Assessment of graft function after Single-Lung Transplantation (SLT) by single-breath washout in lateral decubitus

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Abstracts

at the time of BOS development but had no IL10 production. In contrast, matched BOS-ve recipients had high (⬎100 spots/ 100,000 cells) IL10 secretion with low levels of IFN-␥. On coculturing, there was marked inhibition to the collagen-specific proliferation and IFN-␥ in BOS⫹ve cells which was lost in presence of anti-IL10 in the BOS⫹ve culture. Interestingly, there was also low IL10 secretion in BOS⫹ve after co-culture which persisted despite adding anti-IL10. Conclusion: BOS⫹ve patients had high proliferation and IFN-␥ secretion to collagen-V while BOS-ve had predominantly IL10. The inhibition to BOS⫹ve cells on coculture was mediated by IL10 from BOS-ve cells which was lost with anti-IL10. Hence, IL10 could be crucial in preventing development of collagen-specific autoreactive T cells in lung transplant recipients. 56 HLA-SPECIFIC ANTIBODIES ARE ASSOCIATED WITH LYMPHOCYTIC BRONCHIOLITIS AND DECREASED PULMONARY FUNCTION AFTER LUNG TRANSPLANTATION A.L. Girnita, R. Duquesnoy, S.A. Yousem, A.T. Iacono, K.J. Spichty, K.R. McCurry, A. Zeevi, Pathology, UPMC, Pittsburgh, PA Lymphocytic bronchitis/bronchiolitis (LBB) is considered a form of airway rejection in lung transplantation (LT) and/or a risk factor for bronchiolitis obliterans syndrome (BOS). The association of HLAspecific antibodies (Ab) with LBB is not described. Methods and Results: Of 51 lung-recipients who were prospectively tested by ELISA during a 4.5 ⫾ 1.8 year-period, 14 developed Ab. LBB of at least ISHLT grade B(2) was diagnosed in 18 patients (35%). The diagnosis of BOS was established accordingly with ISHLT published criteria, while surveillance spirometry in accordance with American Thoracic Society criteria. The FEV1 values at 12, 18, 24, 36 mo post-LT were considered, when other causes for lower FEV1 (especially infections and bronchial stenosis) were excluded. The multivariate analysis also included: donor and recipient age, sex, the type of LT – single/double, number of HLA A, B, DR mismatches, biopsy proven acute cellular rejection and CMV pneumonitis. The prevalence of BOS was higher in patients with LBB (69%), compared to 18.7% in patients without LBB (p⬍0.05, relative risk ⫽ 3.7). Furthermore, the prevalence of grade 2 and 3 BOS was significantly higher in patients with LBB (8/18) versus no LBB (2/33, p ⬍ 0.005, relative risk ⫽ 8.8). Ab were associated with LBB (8 patients with LBB out of 14 Ab producers versus 10 LBB in 37 patients without Ab, p ⬍ 0.05) and also with BOS (10/14 Ab versus 9/37 no Ab, p⬍0.005). The risk factors for decreased ventilatory function at 2 and 3 years post-LT were Ab (mean FEV1⫽ 45% vs 63% in patients without Ab, p⬍0.001), and LBB (mean FEV1⫽ 51% in LBB-patients, versus 68% in patients without LBB, p⬍0.05). Conclusions: A significant proportion (25%) of the cohort developed Ab post-LT. The anti-HLA antibodies showed their impact by a higher prevalence of LBB, BOS, and a decreased pulmonary function, overall. The presence of anti-HLA antibodies exhibited a cumulative effect on BOS when it was associated with lymphocytic bronchiolitis. 57 SURVIVAL AFTER BILATERAL LUNG TRANSPLANTATION DEPENDS ON THE MAXIMUM LUNG FUNCTION ACHIEVED POST-TRANSPLANT AND THE DEVELOPMENT OF BRONCHIOLITIS OBLITERANS SYNDROME (BOS) D. Hadjiliadis,1 C.S. Berbrayer,1 O. Hadjiliadis,2 C. Chaparro,1 S. Keshavjee,1 1Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada; 2Department of Statistics, Columbia University, New York, NY

