呼气相薄层CT诊断异基因造血干细胞移植术后气体潴留及预测闭塞性细支气管炎综合征

目的探讨造血干细胞移植术后闭塞性细支气管炎综合征(BOS)最佳呼气相薄层CT气体潴留评估方法。方法采用三层五分法及视觉评估法两种阅片方法回顾性分析29例造血干细胞移植术后BOS患者呼气相薄层CT表现,对比呼气相薄层CT气体潴留影像学评分对于气体潴留的诊断价值和视觉评估法、三层五分法及肺功能检查(PFTs)3种方法对于BOS的早期预测价值。结果 PTTs分级:17例BOS0,7例BOS-p,2例BOS1,1例BOS2,2例BOS3,PFTs预测BOS发生的敏感度为41.38%(12/29)。三层五分法ROC曲线下面积(0.566)大于视觉评估法(0.485)。三层五分法评估的敏感度为25.00%(3/12),特异度为82.35%(14/17),阳性预测值(PPV)为50.00%(3/6),阴性预测值(NPV)为60.87%(14/23),预测BOS的敏感度为55.17%(16/29);视觉评估法敏感度为41.67%(5/12),特异度为58.82%(10/17),PPV为41.67%(5/12),NPV为58.82%(10/17),预测BOS的敏感度为79.31%(22/29)。结论对于诊断气体潴留,三层五分法的价值大于视觉评估法;对早期预测BOS,视觉评估法的预测价值最高,三层五分法次之,PFTs最小。     

Montelukast for bronchiolitis obliterans syndrome after lung transplantation: a pilot study

Bronchiolitis obliterans syndrome (BOS) remains the major hurdle to improve long‐term survival after lung transplantation, as its treatment remains troublesome. In this pilot study, we investigated the effect of montelukast (a leukotriene receptor antagonist) on the FEV₁ decline after diagnosis of BOS and compared this with a control group. In both groups, 11 patients were included with BOS stage <3 and bronchoalveolar lavage (BAL) neutrophilia <15%, already being treated or concurrently being started on azithromycin. Control patients were selected retrospectively. After adding montelukast (10 mg/day) to the immunosuppressive regimen, the FEV₁ decline significantly decreased from 112 ± 26 ml/month before BOS diagnosis to 13 ± 13 ml/month after 6 months of montelukast therapy (P = 0.001). In the control group, there was no significant change in the rate of FEV₁ decline: 103 ± 20 ml/month before BOS diagnosis to 114 ± 27 ml/month (P = 0.55). Adding montelukast may be a promising treatment option in patients with low neutrophilic (<15%) BOS after lung transplantation, already or concurrently being treated with azithromycin.     

Bronchoalveolar Lavage as a Tool to Predict,Diagnose and Understand Bronchiolitis Obliterans Syndrome

Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long‐term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin‐8, alpha defensins and MMP‐9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in‐depth and mechanistic insights into the pathogenesis of this complex disease.     

Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients

Dhillon GS, Valentine VG, Levitt J, Patel P, Gupta MR, Duncan SR, Seoane L, Weill D. Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients.
Clin Transplant 2012: 26: 105–110.
© 2011 John Wiley & Sons A/S. Abstract: Background: Bronchiolitis obliterans syndrome (BOS) is the major limitation to long‐term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined. Methods: Survival and BOS‐free survival of 102 lung allograft recipients (LARs), transplanted at a single center between July 1995 and December 2001 who routinely received clarithromycin, were compared with two different control groups. The first control group consisted of 44 LARs from the same center who were transplanted from January 2002 onwards and did not receive clarithromycin. The second control group consisted of a contemporaneous cohort of 5089 recipients, transplanted between 1995 and 2001, reported to the United Network for Organ Sharing database. Results: When compared with the first control group, BOS‐free survival was reduced in LARs receiving clarithromycin. Univariate (hazard ratio [HR] 3.13, p‐value = 0.004) and multivariate (HR 3.49, p‐value = 0.04) analyses showed that routine use of clarithromycin was associated with an increased risk of developing BOS. When compared with the second control group, the five‐yr survival of clarithromycin group was similar (p‐value = 0.24). Conclusions: Routine use of clarithromycin does not delay development of BOS or improve survival.     

