consent (IRB# 2012H0306). For purposes of this analysis, we queried the UNOS/OPTN thoracic database for all lung transplants from January 1, 2001 to July 6, 2011. The last status update in the dataset was performed on 7/6/2012; therefore, the cutoff date of 7/ 6/2011 was selected to allow for the potential for at least a year of follow-up time per patient. Patients included in the study had a diagnosis of CF, were between the ages of 6 and 55 years, and had

received cadaveric lung transplants. Patients undergoing

re-transplant were excluded. Additionally, daclizumab and OKT3 are no longer available for clinical use and therefore patients who received either of these induction agents were excluded from the study. We grouped the lung transplant recipients into either: having received no induction (NONE) or having received induction agents (INDUCED) of basiliximab, alemtuzumab, thymoglobulin (Thymo), anti-lymphocyte globulin (ALG), or anti-thymocyte globulin (ATG). The primary endpoint was overall survival after transplant for patients in the INDUCED vs. NONE groups. 2.2. Statistical methods

All demographic characteristics were summarized for the INDUCED and NONE groups separately. Kaplan–Meier estimates of the survival function were produced to assess crude differences in overall survival, and the log-rank test was performed to test for differences in survival functions. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for INDUCED vs. NONE for both a minimally adjusted and multivariable model. All variables included in these models were selected due to their clinical relevance. The minimally adjusted model includes INDUCED, recipient age at transplant and year of transplant; the baseline hazard was also stratified by UNOS region. The multivariable model included INDUCED, diagnosis, year of transplant, end-match LAS, ischemic time, age, gender, chronic steroid use, diabetes, body mass index (BMI), O2requirement at

rest at transplant, forced expiratory volume in one second (FEV1) % predicted at transplant, and forced vital capacity (FVC) % predicted at transplant. In both models, interactions between INDUCED and all other covariates were assessed using a

significance level of α = 0.01. Due to evidence of

non-proportionality, the interactions between age and year of transplant with time (log-transformed) were included in the model; the baseline hazard was also stratified by UNOS region.

As a sensitivity analysis to our multivariable models, we developed a score to measure the propensity that a patient would be induced. The following variables were used in a logistic regression model to create the propensity score: UNOS region, year of transplant, end match LAS, age, gender, gender match, race, BMI, ischemic time, total bilirubin at

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transplant (mg/dl), diabetes, steroids, O2requirement at rest at

transplant, FEV1 % predicted at transplant, and FVC % predicted at transplant. From the logistic model, a propensity score was estimated for each patient and a total of 616 induced patients were matched to 616 patients without induction using nearest neighbor matching without replacement and a conservative caliper of 0.2. We checked for balance of all covariates listed inTable 1(for categorical variables, we compared the proportion in each level) as well as those used in the propensity score in the matched sample by calculating standardized biases as well as testing for differences between the two groups using t-tests; the maximum standardized bias wasb0.08, and all t-tests were not significant

(pN 0.40 for all comparisons). The HR and 95% CI for

INDUCED vs. NONE were calculated using a Cox proportional hazards model in the matched sample. Standard errors were computed using the sandwich (robust covariance matrix) estimation procedure based on the matched pairs. The same covariates from the multivariable model were included to adjust for any residual confounding. As a final check, we also divided the patients into five subclasses (strata) based on their propensity score and then estimated the effect of induction within each subclass. The Cox model included the same covariates from the multivariable model. An overall estimate of the hazard ratio was then calculated by weighting each subclass estimate by the number of induced patients. All analyses were performed using SAS/STAT software version 9.2 (SAS Institute Inc., Cary, NC). 3. Results

3.1. Study cohort

Of 23,951 patients listed in the registry, a total of 1721 met all of the inclusion/exclusion criteria and were included in the

study (Table 1). Overall, 791/1721 (46%) of the patients in

the analysis cohort received an antibody-based induction agent (INDUCED). Among those patients, the majority (65%) received basiliximab, while 25% received ALG, ATG, or thymoglobulin. A smaller percentage (10%)

received alemtuzumab (Table 2).

A summary of demographic and clinical characteristics by induction status is shown inTable 3. The mean patient age was 28.0 (SD = 9.7) years for the INDUCED group and 28.5 (SD = 9.5) years for the NONE group. As anticipated, the cohort was predominately Caucasian, since CF has a much higher predilection for that patient population. Chronic steroid treatment prior to LTx was common (29%) with equivalent frequency of use between the two groups. Patients in both group had common characteristics of advanced lung disease due to CF, with need for oxygen supplementation, malnutrition measured by low BMI, and evidence of very severe obstruction on pulmonary function testing. Most donor organs had ischemic times of 4–6 h in both groups. A greater proportion of patients who were not induced were transplanted before May 1, 2005 (when the LAS system was implemented) compared to those who were induced (38% vs. 30%; p = 0.013).

