Exhaled nitric oxide after lung transplantation: impact of the native lung.

It has already been demonstrated that exhaled nitric oxide (eNO) is increased in lung transplant patients with chronic rejection, although it is not known whether the diseased native lung after single lung transplantation (SLTx) contributes to the increased eNO values. This study aimed to compare the eNO values in stable lung transplant patients (SLTx versus sequential (S)SLTx and heart (H)LTx) and in patients with established chronic rejection. Altogether, 42 LTx patients (25 females, 13 SLTx, 18 SSLTx, 11 HLTx), with a mean follow-up of 1149 days and a mean age of 44.6 yrs at transplantation, were included. Twenty-six patients had no signs of chronic rejection (five SLTx and 21 SSLTx/HLTx). There was no difference in their eNO values (10.2 in SLTx versus 12.2 (parts per billion) ppb in SSLTx/HLTx). Sixteen patients (eight SLTx and eight SSLTx/HLTx) had a chronic rejection (eight bronchiolitis obliterans syndrome (BOS) potential stage, four BOS stage 1, three BOS stage 2 and one BOS stage 3). Their eNOs were 18.1 (SLTx) and 17.0 (SSLTx/HLTx) ppb, respectively, which were significantly different to the stable LTx patients and showed a trend towards significance for SSLTx/HLTx. There was no significant difference in eNO between the patients with chronic rejection who underwent SLTx and those who underwent SSLTx/HLTx. The diseased native lung after single lung transplantation probably does not contribute much to the exhaled nitric oxide values, either in stable lung transplant patients or in lung transplant patients with chronic rejection.     

Chronic allograft rejection (obliterative bronchiolitis)

Lung and heart-lung transplantation are currently recognized as effective treatment for selected patients with end-stage lung or heart-lung disease. Although the survival rates have improved in recent years, long-term survival is still hampered by the development of chronic rejection. Histologically chronic rejection is manifested by obliterative bronchiolitis (OB), a process that leads to airways obstruction, with a gradual decline in pulmonary function tests. Extensive research efforts have attempted to unravel the pathophysiology of OB and identify key cytokines and growth factors involved in the process. Since the histological diagnosis of chronic rejection remains difficult, a clinical grading system has been proposed, determined as bronchiolitis obliterans syndrome (BOS), divided into four and, more recently, five categories, depending on the severity of airflow obstruction. This paper reviews the current knowledge of chronic rejection after heart-lung and lung transplantation.     

Evaluation of lung function during pulmonary rejection and infection in heart-lung transplant patients. Hannover Lung Transplant Group.

Pulmonary rejection and infection are the most important complications after lung transplantation. To evaluate the diagnostic value of pulmonary function testing for early detection and discrimination of these complications, seven heart-lung recipients were examined. The diagnosis of each complication was confirmed by clinical and laboratory findings including transbronchial biopsies and bronchoalveolar lavage. Eight episodes of rejection, ten episodes of viral infection and six episodes of bacterial pneumonia were analyzed. Pulmonary rejection was associated with a significant fall in the FEV1/IVC% and the FEF50%. In viral infection, the most impressive finding was a reduction in the DCO, whereas no obstructive or restrictive airway dynamics were observed. During bacterial pneumonia, pulmonary function measurement revealed a decrease in IVC without signs of obstructive airway dynamics. Adequate treatment resulted in reconstitution of pretreatment values. Assessment of lung function provides valuable information for the diagnosis of pulmonary complications following HLTx.     

