Bronchiolitis Obliterans Syndrome Group Research Articles

Periostin in Bronchiolitis Obliterans Syndrome after Lung Transplant.

The utility of measuring serum periostin levels for predicting the occurrence of bronchiolitis obliterans syndrome (BOS) after lung transplantation remains underexplored. We analyzed differentially expressed genes (DEGs) between initially transplanted lung tissue and lung tissue with BOS from four patients. Periostin levels were assessed in 97 patients who had undergone lung transplantation 1 year post-transplantation and at the onset of BOS. The association between periostin levels and BOS, as well as their correlation with the decline in forced expiratory volume in one second (FEV1), was evaluated. Periostin levels in the BOS group were significantly higher than those in the control group (p < 0.001) and the stable group (p < 0.001). Periostin levels at the onset of BOS were significantly higher than those 1 year post-transplantation in the BOS group (p < 0.001). The serum periostin levels at the time of BOS diagnosis showed a positive correlation with the reduction in FEV1 (%) (r = 0.745, p < 0.001). The increase in the serum periostin levels at the time of BOS diagnosis compared with those 1 year post-transplantation was positively correlated with reduction in FEV1 (%) (r = 0.753, p < 0.001). Thus, serum periostin levels may serve as biomarkers for predicting a decline in lung function in patients with BOS after lung transplantation.

Detection of Bronchiolitis Obliterans Syndrome Using Nitrogen Multiple Breath Washout in Children Posthemopoietic Stem Cell Transplant

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI2.5) derived from the nitrogen multiple breath washout (N2MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N2MBW in children post-HSCT, and in an exploratory analysis, determine if LCI2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N2MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI2.5, while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV1). Ninety-nine percent of N2MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI2.5 ranging from 3 to 5 units and mean reductions in FEV1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI2.5 and FEV1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N2MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI2.5 did not lead to earlier detection of BOS, when compared to spirometry.

Retrospective Analysis of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation

Objective: To explore the incidence, clinical features,risk factors and survival prognosis of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) by using large samples form a single center.Provide a prerequisite for improving the early diagnosis of BOS after allo-HSCT.Methods: We retrospectively investigated the case data of 802 patients who underwent allo-HSCT in our institute in petiod of January 1, 2015 to December 31, 2019 and survived more than 100 days. Adopt a multidisciplinary discussion method in the Department of Hematology, Respiratory and Radiology,according to the 2014 National Institutes of Health (NIH) ,diagnose and assess the severity of patiencts with BOS.Describe the clinical characteristics of BOS, and then analyze the risk factors and survival prognosis.Result: Among the 802 patients，46 patients（5.74%), 26males and 20 females with a median age of 32 years was diagnosed BOS.The median time to first appearance of respiratory symptoms was 13.5 months after transplantation, and the median time to diagnosis was 14.4 months.The cumulative incidence rate for 1- year, 2- year, and 5 -year after allo-HSCT is 3.7%, 6.5%, and 8.4%,while the cumulative incidence rate for patients already diagnosed with cGVHD is 7.5%、12.4% and 15.0% . Univariate analysis showed several risk factors associated with the onset of BOS,including the presence of preoperative or postoperative pneumonia,free of ATG ,use of DLI,peripheral blood stem cell transplantation, occurrence of GVHD and the severity and number of these episodes .And multivariate analysis denotes :free of ATG ,use of DLI,and number of organs affected by cGVHD were the variables correlated with increased incidences of BOS. At the onset of BOS, FEV1, FEV1%pred, FEV1/FVC ,FEV1/FVC %pred were significantly lower than those before transplantation. Compare before and after onset, the average decrease rate of FEV1 is 0.17L/month, while FEV1%pred is 5.15%/month.We also recorded the last follow-up lung function to evaluate the treatment efficacy : after treatment, the average FEV1 was 2.46L, the average of FEV1%pred was 36.61%, the average of FEV1/FVC was 45.80%, and the average of FEV1/FVC%pred was 56.36%, before and after treatment., FEV1%pred has no statistical difference (P=0.455).Not only that, there was no statistical difference in the treatment effect among different severity of BOS.The median follow-up time after the diagnosis of BOS was 19 months, and there was no statistical difference in the survival rate between the BOS and non-BOS groups at the end of the follow-up. The analysis result shows that early-onset BOS is a independent risk factors for poor survival time of BOS.Compare BOS with other non-infectious lung complications,the severity of BOS and cGVHD involving extrapulmonary organs are statistically different.Conclusion: BOS is a serious refractory complication after allo-HSCT.Early detection of potential patients with BOS is very difficult , and because most of the BOS patients did not respond to the therapy well, eventually lead to the irreversibility of deterioration of PFT. Compared with other non-infectious lung complications, strong association with severe cGVHD and deterioration of lung function characterized by obstructive ventilation disorder，etc.It suggests that the clinical need to deepen the recognition of BOS, continue to explore the early diagnosis method of BOS , more importantly , strive to give effective treatment at the early stage to improve the prognosis.KEYWORDS Bronchiolitis obliterans Allogeneic hematopoietic stem cell transplantation Risk factors Non-infectious pulmonary complications DisclosuresNo relevant conflicts of interest to declare.