The Journal of Heart and Lung Transplantation February 2005

Overview: Development of BOS (which takes into account drops in lung function compared to post-transplant maximums) remains one of the stronger predictors of survival after lung transplantation. However, the effect of maximum lung function achieved posttransplant on survival remains unknown. Methods: All patients that underwent bilateral lung transplantation and had at least two sets of pulmonary function tests post-transplant, at the University of Toronto between 1/98 and 12/03 were included. Age, gender, pre-transplant diagnosis, post-transplant maximum forced expiratory volume in one second (FEV1) achieved and predicted, forced vital capacity (FVC) achieved and predicted, FEV1/FVC, development and timing of BOS and survival were obtained. Survival was estimated using the Kaplan-Meier method and the log-rank test was used for comparison of survival between groups. The Cox proportional hazards method was used for multivariable analysis. Results: 194/232 (83.6%) patients had pulmonary function tests post-transplant. Mean age was 44.7⫾13.9 and mean follow up was 2.5⫾1.6 years. The mean percent predicted FEV1 and FVC posttransplant were 100⫾27 and 94⫾21. Survival was better in patients achieving percent predicted FEV1 over 100 (1-yr: 92.2% vs. 87.1%; 3-yr: 81.9% vs. 61.8%; p⫽0.012). Survival was better in patients achieving percent predicted FVC over 95 (1-yr: 96.6% vs. 82.9%; 3-yr: 79.0% vs. 65.4%; p⫽0.006). After multivariable analysis the percent predicted FEV1 and FVC and the development of BOS had an independent effect on survival. Discussion: The current study suggests that maximum lung function achieved post-transplant predicts survival in addition to BOS. Future studies will assess whether survival differences in patients with different diagnoses can be in part explained by the maximum post-transplant lung function achieved. 58 ASSESSMENT OF GRAFT FUNCTION AFTER SINGLE-LUNG TRANSPLANTATION (SLT) BY SINGLE-BREATH WASHOUT IN LATERAL DECUBITUS A. Van Muylem,1 C. Knoop,1 M. Estenne,1 1Department of Chest Medicine, Erasme University Hospital, Brussels, Belgium We have previously shown that the increase in the slope of alveolar plateau for nitrogen (SN2) obtained during a single-breath washout test performed in seated posture detects bronchiolitis obliterans before standard pulmonary function in recipients of bilateral lung transplantation (AJRCCM 2000;162:1047); this technique, however, is not applicable to recipients of SLT because of the confounding influence of the native lung. In the present study, we tested the hypothesis that measuring SN2 in the right and left lateral decubitus may allow to distinguish between the graft and the native lung. Because the dependent and independent lungs empty according to a gravity-based sequence with the independent lung contributing preferentially at the end of expiration, we hypothesized that SN2 would differ according to the position of the graft. We studied 12 SLT patients (7 F and 5 M, age 55⫾9 yrs) who had been transplanted for emphysema (n⫽9) or IPF (n⫽3) 1194 days (range 48 – 4393) earlier and were in stable clinical condition; SN2 over the last 25% of the expiratory volume was measured with the patient in the right and left lateral decubitus. In all patients, SN2 was much greater with the native lung in the independent position than with the graft in the independent position, reflecting the predominant contribution of the independent lung to the late part of expiration; in 5 patients SN2 was even negative when the graft was in the independent position. Expressed in % of mean N2 concentration per % of expired volume, SN2 averaged 0.764⫾0.343 (native independent) and 0.058⫾0.326 (graft independent) (p⬍0.001). We conclude that measuring SN2 in lateral decubitus allows to distinguish between the graft and the native lung; this technique may therefore be useful to monitor the

The Journal of Heart and Lung Transplantation Volume 24, Number 2S

Abstracts

ofunction of the graft after SLT and detect the development of bronchiolitis obliterans. 59 ROLE OF SURFACTANT PROTEINS AND PHOSPHOLIPIDS AS MARKERS OF BOS F. D’Ovidio,1 R. Ridsdale,1 M. Mura,1 H. Takahashi,2 C. Gutierrez,1 M. Hutcheon,1 L. Singer,1 A. Pierre,1 D. Hadjiliadis,1 C. Chaparro,1 T. Waddell,1 M. Liu,1 M. Post,1 S. Keshavjee,1 1 University of Toronto, Toronto, Canada; 2University of Sapporo, Sapporo, Japan Bronchiolitis obliterans is the major limiting factor for long-term success of lung transplantation. Strategies for early detection of the clinical correlate BOS, are a research priority. Surfactant proteins (SP A, D) and phospholipids, key players in lung innate immunity, have been associated with various lung diseases. We studied their role as markers of BOS development. Methods: Lung-Tx pts (98) were prospectively followed by PFTs, and bronchoscopies. BAL was assayed for: SP A and D ng/ml; phospholipids (PC; DPPC; PG; PI; LysoPC; SM) expressed as ratio to total lipids. Serum was assayed for SP. BAL SP values ⬍25th percentile were judged low; serum SP values ⬎75th percentile were high. Results: BOS was diagnosed in 27 pts.

BAL SPA BAL SPD BAL DPPC BAL SM serum SPA serum SPD

Non BOS

BOS

1990 (148–6348) 643 (104–788) 51 (43–59) 0.4 (0.2–1) 45 (15–131) 78 (23–235)

852 (30–3687) 395 (14–1665) 46 (16–58) 1.6 (0.3–11) 77 (40–141) 124 (44–322)

The table shows the median and range of values for the parameters that showed significant differences (Mann-Whitney p⬍0.009 for all) when comparing BOS vs non-BOS pts. Time to BOS diagnosis was shorter in pts with low BAL SP and in pts with high serum SPD levels. Only samples collected prior to BOS diagnosis were used for the actuarial analysis.

