zithromax and Bronchiolitis-Obliterans

Bronchiolitis obliterans syndrome (BOS) is a devastating complication that occurs after transplantation. Although azithromycin is currently used for the treatment of BOS, the evidence is sparse and controversial. The aim of this meta-analysis is to evaluate the effects of azithromycin on forced expiratory volume in 1 second (FEV1) and patient's survival.. PubMed, Embase, Cochrane library, Web of Science databases, and the ClinicalTrials.gov registry were systematically searched from inception until December 2020 for relevant original research articles. Random-effects models were used to calculate pooled-effect estimates.. Searches identified 15 eligible studies involving 694 participants. For FEV1 (L), there was a significant increase after short-term (≤12 weeks; P = .00) and mid-term (12-24 weeks; P = .01) administration of azithromycin. For FEV1 (%) compared to baseline, there was a significant increase after short-term (≤12 weeks) administration of azithromycin (P = .02), while there were no statistically significant differences in the medium and long term. When pooled FEV1% was predicted, it exhibited a similar trend to FEV1 (%) compared to baseline. In addition, we discovered that azithromycin reduced the risk of death (hazard ratio = 0.26; 95% confidence interval = 0.17 to 0.40; P = .00) in patients with BOS post-lung transplantation.. Azithromycin therapy is both effective and safe for lung function improvement in patients with posttransplant BOS after the short- and medium-term administration. Additionally, it has been demonstrated a significant survival benefit among patients with BOS post-lung transplant. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed to confirm the effect of azithromycin on patients with posttransplant BOS.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Forced Expiratory Volume; Humans; Lung Transplantation; Prospective Studies; Syndrome

The first clinical indication of non-antibiotic benefits of macrolides was in the Far East, in adults with diffuse panbronchiolitis. This condition is characterised by chronic airway infection, often with Pseudomonas aeruginosa, airway inflammation, bronchiectasis and a high mortality. Low dose erythromycin, and subsequently other macrolides, led in many cases to complete remission of the condition, and abrogated the neutrophilic airway inflammation characteristic of the disease. This dramatic finding sparked a flurry of interest in the many hundreds of macrolides in nature, especially their anti-inflammatory and immunomodulatory effects. The biggest subsequent trials of azithromycin were in cystic fibrosis, which has obvious similarities to diffuse panbronchiolitis. There were unquestionable improvements in lung function and pulmonary exacerbations, but compared to diffuse panbronchiolitis, the results were disappointing. Case reports, case series and some randomised controlled trials followed in other conditions. Three trials of azithromycin in preschool wheeze gave contradictory results; a trial in pauci-inflammatory adult asthma, and a trial in non-cystic fibrosis bronchiectasis both showed a significant reduction in exacerbations, but none matched the dramatic results in diffuse panbronchiolitis. There is clearly a huge risk of antibacterial resistance if macrolides are used widely and uncritically in the community. In summary, Azithromycin is not the answer to anything in paediatric respiratory medicine; the paediatric respiratory community needs to refocus on the dramatic benefits of macrolides in diffuse panbronchiolitis, use modern - omics technologies to determine the endotypes of inflammatory diseases and discover in nature or synthesise designer macrolides to replicate the diffuse panbronchiolitis results. We must now find out how to do better!

Topics: Anti-Bacterial Agents; Asthma; Azithromycin; Bronchiectasis; Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis, Viral; Child; Child, Preschool; Ciliary Motility Disorders; Cystic Fibrosis; Disease Progression; Drug Resistance, Bacterial; Haemophilus Infections; Humans; Infant; Lung Diseases, Interstitial; Lung Transplantation; Macrolides; Respiratory Sounds; Stem Cell Transplantation

