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441 Possible Disease Markers in BAL Fluid of BOS Patients
S150
The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
440
Pneumology, University of Pavia & IRCCS San Matteo Foundation, Pavia, Italy; 2Department of Neurological Sciences, University of Pavia and IRCCS Neurological National Institute C. Mondino, Pavia, Italy.
Post Lung Transplant Exercise Testing and Mortality H.F. Armstrong, M.N. Bartels. Rehabilitation and Regenerative Medicine, Columbia University Medical Center, New York, NY. Purpose: Cardiopulmonary exercise testing (CPET) is a known predictor of all cause mortality in heart failure, emphysema and normal populations but has not been used post lung transplant (LnTx). We hypothesize that CPET at 1 year post LnTx is a predictor of all cause mortality, conditioned on one-year survival. Methods and Materials: An IRB approved retrospective chart review was done of all LnTx between 7/01 and 6/09 at the Columbia University Medical Center (CUMC). Initial CPET performed post LnTx with complete pulmonary function test (PFT) data 1 to 2 ½ years post transplant were included for analysis. Peak watts percent predicted (PW%) and FEV1 percent predicted (FEV1%) were used. Date of death was obtained from the Social Security Index Database. Cause of death was from the final note in transplant chart. FEV1%/PW% Hazard Ratios
FEV1% >100% FEV1% 80-99% FEV1% 51-79% FEV1% <50% PW% >60% PW% 49-59% PW% 37-49% PW% <37%
Hazard Ratio
p-value
1 (referent) 4.271 1.445 5.818 1 (referent) 2.532 3.393 5.801
.002 .009 .540 .009 .033 .124 .042 .004
FEV1 %- Percent Predicted Forced Expired Volume in 1 Second; PW %- Percent Predicted Peak Watts
Purpose: Recently, great research interest has been focused on immunological mechanisms of lung graft rejection in particular of Bronchiolitis Obliterans Syndrome (BOS). A systematic evaluation of BAL fluid (BALf) proteome in BOS has been previously attempted by means of 2-DE and MALDI-TOF analysis and possible predictive markers of disease were identified (Surfactant protein A⫽SP-A, Clara Cell protein 16⫽CCP-16 whose expression decreased significantly in BOS patients with respect to stable lung recipients⫽SLRs; human alpha-defensins and lysozyme which were found increased in BOS). In addition, several pro-inflammatory factors have been evaluated in BALf and found to vary significantly in BOS (IL10,IL12, CXCL10, CXCL9, CXCL8, ␥-IFN and TNF-␣). Aim of this study was to evaluate previously identified markers in BALf obtained from 16 lung recipients who developed BOS (both pre-BOS and BOS) and a group of 14 SLRs (mean follow-up 14.5⫾6.7 months). Methods and Materials: ␣-1, ␣-2 and -defensins were analysed by means of Surface-Enhanced Laser Desorption/Ionization Mass Spectrometry using a reverse-phase array and evaluating peak intensity. All others were evaluated by ELISA. Marker levels observed in BOS were compared to 1st or 3rd quartile values observed in SLRs group. Results: This analysis revealed that BOS patients had an hetherogeneous behaviour with respect to BALf CC-16, SP-A and ␣-1 defensin levels, in fact only 5 out of 16 BOS patients had SP-A and CC16 values below 1st quartile of SLRs. Analogously ␣-1 defensins were increased respect to SLRs in only 8/16 BOS. No correlation was found with BAL cytology or functional features of BOS. As for cytokines, IL10 and IL12 were consistently below 1st quartile of SLRs (3.9 and 2.7, respectively) even in pre-BOS stage, while ␥-IFN, CXCL10 and CXCL9 levels were significantly higher in BOS, but exceeded 3rd quartile only in 50% of patients. Conclusions: In conclusion, this study highlighted the possible utility of IL10 and IL12 as early disease markers, while a possibly limited clinical value of other factors, such as SP-A, CC-16 and ␣-defensin, was detected. 442
Results: For every 10% increase in PW%, subjects have a decreased risk of death (0.665 times as likely). PW% was put into 4 quartiles and adjusted for 4 FEV1% groups. Kaplan Meier for PW% can be seen in Figure 1.