The effect of bronchiolitis obliterans syndrome on health related quality of life

Bronchiolitis obliterans syndrome (BOS) is the most important factor limiting long-term survival after lung transplantation, and has a substantial impact on patients' daily life in terms of disability and morbidity. Aim of our study was to examine the effects of BOS on health related quality of life (HRQL) in lung transplantation patients. Data on HRQL from 29 patients who developed BOS at least 18 months earlier were studied longitudinally. HRQL measures were: the Nottingham Health Profile (NHP), the State Trait Anxiety Inventory (STAI), the Self-rating Depression Scale (ZUNG), and the Index of Well Being (IWB). Furthermore questions concerning activities of daily life and dyspnea were asked. The majority of the patients were male, and the most common diagnosis was emphysema. After the onset of BOS, significantly more restrictions were reported on the dimensions energy and mobility of the NHP. These restrictions appeared to increase over time. After the onset of BOS, STAI scores remained more or less stable and close to the value of the general population. ZUNG scores were significantly higher after the onset of BOS, and patients experienced a lower level of well being than the general population. The percentage of patients that reported to be able to perform activities of daily life without effort declined dramatically after the onset of BOS. Furthermore, the percentage of patients complaining of dyspnea increased after the onset of BOS. In conclusion, our study showed that HRQL was negatively affected by the onset of BOS. However, in spite of these less favorable long-term results, even patients who develop BOS may at least temporarily benefit from a lung transplantation.     

Lung transplantation for patients with end-stage Sauropus androgynus-induced bronchiolitis obliterans (SABO) syndrome

Sauropus androgymus (SA), a vegetable of the Euphorbiaceae family, is a common food source in Malaysia. In Taiwan, over 30 patients have developed progressive respiratory failure after consuming the extract from raw SA leaves as a means of losing weight. Symptoms consistent with a severe obstructive ventilatory defect progressed, despite cessation of SA intake and treatment with bronchodilators, corticosteroids, cytotoxic agents and plasmaphresis. Five patients with end-stage Sauropus androgynus-induced bronchiolitis obliterans (SABO) syndrome underwent lung transplantation. There was no early mortality. One patient died of post-transplant lymphoproliferative disorder and another patient died of bronchial stenosis with infection, 5 and 3.5 months, respectively, post-transplantation. The remaining 3 patients have been followed from 29 to 34 months, with improved general condition and pulmonary function. Perfusion/ventilation scans revealed that these improvements were exclusively attributed to the functional grafts. We believe that lung transplantation is the only effective modality of treatment for patients with end-stage SABO syndrome.     

双肺移植同期Nuss手术治疗造血干细胞移植术后闭塞性细支气管炎综合征合并胸廓畸形长期生存1例

目的  探讨双肺移植同期Nuss手术治疗造血干细胞移植术后闭塞性细支气管炎综合征（BOS）合并漏斗胸的疗效。方法  2015年3月24日,1例造血干细胞移植术后BOS合并漏斗胸患者在南京医科大学附属无锡市人民医院胸外科暨肺移植中心接受体外膜肺氧合（ECMO）辅助下双肺移植术,同期行Nuss手术矫治漏斗胸,手术顺利,术后予抗炎、抗真菌预防治疗,予他克莫司+吗替麦考酚酯+肾上腺皮质激素三联免疫抑制方案治疗。结果  患者术后恢复顺利,于术后25 d出院,术后2年拆除胸部Nuss钢板,胸廓畸形得到纠正,术后接受长期随访,截止至投稿日,患者存活3年余,肺功能恢复良好,生活质量满意。结论  双肺移植同期Nuss手术是治疗终末期BOS合并胸廓畸形的有效办法。     

