Airway inflammation and lung function decline in childhood post-infectious bronchiolitis obliterans

Post-infectious bronchiolitis obliterans (PBO) is a rare form of chronic obstructive lung disease in children with few data on the pulmonary function outcome and underlying inflammatory process. The aim of this study was to determine the change in lung function over time and to investigate by bronchoalveolar lavage (BAL) the inflammatory characteristics of pulmonary involvement. Eleven Caucasian children with PBO were evaluated to estimate the average rate of change in lung function indices using a mixed model. The differential cytology and lymphocyte subsets of BAL fluid were analyzed. The median follow-up was 10.2 (IQR 3.2-12) years. The estimated forced expiratory volume in 1 sec (FEV1) had a baseline intercept of 57% predicted (62% predicted after bronchodilator) at 10 years of age which fell at a rate of 1.01% per year whereas the estimated forced expiratory flow 25-75 (FEF25-75) had a baseline intercept of 36% predicted (42% predicted after bronchodilator) at 10 years of age which fell at a rate of 1.04% per year. The estimated FEV1/FVC ratio had a baseline intercept of 70% (74% after bronchodilator) at 10 years of age which declined with an average slope of 1.02% per year (-1.10% per year after bronchodilator). Although the baseline and post-bronchodilator level of estimated FVC was abnormal (68% and 69% predicted, respectively) it did not change significantly with time. The median disease duration at BAL evaluation was 3.7 (IQR 0.7-8) years. The percentage differential cell counts were characterized by a significant increase in neutrophils (median 50%, IQR 1-66%), and a slight increase of lymphocytes (median 14%, IQR 7.5-15%). In conclusion, pulmonary function in childhood PBO is characterized by significant airway obstruction which deteriorates over time. The presence of an ongoing inflammatory process could explain the decline in lung function over time.     

Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation.

Bronchiolitis obliterans syndrome (BOS) is a severe complication after lung transplantation (LTX). In a retrospective cohort study 12 stable healthy recipients (non-BOS) and eight patients with BOS were enrolled after LTX and matrix metalloproteinases (MMP)-9, TIMP-1 and cell characteristics in bronchoalveolar lavage (BAL) samples (n = 145) were analysed. BALs from patients with BOS were further divided according to whether they were obtained before (pre-BOS) or after manifestation of BOS (BOS group). The MMP-9/TIMP-1 ratio was significantly increased in the BOS group compared with non-BOS or pre-BOS; furthermore, the ratio was negatively correlated with forced expiratory volume in one second. In zymography, the active form of MMP-9 was detected predominantly in the BOS group. In addition, zymography showed the banding pattern of neutrophil-derived MMP-9, indicating that polymorphonuclear neutrophils (PMNs) were the main source of MMP-9. According to that, MMP-9 was significantly correlated with the number of PMN. In immunocytochemistry, MMP-9 was also associated predominantly with PMN. This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 over time during manifestation of a fibroproliferative lung disease in patients. It demonstrates development of bronchiolitis obliterans syndrome after lung transplantation is associated with an imbalance of matrix metalloproteinases-9/tissue inhibitors of metalloproteinase-1 ratio.     

Bronchiolitis obliterans syndrome in lung transplant recipients: correlation of computed tomography findings with bronchiolitis obliterans syndrome stage

The purpose of this study was to correlate the extent of computed tomographic (CT) findings with the severity of respiratory dysfunction in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). Eighty-nine conventional and 61 thin-section CT scans performed in 44 transplant recipients (17 bilateral, 27 single) with BOS were reviewed for mosaic attenuation, degree of bronchial dilation, bronchial thickening, central and peripheral bronchiectasis, mucus plugging, and air trapping. Findings on conventional and thin-section CT scans were correlated with BOS stage for bilateral and single-lung transplant recipients. In bilateral-lung recipients, a significant correlation existed, although weak, between BOS stage and findings of degree of bronchial dilation (P < 0.01), bronchial wall thickening (P = 0.01), peripheral bronchiectasis (P = 0.01), and mosaic attenuation (P = 0.01) on conventional CT; and bronchial wall thickening (P = 0.01) and mosaic attenuation (P = 0.03) on thin-section CT. In single-lung recipients, BOS stage correlated only with the finding of central bronchiectasis (P = 0.02) on conventional CT scans. No correlation was found between the extent of air trapping and BOS stage in either single- or bilateral-lung transplant recipients. CT findings are relatively poor indices of airflow obstruction in lung transplant recipients with BOS, particularly in those with single-lung transplants for emphysema.     

