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Insufficient Post-Transplant Immunosuppression Induces Restrictive Allograft Syndrome-Like Fibrosis in the Pleura and Lung Parenchyma After Lung Transplantation
S108
The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016
(Fig. C). However, spleen culture showed no significant difference among groups; the serum of limited CsA group showed only slightly higher reactivity (less than twofold) than the other groups. Conclusion: This study demonstrated that DSA reacting with the donor MHC class I molecules are produced locally in chronically rejected lung allografts. Locally produced DSA may be underestimated in the serum test but could play an important role in the progression of CLAD after LTx.
proportion of transbronchial biopsies obtained within 30 days of detection of C1q+ DSA.
Histopathologic features by presence or absence of C1q DSA
A grade rejection A2 or higher B grade rejection B1R B2R C grade rejection C1 C4d Positive Negative Not done Neutrophilic margination Acute capillaritis Acute Lung injury ALI present DAD Other Organizing pneumonia Aspiration
Serum samples with C1Q DSA positive n = 37 (%)
Serum samples with no C1Q DSA n = 80 (%)
13 (35.0)
11 (13.8)
1 (2.7) 2 (5.4)
3 (3.75) 1 (1.25)
3 (8.1)
2 (2.50)
1 ( 2.7) 30 (81.0) 6 (16.2) 2 (5.4) 0
5 (6.25) 67 (83.75) 8 (10.0) 7 ( 8.75) 0
0 0
1 (1.25) 2 (2.5)
0 0
2 (2.5) 1 (1.25)
p = 0.008 p = 0.4
p = 0.16 p = 0.48
p = 0.14 p = 0.17
2( 73)
Complement-Fixing Donor Specific Antibody and Pathologic Findings in Lung Allografts L. Chhatwani ,1 J. Mooney,1 K. Patel,1 A. Emtiazjoo,2 A. Lawrence,1 G. Berry,3 D. Tyan,3 G. Dhillon.1 1Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA; 2Pulmonary and Critical Care Medicine, University of Florida, Gainesville, FL; 3Department of Pathology, Stanford University, Stanford, CA.
Insufficient Post-Transplant Immunosuppression Induces Restrictive Allograft Syndrome-Like Fibrosis in the Pleura and Lung Parenchyma After Lung Transplantation E. Miyamoto ,1 M. Sato,2 H. Motoyama,1 A. Aoyama,1 T. Menju,1 K. Shikuma,1 T. Sowa,1 M. Saito,1 A. Takahagi,1 S. Tanaka,1 M. Takahashi,1 K. Ohata,1 T. Kondo,1 K. Hijiya,1 T.F. Chen-Yoshikawa,1 T. Sato,1 M. Sonobe,1 H. Date.1 1Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan; 2Thoracic Surgery, The University of Tokyo, Tokyo, Japan.
Purpose: Given the increasing recognition of the role of humoral immunity in the development of lung allograft dysfunction, efforts to further our understanding of histopathologic features of pulmonary antibody- mediated rejection are ongoing. A novel C1q assay that identifies complement-fixing antibodies has predicted worse clinical outcomes in kidney and pediatric heart transplant. In this study, we evaluate histopathologic features of transbronchial biopsies of lung transplant recipients with complement-fixing DSA. Methods: Biopsy specimens from lung recipients, who underwent transplant between June 2008 to March 2013 at our center, were retrospectively selected and grouped according to the presence or absence of complement-fixing DSA. Patients were tested for DSA based on clinical indication, primarily evaluation of allograft dysfunction. Inclusion criteria required biopsy within 30 days of a positive or negative test for DSA. Biopsies were reviewed by an expert pulmonary pathologist blinded to DSA results and evaluated for presence of acute rejection, neutrophilic margination, acute capillaritis and acute lung injury (ALI) and C4d staining by immunohistochemical method. Results: 117 serum samples were tested for DSA based on clinical indication with concurrent transbronchial biopsies performed within 30 days. Of these, 37 samples were C1q+ DSA and 80 samples showed no DSA by C1q. A higher proportion of biopsies with acute cellular rejection grade A2 or higher were noted in the C1q+ DSA group (35%) compared to C1q- samples (13%). Among C1q+ DSA samples, C4d staining was present in 1 and neutrophilic margination in 2 biopsy specimens. Conclusion: There was no distinct pattern of histopathologic features observed in the C1q+ DSA group compared with the C1q- DSA group. The presence of C4d immunohistochemical positivity was not a histopathologic feature of C1q+ DSA. Acute cellular rejection was observed in a higher
