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Retrospective validation of BOS-P as a predictor of bos in single lung transplant recipients
76
Abstracts
Introduction: Human -defensin-2 [HBD2] is an antimicrobial, NaCl-sensitive, cationic peptide that participates in the innate host defense of respiratory and other mucosal tissues. Increased levels of HBD2 have been measured in the airways during chronic inflammation and infection. The cytokines, interleukin-1 and TNF-␣, upregulate HBD2 mRNA expression in vitro, thus contributing to the hypothesis that HBD2 is inducible under proinflammatory stimuli. Further, HBD2 may promote “adaptive immune responses” by recruitment of dendritic and T-cells through interaction with the chemokine receptor, CCR6. Therefore, we questioned whether HBD2 levels were increased in BAL after lung transplantation ⬍ and may be related to the pathogenesis of BOS. Methods: We performed a preliminary cross-sectional study which assessed HBD2 and lysozyme concentrations by semiquantitative Western Blot analysis in BAL obtained with concurrent lung biopsies [TBB]. Subject groups included: (i) Pre-transplant [PRE; N⫽9], (ii) Nine LT recipients with normal TBB histology [NORMAL; N⫽22] and (iii) Six LT recipients with Bronchiolitis Obliterans Syndrome [BOS; N⫽8]. Results: HBD2 concentrations [Mean⫾SE] were as follows, for PRE: 0.204 ⫾ 0.18, NORMAL: 0.082 ⫾ 0.06, and BOS: 1.27 ⫾ 0.43 ng/ml [p⫽0.001; Kruskal-Wallis ANOVA]. For lysozyme, BAL concentrations were for PRE: 119.9 ⫾ 90.9, NORMAL: 174.9 ⫾ 101.6, and BOS: 51.2 ⫾ 13.8 g/ml [p⫽NS]. Conclusions: Similar to normal lungs, HBD2 was not typically present in allografts during periods of quiescence, however was increased during an airway inflammatory milieu such as BOS. We speculate that elaboration of inflammatory cytokines during such conditions as allograft infection, may induce expression of HBD2 by respiratory epithelium and, via complex interactions with dendritic cells, promote the development of BOS. Further, measurement of BAL HBD2 may serve as a valuable marker for BOS. 59 BOS 0-p AFTER LUNG TRANSPLANTATION: DOES EXHALED NITRIC OXIDE DISCRIMINATE BETWEEN STABILIZATION OF THE PULMONARY FUNCTION OR FURTHER CHRONIC REJECTION? G.M. Verleden,1 L. Dupont,1 D. Van Raemdonck,2 M. Mallet,1 M. Delcroix,1 J. Vanhaecke,3 1Department Pulmonary Diseases, University Hospital Gasthuisberg, Leuven, Belgium; 2Department Thoracic Surgery, University Hospital Gasthuisberg, Leuven, Belgium; 3Department Cardiology, University Hospital Gasthuisberg, Leuven, Belgium Background: Chronic rejection (obliterative bronchiolitis or BOS) remains the most devastating condition that still precludes long-term survival after lung transplantation (LTx). Exhaled nitric oxide (eNO) is increased in chronic rejection and this increase may precede the diagnosis of BOS 1 for more than 6 months (Verleden et al. ISHLT, 2001). Recently a new BOS classification including BOS 0-p (potential BOS) has been proposed. In the present study, we wanted to evaluate whether eNO may discriminate between those patients in BOS O-p who will develop BOS ⬎0 and those who will remain stable. Patients and Methods: From 1997 on, 12 patients (8 females) fulfilled the FEV1-criteria for BOS 0-p. Their mean age at Tx was 41.8⫾11.0 y. Heart-Lung Tx was performed in 4, seg. single (S) LTx in 4 and SLTx in another 4. BOS 0-p was diagnosed at postoperative day 853⫾454 (range 183-1751). Five patients ultimately developed BOSⱖ1 (group A, 1 BOS 1, 1 BOS 2, 3 BOS 3), whereas 7 remained stable (group B) with a further follow-up of