The value of D-dimer in lung transplant recipients with bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) following lung transplantation is common and potentially devastating. Its exact cause is undefined, but multiple immune and nonimmune processes contribute to its pathogenesis. The diagnosis of BOS syndrome is based on clinical presentation of progressive decline in the lung functions together with appropriate pathological findings. Severe acute rejection and recurrent acute rejection have been shown to confer the greatest risk for obliterative bronchiolitis, signifying the central importance of alloimmunity in the disease process. BOS is associated with activation of the coagulation system, and is a major cause of lung allograft loss. The aim of the study was to determine if there is an association between D-dimer levels and functional exercise capacity in lung transplant recipients with BOS. This prospective group comparison study was conducted at a tertiary-care, university-affiliated medical center. The sample included 46 patients (29%) who underwent lung transplantation between January 1997 and May 2006 and had positive findings on screening for BOS. Blood samples were collected for measurement of plasma D-dimer levels by the rapid MiniQuant assay. Correlational analysis was used to determine the association of D-dimer levels with demographic clinical data, pulmonary function, and functional exercise capacity parameters, including the 6-min walk test and cardiopulmonary exercise testing. D-dimer levels were associated with FEV1 (r=-0.43, p=0.001), 6-min walk test (r=-0.53, p=0.04), and VO2/kg/min (r=-0.36, p=0.04). No correlations were noted between D-dimer levels and total lung capacity, diffusion capacity, and oxygen saturation. On multivariate logistic regression, only FEV1 was a significant predictor of BOS (OR 0.885, CI: 0.812-0.965). We conclude that in lung transplant recipients with BOS, D-dimer levels are highly associated with functional exercise capacity and may serve as a useful marker for noninvasive monitoring. Further coagulation assays are needed to complete our observations.     

Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome

RATIONALE: Primary graft dysfunction is a common complication after lung transplantation and a significant risk factor for short- and long-term mortality. OBJECTIVE: We examined the impact of primary graft dysfunction on bronchiolitis obliterans syndrome. METHODS: We performed a retrospective cohort study of 334 adult lung transplant recipients at our program and graded the severity of primary graft dysfunction according to the International Society for Heart and Lung Transplantation definition. We evaluated the impact of primary graft dysfunction on acute rejection, lymphocytic bronchitis, and bronchiolitis obliterans syndrome stage 1, using univariable and multivariable Cox proportional hazards models. MAIN RESULTS: Among the 334 recipients, 65 did not have primary graft dysfunction (grade 0), 130 had grade 1, 69 had grade 2, and 70 had grade 3. In the univariable analysis, all grades of primary graft dysfunction were associated with a significantly increased risk of bronchiolitis obliterans syndrome stage 1 (grade 1: relative risk [RR] = 1.73; grade 2: RR = 2.13; and grade 3: RR = 2.53, compared with grade 0). The multivariable model demonstrated that the increased risk of bronchiolitis obliterans syndrome associated with primary graft dysfunction was independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections. However, there was no association between primary graft dysfunction and acute rejection or lymphocytic bronchitis. CONCLUSIONS: Primary graft dysfunction is associated with an increased risk of bronchiolitis obliterans syndrome independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections, and this risk is directly related to the severity of primary graft dysfunction.     

Effect of maintenance azithromycin on established bronchiolitis obliterans syndrome in lung transplant patients

BACKGROUND:

Bronchiolitis obliterans syndrome (BOS), the main cause of late mortality following lung transplantation, is defined as an irreversible decline in forced expiratory volume in 1 s (FEV₁).Previous studies using azithromycin for BOS in lung transplant patients have demonstrated a potential reversibility of the decline in FEV₁.