The purpose of this article is to review the high-resolution CT characteristics of individual obstructive and restrictive chronic lung allograft dysfunction (CLAD) phenotypes to aid in making accurate diagnoses and guiding treatment.. Long-term survival and function after lung transplant are considerably worse compared with after other organ transplants. CLAD is implicated as a major limiting factor for long-term graft viability. Historically thought to be a single entity, bronchiolitis obliterans syndrome, CLAD is actually a heterogeneous group of disorders with distinct subtypes.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Graft Rejection; Humans; Lung Transplantation; Phenotype; Postoperative Complications; Respiratory Function Tests; Risk Factors; Syndrome; Tomography, X-Ray Computed; Transplantation, Homologous

Constrictive Bronchiolitis (CB) has been reported in US Operation Iraqi Freedom/Enduring Freedom (OIF/OEF) deployers but not in those from prior US conflicts. A 62-year old presented with progressive dyspnea 13 years after deployment to the Persian Gulf in 1991-1992, where he was exposed to burning oil well fire emissions, dust storms, and other potential airborne hazards. In 2014, after a chest computed tomography (CT) scan demonstrated diffuse mosaic attenuation, he underwent surgical lung biopsy, which revealed CB. Deployers from both GWI and OIF/OEF share many exposures. As respiratory symptoms are a feature associated with Gulf War medically unexplained illness, there may be a role for renewed interest in evaluating GWI Veterans with unexplained respiratory symptoms for conditions such as CB, which may result from exposures relevant to deployers from both conflicts.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Azithromycin; Biopsy; Bronchiolitis Obliterans; Fires; Forced Expiratory Volume; Gulf War; Humans; Inhalation Exposure; Male; Middle Aged; Occupational Exposure; Oil and Gas Fields; Pulmonary Diffusing Capacity; Respiratory Therapy; Tomography, X-Ray Computed; Veterans; Vital Capacity

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Forced Expiratory Volume; Hematopoietic Stem Cell Transplantation; Humans; Treatment Outcome

Chronic lung allograft dysfunction (CLAD) was recently introduced as an overarching term mainly to classify patients with chronic rejection after lung transplantation, although other conditions may also qualify for CLAD. Initially, only the development of a persistent and obstructive pulmonary function defect, clinically identified as bronchiolitis obliterans syndrome (BOS), was considered as chronic rejection, if no other cause could be identified. It became clear in recent years that some patients do not qualify for this definition, although they developed a chronic and persistent decrease in FEV1 , without another identifiable cause. As the pulmonary function decline in these patients was rather restrictive, this was called restrictive allograft syndrome (RAS). In the present review, we will further elaborate on these two CLAD phenotypes, with specific attention to the diagnostic criteria, the role of pathology and imaging, the risk factors, outcome, and the possible treatment options.

Topics: Allografts; Azithromycin; Bronchiolitis Obliterans; Chronic Disease; Disease Progression; Forced Expiratory Volume; Fundoplication; Gastroesophageal Reflux; Graft Rejection; Humans; Lung Transplantation; Neutrophils; Phenotype; Postoperative Complications

Azithromycin has been shown to reverse or halt the decline of forced expiratory volume in one s (FEV1) in patients with bronchiolitis obliterans (BOS) syndrome following lung transplant. The overall effect of azithromycin on the absolute values of FEV1 has not been compared between reported studies. We studied the effects of azithromycin on lung function in patients with post-lung transplant BOS syndrome.. A meta-analysis was performed using studies identified following an extensive database search. To be included, studies were published in English or French and explicitly reported percentage change in FEV1 or hazard ratios.. A total of 10 studies were included in this review. One hundred and forty patients were evaluated after treatment with azithromycin for an average follow-up period of seven months. The mean percentage increase in FEV1 was 8.8 (CI 5.1-12.47) p < 0.001. The pooled hazard ratio was 0.25 (CI 0.06-0.56) p = 0.041 for a mean follow-up period of 2.9 yr.. This study demonstrated a significant improvement in lung function in patients with BOS syndrome following lung transplant after seven months of treatment. It remains uncertain whether this improvement stays after seven months. We also found that patients on azithromycin were less likely to die from BOS syndrome compared with patients who were not on azithromycin.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Humans; Lung Transplantation; Prognosis; Respiratory Function Tests; Syndrome