The Journal of Heart and Lung Transplantation January 2002 at least 6 months. Two of the BOS 3 patients died from their chronic rejection, the other was retransplanted. Results: At the time of BOS O-p diagnosis, there was no difference in eNO between the 2 groups, neither was there a difference in the 6 months preceding the diagnosis. After BOS 0-p was diagnosed, the eNO remained increased in group A compared to group B (unpaired t-test), with a trend towards a significant difference at 4 and 6 months. The results of the eNO measurements are summarized in the table. Conclusion: In patients who develop BOS O-p, there seems to be a further evolution to BOS ⱖ1 when the eNO remains increased. The non-invasive measurement of eNO may therefore discriminate between stabilization of the pulmonary function or further evolution to manifest chronic rejection. eNO (ppb)
ⴚ6 months ⴚ4 months ⴚ2 months BOS O-p ⴙ2 months ⴙ4 months ⴙ6 months
GROUP A 11.0 (3.5) GROUP B 14.0 (7.7) p-value 0.43
17.2 (6.6) 12.1 (3.5) 0.11
20.6 (10.9) 14.4 (6.8) 0.25
18.4 (5.5) 19.2 (8.1) 13.1 (4.9) 15.0 (8.1) 0.11 0.4
17.2 (11.7) 11.7 (4.6) 0.056
21.2 (12.4) 10.0 (2.2) 0.055
60 RETROSPECTIVE VALIDATION OF BOS-P AS A PREDICTOR OF BOS IN SINGLE LUNG TRANSPLANT RECIPIENTS S.D. Nathan,1 J. Wolhrab,1 S.D. Barnett,2 1Inova Transplant Center, Inova Fairfax Hospital, Falls Church, VA; 2Inova Heart Center, Inova Fairfax Hospital, Falls Church, VA The bronchiolitis obliterans syndrome was initially proposed in 1993. It has been used to describe chronic allograft dysfuntion assumed mostly to be due to chronic rejection. Recently an update of the diagnostic criteria has been proposed with a new category of potential-BOS (BOS 0-p) being defined. BOS-p is defined by an FEV1 of 81-90% and/or FEF25-75% ⬍75% of baseline. Using a ROC, we retrospectively tested the diagnostic accuracy of the midflow rates for the subsequent development of BOS in a group of 43 SLTR’s (COPD⫽25, IPF⫽18). We also performed an intracriterion analysis by comparing the two indices that constitute BOS-p. Results: FEF25-75 ⬍ 75% of B was a highly sensitive predictor of BOS. Of the 29 individuals diagnosed with BOS by an FEV1 ⬍ 90% of B, 25 (Sensitivity - 86.2%; Positive Predictive Value 80.7%) tested positive by FEF25-75 ⬍ 75% of B. Of the 14 non-BOS patients, 8 correctly tested negative by FEF25-75 ⬍ 75% of B (Specificity - 57.1%; Negative Predictive Value 66.7%). Conclusion: The FEF25-75% ⬍75% of baseline is a very sensitive indicator for the subsequent development of BOS, however it is also quite non-specific. In order to improve the specificity, a lower cutoff would be needed. The risk of BOS is perhaps most usefully stratified via a ROC curve of the FEF25-75%, where different cutoffs can be applied in different clinical situations. 13.8% of BOS-p defined by the FEV1⬍90%, did not fulfill the midflow criterion. Therefore, this second criterion does increase the sensitivity of BOS-p further. FEF 25–75
FP Rate
Sens.
Spec.
