Quantitative chest CT for subtyping chronic lung allograft dysfunction and its association with survival.

Chronic lung allograft dysfunction (CLAD) is a major cause of mortality in lung transplant recipients. CLAD can be sub-divided into at least 2 subtypes with distinct mortality risk characteristics: restrictive allograft syndrome (RAS), which demonstrates increased overall computed tomography (CT) lung density in contrast with bronchiolitis obliterans syndrome (BOS), which demonstrates reduced overall CT lung density. This study aimed to evaluate a reader-independent quantitative density metric (QDM) derived from CT histograms to associate with CLAD survival. A retrospective study evaluated CT scans corresponding to CLAD onset using pulmonary function tests in 74 patients (23 RAS, 51 BOS). Two different QDM values (QDM1 and QDM2) were calculated using CT lung density histograms. Calculation of QDM1 includes the extreme edges of the histogram. Calculation of QDM2 includes the central region of the histogram. Kaplan-Meier analysis and Cox regression analysis were used for CLAD prognosis. Higher QDM values were significantly associated with decreased survival. The hazard ratio for death was 3.2 times higher at the 75th percentile compared to the 25th percentile using QDM1 in a univariate model. QDM may associate with CLAD patient prognosis.

BALF cytokines in different phenotypes of chronic lung allograft dysfunction in lung transplant patients.

The long-term success of lung transplantation (LT) is limited by chronic lung allograft dysfunction (CLAD). Different phenotypes of CLAD have been described, such as bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). The purpose of this study was to investigate the levels of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) as markers of these CLAD phenotypes. BALF was collected from 51 recipients who underwent (bilateral and unilateral) LT. The study population was divided into three groups: stable (ST), BOS, and RAS. Levels of interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using the multiplex technology. BALF neutrophilia medians were higher in BOS (38%) and RAS (30%) than in ST (8%) (P=.008; P=.012). Regarding BALF cytokines, BOS and RAS patients showed higher levels of INF-γ than ST (P=.02; P=.008). Only IL-5 presented significant differences between BOS and RAS (P=.001). BALF neutrophilia is as a marker for both CLAD phenotypes, BOS and RAS, and IL-5 seems to be a potential biomarker for the RAS phenotype.

Differential cytokine, chemokine and growth factor expression in phenotypes of chronic lung allograft dysfunction.

BACKGROUND: Chronic lung allograft dysfunction is a heterogeneous entity limiting long-term survival after lung transplantation. Different clinical phenotypes (bronchiolitis obliterans syndrome [BOS]-neutrophilic BOS-restrictive allograft syndrome [RAS]) have been identified but the mechanisms remain elusive. METHODS: In this study, we measured 34 different cytokines, chemokines, and growth factors in bronchoalveolar lavage fluid of 20 stable patients, 20 patients suffering from non-neutrophilic BOS, 17 from neutrophilic BOS, and 20 from RAS using classic enzyme-linked immunosorbent assay and multiplex technology. RESULTS: Total cell count and % neutrophils were elevated in neutrophilic BOS and RAS compared to stable and non-neutrophilic BOS patients, whereas also the % eosinophils was elevated at diagnosis of RAS. Levels of interleukin (IL)-1ß (P<0.01), IL-1Rα (P<0.001), IL-6 (P<0.001), IL-8/CXCL8 (P<0.001), IP-10/CXCL10 (P<0.05), MCP-1/CCL2 (P<0.05), macrophage inflammatory protein (MIP)-1α/CCL3 (P<0.001), MIP-1ß/CCL4, and vascular endothelial growth factor (VEGF; P<0.05) were differentially regulated in RAS compared to stable, whereas in neutrophilic BOS IL-1ß (P<0.001), IL-1Rα (P<0.01), IL-7 (P<0.05), IL-8/CXCL8 (P<0.001), MCP-3/CXCCL7 (P<0.05) and MIP-1α/CCL-3 (P<0.05) were significantly upregulated compared to stable patients. We could not detect any differences between non-neutrophilic BOS and stable patients. Interestingly, bronchoalveolar lavage IL-6, interferon gamma-induced protein (IP)-10/CXCL10 and interferon-inducible T-cell alpha chemoattractant/chemokine (C-X-C motif) ligand 11 (ITAC/CXCL10) were associated with survival after diagnosis in RAS patients. CONCLUSION: There were major differences in cytokine and chemokine expression in our different study groups. Especially IL-6, but also IP-10/CXCL10, and VEGF may be interesting mediators in RAS.