The Role of Galectins in Chronic Lung Allograft Dysfunction

BackgroundGalectins are proteins that bind β-galactosides such as N-acetyllactosamine present in N-linked and O-linked glycoproteins and that seem to be implicated in inflammatory and immune responses as well as fibrotic mechanisms. This preliminary study investigated serum galectins as clinical biomarkers in lung transplant patients with chronic lung allograft dysfunction (CLAD), phenotype bronchiolitis obliterans syndrome (BOS).Materials and MethodsNineteen lung transplant patients [median age (IQR), 55 (45–62) years; 53% males] were enrolled in the study. Peripheral blood concentrations of galectins-1, 3 and 9 were determined with commercial ELISA kits.ResultsGalectin-1 concentrations were higher in BOS than in stable LTX patients (p = 0.0394). In logistic regression analysis, testing BOS group as dependent variable with Gal-1 and 3 as independent variables, area under the receiver operating characteristics (AUROC) curve was 98.9% (NPV 90% and PPV 88.9%, p = 0.0003). With the stable LTX group as dependent variable and Gal-1, 3 and 9 as independent variables, AUROC was 92.6% (NPV 100% and PPV 90%, p = 0.0023). In stable patients were observed an inverse correlation of Gal-3 with DLCO% and KCO%, and between Gal-9 and KCO%.ConclusionGalectins-1, 3 and 9 are possible clinical biomarkers in lung transplant patients with diagnostic and prognostic meaning. These molecules may be directly implicated in the pathological mechanisms of BOS. The hypothesis that they could be new therapeutic targets in BOS patients is intriguing and also worth exploring.

Clinical Characteristics of Patients with Chronic Lung Allograft Dysfunction Listed for Lung Re-Transplant

<h3>Purpose</h3> Chronic lung allograft dysfunction(CLAD) is the barrier to improve long term outcome of lung transplantation. This study aims to examine prevalence and characteristics of patients with CLAD who were listed for lung re-transplant. <h3>Methods</h3> This is a retrospective observational study. Adult patients (>18 YO) listed for lung re-transplant due to bronchiolitis obliterans syndrome(BOS) or restrictive allograft syndrome(RAS) were identified from SRTR database. Numerical data were reported in mean and standard deviation. Categorical data were reported in count and percent. T-test and Chi-square test were performed to compare 2 groups. <h3>Results</h3> 1546 adult CLAD patients were included. 85.51% of these patients have BOS phenotype. Mean age was 42.79. There was no significant difference in age, mPAP, history of smoking, previous malignancy, or pan-resistant infection between BOS and RAS groups. Oxygen requirement at listing time was significantly higher in RAS group (5.64±6.33 vs 2.93±3.31, p < 0.01). Proportion of patients who were on ECMO at listing time is significantly higher in RAS group (4.02% vs 0.91%, p<0.01). LAS of RAS group was significantly higher(52.07±18.71 vs 43.60±17.71, p < 0.01). 67.86% of RAS group received re-transplant compared to 59.15% of BOS group (p = 0.014). <h3>Conclusion</h3> RAS patients have worse clinical condition at listing time compared to BOS patients. They required higher FO2 supplement and have higher LAS. More proportion of patients with RAS received re-transplant compared to patients with BOS which reflects the above findings.