Conclusions: An increase in PW% is a strong independent predictor of mortality post LnTx after adjusting for FEV1%. The independence of PW% as a predictor of mortality may indicate a benefit in looking at CPET in order to better predict outcomes in LnTx. We propose that PW% can be used in conjunction with FEV1% to build a model to predict mortality in LnTx patients. 441 Possible Disease Markers in BAL Fluid of BOS Patients N. Solari,1 A. Ghiroldi,2 V. Pappalardo,1 S. Miserere,1 M. Morosini,1 B. Bini,1 A. Cascina,1 T. Oggionni,1 F. Meloni.1 1Department of Haematological Pneumological and Cardiovascular Sciences, Section of
An Evaluation of the Impact of Statin Use on the Progression to Bronchiolitis Obliterans in Lung Allografts J.A. Iuppa,1 A.R. Wills,1 L.J. Bowman,1 G.A. Patterson,2 E.P. Trulock,3 R.R. Hachem.3 1Pharmacy Department, Barnes-Jewish Hospital, St. Louis, MO; 2Division of Cardiothoracic Surgery, Washington University-School of Medicine, St. Louis, MO; 3Division of Pulmonary and Critical Care Medicine, Washington University-School of Medicine, St. Louis, MO. Purpose: The purpose of this study was to determine the effect of statin therapy on the development of BOS and survival in lung transplantation. Methods and Materials: We conducted a retrospective cohort study evaluating 169 consecutive patients that received lung transplants between January 1, 2006 and December 31, 2008. Fifty-one patients prescribed statins were compared to 101 patients that did not receive statins. Between group comparisons of categorical variables were made using the chi-square test. Both freedom from BOS and patient survival were calculated by the Kaplan-Meier method and compared by the log rank test. Results: Baseline characteristics were similar between the groups; however patients in the statin group (SG) were older (55.1 years vs. 52.1 years; p ⫽ 0.011), and more commonly received transplantation for underlying pulmonary fibrosis (45.1% vs. 20.8%; p ⫽ 0.002). In the control group (CG), a larger percentage of patients were transplanted for cystic fibrosis (26.7% vs. 2.0%; p ⬍ 0.01). Statin therapy was primarily indicated for hyperlipidemia [94.1% (48/51)]. During the study period, no difference was identified in the development of BOS overall (45.5% CG vs. 47.1% SG; p ⫽ 0.860), or in patients that began therapy early in the first year post-transplantation (45.5% in CG vs. 52.2% in SG; p ⫽ 0.319). The median time to development of BOS was 365 days in the CG and 366 days in SG (p ⫽ 0.105). There was no significant difference between the groups in freedom from BOS over time (figure 1, log rank p ⫽ 0.086) or death censored median survival time (log rank p ⫽ 0.964). Conclusions: Statins are not associated with a reduction in the development of BOS, and do not affect time to BOS or time to death.
The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
440
Pneumology, University of Pavia & IRCCS San Matteo Foundation, Pavia, Italy; 2Department of Neurological Sciences, University of Pavia and IRCCS Neurological National Institute C. Mondino, Pavia, Italy.
Post Lung Transplant Exercise Testing and Mortality H.F. Armstrong, M.N. Bartels. Rehabilitation and Regenerative Medicine, Columbia University Medical Center, New York, NY. Purpose: Cardiopulmonary exercise testing (CPET) is a known predictor of all cause mortality in heart failure, emphysema and normal populations but has not been used post lung transplant (LnTx). We hypothesize that CPET at 1 year post LnTx is a predictor of all cause mortality, conditioned on one-year survival. Methods and Materials: An IRB approved retrospective chart review was done of all LnTx between 7/01 and 6/09 at the Columbia University Medical Center (CUMC). Initial CPET performed post LnTx with complete pulmonary function test (PFT) data 1 to 2 ½ years post transplant were included for analysis. Peak watts percent predicted (PW%) and FEV1 percent predicted (FEV1%) were used. Date of death was obtained from the Social Security Index Database. Cause of death was from the final note in transplant chart. FEV1%/PW% Hazard Ratios
FEV1% >100% FEV1% 80-99% FEV1% 51-79% FEV1% <50% PW% >60% PW% 49-59% PW% 37-49% PW% <37%
Hazard Ratio
p-value
1 (referent) 4.271 1.445 5.818 1 (referent) 2.532 3.393 5.801
.002 .009 .540 .009 .033 .124 .042 .004
FEV1 %- Percent Predicted Forced Expired Volume in 1 Second; PW %- Percent Predicted Peak Watts