Hypereosinophilic obliterative bronchiolitis: a distinct, unrecognised syndrome.

Biopsy-proven cases of eosinophilic bronchiolitis have only been reported in isolation, and all come from Japan. We present six patients with hypereosinophilic obliterative bronchiolitis (HOB), defined by the following criteria: 1) blood eosinophil cell count >1 G·L(-1) and/or bronchoalveolar lavage eosinophil count >25%; 2) persistent airflow obstruction despite high-dose inhaled bronchodilators and corticosteroids; and 3) eosinophilic bronchiolitis at lung biopsy (n=1) and/or direct signs of bronchiolitis (centrilobular nodules and branching opacities) on computed tomography (n=6). Chronic dyspnoea and cough which was often severe, without the characteristic features of asthma, were the main clinical manifestations. Atopy and asthma were present in the history of three and two patients, respectively. One patient met biological criteria of the lymphoid variant of idiopathic hypereosinophilic syndrome. Mean blood eosinophil cell count was 2.7 G·L(-1) and mean eosinophil differential percentage at bronchoalveolar lavage was 63%. Mean initial forced expiratory volume in 1 s/forced vital capacity ratio was 50%, normalising with oral corticosteroid therapy in all patients. HOB manifestations recurred when oral prednisone was decreased to 10-20 mg·day(-1), but higher doses controlled the disease. HOB is a characteristic entity deserving to be individualised among the eosinophilic respiratory disorders. Thorough analysis is needed to determine whether unrecognised and/or smouldering HOB may further be a cause of irreversible airflow obstruction in chronic eosinophilic respiratory diseases.

[Lung transplantation and rejection. Basic principles, clinical aspects and histomorphology]. / Lungentransplantation und Abstoßung. Grundlagen, klinische Aspekte und Histomorphologie.

Lung transplantation is the ultimate therapeutical approach for the treatment of both children and adults with terminal congenital or acquired lung disease. In contrast to survival rates during the first year following transplantation, the long-term survival for patients after lung transplantation has not significantly improved in the past. In addition to other complications, acute cellular rejection constitutes a major cause for diminished function of pulmonary grafts, and can, among other factors, be causative for chronic rejection (bronchiolitis obliterans syndrome, BOS). In 2006, the International Society for Heart and Lung Transplantation (ISHLT) provided a revised version of the grading system for acute and chronic rejection of pulmonary grafts.

Development of an automatic classification system for differentiation of obstructive lung disease using HRCT.

The motivation is to introduce new shape features and optimize the classifier to improve performance of differentiating obstructive lung diseases, based on high-resolution computerized tomography (HRCT) images. Two hundred sixty-five HRCT images from 82 subjects were selected. On each image, two experienced radiologists selected regions of interest (ROIs) representing area of severe centrilobular emphysema, mild centrilobular emphysema, bronchiolitis obliterans, or normal lung. Besides 13 textural features, additional 11 shape features were employed to evaluate the contribution of shape features. To optimize the system, various ROI size (16 x 16, 32 x 32, and 64 x 64 pixels) and other classifier parameters were tested. For automated classification, the Bayesian classifier and support vector machine (SVM) were implemented. To assess cross-validation of the system, a five-folding method was used. In the comparison of methods employing only the textural features, adding shape features yielded the significant improvement of overall sensitivity (7.3%, 6.1%, and 4.1% in the Bayesian and 9.1%, 7.5%, and 6.4% in the SVM, in the ROI size 16 x 16, 32 x 32, 64 x 64 pixels, respectively; t test, P < 0.01). After feature selection, most of cluster shape features were survived ,and the feature selected set shows better performance of the overall sensitivity (93.5 +/- 1.0% in the SVM in the ROI size 64 x 64 pixels; t test, P < 0.01). Adding shape features to conventional texture features is much useful to improve classification performance of obstructive lung diseases in both Bayesian and SVM classifiers. In addition, the shape features contribute more to overall sensitivity in smaller ROI.