Table 1

Flowsheet of study inclusion and exclusion criteria.

Lung transplant recipients N = 23,951

First time transplant N = 23,023

Survived POD 0 N = 22,748

Deceased donor transplants N = 22,521

Patients age 6-55 years N = 11,819

Re-transplants or multiple transplants on the same day

Survival status is present and patient and graft survival time is greater than 0

Other than deceased donors

Age <6 or >55 years old

Decade of 2000’s N = 6268

Transplant year <1/1/2001 or >7/6/2011

Fina l cohort N = 1721

Non-cystic fibrosis diagnoses Cystic fibrosis diagnosis

N = 61,965

Multiple induction agents or excluded agents

Table 2

Induction agent status.

Antibody based induction agent N (%)

No 930 (54%)

Yes: 791 (46%)

Basiliximab 511 (65%)

Alemtuzumab 79 (10%)

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Table 3

Demographics by induction status.

Variable Level Antibody based induction agent p-Value

No (n = 930) Yes (n = 791)

Recipient age at transplant Mean(SD) 28.5 (9.5) 28 (9.7) 0.265

(Min, max) (7, 55) (7, 55)

Recipient race Caucasian 865 (93%) 762 (96%) 0.010

African American 18 (2%) 7 (1%)

Other 47 (5%) 22 (3%)

Donor race Caucasian 596 (64%) 524 (66%) 0.415

African American 146 (16%) 127 (16%)

Other 188 (20%) 140 (18%)

Donor/recipient race match No match 355 (38%) 279 (35%) 0.214

Match 575 (62%) 512 (65%)

Recipient gender F 459 (49%) 391 (49%) 0.975

M 471 (51%) 400 (51%)

Donor gender F 422 (45%) 364 (46%) 0.790

M 508 (55%) 427 (54%)

Donor/recipient gender match No match 315 (34%) 289 (37%) 0.248

Match 615 (66%) 502 (63%)

Transplant type Double 928 (N99%) 789 (N99%) N.999

Single 2 (b1%) 2 (b1%)

Serum creatinine at transplant Missing 14 2 0.231

Creatinine≤ 2 902 (98%) 782 (99%)

CreatinineN 2 14 (2%) 7 (1%)

Chronic steroid use Missing 75 20 0.361

N 582 (68%) 541 (70%) Y 273 (32%) 230 (30%) Diabetes Missing 11 6 0.395 N 556 (61%) 459 (58%) Y 363 (40%) 326 (42%) CMV match Missing 34 29 0.006 No Match 510 (57%) 484 (64%) Match 386 (43%) 278 (36%)

Calculated recipient BMI #Missing Missing = 3 Missing = 0 0.302

Mean(SD) 19.3 (3) 19.1 (2.6)

(Min, max) (5.1, 37.6) (12.6, 32.2)

Lung allocation score (LAS) at match time Missing 2 2 0.013

Pre-LAS (transplant before 5/1/2005) 353 (38%) 237 (30%)

28.3–36.6 140 (15%) 141 (18%) 36.6–40.0 143 (15%) 139 (18%) 40.0–47.2 149 (16%) 133 (17%) 47.2–95.2 143 (15%) 139 (18%) Year of transplant 2001 88 (9%) 37 (5%) b.001 2002 81 (9%) 48 (6%) 2003 64 (7%) 66 (8%) 2004 86 (9%) 74 (9%) 2005 101 (11%) 55 (7%) 2006 98 (11%) 84 (11%) 2007 88 (9%) 70 (9%) 2008 76 (8%) 85 (11%) 2009 92 (10%) 98 (12%) 2010 102 (11%) 107 (14%) 2011 54 (6%) 67 (8%)

Ischemic time (hours) #Missing Missing = 63 Missing = 84 0.065

Mean(SD) 5.7 (1.6) 5.9 (1.6)

(Min, max) (1.1, 11.9) (1.2, 12)

O2requirement at rest at transplant #Missing Missing = 69 Missing = 17 0.150

Mean(SD) 3.6 (3.5) 3.9 (3.9)

(Min, max) (0, 20) (0, 26.3)

FEV1 % predicted at transplant #Missing Missing = 56 Missing = 20 0.018

Mean(SD) 27.2 (14.5) 25.4 (12.6)

(Min, max) (5, 106) (8, 120)

FVC % predicted at transplant #Missing Missing = 49 Missing = 16 0.104

Mean(SD) 40.7 (13.8) 39.5 (12.9)

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3.2. Overall survival

Overall, 41% (705/1721) of patients died during the post-transplant period. The data for survival time by induction status is summarized inTable 4. Kaplan–Meier estimates of the

survival function for INDUCED vs. NONE are illustrated in

Fig. 1. The median survival within the INDUCED group was 93.8 months (95% CI: 73.8, --) as compared to 61.8 months (95% CI: 55.8, 73.8) for the NONE group, log rank p-value b0.001. Due to censoring, we were unable to calculate an upper bound for the 95% CI for overall induction.