同种异体大鼠气管腹腔移植后闭塞性细支气管炎发生机制探讨

目的建立肺移植后闭塞性细支气管炎动物模型,对其发病机制进行初步探讨。方法新鲜SD大鼠气管（每段5环）异位移植到SD大鼠（Ⅰ组）和Wistar大鼠（Ⅱ、Ⅲ组）腹腔并用大网膜包裹,Ⅰ、Ⅱ组不接受环孢菌素A（CsA）,Ⅲ组全程接受CsA10mg·kg^-1·d^-1。分别在3、14、28d后取出移植气管检测形态学改变和Th1（IL-2、IFN-γ）／Th2（IL-4、IL-10）细胞因子表达,并观察CsA对上述指标的影响。结果术后3d时3组气管形态学变化差异无统计学意义（P〉0．05）。14d时Ⅰ组气管形态基本恢复;Ⅱ、Ⅲ组上皮细胞几乎全部缺失,差异无统计学意义（P〉0．05）,与Ⅰ组区别明显（P〈0．01）;Ⅱ组管腔阻塞（28．5±5．0）％,淋巴细胞密集浸润,Ⅲ组阻塞（19．4±2．9）％,较多淋巴细胞分布,3组差异有统计学意义（P〈0．01）。28d时Ⅰ组形态正常,Ⅱ组管腔阻塞（94．8±3．6）％,浸润淋巴细胞有所减少,Ⅲ组阻塞（36．6±7．6）％,淋巴细胞分布减少,3组差异有统计学意义（P〈0．01）。Ⅱ组Th1／Th2细胞因子表达比Ⅰ组明显升高。与Ⅰ组相比,Ⅱ组Th1细胞因子表达比Th2细胞因子升高更为显著。Ⅲ组IL-2表达比Ⅱ组明显减少,但2组IFN-γ、IL-4、IL-10表达差异没有统计学意义。结论同种异体移植物在上皮细胞损害、纤维性细胞增生以及淋巴细胞浸润等方面较同系移植物有明显变化。Th1／Th2促进了同种异体大鼠异位移植气管闭塞性细支气管炎（OB）的发生,其细胞因子可能介入了OB的发病机制。CsA减少管腔阻塞和淋巴细胞浸润,但对于移植物上皮没有明显保护作用。CsA抑制IL-2基因转录,在一定程度上减少了OB病理性损害。     

Development of bronchiolitis obliterans syndrome despite blood chimerism in human lung transplant recipients

Bronchiolitis Obliterans Syndrome (BOS) remains the overwhelming obstacle to the success of lung transplantations (LTx). The presence of donor-specific microchimerism (DSM) and its association with lung allograft function is not well defined. To investigate the relationship between chimerism and BOS, blood was obtained from 21 LTx recipients. Genomic DNA was isolated from patient blood, and PCR-based techniques were used to identify recipient and donor HLA-DR. Fifty percent of the LTx recipients with BOS exhibited DSM at “T₁” time post transplant, and 40 % at one year follow-up (T₂). However, 54 % exhibited DSM in the BOS-free group at T₁, and 44 % at T₂. Of the BOS-free, DSM-positive patients at T₁, 29 % developed BOS by T₂. In contrast, 50 % of BOS-free DSM-negative patients 50 % developed BOS (P > 0.05). Double LTx had a higher prevalence of DSM (73 %) and a lower prevalence of BOS (46 %) than single LTx (50 % and 80 % respectively, P > 0.05). One-HLA-DR-antigen-matched LTx recipients show a low prevalence of DSM compared to non-matched (P < 0.05). This study demonstrates that the development of BOS in LTx recipients could also occur in the presence of blood chimerism. Received: 10 February 1999 Received after revision: 29 July 1999 Accepted: 1 September 1999     

Neutrophil elastase and obliterative bronchiolitis

Abstract Bronchoalveolar lavage levels of elastase were assayed to determine the timing and magnitude of elevations in elastase relative to both fibrosis, as indicated by hyaluronate (HA) levels, and decline in FEV, characteristic of the clinical syndrome of obliterative bronchiolitis (OB). Samples were collected from 48 heart-lung or single lung transplant recipients. Regression analysis was performed and demonstrated that high levels of elastase occurred with active decline in lung function and in association with high levels of HA. This study suggested that intense neutrophil elastase release occurs concurrent with the development of OB and may contribute to the destruction of bronchiolar architecture.     

阿奇霉素对肺移植术后闭塞性细支气管炎小鼠Th17/Treg平衡的影响

目的 探讨阿奇霉素对肺移植术后闭塞性细支气管炎的影响及对辅助性T（Th）17细胞/调节性T细胞（Treg）平衡的作用。 方法 无特定病原体（SPF）级C57BL/6小鼠24只、Balb/c小鼠48只。以C57BL/6小鼠为供体,Balb/c小鼠为受体,将Balb/c小鼠随机分成4组,每组12只,分别为实验对照组（C组）、阿奇霉素对照组（Cazm组）、移植组（T组）、移植治疗组（Tazm组）。T组和Tazm组建立气管异位移植模型模拟肺移植术后闭塞性细支气管炎。于移植后1 d起,给予Cazm组和Tazm组小鼠阿奇霉素30 mg/kg每周灌胃3次,分别于移植后14 d和28 d取出移植气管,收集外周血。取出移植气管行苏木素-伊红（HE）染色观察病理学变化,采用逆转录聚合酶链反应（RT-PCR）法检测外周血细胞ROR-γt和Foxp3信使核糖核酸（mRNA）的表达,采用酶链免疫吸附试验（ELISA）法检测血浆Th17、Treg相关细胞因子的水平变化。 结果 气管异位移植后,与C组气管相比,T组和Tazm组移植气管出现闭塞并有炎症浸润,Tazm组程度要轻于T组。与T组相比,Tazm组ROR-γt mRNA表达水平降低（P < 0.05）,两者Foxp3 mRNA表达差异无统计学意义（P>0.05）。与T组相比,Tazm组细胞因子白细胞介素（IL）-6、IL-17水平降低（均为P < 0.05）。 结论 阿奇霉素持续治疗可延缓移植后闭塞性细支气管炎的进展,可能与抑制Th17细胞分化及其介导的炎症作用相关。     