Bronchiolitis obliterans syndrome: utility of the new guidelines in single lung transplant recipients.

BACKGROUND: Bronchiolitis obliterans syndrome is defined by a >20% decrease from baseline in the forced expiratory volume in 1 second (FEV(1)). Recently, a consensus panel under the auspices of the International Society for Heart and Lung Transplantation proposed a new stage, designated "potential BOS" or BOS 0-p. This study sought to validate retrospectively this new stage in a cohort of single-lung transplant recipients. METHODS: A retrospective analysis of serial pulmonary function tests in 43 single-lung transplant recipients was performed. Baseline FEV(1) and midflow rate (FEF(25-75%)) were determined and compared with the most recent set of pulmonary function tests in clinically stable patients. RESULTS: The sensitivity of the FEF(25-75%) at

Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation.

OBJECTIVES: Bronchiolitis obliterans is the greatest limitation to the long-term applicability of lung transplantation. Although alloimmune events are important, nonimmune events, such as gastroesophageal reflux, might contribute to lung injury and the development of bronchiolitis obliterans syndrome. METHODS: We retrospectively studied the 396 patients who underwent lung transplantation at the Duke Lung Transplant Program from April 1992 to April 2002. Reflux was assessed for using an ambulatory 24-hour esophageal pH probe. RESULTS: Reflux assessment with an esophageal pH probe was obtained in 128 patients after lung transplantation. Abnormal pH study results were present in 93 (73%) patients. Forty-three patients underwent a surgical fundoplication. There was no in-hospital or 30-day mortality in the patients undergoing fundoplication. At the time of fundoplication, 26 patients met the criteria for bronchiolitis obliterans syndrome. After fundoplication, 16 patients had improved bronchiolitis obliterans syndrome scores, with 13 of these patients no longer meeting the criteria for bronchiolitis obliterans syndrome. In patients at least 6 months after lung transplantation and 6 months after fundoplication, the forced expiratory volume in 1 second improved by an average of 24% (mean forced expiratory volume in 1 second before fundoplication, 1.87 L; mean forced expiratory volume in 1 second after fundoplication, 2.19 L/sec; P <.0002). Overall actuarial survival was significantly better in patients who had either normal pH studies or who had fundoplication. CONCLUSIONS: Gastroesophageal reflux disease is very common after lung transplantation and appears to contribute to mortality and development of bronchiolitis obliterans syndrome. Fundoplication in lung transplant recipients with gastroesophageal reflux disease is associated with significant improvements in lung function, particularly if performed before the late stages of bronchiolitis obliterans syndrome.

Bronchiolitis obliterans.

Bronchiolitis obliterans (BO) is a disease of small airways that results in progressive dyspnea and airflow limitation. It is a common sequela of bone marrow, lung, and heart-lung transplantation, but can also occur as a complication of certain pulmonary infections, adverse drug reaction, toxic inhalation, and autoimmune disorders. Non-transplant-related BO is rare and can mimic asthma and chronic obstructive pulmonary disease (COPD). In transplant-related BO, the diagnosis can be suggested by obstructive changes in serial pulmonary function testings, while open lung biopsy is usually required in non-transplant cases. High-resolution computerized tomography (HRCT) is also a helpful tool to diagnose and assess the severity of BO. The treatment of BO, regarding of the cause, is usually disappointing. Systemic corticosteroid immunosuppression and retransplantation have been described with variable success.

