Bronchial hyperreactivity after lung transplantation predicts early bronchiolitis obliterans

Nonspecific bronchial hyperreactivity (NSBHR) has been observed in patients who have undergone lung transplantation, but studies have provided conflicting reports as to the incidence and significance of this finding. To delineate more clearly the natural history of NSBHR after lung transplantation, data from 111 consecutive patients undergoing double lung transplantation between February 1988 and May 1994 were reviewed. Methacholine challenge testing was requested in conjunction with regular postoperative follow-up. Among 60 patients tested at 3 mo, 18 (30%) had a positive methacholine challenge; at 6 mo, the incidence was 14 of 59 (24%). Of 21 patients for whom complete testing was performed for 12 mo or longer, 13 (62%) had exclusively negative challenges. Patients with a positive challenge at 3 mo were significantly more likely to develop bronchiolitis obliterans syndrome (BOS) (p < 0.006). Mean time to development of BOS was 16.9 mo in the group with positive challenges versus 43.9 mo for those with negative challenges. We conclude that increased NSBHR is a common, but by no means universal, finding after lung transplantation. Furthermore, early positive methacholine challenges are associated with development of BOS. We hypothesize that NSBHR may represent an early marker of chronic rejection in these patients.     

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.     

Persistent increases of BAL neutrophils as a predictor of mortality following lung transplant

STUDY OBJECTIVES: To evaluate whether findings from surveillance bronchoscopy predict survival following lung transplantation. DESIGN: Retrospective review and analysis of 498 bronchoscopies with transbronchial biopsy (TBB) and BAL performed in 34 patients after lung transplantation. SETTING: University-based, tertiary referral medical center. PATIENTS: Thirty-four patients after lung transplantation. The mean age at transplantation was 49+/-9 years; 20 (59%) were female. Twenty-four (71%) underwent single and 10 (29%) underwent bilateral lung transplantation. The most common pretransplantation diagnostic groups were emphysema/COPD without concomitant alpha1-antiprotease deficiency (n = 13) and other obstructive disease processes (n = 10). INTERVENTIONS: Over follow-up, subjects underwent multiple bronchoscopies with TBB and BAL. The median number per subject was 15 (25 to 75% range 13 to 17). MEASUREMENTS AND RESULTS: We calculated the overall median BAL WBCs and median percent neutrophils (polymorphonuclear leukocytes [PMNs]) among all of the BALs performed for each subject. We then calculated the mean +/- SD of those median values. We used Cox proportionate hazards to assess mortality risk. The median overall follow-up observation period for the cohort was 560 days. There were 11 deaths during this period. Twenty-four subjects (71%) had acute rejection (AR) grades 2 to 4 (mild to severe), and nine (27%) had obliterative bronchiolitis (OB) diagnosed by TBB at any point. The mean value for BAL WBCs was 366+/-145 x 10(3) per milliliter; for percentage PMNs, the mean was 7+/-10%. Adjusting for age, gender, single vs bilateral lung transplantation, pretransplantation diagnostic group, presence of AR, presence of OB, BAL WBC concentration, and lymphocyte CD4/CD8 ratio, PMN percent was a significant predictor of mortality (p = 0.02). CONCLUSIONS: Ongoing inflammation manifested by an increased percentage PMNs over repeated bronchoscopies predicts mortality following lung transplantation. Biopsy data alone may be insufficient to identify posttransplantation patients at risk of poor outcome.     

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.     

Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients

RATIONALE: Bronchiolitis obliterans syndrome (BOS), defined by loss of lung function, develops in the majority of lung transplant recipients. However, there is a paucity of information on the subsequent course of lung function in these patients. OBJECTIVES: To characterize the course of FEV(1) over time after development of BOS and to determine the predictors that influence the rate of functional decline of FEV(1). METHODS: FEV(1)% predicted (FEV(1)%pred) trajectories were studied in 111 lung transplant recipients with BOS by multivariate, linear, mixed-effects statistical models. MEASUREMENTS AND MAIN RESULTS: FEV(1)%pred varied over time after BOS onset, with the steepest decline typically seen in the first 6 months (12% decline; p < 0.0001). Bilateral lung transplant recipients had significantly higher FEV(1)%pred at BOS diagnosis (71 vs. 47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%; p = 0.0001). Female gender and pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV(1)%pred in the first 6 months after BOS diagnosis (p = 0.02 and 0.04, respectively). A fall in FEV(1) greater than 20% in the 6 months preceding BOS (termed "rapid onset") was associated with shorter time to BOS onset (p = 0.01), lower FEV(1)%pred at BOS onset (p < 0.0001), steeper decline in the first 6 months (p = 0.03), and lower FEV(1)%pred at 2 years after onset (p = 0.0002). CONCLUSIONS: Rapid onset of BOS, female gender, pretransplant diagnosis of idiopathic pulmonary fibrosis, and single-lung transplantation are associated with worse pulmonary function after BOS onset.     

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.     

Rapid acute onset of bronchiolitis obliterans syndrome in a lung transplant recipient after respiratory syncytial virus infection

Bronchiolitis obliterans syndrome (BOS) can have either an acute or chronic onset with an abrupt or insidious course. The diagnosis is typically achieved by physiological criteria with development of a sustained decline in expiratory flow rates for at least 3 weeks. We review the rapid development of acute BOS and bronchiectasis after respiratory syncytial virus infection in a lung transplant recipient, who had been doing well with normal pulmonary function for 3 years after lung transplantation.     

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.     

Increased macrophage inflammatory protein-1alpha and -1beta in BAL fluid of bronchiolitis obliterans organizing pneumonia

OBJECTIVE: CC chemokines are mainly chemotactic for monocytes and lymphocytes. The aim of this study was to evaluate the involvement of the CC chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in the pathogenesis of bronchiolitis obliterans organizing pneumonia (BOOP). METHODOLOGY: The concentrations of MIP-1alpha and MIP-1beta in BAL fluid (BALF) obtained from patients with BOOP (n = 13) and control patients (CP, n= 18) were measured by enzyme-linked immunosorbent assay. RESULTS: MIP-1alpha in BALF was significantly higher in patients with BOOP (mean +/- SD; 123.8 +/- 98.0 pg/mL) than in CP (62.5 +/- 46.1 pg/mL). Significantly higher MIP-1beta was also detected in patients with BOOP (51.6 +/- 72.5 pg/mL) than in CP (6.4 +/- 3.7 pg/mL). The concentration of MIP-1alpha significantly correlated with the percentage of lymphocytes in BALF, and the concentration of MIP-1beta significantly correlated with the numbers of lymphocytes, neutrophils and eosinophils in BALF. Both MIP-1alpha and MIP-1beta in BALF were decreased after corticosteroid therapy and this was accompanied by decreased lymphocytes in BALF. CONCLUSION: This study suggests that MIP-1alpha and MIP-1beta may play important roles in the recruitment of immuno-inflammatory cells into the lungs, and may contribute to the pathogenesis of BOOP.     

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.     

Farmer's lung cases of a farmer and his son with high BAL fluid beta-D glucan levels]

A farmer and his son, who treated straw in a cowshed, were admitted to our hospital because of severe dyspnea during summer time. Their chest X-ray films revealed bilateral reticulonodular shadows in the middle to lower lung fields. Bronchoalveolar lavage (BAL) fluid analyses showed a high proportion of lymphocytes and an increased CD4/8 ratio. They were diagnosed with farmer's lung and treated with pulse therapy with methylprednisolone and tapering of steroid. Hypoxemia and interstitial shadow improved, though the farmer relapsed one day after getting home. Immune precipitation showed positive reactions against Aspergillus fumigatus, Aspergillus terreus and Nocardiopsis alba. Their beta D-glucan levels in BAL fluid were higher than those of healthy normal volunteers, whereas their beta D-glucan levels in serum were below the detection levels. Ventilation of the cowshed and wearing a mask should prevent recurrence of the disease.     