Purpose: Restrictive allograft syndrome (RAS) is a form of chronic lung allograft dysfunction that shows pleuroparenchymal fibroelastosis. The prognosis of RAS is poor and the mechanism remains unclear. We hypothesized that insufficiency of post-transplant immunosuppression can induce RAS. Methods: Lewis rats received orthotopic left lung transplantation (LTx) from either Lewis rats (syngeneic controls, n= 5) or Brown-Norway rats (major histocompatibility complex mismatched donors). For the allogeneic LTx, we tested three immunosuppression protocols: administration of cyclosporine until day 14 (short immunosuppression (IS)), day 21 (medium IS), and day 35 (long IS) (n= 5/group). Lung grafts were histologically examined at day 98. The degrees of fibrosis in the lung parenchyma and airways were analyzed by using a computer-based quantification method for Masson trichrome staining. Results: The short IS group showed intense fibrosis in the pleura and lung parenchyma, particularly the subpleural area, which are the pathological features of human RAS (Fig. A). The percentage of the parenchymal fibrosis in the short IS group was indeed significantly higher than the other groups (Fig. B); the percentage of parenchymal fibrosis showed very strong inverse correlation with the length of immunosuppression (r= 0.75, p= 0.0013). Similar to human RAS, airway obliteration was also observed mostly in the short IS group (Fig. C), while the correlation of airway obliteration with the length of immunosuppression was only mild (r= 0.55, p= 0.0324). Conclusion: This study demonstrated that attenuation of post-transplant immunosuppression induces pleural and parenchymal fibrosis and associated airway obliteration similar to the pathological features of human RAS, suggesting that insufficient immunosuppression could be a cause of RAS after LTx.
2( 72)
Abstracts S109 2( 75) Physician Prediction of Outcomes in Ambulatory Patients with Advanced Heart Failure M.M. Kittleson ,1 C.B. Patel,2 R.S. Cantor,3 A.D. DeVore,4 A.V. Ambardekar,5 J.T. Thibodeau,6 L.M. Cadaret,7 S.V. Pamboukian,8 J. Teuteberg,9 R.C. Forde-McLean,10 M.M. Mountis,11 M. Palardy,12 G.C. Stewart,13 M.A. Hamilton.1 1Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA; 2Division of Cardiology, Duke University Medical Center, Durham, NC; 3Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL; 4Cardiology, Duke Clinical Research Institute, Durham, NC; 5Medicine-Cardiology, University of Colorado, Aurora, CO; 6Internal Medicine/Cardiology, UT Southwestern, Dallas, TX; 7Internal Medicine, The University of Iowa, Iowa City, IA; 8Cardiovascular Diseases, The University of Alabama at Birmingham, Birmingham, AL; 9Heart and Vascular Institute, The University of Pittsburgh, Pittsburgh, PA; 10Cardiology, University of Pennsylvania, Philadelphia, PA; 11Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH; 12Internal Medicine/Cardiovascular, The University of Michigan, Ann Arbor, MI; 13Advanced Heart Disease, Brigham and Women’s Hospital, Boston, MA.
2( 74) Accuracy of Seattle Heart Failure Model and HeartMate II Risk Score in Non-Inotrope Dependent Advanced Heart Failure Patients: Insights from the ROADMAP Study D.E. Lanfear ,1 W.C. Levy,2 J. Stehlik,3 J.D. Estep,4 J.G. Rogers,5 K.B. Shah,6 A.J. Boyle,7 J. Chuang,8 D.J. Farrar,8 R.C. Starling.9 1Henry Ford Hospital, Detroit, MI; 2University of Washington, Seattle, WA; 3University of Utah, Salt Lake City, UT; 4Houston Methodist Hospital, Houston, TX; 5Duke University, Durham, NC; 6Virginia Commonwealth University, Richmond, VA; 7Piedmont Hospital, Atlanta, GA; 8St. Jude Medical, Pleasanton, CA; 9Cleveland Clinic, Cleveland, OH. Purpose: In advanced heart failure (HF) patients (pts) not on inotropes, optimal timing for left ventricular assist device (LVAD) is unclear. Validated methods exist for predicting survival in HF (Seattle HF model-SHFM), and after LVAD (HeartMate II Risk Score-HMRS), but utility in this patient group is not established. Methods: ROADMAP is a prospective, 41-center, non-randomized study of 200 NYHA Class IIIB/IV pts not on inotropes who met FDA indications for LVAD, comparing the effectiveness of HeartMate II LVAD support vs Optimal Medical Management (OMM). We tested SHFM predicted survival compared to observed in the OMM arm (n= 103), and HMRS vs observed in all LVAD pts (n= 111). We also assessed calibration for each score. Risk strata cutoffs were from the original works. Results: Of 103 OMM pts, 18 had a delayed LVAD due to clinical deterioration. SHFM predicted survival by intention to treat (AUC= 0.71, p< 0.001), but not when considering delayed LVADs as treatment failures (AUC= 0.56, p= 0.097), underestimating risk in lower risk groups (figure, left). In this relatively lower risk LVAD cohort, the HMRS overestimated risk (figure, right) showing marginal discrimination at 3 months (AUC= 0.71, p= 0.23) and 1 year (AUC= 0.62, p= 0.037. Conclusion: In non-inotrope advanced HF pts in ROADMAP, the SHFM was predictive of mortality but underestimated the risk of deterioration to rescue LVAD, while the HMRS overestimated post-LVAD mortality. Improved risk stratification is needed for these patients.
