Ross D J, Lewis M I, Kramer M, Vo A, Kass R M
Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center Lung Transplant Program, UCLA School of Medicine, Los Angeles, CA 90048, USA.
Chest. 1997 Nov 5;112(5):1175-9. doi: 10.1378/chest.112.5.1175.
In a consecutive case series (level V evidence) involving 10 recipients of unilateral lung transplantation (LT) with bronchiolitis obliterans, in conjunction with Fujisawa protocol 93-0-003, the physiologic responses to FK 506 (tacrolimus) "rescue" immunosuppression were assessed. Recipients were 22+/-18 months post-LT and demonstrated progressive allograft dysfunction that was refractory to pulsed-dose methylprednisolone therapy. All recipients received induction immunosuppression with Minnesota antilymphocyte globulin (10 to 15 mg/kg/d) for 5 to 10 days, cyclosporine (CsA) (whole-blood Abbott TDX fluorescence polarization immunoassay (Abbott Inc, Abbott Park, IL)=600 to 800 ng/mL), azathioprine (2 mg/kg/d), and prednisone (tapered to 0.2 mg/kg/d). The "rescue" regimen consisted of oral FK 506 adjusted to maintain a whole-blood Abbott IMX microparticle enzyme immunoassay (Abbott Inc, Abbott Park, IL) of 10 to 15 ng/mL with an initial increase in prednisone (1.0 mg/kg/d) during conversion that was subsequently tapered to 0.2 mg/kg/d. Spirometry was performed monthly in accordance with accepted American Thoracic Society criteria. Recipients were classified in accordance with the International Society for Heart and Lung Transplantation (ISHLT) "Working Formulation for Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts" as stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the protocol. The deltaFEV1/month relationships during CsA- and FK 506-based regimens were analyzed by linear regression and compared by signed rank test (p<0.05).
The deltaFEV1/month slopes were -0.0687+/-0.0221 and +0.0300+/-0.033 L/mo (mean+/-SEM) for CsA and FK 506, respectively (p=0.037). Although no significant spirometric improvement was noted in most recipients, no further decline in FEV1 occurred after conversion to FK 506. Recipients with less severe chronic dysfunction (ie, obliterative bronchiolitis [OB] stages Ib and IIb) stabilized their spirometric indexes at higher levels. Two recipients with OB stage IIIb died of hypercapnic respiratory failure at 6 and 8 months after conversion.
The deltaFEV1/mo slopes stabilized after FK 506 conversion. Earlier conversion may be beneficial in stabilizing FEV1 at a higher plateau. Significant economic impact may be anticipated with FK 506 compared to alternative cytolytic strategies for OB. However, multicenter prospective controlled investigations are necessary to further address the potential role of FK 506 after LT (level I evidence). Furthermore, the ISHLT "Staging of OB Syndrome" may have significant clinical implications vis-à-vis prognosis and potential therapies.
在一个连续病例系列研究（V级证据）中，纳入了10例接受单侧肺移植（LT）且患有闭塞性细支气管炎的受者，按照藤泽协议93 - 0 - 003，评估了对FK 506（他克莫司）“挽救性”免疫抑制的生理反应。受者在LT术后22±18个月，表现出移植肺功能进行性减退，对冲击剂量甲泼尼龙治疗无效。所有受者均接受诱导免疫抑制治疗，使用明尼苏达抗淋巴细胞球蛋白（10至15 mg/kg/d），持续5至10天，同时使用环孢素（CsA）（全血雅培TDX荧光偏振免疫测定法（雅培公司，伊利诺伊州雅培公园）=600至800 ng/mL）、硫唑嘌呤（2 mg/kg/d）和泼尼松（逐渐减量至0.2 mg/kg/d）。“挽救性”方案包括口服FK 506，调整剂量以维持全血雅培IMX微粒酶免疫测定法（雅培公司，伊利诺伊州雅培公园）检测值在10至15 ng/mL，转换期间泼尼松初始剂量增加（1.0 mg/kg/d），随后逐渐减量至0.2 mg/kg/d。根据美国胸科学会认可的标准，每月进行一次肺功能测定。根据国际心肺移植学会（ISHLT）“肺移植慢性功能障碍命名标准化及临床分期工作方案”，在进入该方案时，受者被分类为Ib期（n = 2）、IIb期（n = 4）和IIIb期（n = 4）。通过线性回归分析基于CsA和FK 506方案期间的每月△FEV1关系，并通过符号秩检验进行比较（p<0.05）。
CsA和FK 506方案的每月△FEV1斜率分别为 - 0.0687±0.0221和 + 0.0300±0.033 L/月（均值±标准误）（p = 0.037）。尽管大多数受者肺功能测定未显示出显著改善，但转换至FK 506后，FEV1未进一步下降。慢性功能障碍较轻的受者（即闭塞性细支气管炎[OB] Ib期和IIb期）肺功能指标稳定在较高水平。两名OB IIIb期受者在转换治疗后6个月和8个月死于高碳酸血症性呼吸衰竭。
转换至FK 506后，每月△FEV1斜率稳定。早期转换可能有利于将FEV1稳定在更高平台。与OB的其他细胞溶解策略相比，FK 506可能会产生重大经济影响。然而，需要多中心前瞻性对照研究来进一步探讨LT后FK 506的潜在作用（I级证据）。此外，ISHLT“OB综合征分期”可能对预后和潜在治疗具有重要临床意义。