Clinical analysis of bronchiolitis obliterans syndrome after haplo- hematopoietic stem cell transplantation

目的探讨单倍型造血干细胞移植（haplo-HSCT）后闭塞性细支气管炎综合征（BOS）的临床特征、危险因素以及预后。方法回顾性分析苏州大学附属第一医院2013年1月至2015年12月444例行haplo-HSCT且总生存（OS）期>100 d患者的临床资料。结果至2018年1月1日随访结束，共计25例（5.63%）患者发生BOS（BOS组），中位发病时间为移植后448（165~845）d，移植后1、2、3年BOS累积发生率分别为1.6%（95%CI 1.5%~1.6%）、4.8%（95%CI 4.7%~4.8%）、5.8%（95%CI 5.7%~5.8%）；在慢性移植物抗宿主病（cGVHD）患者中，移植后1、2、3年BOS累积发生率分别为2.8%（95%CI 2.7%~2.8%）、9.5%（95%CI 9.4%~9.5%）、11.5%（95%CI 11.4%~11.6%）。多因素分析结果显示疾病高危、Ⅱ~Ⅳ度急性移植物抗宿主病（aGVHD）、BOS发生前存在其他部位cGVHD是BOS发生的独立危险因素。BOS组、非BOS组移植后3年OS率分别为71.8%（95%CI 53.9%~89.6%）、72.4%（95%CI 68.1%~76.7%）（P=0.400）；然而，半标志性分析结果显示，BOS组从BOS诊断至随访截止1、3年OS率分别为78.4%（95%CI 61.5%~95.3%）、37.0%（95%CI 2.5%~71.5%），非BOS组从移植后448 d（标志点）至随访截止1、3年OS率分别为93.9%（95%CI 91.3%~96.4%）、89.3%（95%CI 84.8%~93.0%）（P<0.001）。BOS组3年移植相关死亡率（TRM）显著高于非BOS组（28.2%对10.9%，P<0.001）。重度BOS患者OS率显著低于轻、中度BOS患者（P=0.049）。结论BOS是haplo-HSCT后重要并发症，疾病高危、Ⅱ~Ⅳ度aGVHD、BOS发生前存在其他部位cGVHD是BOS发生的独立危险因素。BOS患者预后较差。

Cytotoxic T Cells Early after Lung Transplantation Precede the Restrictive Allograft Syndrome

Purpose The outcome after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), subclassified into bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). RAS tends to an earlier, more severe and more rapid course as compared to BOS. Underlying differences of the immunologic phenotype, potentially unveiling therapeutic targets, have not yet been well-defined. Methods From June 2013 to August 2015, we collected whole blood samples from 142 consecutively transplanted patients 3 weeks after lung transplantation, excluding only those patients with missing blood samples or who did not consent to have the samples drawn. The samples were analyzed by flow cytometry. CD3+ CD8+ T cells were defined as cytotoxic T cells. Follow up ended as of 09/2018 and full data was available from 138 patients. CLAD diagnosis was made according to ISHLT consensus criteria based on a persistent >20% decline of FEV1 in spirometry. RAS was diagnosed in the presence of a >20% decline of FEV1 concomitant with a >10% decline of the total lung capacity and confirmed by CT scans. Results In this cohort, 115 patients did not develop CLAD at the end of follow up (control group). BOS was observed in 18 patients, whereas RAS was observed in 5 patients. In the BOS group, 7 patients were graded 1, 1 patient was graded 2, and 10 patients were graded 3. There was no significant difference in the percentage of CD8 T cells amongst lymphocytes between the control and the CLAD group (5.2±8.2% vs. 5.7±7.1%, respectively: p=0.40), three weeks after transplantation. In addition, there was also no significant difference between the control and the BOS subgroup (5.2±8.2% vs. 3.9±5.8%, respectively: p=0.27). However, a significant difference was detected between the BOS and RAS groups (3.9±5.8 vs. 12.0±8.6%, respectively: p Conclusion The development of the most severe and frequently early subtype of chronic lung rejection, the restrictive allograft syndrome, is preceeded by a high frequency of cytotoxic effector CD8+ T cells in peripheral blood as early as three weeks post transplantation. Cytotoxic T cells are also known to contribute to acute rejections and might be targeted by multiple immunosuppressive treatments.