Purpose: Recently, great research interest has been focused on immunological mechanisms of lung graft rejection in particular of Bronchiolitis Obliterans Syndrome (BOS). A systematic evaluation of BAL fluid (BALf) proteome in BOS has been previously attempted by means of 2-DE and MALDI-TOF analysis and possible predictive markers of disease were identified (Surfactant protein A⫽SP-A, Clara Cell protein 16⫽CCP-16 whose expression decreased significantly in BOS patients with respect to stable lung recipients⫽SLRs; human alpha-defensins and lysozyme which were found increased in BOS). In addition, several pro-inflammatory factors have been evaluated in BALf and found to vary significantly in BOS (IL10,IL12, CXCL10, CXCL9, CXCL8, ␥-IFN and TNF-␣). Aim of this study was to evaluate previously identified markers in BALf obtained from 16 lung recipients who developed BOS (both pre-BOS and BOS) and a group of 14 SLRs (mean follow-up 14.5⫾6.7 months). Methods and Materials: ␣-1, ␣-2 and -defensins were analysed by means of Surface-Enhanced Laser Desorption/Ionization Mass Spectrometry using a reverse-phase array and evaluating peak intensity. All others were evaluated by ELISA. Marker levels observed in BOS were compared to 1st or 3rd quartile values observed in SLRs group. Results: This analysis revealed that BOS patients had an hetherogeneous behaviour with respect to BALf CC-16, SP-A and ␣-1 defensin levels, in fact only 5 out of 16 BOS patients had SP-A and CC16 values below 1st quartile of SLRs. Analogously ␣-1 defensins were increased respect to SLRs in only 8/16 BOS. No correlation was found with BAL cytology or functional features of BOS. As for cytokines, IL10 and IL12 were consistently below 1st quartile of SLRs (3.9 and 2.7, respectively) even in pre-BOS stage, while ␥-IFN, CXCL10 and CXCL9 levels were significantly higher in BOS, but exceeded 3rd quartile only in 50% of patients. Conclusions: In conclusion, this study highlighted the possible utility of IL10 and IL12 as early disease markers, while a possibly limited clinical value of other factors, such as SP-A, CC-16 and ␣-defensin, was detected. 442
Results: For every 10% increase in PW%, subjects have a decreased risk of death (0.665 times as likely). PW% was put into 4 quartiles and adjusted for 4 FEV1% groups. Kaplan Meier for PW% can be seen in Figure 1.
Conclusions: An increase in PW% is a strong independent predictor of mortality post LnTx after adjusting for FEV1%. The independence of PW% as a predictor of mortality may indicate a benefit in looking at CPET in order to better predict outcomes in LnTx. We propose that PW% can be used in conjunction with FEV1% to build a model to predict mortality in LnTx patients. 441 Possible Disease Markers in BAL Fluid of BOS Patients N. Solari,1 A. Ghiroldi,2 V. Pappalardo,1 S. Miserere,1 M. Morosini,1 B. Bini,1 A. Cascina,1 T. Oggionni,1 F. Meloni.1 1Department of Haematological Pneumological and Cardiovascular Sciences, Section of
An Evaluation of the Impact of Statin Use on the Progression to Bronchiolitis Obliterans in Lung Allografts J.A. Iuppa,1 A.R. Wills,1 L.J. Bowman,1 G.A. Patterson,2 E.P. Trulock,3 R.R. Hachem.3 1Pharmacy Department, Barnes-Jewish Hospital, St. Louis, MO; 2Division of Cardiothoracic Surgery, Washington University-School of Medicine, St. Louis, MO; 3Division of Pulmonary and Critical Care Medicine, Washington University-School of Medicine, St. Louis, MO. Purpose: The purpose of this study was to determine the effect of statin therapy on the development of BOS and survival in lung transplantation. Methods and Materials: We conducted a retrospective cohort study evaluating 169 consecutive patients that received lung transplants between January 1, 2006 and December 31, 2008. Fifty-one patients prescribed statins were compared to 101 patients that did not receive statins. Between group comparisons of categorical variables were made using the chi-square test. Both freedom from BOS and patient survival were calculated by the Kaplan-Meier method and compared by the log rank test. Results: Baseline characteristics were similar between the groups; however patients in the statin group (SG) were older (55.1 years vs. 52.1 years; p ⫽ 0.011), and more commonly received transplantation for underlying pulmonary fibrosis (45.1% vs. 20.8%; p ⫽ 0.002). In the control group (CG), a larger percentage of patients were transplanted for cystic fibrosis (26.7% vs. 2.0%; p ⬍ 0.01). Statin therapy was primarily indicated for hyperlipidemia [94.1% (48/51)]. During the study period, no difference was identified in the development of BOS overall (45.5% CG vs. 47.1% SG; p ⫽ 0.860), or in patients that began therapy early in the first year post-transplantation (45.5% in CG vs. 52.2% in SG; p ⫽ 0.319). The median time to development of BOS was 365 days in the CG and 366 days in SG (p ⫽ 0.105). There was no significant difference between the groups in freedom from BOS over time (figure 1, log rank p ⫽ 0.086) or death censored median survival time (log rank p ⫽ 0.964). Conclusions: Statins are not associated with a reduction in the development of BOS, and do not affect time to BOS or time to death.