Chronic lung allograft dysfunction is a major challenge in long-term management of lung transplant recipients. Both alloimmune-dependent factors (rejection) and alloimmune-independent factors contribute to the development of chronic lung allograft dysfunction. Thus, use of the term "chronic rejection" tends to be intentionally avoided among specialists in the field, although "chronic rejection" is still an acceptable lay word understood by many patients. Several different phenotypes have been identified in chronic lung allograft dysfunction, including restrictive allograft syndrome, neutrophilic reversible allograft dysfunction, and fibrous bronchiolitis obliterans syndrome. Restrictive allograft syndrome is characterized by restrictive physiology and peripheral foci of inflammation and fibrosis, which contrasts the obstructive physiology and pathological foci in small airways in conventional bronchiolitis obliterans syndrome. Among patients with bronchiolitis obliterans syndrome, there is a subpopulation that responds relatively well to azithromycin. Because these patients show airway neutrophilia, this subtype of chronic lung allograft dysfunction was named neutrophilic reversible allograft dysfunction. Conversely, patients with bronchiolitis obliterans syndrome unresponsive to azithromycin show airway fibrosis with less inflammation (fibrous bronchiolitis obliterans syndrome). In general, restrictive allograft syndrome shows poorer survival than does bronchiolitis obliterans syndrome, and early-onset bronchiolitis obliterans syndrome (within 2 years) shows a worse prognosis than does late-onset bronchiolitis obliterans syndrome. Until preventive and therapeutic options are refined, chronic lung allograft dysfunction will remain a major life-limiting factor. It has significant psychological, physical, social, and economic impacts. Early introduction of palliative care is another important strategy to improve patients' quality of life.

Topics: Azithromycin; Bronchiolitis Obliterans; Chronic Disease; Humans; Lung; Lung Transplantation; Primary Graft Dysfunction; Syndrome; Terminology as Topic; Transplantation, Homologous

Chronic lung allograft rejection is the single most important cause of death in lung transplant recipients after the first postoperative year, resulting in a 5-year survival rate of approximately 50%, which is far behind that of other solid organ transplantations. Spirometry is routinely used as a clinical marker for assessing pulmonary allograft function and diagnosing chronic lung allograft rejection after lung transplantation (LTx). As such, a progressive obstructive decline in pulmonary allograft function (forced expiratory volume in 1 sec [FEV1]) in absence of all other causes (currently defined as bronchiolitis obliterans syndrome [BOS]) is considered to reflect the evolution of chronic lung allograft rejection. BOS has a 5-year prevalence of approximately 45% and is thought to be the final common endpoint of various alloimmunologic and nonalloimmunologic injuries to the pulmonary allograft, triggering different innate and adaptive immune responses. Most preventive and therapeutic strategies for this complex process have thus far been largely unsuccessful. However, the introduction of the neomacrolide antibiotic azithromycin (AZI) in the field of LTx as of 2003 made it clear that some patients with established BOS might in fact benefit from such therapy due to its various antiinflammatory and immunomodulatory properties, as summarized in this review. Particularly in patients with an increased bronchoalveolar lavage neutrophilia (i.e., 15%-20% or more), AZI treatment could result in an increase in FEV1 of at least 10%. More recently, it has become clear that prophylactic therapy with AZI actually may prevent BOS and improve FEV1 after LTx, most likely through its interactions with the innate immune system. However, one should always be aware of possible adverse effects related to AZI when implementing this drug as prophylactic or long-term treatment. Even so, AZI therapy after LTx can generally be considered as safe.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Chronic Disease; Graft Rejection; Humans; Immunologic Factors; Lung Transplantation; Transplantation, Homologous

Chronic allograft dysfunction, manifesting as bronchiolitis obliterans syndrome (BOS), is the major cause of morbidity and mortality in human lung transplant recipients. While alloimmunity has a definite role, there is increasing interest in overall allograft injury and subsequent inflammation and remodeling. This review deals with nonalloimmune factors that may potentiate alloimmune injury. We discuss infection and reflux/aspiration as examples of allograft injury, which may lead to chronic loss of graft function and BOS. Surgical and nonsurgical treatments aimed at preventing these insults and improving survival are considered. The need for further evidence, including randomized-controlled trials, to evaluate the role of medical and surgical therapies is emphasized by the current literature.