Histopathologic Acute Lung Injury after Allogeneic Hematopoietic Cell Transplantation: Clinical Findings, Radiologic Features, Treatments and Outcomes

BACKGROUNDRespiratory failure syndromes are common after allogeneic hematopoietic cell transplantation (allo-HCT), and are associated with substantial morbidity and mortality. These syndromes are incompletely understood, and may be associated with histopathologic evidence of acute lung injury (ALI). The role of biopsy in this setting is controversial, with uncertain benefits and considerable procedural risk. We report the clinical, radiologic and histopathologic features of patients with biopsy-proven ALI following allo-HCT in a large multi-site retrospective series.METHODSThe medical records of 1,864 consecutive adults who underwent allo-HCT at Mayo Clinic, Minnesota (n = 916), Arizona (n = 694), and Florida (n = 254) (Jan 2005-Dec 2017) were reviewed. A total of 152 patients underwent a lung biopsy: 126 bronchoscopic, 22 surgical, and 4 CT-guided biopsies (Figure 1). Patients with a histopathologic diagnosis of ALI were included in the study, and were classified into clinicopathologic subgroups per published American Thoracic Society guidelines (Am J Resp Crit Care Med, 2011). Patients whose diagnosis remained uncertain after a detailed review of the medical records were included in a separate subgroup as undifferentiated ALI. Transplant characteristics, radiologic features, pulmonary function test (PFT) results, treatments, and outcomes were compared between groups.RESULTSClinicopathologic diagnoses in 62 patients with biopsy-proven ALI consisted of an infectious etiology in 15 (24%), cryptogenic organizing pneumonia (COP) in 15 (24%), idiopathic pneumonia syndrome (IPS) in 9 (15%), bronchiolitis obliterans syndrome (BOS) in 9 (15%), diffuse alveolar hemorrhage in 3 (5%), periengraftment respiratory distress syndrome in 2 (3%), and undifferentiated ALI in 9 (15%) patients (Figure 2). Transplant characteristics were comparable between groups. Infectious pneumonia and IPS were the most common diagnoses during the first 100 days post HCT (50% and 36%, respectively). Between 100 and 365 days, a range of diagnoses were seen including infectious pneumonia (20%), COP (23%), IPS (14%), BOS (23%), and undifferentiated ALI (20%) (Table 1). In 14/15 (93%) infectious pneumonia cases, biopsy did not change management and diagnosis was concurrently established by bronchoalveolar lavage (BAL) or non-invasive testing.Patients with IPS, BOS, and undifferentiated ALI more commonly had a pleural effusion (66%, 44%, and 44%, respectively). Nodular infiltrates were most commonly seen in patients with infectious pneumonia (55%). Other radiographic findings were not clearly discriminative. BOS and infectious pneumonia were more commonly associated with an obstructive PFT (78% and 33%, respectively), whereas restrictive pattern was more frequently seen in COP and IPS (50% and 57%, respectively) (Table 2). Despite a histopathologic diagnosis of ALI, 9 (15%) patients had clear clinical and radiographic evidence of BOS.Steroids were used commonly in noninfectious syndromes: 93% of patients with COP and in 100% of IPS patients. Of 4 patients with IPS who received Etanercept, 2 (50%) showed complete recovery, whereas the remaining 5 patients who did not receive Etanercept died from fulminant respiratory failure. Most common treatment response was complete recovery in COP (73%), fulminant respiratory failure leading to death in IPS (78%), and chronic respiratory failure in BOS (78%). Estimated OS was shortest in the group with IPS and undifferentiated ALI (median 5 and 17 mons, respectively), whereas patients with COP had the best prognosis (mOS not reached) followed by the infectious pneumonia and the BOS groups (mOS of 59 and 55 mons, respectively). Pulmonary complications were the most common cause of death in patients with non-infectious ALI. Lung biopsy was associated with post-procedural pneumothorax in 17 (27%) patients; 12 of whom required a chest tube.CONCLUSIONSIn this largest case series to date of histopathologic ALI after allo-HCT, biopsy does not appear to meaningfully change management in the majority of patients, and is associated with substantial procedural risk. Histopathologic findings do not clearly correlate with the clinical and radiographic picture in a sizeable proportion of the patients. PFT results, BAL findings, the timing of the onset of respiratory failure after HCT, and the response to steroids seem to be of greater diagnostic and/or prognostic value. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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 30days before and 180days 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.