Conclusions: Pulmonary surfactant proteins and phospholipids are strongly associated with BOS. In particular BAL and serum SP are associated with subsequent BOS development. Our findings further support a role of lung graft innate immunity within the development of bronchiolitis obliterans. 60 EVEROLIMUS IN DE NOVO CARDIAC TRANSPLANT RECIPIENTS: 48-MONTH (M) FOLLOW-UP J.M. Hare,1 S. Perrone,2 H. Eisen,3 K. McCurry,4 P. Hauptman,5 S. Simonsen,6 M. Crespo,7 J. Arizon,8 J. Kobashigawa,9 J. Jarcho,10

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Cardiology, Johns Hopkins Hosp., Baltimore, MD; 2Cardiaco, Fundacion Favaloro, BA, Argentina; 3Cardiology, Temple Univ., Philadelphia, PA; 4Cardio/Thor, U Pittsburgh, Pittsburgh, PA; 5 Cardiology, St. Louis Univ. Med Center, St. Louis, MO; 6Surg., RiksHospitalet, Oslo, Norway; 7Cardiaca, Hosp. Juan Canalejo, Madrid, Spain; 8Cardiaco, Hosp. Reina Sofia, Cordoba, Spain; 9 Heart Transplant Prog, UCLA, Los Angeles, CA; 10Cardiology, Brigham Woman’s Hosp, Boston, MA 1

Aims: Everolimus (E) is an investigational proliferation signal inhibitor that significantly reduced rejection and vasculopathy at 1 and 2 years. This abstract reports on 48M results of an international trial comparing safety and efficacy of E to AZA in de novo heart transplant recipients. Methods: Patients (N⫽634) were randomized to three groups: E 1.5mg/day (N⫽209), 3mg/day (N⫽211), or AZA 1–3mg/kg/day (N⫽214) with standard dose cyclosporine (CsA, Neoral), steroids and statins. Results: Incidence of efficacy failure (composite endpoints: BPAR ⬎Grade 3A, AR with HDC, graft loss, death, or loss to follow-up) was significantly lower in patients treated with E 1.5mg (p⫽0.037) or E 3mg (p⬍0.001) than AZA (incidence: 50.7%, 39.3% and 60.7%), however there were no differences seen relative to patient survival (84.7%, 83.9%, and 86.0%). Viral infection occurred less frequently, and CMV rates were significantly (p⬍0.0001) lower with E 1.5 and 3mg (7.2%, 7.1%) than AZA (21.0%). The trend toward fewer MACE events in the E arms did not reach significance. Incidence of bacterial infections was higher with E 3mg (43.1% v 27.6%) or E 1.5mg (37.8% v 27.6%) v AZA. Serum creatinine (182, 223, and 147 umol/L) was higher in E patients (p⬍0.05). Serum triglycerides and cholesterol were elevated in E patients (p⬍0.05), but there were no differences in HDL or LDL (mean values or increase from baseline). Conclusion: Both E doses again demonstrated superior efficacy compared to AZA by decreasing the incidence of acute rejection, the composite endpoints, and CMV rates. The E 1.5mg dose exhibited a better safety profile, overall, than the 3mg dose. 61 12 MONTH REPORT OF A 3 ARM MULTICENTER COMPARISON OF TACROLIMUS (TAC), MMF OR TAC/SIROLIMUS(SRL) AND STEROIDS VS CYCLOSPORINE MICROEMULSION(CYA), MMF AND STEROIDS IN DE NOVO CARDIAC TRANSPLANT RECIPIENTS J.W. Kobashigawa, MD,1 L.W. Miller, MD,2 G.M. Felker, MD,3 S.D. Russel, MD,3 G.A. Ewald, MD,4 M. Zucker, MD,5 L. Goldberg, MD,6 H.J. Eisen, MD,7 B.K. Rayburn, MD,8 L.E. Wagoner, MD,9 E. Philbin, MD,10 N. Pereira, MD,11 B. Czerska, MD,12 R.L. Kormos, MD13 M. Weston, MD,14 J. Conte, MD,15 J. Hosenpud, MD,16 K. Aaronson, MD,17 J. Hill, MD,18 J.G. Copeland, MD,19 L. Czer, MD,20 A. Anderson, MD,21 G.W. Dec, MD,22 G. Torre-Amione, MD,23 C.W. Yancy, MD,24 J.D. Vega, MD,25 J.A. Jarcho, MD,26 D. Mancini, MD,27 G. Bhat, MD,28 R. First, MD,29 W. Fitzsimmons, MS, PharmD,29 D. Tolzman, BSN,29 K. Salm, BSN,29 J. Gao, MD,30 1University of California, Los Angeles, CA; 2University of Minnesota, Minneapolis, MN; 3Duke University, Durham, NC; 4Barnes Hospital, St. Louis, MO; 5Beth Israel, Newark, NJ; 6University of Pennsylvania, Philadelphia, PA; 7 Temple University, Philadelphia, PA; 8University of Alabama, Birmingham, AL; 9University of Cincinnati, Cincinnati, OH; 10 Albany Medical College, Albany, NY; 11Medical University of South Carolina, Charleston, SC; 12Henry Ford Hospital, Detroit, MI; 13University of Pittsburgh, Pittsburgh, PA; 14Tampa General Hospital, Tampa, FL; 15Johns Hopkins, Baltimore, MD; 16St. Luke’s, Milwaukee, WI; 17University of Michigan, Ann Arbor, MI; 18 University of Florida, Gainesville, FL; 19University of Arizona,