Topics: Azithromycin; Bronchiolitis Obliterans; Gastroesophageal Reflux; Gram-Negative Bacterial Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung Diseases; Lung Transplantation; Pneumonia; Pneumonia, Aspiration; Transplantation, Homologous

Lung transplantation has come of age and is now considered a valid treatment for selected patients with end-stage lung disease. In recent years, survival rates have much improved, although the development of chronic rejection, characterized by a progressive and irreversible decline in FEV(1), which is clinically defined as bronchiolitis obliterans syndrome (BOS) remains the major obstacle to long-term survival. Extensive research efforts with special emphasis on innate immunity have recently led to new insights with the identification of at least two different phenotypes: on the one hand there is an azithromycin-responsive phenotype (the so-called neutrophilic reversible allograft/airways dysfunction (NRAD), on the other hand there is an azithromycin-unresponsive phenotype (the fibroproliferative form of BOS or classical obliterative bronchiolitis). The present review intends to give the scientific evidence for these two subtypes, and to clarify the role of azithromycin in the treatment of BOS.

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; Female; Graft Rejection; Humans; Lung Transplantation; Neutrophils; Respiratory Mechanics; Risk Factors

Bronchiolitis obliterans syndrome (BOS) is the most important cause of late mortality following lung transplantation, resulting in major morbidity and a huge burden on healthcare resources. Treatment options are limited, resulting in a mere stabilisation of the lung function decline. Recent introduction of the macrolide antibiotic azithromycin raised new hope after demonstrating lung function improvement in subsets of patients. The present study aimed to provide an overview of the clinical effects on azithromycin in the setting of BOS after lung transplantation, with special emphasis on the anti-inflammatory actions. Moreover, the authors proposed a new frame of thinking centred on a dichotomy in the pathogenesis and clinical phenotype of BOS. Subsets of BOS patients were identified who do or do not respond to azithromycin (regarding forced expiratory volume in one second (FEV(1)), bronchoalveolar lavage (BAL) neutrophilia/interleukin-8). These observations have shed new light on the current belief that BOS represents a homogenous clinical entity in which the neutrophil is the main culprit. Recent clinical observations, supported by research findings, have revealed a dichotomy in the clinical spectrum of BOS with neutrophilic (partially) reversible allograft dysfunction (responding to azithromycin) and fibroproliferative BOS (not responding to azithromycin). This concept is reinforced by unique data obtained in BOS patients, consisting of histology specimens, physical and radiological examination, FEV(1 )and BAL examination. The acceptance of this dichotomy can improve understanding of the heterogeneous pathological condition that constitutes bronchiolitis obliterans syndrome, thus encouraging a more accurate diagnosis and, ultimately, better tailored treatment for each bronchiolitis obliterans syndrome patient.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Humans; Interleukin-8; Lung; Lung Transplantation; Macrolides; Research Design; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) is the leading cause of death in lung transplant recipients (LTR). BOS is thought to result from chronic immunologic/inflammatory insults leading to peri-bronchiolar leukocyte infiltration, with a subsequent exuberant tissue re-modelling and fibro-obliteration of the luminal space of the allograft airways. Diagnosis is based on functional criteria and severity is graded on the degree of Forced Expiratory Volume in 1 second (FEV1) impairment. Current strategies to improve pulmonary function once BOS is established have demonstrated little or no impact on disease progression and re-transplantation remains the only therapeutic option. Among the alternative treatments which have been attempted in the last few years, long-term azithromycin treatment seems to be the most promising therapeutic device for BOS treatment. Azithromycin is a macrolide antibiotic, endowed with a broad spectrum of anti-inflammatory/immunomodulatory activities. Long-term oral azithromycin therapy can significantly improve FEV1 in about 42% of patients with established BOS. Moreover, reduced neutrophilia, chemokine release and bacterial exacerbations have been demonstrated. These observations suggest that the drug can down-regulate pulmonary inflammation, even if the precise underlying mechanisms still need to be determined.