New trends in combined transplantation of the heart and lungs

Heart-lung transplantation is a surgical alternative for patients with end-stage lung disease with associated right heart failure. While the procedure is very promising, the morbidity and mortality remain high. The current understanding of the proper selection of candidates, procurement and preservation of donor organs, operative procedure and postoperative care continues to evolve. At the University of Pittsburgh, 70 heart-lung transplantations have been performed since 1982. Early infection and chronic rejection are the major factors influencing survival. Early (less than 2 weeks) intrathoracic infection occurred in 43% of heart-lung transplant recipients, with pneumonia being the most frequent infection. The incidence of pneumonia in heart-lung transplant recipients is twice that in a comparable group of heart recipients. Subclinical pneumonitis in the donor lung, abnormal muco-ciliary clearance and altered allogenic response in the transplanted lung are significant factors associated with the increased incidence of early infections. Chronic rejection, manifested as bronchiolitis obliterans, has occurred in 54% of heart-lung transplantation recipients. Infection caused by cytomegalovirus, Epstein-Barr virus and Pneumocystis carinii have been shown to increase the incidence of bronchiolitis obliterans, as have episodes of acute rejection. Recent reports of a 61% 2-year survival rate represent a substantial improvement over earlier trials. With a better understanding of the pathogenesis of infection in the transplanted lung as well as improved immunosuppressive agents, further improvements in survival can be expected.     

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.     

Clostridium difficile colitis in lung transplantation

Purpose. Clostridium difficile colitis (CDC) is the most common nosocomial infection of the gastrointestinal tract in patients with recent antibiotic use or hospitalization. Lung transplant recipients receive aggressive antimicrobial therapy postoperatively for treatment and prophylaxis of respiratory infections. This report describes the epidemiology of CDC in lung recipients from a single center and explores possible associations with bronchiolitis obliterans syndrome (BOS), a surrogate marker of chronic rejection.
Methods. Patients were divided into those with confirmed disease (CDC+) and those without disease (CDC−) based on positive C. difficile toxin assay. Because of a bimodal distribution in the time to develop CDC, the early postoperative CDC+ group was analyzed separately from the late postoperative CDC+ cohort with respect to BOS development.
Results. Between 1990 and 2005, 202 consecutive patients underwent 208 lung transplantation procedures. Of these, 15 lung recipients developed 23 episodes of CDC with a median follow-up period of 2.7 years (range, 0–13.6). All patients with confirmed disease had at least 1 of the following 3 risk factors: recent antibiotic use, recent hospitalization, or augmentation of steroid dosage. Of the early CDC+ patients, 100% developed BOS, but only 52% of the late CDC+ patients developed BOS, either preceding or following infection.
Conclusion. CDC developed in 7.4% of lung transplant patients with identified risk factors, yielding a cumulative incidence of 14.7%. The statistical association of BOS development in early CDC+ patients suggests a relationship between early infections and future chronic lung rejection.     

Persistent high BAL fluid granulocyte activation marker levels as early indicators of bronchiolitis obliterans after lung transplant.

The major cause of mortality in the long-term in lung transplant recipients is chronic rejection. This is a fibroproliferative process in the small airways leading to obliterative bronchiolitis and progressive loss of lung function, both constituting the clinical entity bronchiolitis obliterans syndrome (BOS). Granulocyte activation has been implicated as one factor behind BOS. Granulocyte markers in bronchoalveolar lavage (BAL) fluid were prospectively and longitudinally studied in order to identify possible association with BOS. BAL fluid from 266 bronchoscopy procedures performed in twelve single lung, eight bilateral lung and five heart/lung transplant recipients were analysed. The majority (19 of 25) were studied for a period of 2 yrs after surgery. Myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin-8 (IL-8) levels were used as indirect markers of activation and attraction of granulocytes. Five patients developed BOS. Ninety-eight episodes of acute rejection, nine of bacterial infection, 19 of cytomegalovirus pneumonitis, nine of Pneumocystis carinii infection, two of aspergillus infection and two of respiratory syncytial virus infection were diagnosed. BOS patients had significantly higher mean levels of MPO, ECP and IL-8 compared to patients without BOS, irrespective of acute rejection status. Over time, the five patients with BOS had significantly elevated BAL fluid levels of MPO and ECP as well as neutrophil percentages, and in four patients this increase preceded the clinical diagnosis of BOS by several months. Elevated bronchoalveolar lavage fluid neutrophil percentage as well as levels of the granulocyte activation markers myeloperoxidase and eosinophil cationic protein appear to be early signs of development of BOS in lung transplant recipients.     