Low Levels of Exhaled Surfactant Protein A Associated With BOS After Lung Transplantation.

BackgroundThere is no clinically available marker for early detection or monitoring of chronic rejection in the form of bronchiolitis obliterans syndrome (BOS), the main long-term complication after lung transplantation. Sampling and analysis of particles in exhaled air is a valid, noninvasive method for monitoring surfactant protein A (SP-A) and albumin in the distal airways.MethodsWe asked whether differences in composition of exhaled particles can be detected when comparing stable lung transplant recipients (LTRs) (n = 26) with LTRs who develop BOS (n = 7). A comparison between LTRs and a matching group of healthy controls (n = 33) was also conducted. Using a system developed in-house, particles were collected from exhaled air by the principal of inertial impaction before chemical analysis by immunoassays.ResultsSurfactant protein A in exhaled particles and the SP-A/albumin ratio were lower (P = 0.002 and P = 0.0001 respectively) in the BOS group compared to the BOS-free group. LTRs exhaled higher amount of particles (P < 0.0001) and had lower albumin content (P < 0.0001) than healthy controls.ConclusionsWe conclude that low levels of SP-A in exhaled particles are associated with increased risk of BOS in LTRs. The possibility that this noninvasive method can be used to predict BOS onset deserves further study with prospective and longitudinal approaches.

Parametric Response Mapping of Bronchiolitis Obliterans Syndrome Progression After Lung Transplantation.

Bronchiolitis obliterans syndrome (BOS) remains a major complication after lung transplantation. Air trapping and mosaic attenuation are typical radiological features of BOS; however, quantitative evaluation remains troublesome. We evaluated parametric response mapping (PRM, voxel-to-voxel comparison of inspiratory and expiratory computed tomography [CT] scans) in lung transplant recipients diagnosed with BOS (n = 20) and time-matched stable lung transplant recipients (n = 20). Serial PRM measurements were performed prediagnosis, at time of BOS diagnosis, and postdiagnosis (Tpre , T0 , and Tpost , respectively), or at a postoperatively matched time in stable patients. PRM results were correlated with pulmonary function and confirmed by microCT analysis of end-stage explanted lung tissue. Using PRM, we observed an increase in functional small airway disease (fSAD), from Tpre to T0 (p = 0.006) and a concurrent decrease in healthy parenchyma (p = 0.02) in the BOS group. This change in PRM continued to Tpost , which was significantly different compared to the stable patients (p = 0.0002). At BOS diagnosis, the increase in fSAD was strongly associated with a decrease in forced expiratory volume in 1 s (p = 0.011). Micro-CT confirmed the presence of airway obliteration in a sample of a BOS patient identified with 67% fSAD by PRM. We demonstrated the use of PRM as an adequate output to monitor BOS progression in lung transplant recipients.

Dysregulated MicroRNA Expression and Chronic Lung Allograft Rejection in Recipients With Antibodies to Donor HLA

The pathogenesis of chronic rejection, Bronchiolitis Obliterans Syndrome (BOS) following lung transplantation (LT) is poorly understood. We hypothesized that development of antibodies to HLA (DSA) is associated with dysregulation of microRNA (miRNA) that predisposes BOS. Towards this, miRNA profiling of mononuclear cells from 10 stable LT (DSA(-) BOS(-) ), 10 LT with DSA(+) BOS(-) (DSA group) and 10 LT with DSA(+) BOS(+) (BOS group) were performed. Prediction by mirPath indicated that differential miRNAs in DSA(+) BOS(-) compared to stable are significantly up-regulated (relative fold >2, p < 0.05) for TGF-β and B cell receptor signal pathways. A total of seventy-four miRNAs were up-regulated and six miRNAs were down regulated in LT with DSA(+) BOS(+) when compared to stable (relative fold >2, p < 0.05). There was also significant enrichment of cell cycle and gap junction pathways. An inverse correlation between expression of two key miRNAs and their target genes were observed: miR-369-5p and miR-548d were down regulated in DSA(+) LT while their gene targets in TGF-β signal pathways were up-regulated. In addition, miR-628-5p and miR-134 were down regulated and their target genes (B cell development) were up-regulated. Therefore, we conclude that alloimmunity induced changes in miRNAs affecting the TGF-β and B cell receptor signal pathways play important roles in BOS development.