Topics: Azithromycin; Bronchiolitis Obliterans; Forced Expiratory Volume; Humans; Lung Transplantation; Syndrome

Bronchiolitis obliterans syndrome (BOS) is one of the main causes of mortality after lung and bone marrow transplantation. Up to 75% of lung transplantation patients develop BOS within 5 years, whereas after bone marrow transplantation 14% of the patients develop the disease with 65% mortality within 3 years. Patients demonstrate gradual decrease in pulmonary functions with no significant anatomic/imagine findings. Therapeutic trials with high dose systemic corticosteroids, immune suppression and immunomodulation did not show any significant success. However, macrolides and especially azithromycin have recently been reported as highly efficient for BOS. This review summarizes information on the disease focusing on the clinical experience with azithromycin as a treatment for BOS.

Topics: Anti-Bacterial Agents; Antitubercular Agents; Azithromycin; Bronchiolitis Obliterans; Humans; Tuberculin Test; Tuberculosis

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.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Chronic Disease; Gastroesophageal Reflux; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Respiratory Function Tests; Risk Factors; Syndrome

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Disease Models, Animal; Hematopoietic Stem Cell Transplantation; Humans; Lung; Mice; Risk Factors; Treatment Outcome

Azithromycin stabilises and improves lung function forced expiratory volume in one second (FEV. Eligible patients recruited for the initial randomised placebo-controlled trial received open-label azithromycin after 3 months and were followed up until 6 years after inclusion (n=45) to assess FEV. Long-term treatment with azithromycin slows down the progression of BOS, although the effect of TLI may affect the observed attenuation of FEV

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Survival Rate; Syndrome; Time Factors; Treatment Outcome

Bronchiolitis obliterans syndrome has been associated with increased morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Previous studies have suggested that azithromycin may reduce the incidence of post-lung transplant bronchiolitis obliterans syndrome.. To evaluate if the early administration of azithromycin can improve airflow decline-free survival after allogeneic HSCT.. The ALLOZITHRO parallel-group trial conducted in 19 French academic transplant centers and involving participants who were at least 16 years old, had undergone allogeneic HSCT for a hematological malignancy, and had available pretransplant pulmonary function test results. Enrollment was from February 2014 to August 2015 with follow-up through April 26, 2017.. Patients were randomly assigned to receive 3 times a week either 250 mg of azithromycin (n = 243) or placebo (n = 237) for 2 years, starting at the time of the conditioning regimen.. The primary efficacy end point was airflow decline-free survival at 2 years after randomization. Main secondary end points were overall survival and bronchiolitis obliterans syndrome at 2 years.. Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline-free survival was 32.8% (95% CI, 25.9%-41.7%) with azithromycin and 41.3% (95% CI, 34.1%-50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1.02-1.70; P = .03). Of the 22 patients (5%) who experienced bronchiolitis obliterans syndrome, 15 (6%) were in the azithromycin group and 7 (3%) in the placebo group (P = .08). The azithromycin group had increased mortality, with a 2-year survival of 56.6% (95% CI, 50.2%-63.7%) vs 70.1% (95% CI, 64.2%-76.5%) in the placebo group (unadjusted HR, 1.5; 95% CI, 1.1-2.0; P = .02). In a post hoc analysis, the 2-year cumulative incidence of hematological relapse was 33.5% (95% CI, 27.3%-39.7%) with azithromycin vs 22.3% (95% CI, 16.4%-28.2%) with placebo (unadjusted cause-specific HR, 1.7; 95% CI, 1.2-2.4; P = .002).. Among patients undergoing allogeneic HSCT for hematological malignancy, early administration of azithromycin resulted in worse airflow decline-free survival than did placebo; these findings are limited by early trial termination. The potential for harm related to relapse requires further investigation.. clinicaltrials.gov Identifier: NCT01959100.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Disease-Free Survival; Double-Blind Method; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Intention to Treat Analysis; Male; Middle Aged; Recurrence; Respiratory Function Tests; Transplantation Conditioning; Transplantation, Homologous; Treatment Failure

Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re-evaluated the long-term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention-to-treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD-free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long-term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long-term CLAD prevalence and improves CLAD-free survival, pulmonary function, and functional exercise capacity after LTx.

Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Azithromycin; Bacteremia; Bronchiolitis Obliterans; Cohort Studies; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Graft Survival; Humans; Lung Transplantation; Male; Postoperative Complications; Prognosis; Risk Factors; Syndrome; Transplantation, Homologous

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.

Topics: Acetates; Adult; Aged; Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Cyclopropanes; Disease Progression; Fluticasone; Forced Expiratory Volume; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lung; Male; Middle Aged; Quality of Life; Quinolines; Sulfides; Survival Analysis; Transplantation, Homologous; Treatment Outcome

We conducted a placebo-controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation.. We compared azithromycin (250 mg alternate days, 12 weeks) with placebo. Primary outcome was FEV1 change at 12 weeks.. 48 patients were randomised; (25 azithromycin, 23 placebo). It was established, post randomisation that two did not have BOS. 46 patients were analysed as intention to treat (ITT) with 33 'Completers'. ITT analysis included placebo patients treated with open-label azithromycin after study withdrawal.. The ITT analysis (n=46, 177 observations) estimated mean difference in FEV1 between treatments (azithromycin minus placebo) was 0.035 L, with a 95% CI of -0.112 L to 0.182 L (p=0.6). Five withdrawals, who were identified at the end of the study as having been randomised to placebo (four with rapid loss in FEV1, one withdrawn consent) had received rescue open-label azithromycin, with improvement in subsequent FEV1 at 12 weeks. Study Completers showed an estimated mean difference in FEV1 between treatment groups (azithromycin minus placebo) of 0.278 L, with 95% CI for the mean difference: 0.170 L to 0.386 L (p=<0.001). Nine of 23 ITT patients in the azithromycin group had ≥10% gain in FEV1 from baseline. No patients in the placebo group had ≥10% gain in FEV1 from baseline while on placebo (p=0.002). Seven serious adverse events, three azithromycin, four in the placebo group, were deemed unrelated to study medication.. Azithromycin therapy improves FEV1 in patients with BOS and appears superior to placebo. This study strengthens evidence for clinical practice of initiating azithromycin therapy in BOS.. EU-CTR, 2006-000485-36/GB.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung Transplantation; Male; Middle Aged; Syndrome; Treatment Outcome

The aim of this study was to determine whether prophylactic azithromycin treatment prevents bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). A series of 1187 patients who underwent HCT between December 1993 and November 2013 at our tertiary referral center in South Korea were enrolled. The median age of these patients was 39.0 years, and 668 (56.3 %) were men. Acute leukemia was the most common indication for HCT. During a median follow-up of 30.7 months after HCT, BOS was diagnosed in 82 patients (6.9 %) at a median of 12.3 months after HCT. One hundred patients received prophylactic azithromycin, of whom 12 developed BOS. BOS was significantly more frequent in patients who were treated with than without prophylactic azithromycin (12.0 versus 6.4 %, P = 0.036). Multivariate analysis revealed that a busulfan-based conditioning regimen (HR 2.73, 95 % CI 1.66-6.45) was the only independent predictor of BOS. The prophylactic use of azithromycin was not associated with the development of BOS by multivariate analysis. Although the present study had some limitations such as its non-randomized retrospective design, differences in baseline patient characteristics between the two groups, and the preference for azithromycin use at our hospital, our findings suggest that prophylactic azithromycin seems to not prevent the development of BOS in HCT recipients.

