title: Delayed development of obliterative bronchiolitis syndrome with OKT3 after unilateral lung transplantation. A plea for multicenter immunosuppressive trials.
abstract: There is no consensus regarding the optimal induction immunosuppression regimen after lung transplantation (LT). In addition to the potential benefit of a reduced incidence of early acute allograft rejection, cytolytic induction immunosuppression may impact on long-term allograft function. We retrospectively assessed our incidence of obliterative bronchiolitis syndrome (OBS) stages Ia and IIa in LT survivors given two different cytolytic induction immunosuppression regimens: (between March 1989 and October 1990) OKT3 (5 mg/d)x10 to 14 days (n=11) vs (between November 1990 and April 1993) Minnesota antilymphocyte globulin (MALG) (10 to 15 mg/kgdx5 to 7 days. Cyclosporine (CSA) (whole blood polyclonal assay=600 to 800 ng/mL), azathioprine (1 to 2 mg/kg/d), and maintenance prednisone (0.2 mg/kg/d) were similar. Surveillance spirometry was performed monthly, in accordance with accepted American Thoracic Society criteria. Fiberoptic bronchoscopy with transbronchial biopsies (TBBs) were performed for clinical indications. Surveillance TBBs were not performed during the era of this study. As defined by the ISHLT "Working Formulation for the Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts," latencies to development of OBS stages Ia and IIa were determined by Kaplan-Meir analysis. Stepwise regression (Cox proportional hazards model) was performed for the variables: cytolytic induction regimen, episodes cytomegalovirus (CMV) pneumonitis, episodes CMV infection, serologic CMV donor (+): recipient (-) mismatch, prior pregnancy, HLA (A,B,DR +/- DQ) mismatches, episodes greater than grade A1 acute cellular rejection (ACR). We found that the OKT3 cohort experienced longer latencies for OBS stages Ia and IIa. Latencies to OBS stages Ia for OKT3 ve MALG were 962 +/- 65 vs 354 +/- 85 days (X +/- SEM) respectively. Brookmeyer-Crowley 95% confidence intervals for median latencies were 744 to 1,180 vs 266 to 510 days for OKT3 vs MALG, respectively. The Cox model was significant only for the variable of the induction cytolytic immunosuppression regimen (p=0.0015). By physiologic criteria, a longer course of OKT3 appeared superior to the short-course MALG protocol in delaying chronic lung allograft dysfunction. These effects may be related either to inherent differences in the antilymphocyte preparations or, alternatively, the difference in duration of treatment between groups. Surveillance TBB and treatment of detected occult ACR may serve to negate the observed differences in latencies for OBS.
authors.affiliation: Division of Pulmonary Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Ross
authors.forename: S C
authors.initials: SC
authors.lastname: Jordan
authors.forename: S D
authors.initials: SD
authors.lastname: Nathan
authors.forename: R M
authors.initials: RM
authors.lastname: Kass
authors.forename: S K
authors.initials: SK
authors.lastname: Koerner
mesh_terms: D000208:Acute Disease; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D001379:Azathioprine / Q000627:therapeutic use; D001706:Biopsy; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D001999:Bronchoscopy; D002908:Chronic Disease; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D016001:Confidence Intervals; D016572:Cyclosporine / Q000627:therapeutic use; D003586:Cytomegalovirus Infections / Q000209:etiology; D006084:Graft Rejection / Q000517:prevention & control; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016040:Lung Transplantation / Q000502:physiology; D015337:Multicenter Studies as Topic; D016853:Muromonab-CD3 / Q000627:therapeutic use*; D011024:Pneumonia, Viral / Q000209:etiology; D011241:Prednisone / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013147:Spirometry; D013577:Syndrome; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D000961:Antilymphocyte Serum; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D016853:Muromonab-CD3; D016572:Cyclosporine; D001379:Azathioprine; D011241:Prednisone