Soluble form of fas and fas ligand in BAL fluid from patients with pulmonary fibrosis and bronchiolitis obliterans organizing pneumonia

STUDY OBJECTIVES: The Fas-Fas ligand (FasL) pathway is a representative system of apoptosis-signaling receptor molecules. We previously described that this pathway may play an important role in the pathogenesis of fibrosing lung diseases. In this study, we hypothesized that soluble form of Fas (sFas) and FasL (sFasL) may also be associated with this disorder. MEASUREMENTS AND RESULTS: We measured sFas and sFasL levels in BAL fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), interstitial pneumonia associated with collagen vascular diseases (CVD-IP), and bronchiolitis obliterans organizing pneumonia (BOOP), using enzyme-linked immunosorbent assay. BALF from all patients was obtained before prednisolone therapy. sFasL levels were relatively increased in IPF patients (p = 0.084), and significantly increased in CVD-IP patients (p < 0.05) and BOOP patients (p < 0.05), compared with control subjects. BALF sFasL levels were elevated in the IPF or CVD-IP subgroups with an indication for prednisolone therapy, compared with those without an indication for therapy. The BALF sFasL level in IPF patients was correlated with the number of total cells and lymphocytes. The BALF sFasL level in BOOP patients was relatively or significantly correlated with the number of total cells or lymphocytes, respectively. The BALF sFas level was significantly increased in BOOP patients, but not in IPF or CVD-IP patients. CONCLUSIONS: We conclude that BALF sFasL levels may be associated with the accumulation of inflammatory cells and reflect the degree of lymphocyte alveolitis in IPF. The elevation of sFasL may be associated with the deterioration of IPF and CVD-IP. The elevation of the BALF sFas level may abrogate the cytotoxicity of FasL in BOOP patients, which may be associated with better prognosis of BOOP, compared with IPF or CVD-IP.     

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.     

Quantification of cytomegalovirus DNA in BAL fluid: a longitudinal study in lung transplant recipients

STUDY OBJECTIVES: Cytomegalovirus (CMV) infection is common in patients receiving solid organ transplants, and it is associated with increased morbidity as well as risk for development of chronic rejection. A rapid and sensitive diagnostic method would improve the therapeutic management of CMV infection, including the monitoring of treatment effects. We investigated whether longitudinal determinations of CMV DNA quantities in BAL fluid could be useful for this purpose. DESIGN: CMV DNA levels in 340 BAL samples from 35 consecutive lung transplant recipients were studied during a median of 18 months. Seventeen (49%) of the patients developed CMV disease with pneumonitis. Twenty-seven CMV disease episodes were diagnosed. RESULTS: Patients with CMV disease had a significantly higher mean level of CMV copies per milliliter BAL fluid (1,120 +/- 4,379) compared with those without (180 +/- 1,177, p < 0.01). Viral load as well as acute rejection requiring treatment (>/= A2) were independent risk factors associated with CMV disease. Differences between the groups concerning HLA-DR matching, basic immunosuppressive therapy, and CMV serologic status D/R -/+ vs D/R +/+ were not significant. A diagnostic definition of normality based on the mean level of all episodes without CMV disease +2 SD would discriminate only 9 of the 27 CMV episodes. CONCLUSIONS: Although the viral load is increased during episodes of clinical CMV disease in lung transplant recipients, the quantitative PCR assessment of CMV DNA in BAL fluid is not discriminative enough to be useful as a diagnostic tool for CMV disease.     

Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND: Obliterative bronchiolitis (OB) is the most important cause of long-term morbidity and mortality in lung transplant recipients, and probably results from alloimmune airway injury. Bronchiolitis obliterans syndrome (BOS), defined as a staged decline in pulmonary function, is the clinical correlate of OB. OBJECTIVE: Evaluation of the risk and severity of BOS on the basis of the incompatibility of donor and recipient human leukocyte antigen (HLA) molecules. DESIGN: Retrospective cohort study. SETTING: Large university hospital. PARTICIPANTS: Lung transplant recipients between January 1990 and January 2000. MEASUREMENTS: We determined the BOS stage using internationally promulgated guidelines with a minor modification on all recipients at their 4-year transplant anniversary. Recipients whose graft function had deteriorated or who died due to causes other than BOS were excluded from the study. HLA loci mismatches and other covariables, including recipient age, donor age, cytomegalovirus (CMV) mismatch, cold ischemic time, use of cardiopulmonary bypass, ventilatory days, episodes of acute rejection and CMV pneumonitis, mean trough cyclosporin A (CsA) level, episodes of subtherapeutic CsA levels, and histopathology of OB and diffuse alveolar damage were entered into the analysis of BOS predictors. RESULTS: Sixty-four patients met the inclusion and exclusion criteria of the study at the 4-year posttransplant time point. In univariate analyses, the number of combined HLA-A and HLA-B mismatches was strongly associated with the stage of BOS at 4 years (p = 0.002). This association remained significant after the inclusion of other potential risk factors for BOS in multiple linear regression models. Pretransplant and posttransplant proportional odds models confirmed that the increasing number of combined HLA-A and HLA-B mismatches increased the overall severity of BOS (adjusted odds ratio, 1.84 [p = 0.035] vs 1.69 [p = 0.067], respectively). A trend toward significance was seen with HLA-DR mismatching (p = 0.17). CONCLUSIONS: The degree of HLA class I mismatching between donors and recipients predisposes lung transplant recipients to the development and severity of BOS.     

Dynamic high-resolution electron-beam CT scanning for the diagnosis of bronchiolitis obliterans syndrome after lung transplantation

PURPOSES: To determine the diagnostic capabilities of dynamic high-resolution electron-beam (HREB) CT scanning for diagnosing bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. MATERIALS AND METHODS: At the time of follow-up examinations after lung transplantation, 52 patients were examined by dynamic HREB CT scan. Visual signs of small airway disease were assessed and compared with lung function. For numerical analysis, the mean lung attenuation and its SD were determined and compared with the course of lung function tests. RESULTS: On visual analysis, significant parenchymal attenuation inhomogeneities were present in eight of nine patients with manifest BOS, and in two of four patients who developed BOS during follow-up. Thirteen of 20 patients with persistent normal lung function displayed homogeneous lung attenuation. On numerical analysis, mean lung attenuation was significantly lower in patients who developed BOS during follow-up than in patients with persistent normal lung function (both in expiration and inspiration, p < 0.0001). With an optimal threshold, the sensitivity was 100% (4 of 4 patients) and the specificity was 90% (19 of 20 patients). In patients with BOS at the time of the CT scan examination, parenchymal attenuation was less homogeneous than in patients with persistent normal lung function (p < 0.0001). With an optimal threshold, the sensitivity was 78% (7 of 9 patients) and the specificity was 85% (17 of 20 patients). CONCLUSIONS: Dynamic HREB CT of lung transplant recipients correlates well with lung function criteria of BOS at the time of the CT examination and with the subsequent progression to BOS.     

Utility of high resolution computed tomography in predicting bronchiolitis obliterans syndrome following lung transplantation: preliminary findings

This study was undertaken to evaluate the efficacy of high resolution computed tomography (HRCT) in predicting the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. Fifty lung transplant patients who were clinically stable and without evidence of BOS were evaluated for the presence of four HRCT features reported to be associated with bronchiolitis obliterans: mosaic attenuation on inspiratory CT (mosaic perfusion), mosaic attenuation on expiratory CT (air trapping), bronchiectasis, and tree-in-bud opacities. CT exams were part of an annual surveillance process with the hope of predicting subsequent development of BOS. Diagnosis of BOS was made in 9 of 50 patients as indicated by a fall in FEV1 of greater than 20% of a stable baseline. None of the radiographic features associated with clinically established BOS were both sensitive and specific in the prediction of BOS. Air trapping demonstrated moderate sensitivity (56%, 5/9) and moderate specificity (76%, 35/46) for prediction of BOS in the year following the CT exam. Bronchiectasis, the most reliable indicator of the presence of BOS was a poor predictor of subsequent BOS with an 11% (1/9) sensitivity but had high specificity (96%, 44/46). No high resolution CT features accurately predicted the development of BOS.