Purpose: Ambulatory patients on oral heart failure (HF) therapy are increasingly considered for advanced therapies but thresholds for considering patients are not established. We compared baseline characteristics and outcomes of patients with advanced HF based upon whether clinical assessment by HF cardiologists at transplant/VAD centers predicted need for advanced therapies within the next year. Methods: Ambulatory patients on oral medications for chronic HF with reduced EF were enrolled in the Medamacs registry after one or more HF hospitalization and at least one other high risk criteria. Patients were divided based on their HF cardiologist’s prediction of whether or not they would be likely to warrant urgent Stage D intervention (home inotropes, hospice, ventricular assist device, or urgent transplant) within 1 year. Results: Of the 160 enrolled patients, 110 (69%) were deemed likely to warrant Stage D intervention within a year, 47 (29%) were deemed unlikely or uncertain, and 3 (2%) were excluded due to missing answers. The two groups did not differ consistently in demographics, physical exam findings, or cardiac tests. Despite this, the mortality was twice as high in patients deemed likely to warrant Stage D intervention as compared to those who were not thought to require an intervention (Table 1). Conclusion: Among ambulatory patients with advanced heart failure at VAD/ transplant centers, physician prediction of the need for Stage D interventions is associated with an increased risk of death despite similar traditional risk factors. This suggests that there are other signals which influence experienced physicians in assessing risk. Better appreciation of clinical assessment strategy could improve triage of ambulatory patients to advanced heart failure therapies.
The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016
(Fig. C). However, spleen culture showed no significant difference among groups; the serum of limited CsA group showed only slightly higher reactivity (less than twofold) than the other groups. Conclusion: This study demonstrated that DSA reacting with the donor MHC class I molecules are produced locally in chronically rejected lung allografts. Locally produced DSA may be underestimated in the serum test but could play an important role in the progression of CLAD after LTx.
proportion of transbronchial biopsies obtained within 30 days of detection of C1q+ DSA.
Histopathologic features by presence or absence of C1q DSA
A grade rejection A2 or higher B grade rejection B1R B2R C grade rejection C1 C4d Positive Negative Not done Neutrophilic margination Acute capillaritis Acute Lung injury ALI present DAD Other Organizing pneumonia Aspiration
Serum samples with C1Q DSA positive n = 37 (%)
Serum samples with no C1Q DSA n = 80 (%)
13 (35.0)
11 (13.8)
1 (2.7) 2 (5.4)
3 (3.75) 1 (1.25)
3 (8.1)
2 (2.50)
1 ( 2.7) 30 (81.0) 6 (16.2) 2 (5.4) 0
5 (6.25) 67 (83.75) 8 (10.0) 7 ( 8.75) 0
0 0
1 (1.25) 2 (2.5)
0 0
2 (2.5) 1 (1.25)
p = 0.008 p = 0.4
p = 0.16 p = 0.48
p = 0.14 p = 0.17
2( 73)
Complement-Fixing Donor Specific Antibody and Pathologic Findings in Lung Allografts L. Chhatwani ,1 J. Mooney,1 K. Patel,1 A. Emtiazjoo,2 A. Lawrence,1 G. Berry,3 D. Tyan,3 G. Dhillon.1 1Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA; 2Pulmonary and Critical Care Medicine, University of Florida, Gainesville, FL; 3Department of Pathology, Stanford University, Stanford, CA.