OBJECTIVES:

To examine whether initiating azithromycin reverses decline in FEV₁ in lung transplant recipients with established BOS of at least three months.

METHODS:

Pulmonary function tests were performed every three months in seven lung transplant recipients with established BOS of at least three months. FEV₁ was recorded at six and three months before initiation, at time of initiation, and three, six, nine and 12 months postazithromycin initiation. The primary end point was change in FEV₁. During the study, no immunosuppressive medication changes or acute rejection episodes occurred.

RESULTS:

Mean time from transplant to azithromycin initiation was 64 months (range 17 to 117 months). Mean time from BOS diagnosis to azithromycin initiation was 22 months (range three to 67 months). Rate of FEV₁ decline from six months before azithromycin initiation, and rates of FEV₁ increase from initiation to three and 12 months post-treatment initiation, were not statistically significant (P=0.32, P=0.16 and P=0.18, respectively). Following a trend toward improvement in the first three months after treatment initiation, FEV₁ tended to stabilize.

DISCUSSION:

Although several studies address the possible benefit of maintenance azithromycin in lung transplant patients with BOS, the role of the drug remains unproven in these patients, and would best be addressed by a large randomized controlled trial.     

Staging of bronchiolitis obliterans syndrome using home spirometry.

OBJECTIVES: To compare the detection of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients by clinic pulmonary function laboratory measurement and home spirometry. DESIGN: The subjects served as their own control group. SETTING: A university-based thoracic transplant center. SUBJECTS: Forty-five lung transplant recipients (26 women and 19 men; average +/- SD age, 47.7+/-11.4 years old at the time of transplantation). Lung function declined to at least BOS stage 1 in 17 of the 45 subjects. MEASUREMENTS: All subjects were participants in a home monitoring program utilizing home spirometry measurements. Clinic spirometry and home spirometry measurements were collected concurrently. The determinations of BOS staging were based on home and clinic FEV1 values using retrospective analysis and development of the home-based BOS staging algorithm. RESULTS: BOS stage 1 was detected an average of 341 to 276 days earlier with home spirometry than with clinic pulmonary function testing in the 17 subjects who had a pulmonary decline to BOS stage 1, depending on the persistence of the decline (1 day or 3 days, respectively). The difference in BOS detection time was statistically significant for both persistence requirements (p < 0.001). CONCLUSIONS: Home spirometry detects pulmonary decline earlier than clinic spirometry; home spirometry can be a reliable and safe alternative to frequent pulmonary function testing in lung recipients.     

Post-transplant bronchiolitis obliterans.

Over the last decade, improvements in surgical techniques, lung preservation, immunosuppression, and management of ischaemia/reperfusion injury and infections have made intermediate-term survival after lung transplantation an achievable goal. However, chronic allograft dysfunction in the form of bronchiolitis obliterans remains a major hurdle that threatens both the quality of life and long-term survival of the recipients. It affects up to 50-60% of patients who survive 5 yrs after surgery, and it accounts for >30% of all deaths occurring after the third postoperative year. This article discusses the alloimmune-dependent and -independent risk factors for bronchiolitis obliterans, the current understanding of the pathogenesis of bronchiolitis obliterans based on results of animal and human studies, the clinical staging of the complication, strategies that may contribute to the prevention and/or early detection of bronchiolitis obliterans, and suggestions for future research.     

Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation.

Photopheresis has been successfully used to treat heart allograft rejection and has had some initial success in the treatment of bronchiolitis obliterans (BO) following lung transplantation. This report describes five patients treated with photopheresis after the failure of augmented immunosuppression for BO. Four patients had a temporary stabilization of their airflow obstruction, and minimal side effects of the procedure were noted, although there were consequences from additional augmented immunosuppression (principally sepsis). Photopheresis may provide a safe modality for the treatment of BO that is unresponsive to standard and augmented immunosuppression.     

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.