3.3. Cox proportional hazards modeling

The hazard ratio for INDUCED vs. NONE from the minimally adjusted model was 0.666 (95% CI: 0.565, 0.784;

pb 0.001) (Table 5), indicating that being INDUCED had a

positive effect on survival. Results from the multivariable model were consistent with those from the minimally adjusted model; the hazard ratio for INDUCED vs. NONE from this model was 0.630 (95% CI: 0.521, 0.762; pb 0.001). In both the minimally adjusted and multivariable models, there were no statistically significant interactions between INDUCED and any other covariate. In particular, the interaction between INDUCED and year of transplant was not significant, indicating that the effect of induction did not vary significantly over the study period. Additionally, as a sensitivity analysis to the multivariable models, propensity matching was utilized. The adjusted hazard ratio for INDUCED vs. NONE among this subset of matched patients was

0.668 (95% CI: 0.556, 0.802; pb 0.001), which is consistent

with results from the minimally adjusted and multivariable model. The results from the matched analysis were consistent with the model that split the data into five strata according to

propensity score (HR = 0.666; 95% CI: 0.534, 0.831; pb .001)

as well as the model that adjusted for propensity score (HR = 0.678; 95% CI: 0.573, 0.801; pb .001).

4. Discussion

In this analysis of the UNOS data registry, we have demonstrated a survival benefit with the use of induction immunosuppression in patients with CF undergoing LTx. Our study used the largest currently available database of outcomes from LTx, which includes data from all lung transplant centers in the United States and limits potential biases inherent in single center observational studies. We chose to analyze data in CF patients aged 6–55 years, who received an initial cadaveric LTx from 2001 to July, 2011. This allowed all patients to have at least one year of follow-up in our data set obtained in July, 2012. We intentionally excluded patients who had received OKT3 or daclizumab as these induction agents are no longer available for clinical use. The demographic data of the cohort is consistent with expected characteristics of patients with advanced CF lung disease needing LTx; the group had evidence of hypoxia, severe obstructive lung disease, and malnutrition.

Recently, our group published data that showed a trend towards (but not statistically significant) improved survival for pediatric patients 6–17 years who received induction immuno-suppression for LTx for all indications in that age group[15]. Approximately two-thirds of patients in this study had a diagnosis of CF[15]. A limitation of the pediatric data is the comparatively low numbers of transplantations performed in Table 4

Median survival time by induction status.

Group N Mean follow-up time (months) Number of events (deaths) Median survival time (months) 95% CI for median survival time No induction 930 42.4 435 61.8 (55.8, 73.8) Induction 791 41.4 270 93.8 (73.8, --)

Fig. 1. Kaplan–Meier estimates of post-lung transplant survival in recipients with CF who received induction immunosuppression or not (Log rank p-valueb 0.0001).

Table 5

Summary of modeling results.

Model N Estimated HR:

induced vs. no induction

95% CI p-Value

Minimally adjusted: Contains recipient age, year of transplant, baseline hazard stratified by region.

1721 0.666 (0.565, 0.784) b0.001

Multivariable model: Contains recipient age, LAS, year of transplant, ischemic time, gender, steroid use, diabetes, BMI, O2requirement at rest at

transplant, FEV1 % predicted at transplant, and FVC % predicted at transplant. Baseline hazard stratified by region.

1394 0.630 (0.521, 0.762) b0.001

Propensity score matched: Contains the same covariates as multivariable model. Nearest neighbor matching with caliper = 0.2.

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children, making it more challenging for analysis of survival to reach statistical significance. Our present study captured data from both children and adults with CF. We believe that, taken together, our two studies suggest clinical benefit for induction in patients with CF of all ages, although caution is always justified in applying adult driven data to pediatric patients.

Jaksch and colleagues recently published retrospective data from their large European lung transplant center demonstrating improved overall survival and a lower risk of acute rejection in

CF LTx recipients who received induction with ATG[16]. This

group of investigators speculated that chronic inflammation from CF lung disease stimulates the immune system which may have adverse consequences post-transplant including acute cellular rejection and the development of bronchiolitis obliterans syndrome. Moreover, infectious risks may be counterbalanced by the aggressive use of antimicrobial coverage in the peri-transplant period. Although we did not specifically evaluate the incidence of acute allograft rejection, bronchiolitis obliterans syndrome, or major post-transplant infections in this cohort, our present finding of a survival benefit with induction advances the theory that profound inflammation inherent in CF may be a driving force for adverse immunological events following LTx. Therefore, suppressing the immune system with induction therapy may reduce the ongoing innate inflammation in CF, but future investigations should address the effect of this treatment on acute and chronic allograft rejection in large cohorts of patients with CF.