Insufficient Post-Transplant Immunosuppression Induces Restrictive Allograft Syndrome-Like Fibrosis in the Pleura and Lung Parenchyma After Lung Transplantation E. Miyamoto ,1 M. Sato,2 H. Motoyama,1 A. Aoyama,1 T. Menju,1 K. Shikuma,1 T. Sowa,1 M. Saito,1 A. Takahagi,1 S. Tanaka,1 M. Takahashi,1 K. Ohata,1 T. Kondo,1 K. Hijiya,1 T.F. Chen-Yoshikawa,1 T. Sato,1 M. Sonobe,1 H. Date.1 1Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan; 2Thoracic Surgery, The University of Tokyo, Tokyo, Japan.
Purpose: Given the increasing recognition of the role of humoral immunity in the development of lung allograft dysfunction, efforts to further our understanding of histopathologic features of pulmonary antibody- mediated rejection are ongoing. A novel C1q assay that identifies complement-fixing antibodies has predicted worse clinical outcomes in kidney and pediatric heart transplant. In this study, we evaluate histopathologic features of transbronchial biopsies of lung transplant recipients with complement-fixing DSA. Methods: Biopsy specimens from lung recipients, who underwent transplant between June 2008 to March 2013 at our center, were retrospectively selected and grouped according to the presence or absence of complement-fixing DSA. Patients were tested for DSA based on clinical indication, primarily evaluation of allograft dysfunction. Inclusion criteria required biopsy within 30 days of a positive or negative test for DSA. Biopsies were reviewed by an expert pulmonary pathologist blinded to DSA results and evaluated for presence of acute rejection, neutrophilic margination, acute capillaritis and acute lung injury (ALI) and C4d staining by immunohistochemical method. Results: 117 serum samples were tested for DSA based on clinical indication with concurrent transbronchial biopsies performed within 30 days. Of these, 37 samples were C1q+ DSA and 80 samples showed no DSA by C1q. A higher proportion of biopsies with acute cellular rejection grade A2 or higher were noted in the C1q+ DSA group (35%) compared to C1q- samples (13%). Among C1q+ DSA samples, C4d staining was present in 1 and neutrophilic margination in 2 biopsy specimens. Conclusion: There was no distinct pattern of histopathologic features observed in the C1q+ DSA group compared with the C1q- DSA group. The presence of C4d immunohistochemical positivity was not a histopathologic feature of C1q+ DSA. Acute cellular rejection was observed in a higher
Purpose: Restrictive allograft syndrome (RAS) is a form of chronic lung allograft dysfunction that shows pleuroparenchymal fibroelastosis. The prognosis of RAS is poor and the mechanism remains unclear. We hypothesized that insufficiency of post-transplant immunosuppression can induce RAS. Methods: Lewis rats received orthotopic left lung transplantation (LTx) from either Lewis rats (syngeneic controls, n= 5) or Brown-Norway rats (major histocompatibility complex mismatched donors). For the allogeneic LTx, we tested three immunosuppression protocols: administration of cyclosporine until day 14 (short immunosuppression (IS)), day 21 (medium IS), and day 35 (long IS) (n= 5/group). Lung grafts were histologically examined at day 98. The degrees of fibrosis in the lung parenchyma and airways were analyzed by using a computer-based quantification method for Masson trichrome staining. Results: The short IS group showed intense fibrosis in the pleura and lung parenchyma, particularly the subpleural area, which are the pathological features of human RAS (Fig. A). The percentage of the parenchymal fibrosis in the short IS group was indeed significantly higher than the other groups (Fig. B); the percentage of parenchymal fibrosis showed very strong inverse correlation with the length of immunosuppression (r= 0.75, p= 0.0013). Similar to human RAS, airway obliteration was also observed mostly in the short IS group (Fig. C), while the correlation of airway obliteration with the length of immunosuppression was only mild (r= 0.55, p= 0.0324). Conclusion: This study demonstrated that attenuation of post-transplant immunosuppression induces pleural and parenchymal fibrosis and associated airway obliteration similar to the pathological features of human RAS, suggesting that insufficient immunosuppression could be a cause of RAS after LTx.
2( 72)
Abstracts S109 2( 75) Physician Prediction of Outcomes in Ambulatory Patients with Advanced Heart Failure M.M. Kittleson ,1 C.B. Patel,2 R.S. Cantor,3 A.D. DeVore,4 A.V. Ambardekar,5 J.T. Thibodeau,6 L.M. Cadaret,7 S.V. Pamboukian,8 J. Teuteberg,9 R.C. Forde-McLean,10 M.M. Mountis,11 M. Palardy,12 G.C. Stewart,13 M.A. Hamilton.1 1Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA; 2Division of Cardiology, Duke University Medical Center, Durham, NC; 3Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL; 4Cardiology, Duke Clinical Research Institute, Durham, NC; 5Medicine-Cardiology, University of Colorado, Aurora, CO; 6Internal Medicine/Cardiology, UT Southwestern, Dallas, TX; 7Internal Medicine, The University of Iowa, Iowa City, IA; 8Cardiovascular Diseases, The University of Alabama at Birmingham, Birmingham, AL; 9Heart and Vascular Institute, The University of Pittsburgh, Pittsburgh, PA; 10Cardiology, University of Pennsylvania, Philadelphia, PA; 11Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH; 12Internal Medicine/Cardiovascular, The University of Michigan, Ann Arbor, MI; 13Advanced Heart Disease, Brigham and Women’s Hospital, Boston, MA.
