Elevated Plasma Long Pentraxin-3 Levels and Primary Graft Dysfunction after Lung Transplantation for Idiopathic Pulmonary Fibrosis
1Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA
2Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York
3Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA
4Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA
5Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University, Raleigh-Durham, North Carolina
6Division of Pulmonary, Allergy, and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan
7Division of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois
8Division of Pulmonary, Allergy, and Critical Care, University of Pittsburgh, Pittsburgh, Pennsylvania
9Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York
10Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama
11Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Johns Hopkins University Hospital, Baltimore, Maryland
12Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
13Division of Pulmonary and Critical Care Medicine, Stanford University, Palo Alto, California
14Department of Anesthesia and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA
15Department of Surgery, Johns Hopkins University Hospital, Baltimore, Maryland
16Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
17Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana
We included 40 PGD cases and 79 non-PGD controls (). One control sample was excluded from analysis due to spurious results on the standard curve. A higher percentage of PGD cases required cardiopulmonary bypass than controls (54% vs. 30%, p=0.01) and PGD cases received a larger volume of intraoperative PRBCs than controls (1063 ml vs. 696 ml, p=0.04), but cases and controls were otherwise similar. There were 16 PGD cases and 32 non-PGD controls with COPD, and 24 PGD cases and 47 non-PGD controls with IPF. While pre-transplant PTX3 levels were low compared to post-transplant levels in all patients, pre-transplant levels were significantly higher in subjects with IPF (2.1 ng/ml, IQR 1.3, 7.0) compared to subjects with COPD (0.8 ng/ml, IQR 0.5, 2.0, p<0.001).
Subject characteristics stratified for PGD cases and non-PGD controls
Among all enrolled subjects, GEE modeling identified a non-significant difference in the trend of PTX3 levels across all the three time points between cases and controls (β=0.09, 95%CI -0.005, 0.2, p=0.06) (). The association between median PTX3 concentration and PGD differed according to predisposing diagnosis (p for interaction<0.03). There was no significant difference in PTX3 concentration between COPD cases and controls at any time point (all p>0.08). GEE longitudinal modeling identified a significant difference in the trend of PTX3 levels across all the three time points between IPF cases and controls (β=0.3, 95%CI 0.1, 0.5, p=0.001) but not COPD cases and controls (β=-0.2, 95%CI -0.5, 0.1, p=0.2) (). PTX3 levels were significantly higher in IPF patients with PGD compared to non-PGD IPF controls at 6 hours (45.7 ng/ml vs. 18.0 ng/ml, p=0.02) and 24 hours (88.9 ng/ml vs. 22.7 ng/ml, p=0.007) after reperfusion.
Longitudinal median PTX3 level across the pre-transplant, 6-h post-transplant, and 24-h post-transplant time points.
When subjects were analyzed according to diagnosis, there was a significant association between PTX3 level and the odds of PGD at 6 hours (OR for each 50 ng/ml higher level =1.6, 95%CI 1.1, 2.5, p=0.02) and 24 hours (OR for each 50 ng/ml higher level =1.3, 95%CI 1.1, 1.7, p=0.008) for IPF patients but no association for subjects with COPD at any time point (p>0.30). Evaluation for possible confounding was performed on the IPF subgroup at 6 and 24 hours post-reperfusion (). At 6 hours, use of cardiopulmonary bypass attenuated the association of PTX3 level with PGD. There was no attenuation of this relationship by any covariates for PTX3 levels measured at 24 hours after reperfusion. Surgical transplant type was similarly distributed among both COPD and IPF recipients in this study and transplant type was not found to be a confounder of the relationship between PTX3 and PGD.
Odds ratios for the development of Primary Graft Dysfunction in logistic regression models
A sensitivity analysis using highest PGD grade on any day as an ordinal outcome was performed. There was a significant increase in PTX3 level at 24 hours with increasing severity of PGD (p=0.048) (). This relationship was significant in the IPF subgroup (p=0.006) but not the COPD subgroup (p=0.8).
Figure 2 Median plasma PTX3 concentration 24 hours after transplant in all patients stratified by the highest PGD grade developing in the first 72 hours. Horizontal line indicates median concentration. The upper and lower limits of the box indicate the interquartile (more ...)
Pulmonary hypertension and use of cardiopulmonary bypass have been previously identified as risk factors for PGD (17
). While idiopathic pulmonary arterial hypertension patients were not included in this study, PASP among study subjects ranged from 13-111 mmHg. Spearman rank correlation revealed PASP was not significantly associated with PTX3 level prior to transplant (rho=0.15, p=0.1), or at 6 hours (rho=0.14, p=0.2) or 24 hours (rho=0.19, p=0.06) after reperfusion.