Serum Krebs Von Den Lungen-6 as a Biomarker for Early Detection of Bronchiolitis Obliterans Syndrome in Children Undergoing Allogeneic Stem Cell Transplantation

Bronchiolitis obliterans syndrome (BOS) is a devastating complication after allogeneic stem cell transplantation (allo-SCT). Early identification of high-risk patients is pivotal for success. Lung proteins, KL-6, CCSP, SP-A, and SP-D, measured in the serum may identify high-risk patients for BOS earlier than pulmonary function tests (PFTs) can identify changes or clinical symptoms. Lung proteins were measured in patients' serum at baseline and at 1, 3, 6, 9, 12, 18, and 24 months after transplantation along with history, clinical examination, and PFTs. Serum levels of lung proteins were also measured in healthy control subjects. The primary endpoint was the development of BOS confirmed by pathological biopsy or National Institutes of Health criteria. Between September 2009 and September 2011, 39 patients were enrolled. Six children developed BOS at a median time of 200 days (range, 94 to 282). KL-6 levels were low in control subjects, at a median of .1 U/mL (range, .1 to 1.5). Pre-SCT and 1-month KL-6 levels were significantly higher in surviving patients who developed BOS (n = 6) versus those who did not (n = 18) (pre-SCT: mean, 32.6 U/mL [IQR, 9.7 to 89.3] versus 5.8 U/mL [IQR, 2.1 to 12.6], P = .03; at 1 month: mean, 52.5 U/mL [IQR, 20.2 to 121.3] versus 11.4 U/mL [IQR, 5.7 to 36.0], P = .04). Three- and 6-month KL-6 levels continued to be higher in BOS group but were not statistically significant. CCSP, SP-A, and SP-D were not predictive. KL-6 measured in the serum of children receiving allo-SCT may identify patients at high risk for the development of BOS. These patients will benefit from intensive surveillance protocol and early therapy before irreversible lung damage.

Value of air trapping at inspiratory and expiratory low-dose CT in predicting early bronchiolitis obliterans syndrome after bone marrow transplantation

Objective To determine whether bronchiolitis obliterans syndrome(BOS)after bone marrow transplantation can be predicted in light of air trapping.Methods Thirty-three cases of BOS(BOS group)and 111normal patients(normal group)were comparatively reviewed for the CT characteristics(including frequency,dynamic change and diagnostic potency)of air trapping.The analysis was mainly based on the last CT scans before occurrence of BOS.Results The frequency of air trapping,especially mosaic air trapping or extensive air trapping,was higher in the BOS group than in the normal group(P= 0.03).The median total air trapping score was higher in the BOS group than in the normal group(P=0.01).The increase of air trapping extent with the progress of disease was more common in the BOS group(50.0%,9/18),whereas a decrease of air trapping extent,disappearance or intermittent appearance of air trapping was more common in the normal group(60.0%,15/ 25)during the follow-up period.When mosaic air trapping or extensive air trapping was used as the diagnostic threshold,the specificity was high(90.5%,96.7%),but the sensitivity was low(29.4%,15.8%).Conclusion Occurrence of air trapping is a clue for development of BOS in patients receiving bone marrow transplantation.Mosaic air trapping and extensive air trapping are insensitive but specific CT findings.