⬍.95 ⬍.85 ⬍.75 ⬍.65 ⬍.55 ⬍.45 ⬍.35
85.71 75.00 60.71 42.86 28.57 14.29 7.14
100.00 100.00 93.33 86.67 66.67 40.00 26.67
14.29 25.00 39.29 57.14 71.43 85.71 95.86
of of of of of of of
B B B B B B B
Abstracts
Introduction: Human -defensin-2 [HBD2] is an antimicrobial, NaCl-sensitive, cationic peptide that participates in the innate host defense of respiratory and other mucosal tissues. Increased levels of HBD2 have been measured in the airways during chronic inflammation and infection. The cytokines, interleukin-1 and TNF-␣, upregulate HBD2 mRNA expression in vitro, thus contributing to the hypothesis that HBD2 is inducible under proinflammatory stimuli. Further, HBD2 may promote “adaptive immune responses” by recruitment of dendritic and T-cells through interaction with the chemokine receptor, CCR6. Therefore, we questioned whether HBD2 levels were increased in BAL after lung transplantation ⬍ and may be related to the pathogenesis of BOS. Methods: We performed a preliminary cross-sectional study which assessed HBD2 and lysozyme concentrations by semiquantitative Western Blot analysis in BAL obtained with concurrent lung biopsies [TBB]. Subject groups included: (i) Pre-transplant [PRE; N⫽9], (ii) Nine LT recipients with normal TBB histology [NORMAL; N⫽22] and (iii) Six LT recipients with Bronchiolitis Obliterans Syndrome [BOS; N⫽8]. Results: HBD2 concentrations [Mean⫾SE] were as follows, for PRE: 0.204 ⫾ 0.18, NORMAL: 0.082 ⫾ 0.06, and BOS: 1.27 ⫾ 0.43 ng/ml [p⫽0.001; Kruskal-Wallis ANOVA]. For lysozyme, BAL concentrations were for PRE: 119.9 ⫾ 90.9, NORMAL: 174.9 ⫾ 101.6, and BOS: 51.2 ⫾ 13.8 g/ml [p⫽NS]. Conclusions: Similar to normal lungs, HBD2 was not typically present in allografts during periods of quiescence, however was increased during an airway inflammatory milieu such as BOS. We speculate that elaboration of inflammatory cytokines during such conditions as allograft infection, may induce expression of HBD2 by respiratory epithelium and, via complex interactions with dendritic cells, promote the development of BOS. Further, measurement of BAL HBD2 may serve as a valuable marker for BOS. 59 BOS 0-p AFTER LUNG TRANSPLANTATION: DOES EXHALED NITRIC OXIDE DISCRIMINATE BETWEEN STABILIZATION OF THE PULMONARY FUNCTION OR FURTHER CHRONIC REJECTION? G.M. Verleden,1 L. Dupont,1 D. Van Raemdonck,2 M. Mallet,1 M. Delcroix,1 J. Vanhaecke,3 1Department Pulmonary Diseases, University Hospital Gasthuisberg, Leuven, Belgium; 2Department Thoracic Surgery, University Hospital Gasthuisberg, Leuven, Belgium; 3Department Cardiology, University Hospital Gasthuisberg, Leuven, Belgium Background: Chronic rejection (obliterative bronchiolitis or BOS) remains the most devastating condition that still precludes long-term survival after lung transplantation (LTx). Exhaled nitric oxide (eNO) is increased in chronic rejection and this increase may precede the diagnosis of BOS 1 for more than 6 months (Verleden et al. ISHLT, 2001). Recently a new BOS classification including BOS 0-p (potential BOS) has been proposed. In the present study, we wanted to evaluate whether eNO may discriminate between those patients in BOS O-p who will develop BOS ⬎0 and those who will remain stable. Patients and Methods: From 1997 on, 12 patients (8 females) fulfilled the FEV1-criteria for BOS 0-p. Their mean age at Tx was 41.8⫾11.0 y. Heart-Lung Tx was performed in 4, seg. single (S) LTx in 4 and SLTx in another 4. BOS 0-p was diagnosed at postoperative day 853⫾454 (range 183-1751). Five patients ultimately developed BOSⱖ1 (group A, 1 BOS 1, 1 BOS 2, 3 BOS 3), whereas 7 remained stable (group B) with a further follow-up of