[Bronchiolitis: conceptual review]. / Bronquiolitis: revisión conceptual.

Bronchiolitis is a term which brings together several processes which may confuse anyone who is not familiar with the subject. We will review these processes by focusing on the most common types.

Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group.

In 1990, an international grading scheme for the grading of pulmonary allograft rejection was instituted. The use of this classification has resulted in a uniformity of grading which has allowed inter-institutional collaborations and communication unique in allograft monitoring. In 1995 an expanded group of international pathologists convened and revised the original proposal. This article summarizes the updated classification for pulmonary allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates. Each grade of acute rejection should mention the presence of coexistent airway inflammation, the intensity of which may also be graded. Chronic rejection is divided into bronchiolitis obliterans--active or inactive--and vascular atherosclerosis--accelerated arterial or venous sclerosis.

Bronchiolitis with airflow obstruction.

Bronchiolar lesions are becoming increasingly recognized as an important cause of airflow obstruction. For this reason, it is helpful to have an update of the current clinical, radiographic, and immunologic perspective. Among the bronchiolar airflow disorders, diffuse panbronchiolitis is related to HLA antigen Bw54, and low-dose, long-term erythromycin appears to be effective therapy. Bronchiolitis obliterans can be classified histologically as constrictive bronchiolitis and as proliferative bronchiolitis obliterans. Idiopathic, postfume, postinfectious, and connective tissue disease bronchiolitis obliterans continue to be rare and often have a poor prognosis. Bronchiolitis obliterans associated with lung transplantation is undergoing intensive investigation with regard to pathogenesis, immunologic study, early detection, and treatment. The lesion appears to be a form of chronic organ rejection. The recognition of the distinctive differences among the bronchiolar airflow disorders by clinicians and clinical investigators is essential for improved patient care, for a greater understanding of the pathogenesis of the disorder, and for development of new therapeutic advances.

[Bronchiolitis obliterans in adults]. / Bronchiolite oblitérante de l'adulte.

Bronchiols are defined as small upper airways with a diameter less than 2 mm. Two zones are described, membranous bronchioli with a continuous wall and respiratory bronchioli with a discontinuous wall. On the basis of pathology examinations, three disease processes can be recognized. In the first category, the initial inflammatory reaction in chronic obstructive bronchitis may spread to the bronchioli as can immune or infectious diseases resulting in bronchiolitis obliterans. Lesions originating conjointly in the bronchioli and alveoles form a second group including bronchiolitis obliterans organizing pneumoniae, the BOOP syndrome recently described. Histologically these disease entities show characteristic desquamation of the alveolar endothelium and a fibrinoid exudate. Hypoxaemia due to respiratory failure develops progressively and usually responds to corticosteroid therapy. In a third group, the disease is limited to the bronchioli alone with no large airway involvement. Chronic obstructive disease of the small airways has been described in smokers and people exposed to mineral dust. The clinical course often runs to classical chronic obstructive bronchopneumonia. Bronchiolitis obliterans itself, or constrictive bronchiolitis, is differentiated from BOOP due to the proliferative aspect within the lumen. No aetiological agent has been identified. The term bronchiolitis obliterans covers a wide range of more or less well identified entities which unfortunately have the common feature of generally poor response to treatment.

Proliferative and constrictive bronchiolitis: classification and radiologic features.

The small airways of the lung consist of the terminal bronchioles, respiratory bronchioles, and alveolar ducts. A recently introduced pathologic classification system divides bronchiolitis into proliferative and constrictive types. The histologic classification of small-airways disease into proliferative and constrictive bronchiolitis frequently correlates with the radiographic appearances. Proliferative bronchiolitis is characterized by air-space opacification, whereas constrictive bronchiolitis tends to be associated with lobular areas of decreased attenuation and airway dilatation. The purpose of this essay is to illustrate the radiographic and CT features of these two varieties of bronchiolitis.