Analysis of risk factors for the development of bronchiolitis obliterans syndrome

Chronic rejection after lung transplantation, manifesting as bronchiolitis obliterans syndrome (BOS), has become the dominant challenge to long-term patient and graft survival. In order to elucidate risk factors for development of BOS we utilized the 1995 revision of the working formulation for the classification of lung allograft rejection (), and devised a quantitative method to retrospectively study lung transplant biopsies from all patients who survived at least 90 d. All transbronchial biopsies were regraded 0 to 4 for acute perivascular rejection and lymphocytic bronchitis/bronchiolitis (LBB), and the grades were totaled over a period of time to give two scores, respectively, for each patient. Also examined were timing of acute rejection and LBB episodes and decreased immunosuppression defined as two or more cyclosporine A levels < 200 ng/ml. Sixty-six patients with BOS and 68 with no BOS (NBOS) satisfied our criteria for inclusion in the study. Demographics including age, sex, and primary diagnoses were similar. The mean perivascular score for BOS was 6.2 over a mean follow-up of 822 d (range, 113 to 2,146) compared with 3.2 for NBOS over 550 d (range, 97 to 1,734) mean follow-up. Airway scores were 5.3 and 1.7, respectively, for the same follow-up periods. There was no correlation between length of follow-up and rejection or LBB scores, although mean length of follow-up for the two groups was significantly different. Late acute rejection and LBB were significantly associated with BOS as was decreased immunosuppression. In addition to perivascular rejection, LBB, late acute rejection, and decreased immunosuppression are significant risk factors for the development of BOS. Analysis of the current data leads us to believe that LBB, in the absence of infection, is in fact a manifestation of acute rejection, with similar implications for graft function as acute perivascular rejection.     

Relevance of GERD in Lung Transplant Patients

Lung transplantation has become a valuable treatment for end-stage pulmonary disorders in an attempt to improve quality of life and extend survival. Development of chronic rejection, also known as bronchiolitis obliterans syndrome (BOS), is responsible for the vast majority of deaths after lung transplantation. Up to 50% of lung transplant patients develop BOS within the first 5 years after transplantation. A high prevalence of gastroesophageal reflux and aspiration of gastric components has been described after lung transplantation. Reflux and aspiration have been implicated in the development of BOS and antireflux surgery has been proposed; however, the causal relationship with BOS and the impact of reflux in lung transplantation survival needs to be further elucidated.     

Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary retransplant recipients

RATIONALE: The main hindrance to long-term success of lung transplantation is bronchiolitis obliterans syndrome (BOS), generally thought to be a manifestation of chronic allograft rejection. BOS is associated histologically with epithelial injury, bronchocentric mononuclear inflammation, and fibrosis of small airways known as bronchiolitis obliterans (BO). Few studies have directly compared clinical, radiographic, and histologic findings of BOS and BO, particularly in the era of improved immunosuppression and infection prophylaxis. Patients undergoing pulmonary retransplantation for BOS provide a unique opportunity to investigate these relationships. METHODS: All patients who underwent pulmonary retransplantation for BOS from 1992 to 2004 at Duke University Medical Center were reviewed. Pathology findings in explanted lung allografts were compared with clinical, radiographic, and transbronchial biopsy data. RESULTS: Over the 12-year study period, 12 patients underwent pulmonary retransplantation for BOS. The median time to BOS was 517 days (intraquartile range, 396 to 819.8 days). BOS scores prior to retransplantation were 2 in 2 patients and 3 in 10 patients. We developed a semiquantitative scoring system for epithelial, inflammatory, and fibrotic changes in affected airways to permit better comparison between BO and BOS. Somewhat surprisingly, only 50% (6 of 12 patients) had severe fibrotic changes, although all had some degree of epithelial injury, fibrosis, or inflammation centered around the bronchi and bronchioles. Furthermore, pathology findings other than BO were present in most explanted allografts and included cholesterol clefts (n = 4), focal invasive aspergillosis (n = 1), interstitial fibrosis (n = 2), and chronic vascular rejection (n = 1). CONCLUSIONS: In this series of patients with advanced BOS undergoing retransplantation, at least some degree of BO was present in all explanted allografts. However, the degree of epithelial changes, fibrosis, and inflammation present among affected bronchi varied considerably. Furthermore, a wide range of pathologic processes of potential clinical significance were evident in half of the patients. We conclude that significant histologic heterogeneity exists among patients undergoing retransplantation for BOS, potentially contributing to the variability of patient responses to treatment.     