The Journal of Heart and Lung Transplantation January 2002 at least 6 months. Two of the BOS 3 patients died from their chronic rejection, the other was retransplanted. Results: At the time of BOS O-p diagnosis, there was no difference in eNO between the 2 groups, neither was there a difference in the 6 months preceding the diagnosis. After BOS 0-p was diagnosed, the eNO remained increased in group A compared to group B (unpaired t-test), with a trend towards a significant difference at 4 and 6 months. The results of the eNO measurements are summarized in the table. Conclusion: In patients who develop BOS O-p, there seems to be a further evolution to BOS ⱖ1 when the eNO remains increased. The non-invasive measurement of eNO may therefore discriminate between stabilization of the pulmonary function or further evolution to manifest chronic rejection. eNO (ppb)
ⴚ6 months ⴚ4 months ⴚ2 months BOS O-p ⴙ2 months ⴙ4 months ⴙ6 months
GROUP A 11.0 (3.5) GROUP B 14.0 (7.7) p-value 0.43
17.2 (6.6) 12.1 (3.5) 0.11
20.6 (10.9) 14.4 (6.8) 0.25
18.4 (5.5) 19.2 (8.1) 13.1 (4.9) 15.0 (8.1) 0.11 0.4
17.2 (11.7) 11.7 (4.6) 0.056
21.2 (12.4) 10.0 (2.2) 0.055
60 RETROSPECTIVE VALIDATION OF BOS-P AS A PREDICTOR OF BOS IN SINGLE LUNG TRANSPLANT RECIPIENTS S.D. Nathan,1 J. Wolhrab,1 S.D. Barnett,2 1Inova Transplant Center, Inova Fairfax Hospital, Falls Church, VA; 2Inova Heart Center, Inova Fairfax Hospital, Falls Church, VA The bronchiolitis obliterans syndrome was initially proposed in 1993. It has been used to describe chronic allograft dysfuntion assumed mostly to be due to chronic rejection. Recently an update of the diagnostic criteria has been proposed with a new category of potential-BOS (BOS 0-p) being defined. BOS-p is defined by an FEV1 of 81-90% and/or FEF25-75% ⬍75% of baseline. Using a ROC, we retrospectively tested the diagnostic accuracy of the midflow rates for the subsequent development of BOS in a group of 43 SLTR’s (COPD⫽25, IPF⫽18). We also performed an intracriterion analysis by comparing the two indices that constitute BOS-p. Results: FEF25-75 ⬍ 75% of B was a highly sensitive predictor of BOS. Of the 29 individuals diagnosed with BOS by an FEV1 ⬍ 90% of B, 25 (Sensitivity - 86.2%; Positive Predictive Value 80.7%) tested positive by FEF25-75 ⬍ 75% of B. Of the 14 non-BOS patients, 8 correctly tested negative by FEF25-75 ⬍ 75% of B (Specificity - 57.1%; Negative Predictive Value 66.7%). Conclusion: The FEF25-75% ⬍75% of baseline is a very sensitive indicator for the subsequent development of BOS, however it is also quite non-specific. In order to improve the specificity, a lower cutoff would be needed. The risk of BOS is perhaps most usefully stratified via a ROC curve of the FEF25-75%, where different cutoffs can be applied in different clinical situations. 13.8% of BOS-p defined by the FEV1⬍90%, did not fulfill the midflow criterion. Therefore, this second criterion does increase the sensitivity of BOS-p further. FEF 25–75
FP Rate
Sens.
Spec.
⬍.95 ⬍.85 ⬍.75 ⬍.65 ⬍.55 ⬍.45 ⬍.35
85.71 75.00 60.71 42.86 28.57 14.29 7.14
100.00 100.00 93.33 86.67 66.67 40.00 26.67
14.29 25.00 39.29 57.14 71.43 85.71 95.86
of of of of of of of
B B B B B B B