The Lung Microbiome and Development of Bronchiolitis Obliterans Syndrome after Pediatric Lung Transplantation

Purpose Bronchiolitis obliterans syndrome (BOS) is a major complication following lung transplant. Infection is a known risk factor for the development of BOS. Microbiome analysis has an advantage over traditional culture as it detects uncultivable organisms. In addition, reduced bacterial diversity has been associated with increases in morbidity and mortality. We hypothesize that significant differences exist in the microbiome of post lung transplant patients with BOS vs. non-BOS. Methods and Materials Ninety-four bronchoalveolar lavage specimens from 21 patients were collected during surveillance bronchoscopies throughout the first year post-transplant. Bacterial DNA was extracted, and the V3V5 variable regions of the 16SrRNA gene were amplified using universal barcoded primers. Subsequent 454 sequencing produced an average of 6,000 reads per sample with an average length of 500 bases. Resulting sequences were analyzed by the Genboree Microbiome Workbench. Results In lung transplant recipients (LTRs) who developed BOS, Firmicutes decreased and Proteobacteria increased over time. Conversely, the non-BOS group revealed a longitudinal increase in Firmicutes and a decreased in Proteobacteria. 33 genera were noted in the BOS compared to 49 genera in the non-BOS group, indicating an overall decreased bacterial diversity in the BOS group. Bacterial diversity was similar in both the groups at 2 weeks post transplant but steadily declined in the BOS group while it increased in the non-BOS group during the first year post transplant. Conclusions Longitudinal genus-level variation clearly differed in the BOS vs. non-BOS groups. Moreover, BOS was associated with reduced bacterial diversity, which has been associated with an increase in morbidity and mortality in previous studies of the lung microbiome. Further studies are required to investigate if a change in the lung microbiome of post-transplant individuals is an indication of the future development of BOS.

Chest health surveillance utility in the early detection of bronchiolitis obliterans syndrome in children after allo-SCT

To prospectively assess whether periodic chest health surveillance is beneficial for the early detection of bronchiolitis obliterans syndrome (BOS) in children after allo-SCT. Children up to 18 years of age receiving allo-SCT from September 2009 to September 2011 were included. Surveillance consisted of the following: a 7-item respiratory system questionnaire of cough, wheeze and shortness of breath; focused physical examination; and pulmonary function test (PFT) conducted before SCT and at 1, 3, 6, 9, 12, 18 and 24 months after SCT. Thirty-nine patients were enrolled. Five children developed BOS at a median time of 192 days (range 94-282). Positive response comparisons between the BOS group vs the non-BOS group were NS for history questionnaire (P=0.2), heart rate (P=0.3), respiratory rate (P=0.3) and oxygen saturation monitoring (P=0.8). Differences between the two groups for chest auscultation and PFT were statistically significant (P=0.03 and P=0.01, respectively). However, chest auscultation in the BOS group was only positive after BOS diagnosis. PFT reduction was evident in the asymptomatic phase (BOS group 33%; non-BOS group 4.5%, P=0.01). Changes in PFT, but not history/physical examination, allow the early detection of BOS in children after SCT. Our study is limited by the small sample size.

Comparison of serum KL-6 versus bronchoalveolar lavage neutrophilia for the diagnosis of bronchiolitis obliterans in lung transplantation

Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication after lung transplantation that is characterized by progressive fibrosis in the small airways. However, little is known about sensitive markers for detecting BOS. Our study compared the clinical utility of serum KL-6 level, a marker for pulmonary fibrosis, with that of neutrophilia in bronchoalveolar lavage fluid (BALF) for detecting BOS. Levels of serum KL-6 were evaluated in 152 samples from 53 lung transplant recipients (BOS, 15; non-BOS, 38) and in 27 samples from age- and sex-matched healthy individuals. Pulmonary function tests, arterial blood gas analysis, and BALF cell differentials were simultaneously evaluated. Serum KL-6 levels were significantly increased in the BOS group compared with the non-BOS group and the healthy individuals (p < 0.0001). Receiver operating characteristic curve analysis for detecting BOS showed the largest area under the curve for KL-6 compared with lactate dehydrogenase, C-reactive protein, or neutrophils percentage in BALF. Serum KL-6 correlated with the decline in forced expiratory volume in 1 second (FEV(1)) from post-lung transplant baseline (r = 0.43; p = 0.0001). Serum KL-6 levels are increased and correlate with the decline from baseline in FEV(1) in lung transplant recipients. The diagnostic accuracy of serum KL-6 level is better than that of BALF neutrophilia for detecting BOS.