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.     

Bronchiolitis obliterans syndrome complicating lung or heart-lung transplantation

Lung transplantation is a therapeutic option for patients with end stage lung diseases, but long-term survival remains poor, primarily due to chronic allograft rejection. Bronchiolitis obliterans (BO), a fibrotic process resulting in progressive narrowing of bronchiolar lumens and airflow obstruction, is a manifestation of chronic allograft rejection. The term obliterative bronchiolitis ( OB) is synonymous. Once bronchiolitis obliterans syndrome (BOS) develops, progressive decline in pulmonary function is typical; most patients die of respiratory failure within 5 years of onset. The diagnosis of BOS is usually made by clinical, physiological, and radiographic parameters. The dominant risk factor for BOS is acute allograft rejection, but additional factors play contributory roles [e.g., infections; human leukocyte antigen (HLA) mismatching; and injury to the allograft or airways]. The pathogenesis of BOS is complex and involves myriad cell types (both immune and nonimmune) and release of diverse cytokines and chemokines. Unfortunately, current therapies for BOS are of unproven value. A greater understanding of the pathogenic mechanisms operative in BOS are critical to developing novel strategies to treat and prevent this devastating complication.     

Medium‐term outcome of fundoplication after lung transplantation

Gastroesophageal reflux disease (GERD) in lung transplant recipients has gained increasing attention as a factor in allograft failure. There are few data on the impact of fundoplication on survival or lung function, and less on its effect on symptoms or quality of life. Patients undergoing fundoplication following lung transplantation from 1999 to 2005 were included in the study. Patient satisfaction, changes in GERD symptoms, and the presence of known side effects were assessed. The effect on lung function, body mass index, and rate of progression to the bronchiolitis obliterans syndrome (BOS) were recorded. Twenty‐one patients (13 males), in whom reflux was confirmed on objective criteria, were included, with a mean age of 43 years (range 20–68). Time between transplantation and fundoplication was 768 days (range 145–1524). The indication for fundoplication was suspected microaspiration in 13 and symptoms of GERD in 8. There was one perioperative death, at day 17. There were three other late deaths. Fundoplication did not appear to affect progression to BOS stage 1, although it may have slowed progression to stage 2 and 3. Forced expiratory volume‐1% predicted was 72.9 (20.9), 6 months prior to fundoplication and 70.4 (26.8), six months post‐fundoplication, P= 0.33. Body mass index decreased significantly in the 6 months following fundoplication (23 kg/m² vs. 21 kg/m², P= 0.05). Patients were satisfied with the outcome of the fundoplication (mean satisfaction score 8.8 out of 10). Prevalence of GERD symptoms decreased significantly following surgery (11 of 14 vs. 4 of 17, P= 0.002). Fundoplication does not reverse any decline in lung function when performed at a late stage post‐lung transplantation in patients with objectively confirmed GERD. It may, however, slow progression to the more advanced stages of BOS. Reflux symptoms are well controlled and patients are highly satisfied. Whether performing fundoplication early post‐lung transplant in selected patients can prevent BOS and improve long‐term outcomes requires formal evaluation.     

Is it bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal?