Rescue alemtuzumab for refractory acute cellular rejection and bronchiolitis obliterans syndrome after lung transplantation

Refractory acute cellular rejection (rACR) is associated with death and bronchiolitis obliterans syndrome (BOS) post‐lung transplantation. We report the largest cohort of lung transplant recipients (LTRs) treated with rescue alemtuzumab for rACR or BOS. RACR outcomes included burden of ACR 30 days before and 180 days after rescue assessed by a novel composite rejection standardized score (CRSS, range 0‐6) and freedom from ≥A2 ACR. BOS outcomes included freedom from BOS progression and FEV1 decline >10%. Univariate parametric and nonparametric statistical approaches were used to assess treatment response. Kaplan‐Meier method with log rank conversion was used to assess freedom from events. Fifty‐seven alemtuzumab doses (ACR 40 and BOS 17) given to 51 patients were included. Median time to rescue was 722 (IQR 42‐1403) days. CRSS declined significantly (3 vs 0.67, P<0.001) after rescue. Freedom from ≥A2 was 62.5% in rACR. Freedom from BOS progression was 52.9% at 180 days in the BOS cohort. Freedom from FEV1 decline >10% was 70% in BOS grade 1 and 14.3% in advanced BOS grades 2‐3. Infections developed in 72.5% and 76.5% of rACR and BOS groups. Rescue alemtuzumab appears useful for rACR. Patients with BOS 1 may have transient benefit, and patients with advanced BOS seem not to respond to alemtuzumab.     

Usefulness of Exhaled Nitric Oxide to Guide Risk Stratification for Bronchiolitis Obliterans Syndrome After Lung Transplantation

The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow‐up of 3 months: (1) stable non‐BOS, (2) unstable non‐BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non‐BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non‐BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.     

Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis

BACKGROUND: Bronchiolitis obliterans (BO) is an uncommon and severe form of chronic obstructive lung disease in children that results from an insult to the lower respiratory tract. METHODS: A case-control study of children under the age of 3 years was performed in 109 cases and 99 controls to determine risk factors for the development of BO. Participants were evaluated by immunofluorescence viral tests, pulmonary function tests, and questions to assess tobacco and other exposures. RESULTS: Bronchiolitis due to adenovirus (odds ratio (OR) 49, 95% confidence interval (CI) 12 to 199) and the need for mechanical ventilation (OR 11, 95% CI 2.6 to 45) were strongly and independently associated with an increased risk for BO. Factors not associated with post-infectious BO included age of the child, sex, and environmental tobacco exposure (either in utero or during infancy). CONCLUSIONS: Adenovirus infection and need for mechanical ventilation are significant risk factors for developing BO in children. Further research is needed to determine why these risk factors are so strong and how they may contribute to the development of the disease.     

A case–control study of bronchiolitis obliterans syndrome following allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans syndrome (BOS) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, the pathogenesis and risks for the development of BOS have remained unclear. Therefore, a case–control study was conducted to investigate the risk factors for the development of BOS, which included the largest number of BOS cases; 196 patients with BOS were identified and compared with 1960 control recipients. The following were identified as significantly higher risk factors for the development of BOS: female recipients (OR 1.47, P = 0.019), ABO‐mismatch HSCT (minor mismatch, OR 1.67, P = 0.015; major mismatch, OR 1.73, P = 0.012; bidirectional mismatch, OR 1.96, P = 0.018), busulfan+cyclophosphamide‐based myeloablative conditioning (OR 1.74, P = 0.016), and acute graft‐versus‐host disease (GVHD) involving the skin (OR 1.55, P = 0.011). On the other hand, the risk for the development of BOS was significantly lower in patients receiving cord blood transplantation (OR 0.26, P = 0.0011). With respect to other target organs of chronic GVHD, ocular involvement was significantly associated with BOS (OR 2.53, P < 0.001). Prospective studies are required to elucidate the risk factors for the development of BOS, and future investigations should focus on finding a prophylactic approach against BOS based on these findings.