Exhaled Breath Condensate pH in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome

Assessment of exhaled breath condensate (EBC) pH is a promising method for investigating airway pathology. However, inaccurate measurement techniques may bias pH readings. In this longitudinal study, we tested whether development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients is associated with acidification of EBC. EBC was collected in 15 patients with BOS and 16 stable BOS-free patients during routine clinical visits. From nine BOS patients, samples were collected before and after the onset of BOS, as well. Twenty healthy nontransplant subjects served as controls. EBC pH was measured by the carbon dioxide gas standardization method. EBC pH in patients with and without BOS and controls was similar (BOS group: 6.40±0.04, BOS-free group: 6.45±0.03; controls: 6.39±0.02; P>0.05). In patients who developed BOS during the follow-up, EBC pH before and after the onset of BOS was comparable (pre-BOS: 6.41±0.04 vs. post-BOS: 6.41±0.04; P>0.05). Coefficient of variation for repeated pH measurements in controls and subjects with and without BOS was 2.3%±0.3%, 2.0%±0.3%, and 1.7%±0.2%, respectively (P>0.05). Similarly, the limits of agreement for between-visit variability determined by the Bland-Altman test were comparable among the study groups. These data suggest that assessment of EBC pH is of limited value for the diagnosis of BOS.

Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome

Mannose binding lectin (MBL) is a key mediator of both innate immunity and efferocytosis (phagocytosis of apoptotic cells) in the airway. Defective efferocytosis results in a net increase in apoptotic material that can undergo secondary necrosis, leading to tissue damage and chronic inflammation. We have shown reduced MBL and efferocytosis in other chronic inflammatory lung diseases; we therefore hypothesized that reduced MBL and efferocytosis in the airways may be a determinant of bronchiolitis obliterans syndrome (BOS) after lung transplantation. We investigated MBL (enzyme-linked immunosorbent assay [ELISA]), MBL-mediated complement deposition (UC4, ELISA), and efferocytosis of apoptotic bronchial epithelial cells (flow cytometry) in bronchoalveolar lavage (BAL) and peripheral blood from 75 lung transplant recipients, comprising 16 with stable graft function, 34 stable with proven infection, 25 with BOS, and 14 healthy controls. In plasma, MBL levels were highly variable (0-17.538 μg/ml), but increased in infected patients vs control (p = 0.09) or stable groups (p = 0.003). There was a similar increase in UC4 in infected patients and a significant correlation between MBL and UC4. There was no correlation between MBL and time after transplant. In BAL, MBL levels were less variable (0-73.3 ng/ml) and significantly reduced in patients with BOS vs controls and stable groups. Efferocytosis was significantly reduced in the BOS group vs control and stable groups (mean [SEM] control, 20% [1.3%]; stable, 20.5% [2.5%]; infected, 17.3% [2.8%]; BOS, 11.3% [1.5%], p = 0.04). Low levels of MBL in the airway may play a role in reduced efferocytosis, subsequent tissue damage, and BOS after lung transplantation.

Polymorphisms in innate immunity genes associated with development of bronchiolitis obliterans after lung transplantation

Activation of the immune system is suggested to prevent transplant tolerance and to promote the development of bronchiolitis obliterans syndrome (BOS). The innate immune system is activated by the interaction of pathogen-associated molecular patterns of microorganisms with Toll-like receptors (TLRs). Activation of innate immunity via TLRs was shown to be a barrier to the induction of transplantation tolerance after lung transplantation. We hypothesized that polymorphisms in 10 genes coding for TLR1 to TLR10 might contribute to an altered immune response and the subsequent development of BOS. DNA was collected from 110 lung transplant recipients. Twenty patients developed BOS. The control group comprised 422 individuals. Sixty-four single-nucleotide polymorphisms (SNPs) in 10 genes coding for TLR1 to TLR10 were genotyped. The genotype distribution of TLR2 (rs1898830 and rs7656411), TLR4 (rs1927911) and TLR9 (rs352162 and rs187084) was significantly different between BOS(pos) patients and BOS(neg) patients and controls. The BOS(pos) group had significantly more patients with 3 or 4 of these risk alleles compared with the BOS(neg) and control groups. Polymorphisms in TLR2, TLR4 and TLR9 that recognize bacterial and viral pathogens are associated with BOS after lung transplantation.