Chronic rejection (obliterative bronchiolitis) is the single most important cause of chronic allograft dysfunction and late mortality after lung transplantation. As this condition is difficult to prove using biopsy specimens, a clinical term, bronchiolitis obliterans syndrome (BOS) has been in use for >10 yrs to describe the progressive decrease of pulmonary function. However, before diagnosing a patient as having BOS, based on a sustained and progressive decrease in forced expiratory volume in one second and/or forced mid-expiratory flow between 25-75% of forced vital capacity, different confounding factors have to be eliminated. Treatment of BOS mainly consists of an increase or a change in the immunosuppressive drug regimen, which may lead to more pronounced infectious complications. Recently, two new options have become available to treat patients with BOS, treatment of gastro-oesophageal reflux and azithromycin. In the present paper, the authors give an overview of the current data on these two modalities, which may lead to a restoration of the pulmonary function in some of the patients, illustrating once more the fact that bronchitis obliterans syndrome is not always a manifestation of chronic rejection.     

Iron accumulation in lung allografts is associated with acute rejection but not with adverse outcome

BACKGROUND: Iron content in lung allografts is increased after transplantation. It was hypothesized that this may lead to fibrosis and posttransplant bronchiolitis obliterans syndrome (BOS). METHODS: In a prospective study, we evaluated 399 BAL fluid (BALF) and transbronchial lung biopsy samples obtained concurrently from 72 consecutive lung transplant recipients. RESULTS: The hemosiderin scores (HSs) of the BALF samples increased steadily during the postoperative period (p < 0.001). Patients with at least one acute rejection episode (AR) grade > or = A2 event had higher mean HSs, the difference being significant after the second (p < 0.008) and the sixth postoperative months (p < 0.05). The HS correlated with the number of ARs (p < 0.004), and it significantly increased after the first AR (p < 0.04). Except for oral anticoagulation, no other risk factors for elevated iron content were found. There was no correlation between HS or number of ARs and the development of BOS or survival, respectively. CONCLUSIONS: Progressive iron accumulation in lung allografts seems to be caused mainly by an AR, possibly due to perivascular leakage of erythrocytes. Neither increased HS nor the frequency of ARs were risk factors for subsequent development of BOS. Early detection and treatment of ARs might uncouple their association with BOS.     

Cardiothoracic surgery after heart and heart-lung transplantation

OBJECTIVE: We sought to examine our management and the outcomes of cardiothoracic procedures after heart and heart lung transplantation. METHODS: We performed a retrospective review of cardiothoracic surgical procedures carried out between 1990 and 2004 in patients who had previously undergone heart or heart-lung transplantation at our institution. RESULTS: Twenty-one out of 340 patients (6.2 %) were identified. Cardiothoracic surgery was performed 44.4 +/- 33 months (range 1 - 115 months) after transplantation. Predominant types of surgery were coronary artery bypass grafting due to allograft vasculopathy (n = 5), aortic surgery due to acute dissection (n = 3), biventricular assist device implantation due to acute rejection (n = 1), tricuspid valve repair (n = 1), multiple cardiac surgical procedures including coronary artery bypass grafting, retransplantation, and tricuspid valve replacement (n = 2), explantation of a functionless heterotopic transplanted heart (n = 1). Lung surgery was performed in six patients due to pneumonia (n = 2), primary lung carcinoma (n = 3), lung torsion following heart-lung transplantation (n = 1). All patients underwent either lobectomy or segmental lung resection. Single lung retransplantation (n = 2) after prior heart-lung transplantation due to bronchiolitis obliterans was performed. In one patient a pneumonectomy (n = 1) due to severe chronic rejection of the contralateral lung was performed. Six subsequent deaths after cardiothoracic procedures were recorded after 1, 4, 78, 163, 205, and 730 days, respectively. Causes of death were advanced carcinoma (n = 1), multi-organ failure due to sepsis (n = 2), sudden heart death (n = 2), and advanced heart failure (n = 1). Fifteen out of 21 patients having undergone cardiothoracic procedures (71.4 %) survived the observation period of 56.6 +/- 34 months (range 1 - 114). CONCLUSIONS: Reasons for cardiothoracic procedures after prior heart or heart-lung transplantation were allograft vasculopathy, aortic dissections years after transplantation, chronic rejection, and either lung infections or malignancies. Surgical repair can be performed with an acceptable operative risk and good long-term survival rates.     