2( 74) Accuracy of Seattle Heart Failure Model and HeartMate II Risk Score in Non-Inotrope Dependent Advanced Heart Failure Patients: Insights from the ROADMAP Study D.E. Lanfear ,1 W.C. Levy,2 J. Stehlik,3 J.D. Estep,4 J.G. Rogers,5 K.B. Shah,6 A.J. Boyle,7 J. Chuang,8 D.J. Farrar,8 R.C. Starling.9 1Henry Ford Hospital, Detroit, MI; 2University of Washington, Seattle, WA; 3University of Utah, Salt Lake City, UT; 4Houston Methodist Hospital, Houston, TX; 5Duke University, Durham, NC; 6Virginia Commonwealth University, Richmond, VA; 7Piedmont Hospital, Atlanta, GA; 8St. Jude Medical, Pleasanton, CA; 9Cleveland Clinic, Cleveland, OH. Purpose: In advanced heart failure (HF) patients (pts) not on inotropes, optimal timing for left ventricular assist device (LVAD) is unclear. Validated methods exist for predicting survival in HF (Seattle HF model-SHFM), and after LVAD (HeartMate II Risk Score-HMRS), but utility in this patient group is not established. Methods: ROADMAP is a prospective, 41-center, non-randomized study of 200 NYHA Class IIIB/IV pts not on inotropes who met FDA indications for LVAD, comparing the effectiveness of HeartMate II LVAD support vs Optimal Medical Management (OMM). We tested SHFM predicted survival compared to observed in the OMM arm (n= 103), and HMRS vs observed in all LVAD pts (n= 111). We also assessed calibration for each score. Risk strata cutoffs were from the original works. Results: Of 103 OMM pts, 18 had a delayed LVAD due to clinical deterioration. SHFM predicted survival by intention to treat (AUC= 0.71, p< 0.001), but not when considering delayed LVADs as treatment failures (AUC= 0.56, p= 0.097), underestimating risk in lower risk groups (figure, left). In this relatively lower risk LVAD cohort, the HMRS overestimated risk (figure, right) showing marginal discrimination at 3 months (AUC= 0.71, p= 0.23) and 1 year (AUC= 0.62, p= 0.037. Conclusion: In non-inotrope advanced HF pts in ROADMAP, the SHFM was predictive of mortality but underestimated the risk of deterioration to rescue LVAD, while the HMRS overestimated post-LVAD mortality. Improved risk stratification is needed for these patients.
Purpose: Ambulatory patients on oral heart failure (HF) therapy are increasingly considered for advanced therapies but thresholds for considering patients are not established. We compared baseline characteristics and outcomes of patients with advanced HF based upon whether clinical assessment by HF cardiologists at transplant/VAD centers predicted need for advanced therapies within the next year. Methods: Ambulatory patients on oral medications for chronic HF with reduced EF were enrolled in the Medamacs registry after one or more HF hospitalization and at least one other high risk criteria. Patients were divided based on their HF cardiologist’s prediction of whether or not they would be likely to warrant urgent Stage D intervention (home inotropes, hospice, ventricular assist device, or urgent transplant) within 1 year. Results: Of the 160 enrolled patients, 110 (69%) were deemed likely to warrant Stage D intervention within a year, 47 (29%) were deemed unlikely or uncertain, and 3 (2%) were excluded due to missing answers. The two groups did not differ consistently in demographics, physical exam findings, or cardiac tests. Despite this, the mortality was twice as high in patients deemed likely to warrant Stage D intervention as compared to those who were not thought to require an intervention (Table 1). Conclusion: Among ambulatory patients with advanced heart failure at VAD/ transplant centers, physician prediction of the need for Stage D interventions is associated with an increased risk of death despite similar traditional risk factors. This suggests that there are other signals which influence experienced physicians in assessing risk. Better appreciation of clinical assessment strategy could improve triage of ambulatory patients to advanced heart failure therapies.