Topics: Adolescent; Adult; Aged; Allografts; Azithromycin; Bronchiolitis Obliterans; Female; Follow-Up Studies; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Retrospective Studies; Transplantation Conditioning

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV₁) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005-2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV₁, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV₁ with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092-0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV₁ (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV₁ in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV₁ and reduces BOS 2 yrs after LTx.

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; Disease-Free Survival; Double-Blind Method; Female; Forced Expiratory Volume; Graft Rejection; Humans; Immunosuppressive Agents; Inflammation; Lung Transplantation; Male; Middle Aged; Placebos; Proportional Hazards Models; Transplantation, Homologous; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) is an important complication after hematopoietic SCT (HSCT). Recent observations suggested that azithromycin might improve lung function in BOS after HSCT. We conducted a randomized double-blinded placebo-controlled study on azithromycin in patients with BOS after HSCT. The treatment group (n=10) received oral azithromycin 250 mg daily while the control group (n=12) received placebo daily for 12 weeks. Respiratory symptoms were assessed by the St George Respiratory Questionnaires and spirometry at baseline (drug commencement), 1, 2, 3 (drug cessation) and 4 months (1 month after drug cessation). There was no significant difference in the baseline demographic characteristics between the treatment and the control groups in age, gender, time from HSCT to BOS, time since diagnosis of BOS, chronic GVHD, baseline respiratory symptom scores and baseline forced expiratory volume in 1 s (FEV(1)). Throughout and after 3 months of treatment, there were no significant changes in respiratory symptom scores and FEV(1) measurements between the treatment and the control groups. In conclusion, there was no significant benefit of 3 months of oral azithromycin on the respiratory symptoms and lung function in patients with relatively late BOS after HSCT in this randomized placebo-controlled study.

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Chronic Disease; Double-Blind Method; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Syndrome; Time Factors; Transplantation, Homologous

Bronchiolitis obliterans syndrome (BOS) is a major cause of morbidity and mortality after lung transplantation (LTx). Macrolides are a promising treatment option for BOS. The objective of this study was to determine long-term results of azithromycin treatment in patients with BOS. Variables to predict treatment response were evaluated.. An observational study in a single center was performed. Eighty-one adult LTx-recipients (single, double, combined, and re-do) with at least BOS stage 0p (mean forced expired volume in 1 second [FEV1] 55+/-19%) were included. For treatment, 250 mg of oral azithromycin was administered three times per week.. Twenty-four of 81 (30%) patients showed improvement in FEV1 after 6 months, 22/24 already after 3 months of treatment. By univariate analysis, responders at 6 months had higher pretreatment bronchoalveolar lavage (BAL) neutrophils (51+/-29 vs. 21+/-24%). A cutoff value of <20% in pretreatment BAL had a negative predictive value of 0.91 for treatment response. Thirty-three patients (40%) showed disease progression during follow-up (491+/-165 days). Cox regression analysis identified a rapid pretreatment decline in FEV1 and comedication of an mammalian target of rapamycin inhibitor as positive predictors and proton pump inhibitor comedication and a treatment response at 3 months as negative predictors for disease progression (FEV1<90% baseline).. Azithromycin can improve airflow limitation in a significant proportion of patients with even long-standing BOS. The majority of responders were identified after 3 months of treatment. Results indicate the predictive value of BAL neutrophilia for treatment response and pretreatment course of FEV1 as a variable for disease progression. Beneficial effects on gastroesophageal reflux disease may be a mechanism of action.