State of the Art of Combined Heart-Lung Transplantation for Advanced Cardiac and Pulmonary Dysfunction

Over the last several decades, significant advances and improvements in care of transplant patients have resulted in markedly improved outcomes. A number of options are available for patients with advanced cardiopulmonary dysfunction requiring transplantation. There is a debate about when isolated heart or isolated lung transplantation is no longer possible or advisable and combined heart-lung transplantation is justified. Organ availability and allocation severely limit the latter option to very few well-selected patients. We review practice patterns, trends, and outcomes after triple-organ heart-lung transplant (HLTx) worldwide, as well as our own experience with heart-lung transplant in the modern era.     

A single-season prospective study of respiratory viral infections in lung transplant recipients.

The frequency and complications of respiratory viral infections (RVI) were studied in 50 ambulatory lung transplant patients during a single winter season, using viral antigens, viral cultures and PCR of nasal washes or bronchoalveolar lavages. Patients' survival, episodes of acute rejection and occurrence of bronchiolitis obliterans (BO) or BO syndrome (BOS) were monitored for 1 yr after the study. Overall, 32 (64%) patients had 49 symptomatic episodes. Documented infections included eight due to respiratory syncytial virus (RSV), one due to parainfluenza virus (PIV) and 10 due to influenza (FLU). Four of the FLU infections were serological rises without symptoms. Overall, 17 (34%) patients had documented viral infection; four patients had lower respiratory involvement and two (one RSV, one PIV) were hospitalised for aerosolised ribavirin treatment. After 1 yr there were three (6%) deaths unrelated to RVI. BO or BOS had occurred in one (6%) out of 17 patients with and three (12%) out of 33 without RVI. Respiratory viruses infected one-third of ambulatory lung transplant recipients in a single season. In conclusion, respiratory viral infection was not associated with subsequent graft dysfunction. Larger prospective studies are required to better define the acute and long-term morbidity of these infections.     

Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome

INTRODUCTION: A recent pilot study noted clinical benefit of macrolide therapy in the management of six lung transplant recipients with bronchiolitis obliterans syndrome (BOS), a condition previously regarded as irreversible. OBJECTIVE: To examine the effect of low-dose macrolides on lung function in lung allograft recipients with established BOS and to assess whether this benefit is sustained. METHODS: We retrospectively evaluated the effect of azithromycin (250 mg alternate days) on clinical status and lung function in 20 allograft recipients with established BOS, confirmed by decline in FEV(1) or FEF(25-75); consistent high-resolution computed tomography findings; and exclusion of acute rejection, infection, or anastomatic complications. Azithromycin was introduced at mean 82 months after transplantation. BOS staging at initiation of treatment was BOS 3 (10), BOS 2 (2), BOS 1 (6), and BOS0-p (2). All patients were on maintenance immunosuppression comprising cell-cycle inhibitor, oral corticosteroids, and calcineurin inhibitor. RESULTS: There was a significant increase in FEV(1) of median 110 ml (range, -70 to 730 ml) between baseline and 3 months of azithromycin therapy (p = 0.002). This improvement was sustained beyond 3 months in the majority of patients, who had initially benefited from azithromycin (up to 11 months follow up). CONCLUSIONS: This case series confirms the benefit of azithromycin in not only halting, but reversing the declining lung function seen in patients with BOS. This benefit appears to be maintained over time. Low-dose macrolides offer a new and exciting therapeutic strategy for the treatment of progressive BOS, and further clinical and translational mechanistic studies are required.     

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.