Our study was not specifically designed to analyze differences in survival among individual agents used for induction immuno-suppression. While the majority (65%) of patients in the INDUCED group received basiliximab, there are insufficient numbers of patients who received other agents to draw clear conclusions on the optimal induction agent from this review of registry data. The question of which antibody-based induction agent confers the strongest clinical benefit in CF would be ideally addressed by means of a prospective, randomized controlled trial. A limitation of this study is the inherent challenges of retrospective collection of data from individual centers into large registries. Inconsistent data reporting is possible and a small percentage of patients had incomplete data recorded. Furthermore, the UNOS registry does not include important data specific to CF, such as genotype or presence of microbial pathogens. Although it is common to use antimicrobial agents aimed at known chronic respiratory pathogens in CF patients immediately after LTx, this practice is not standardized with variation existing across centers. The antimicrobial agents used in the peri-transplant period are not included in the UNOS data registry. Therefore we cannot perform an analysis to evaluate the effect of antimicrobial therapy following induction and LTx. Finally, our analysis included both adults and children. Although we found no strong evidence that the effect of induction was different for adults compared to children (by testing the interaction between recipient age and induction), we acknowledge that there may be differences between the two cohorts. Due to the limited number of children in our study, we were unable to separate out adults and children into separate models.

In conclusion, this analysis of data from the UNOS registry suggests a survival benefit of induction immunosuppression in patients with CF undergoing LTx. Future research is needed to determine if a specific induction agent is superior to others with regard to overall survival and the incidence of rejection and infectious complications.

Author participation

Stephen Kirkby: Conception and design, analysis and interpretation of data, critical revision of the manuscript, and drafting of the manuscript.

Bryan A. Whitson: Conception and design, acquisition of data, analysis and interpretation of data.

Robert S. Higgins: Conception and design, analysis and interpretation of data, critical revision of the manuscript, and supervision.

Allison M. Wehr: Statistical calculations and analysis and interpretation of data, and revision of the manuscript.

Amy M. Lehman: Statistical calculations and analysis and interpretation of data, and revision of the manuscript.

Don Hayes, Jr.: Conception and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript.

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References

  1. http://dx.doi.org/10.1016/j.jcf.2014.05.010
  2. O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009;373(9678):1891–904.
  3. Hayes Jr D, Meyer KC. Lung transplantation for advanced bronchiectasis.Semin Respir Crit Care Med 2010;31(2):123
  4. Yusen RD, Christie JD, Edwards LB, Kucheryavaya AY, Benden C,Dipchand AI, et al. The Registry of the International Society for Heart and
  5. Benden C, Edwards LB, Kucheryavaya AY, Christie JD, Dipchand AI,Dobbels F, et al. The Registry of the International Society for Heart and
  6. Thabut G, Christie JD, Mal H, Fournier M, Brugiere O, Leseche G, et al.Survival benefit of lung transplant for cystic fibrosis since lung allocation
  7. Aris RM, Gilligan PH, Neuringer IP, Gott KK, Rea J, Yankaskas JR. Theeffects of panresistant bacteria in cystic fibrosis patients on lung transplant
  8. Hadjiliadis D, Steele MP, Chaparro C, Singer LG, Waddell TK, HutcheonMA, et al. Survival of lung transplant patients with cystic fibrosis
  9. Helmi M, Love RB, Welter D, Cornwell RD, Meyer KC. Aspergillusinfection in lung transplant recipients with cystic fibrosis: risk factors and
  10. Chernenko SM, Humar A, Hutcheon M, Chow CW, Chaparro C,Keshavjee S, et al. Mycobacterium abscessus infections in lung transplant
  11. Chalermskulrat W, Sood N, Neuringer IP, Hecker TM, Chang L, Rivera MP,et al. Non-tuberculous mycobacteria in end stage cystic fibrosis: implications
  12. 2006 update–a consensus report from the Pulmonary Scientific Council of
  13. Bhorade SM, Stern E. Immunosuppression for lung transplantation. ProcAm Thorac Soc 2009;6(1):47
  14. Cai J, Terasaki PI. Induction immunosuppression improves long-term graftand patient outcome in organ transplantation: an analysis of United Network
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  17. Jaksch P, Wiedemann D, Augustin V, Murakozy G, Scheed A, KocherAA, et al. Antithymocyte globulin induction therapy improves survival in
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