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Cohort Studies; Disease Progression; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Kaplan-Meier Estimate; Lung Transplantation; Male; Middle Aged; Severity of Illness Index; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) remains the leading cause of death after lung transplantation. Treatment is difficult, although azithromycin has recently been shown to improve FEV(1). The exact mechanism of action is unclear.. (1) Azithromycin reduces airway neutrophilia and interleukin (IL)-8 and (2) airway neutrophilia predicts the improvement in FEV(1).. Fourteen lung transplant patients with BOS (between BOS 0-p and BOS 3) were treated with azithromycin, in addition to their current immunosuppressive treatment. Before and 3 mo after azithromycin was introduced, bronchoscopy with bronchoalveolar lavage (BAL) was performed for cell differentiation and to measure IL-8 and IL-17 mRNA ratios.. The FEV(1) increased from 2.36 (+/- 0.82 L) to 2.67 L (+/- 0.85 L; p = 0.007), whereas the percentage of BAL neutrophilia decreased from 35.1 (+/- 35.7%) to 5.7% (+/- 6.5%; p = 0.0024). There were six responders to azithromycin (with an FEV(1) increase of > 10%) and eight nonresponders. Using categorical univariate linear regression analysis, the main significant differences in characteristics between responders and nonresponders were the initial BAL neutrophilia (p < 0.0001), IL-8 mRNA ratio (p = 0.0009), and the postoperative day at which azithromycin was started (p = 0.036). There was a significant correlation between the initial percentage of BAL neutrophilia and the changes in FEV(1) after 3 mo (r = 0.79, p = 0.0019).. Azithromycin significantly reduces airway neutrophilia and IL-8 mRNA in patients with BOS. Responders have a significantly higher BAL neutrophilia and IL-8 compared with nonresponders and had commenced treatment earlier after transplantation. BAL neutrophilia can be used as a predictor for the FEV(1) response to azithromycin.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Female; Forced Expiratory Volume; Humans; Interleukin-8; Lung Transplantation; Male; Middle Aged; Neutrophil Infiltration; RNA, Messenger; Treatment Outcome

Bronchiolitis obliterans (BO) is a serious noninfectious pulmonary complication following allogeneic bone marrow transplantation (BMT). Azithromycin, a macrolide antibiotic, may have a beneficial effect in BO through its anti-inflammatory effect. The aim of the current study was to investigate the potential effect of azithromycin on pulmonary function tests (PFTs) in BO complicating BMT. PFTs of 153 post-BMT patients were followed; eight patients out of 153 (12%) developed obstructive airway disease on their PFTs, along with characteristic findings of BO on high-resolution computed tomography of the chest. These patients were given azithromycin 500 mg q.d. for 3 days, followed by 250 mg three times a week for 12 weeks. Clinically significant improvements were achieved both in forced vital capacity, where the mean (95% confidence interval) increase reported was 410 mL (0.16-0.65), which was an average improvement of 21.57%, and in the forced expiratory volume in one second, where the mean increase noticed was 280 mL (0.10-0.44), which was an average improvement of 20.58%. In conclusion, the potential role of azithromycin in the treatment of bronchiolitis obliterans is intriguing and it warrants further testing.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Bone Marrow Transplantation; Bronchiolitis Obliterans; Humans; Middle Aged; Respiratory Function Tests; Treatment Outcome

Short-term improvement in lung function was observed in 5 of 6 lung transplant recipients with bronchiolitis obliterans syndrome (BOS) who were treated with oral azithromycin. We assessed the long-term effect (mean duration 10 months) of treatment with oral azithromycin in 11 lung transplant recipients with BOS. Mean forced expiratory volume in 1 second (FEV1) was 40 +/- 9% at initiation of azithromycin treatment, 39 +/- 10% after 1 month, 39 +/- 12% after 4 months, 38 +/- 10% after 7 months and 38 +/- 10% after 10 months, respectively (statistically non-significant for all data). We conclude that long-term administration with oral azithromycin does not reverse BOS in lung transplant recipients, but may slow progression of the disease.

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Disease Progression; Drug Administration Schedule; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Lung Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) is the leading cause of late mortality after lung transplantation.. We added azithromycin (AZI) (250 mg/day for 5 days, followed by 250 mg every other day) to the current immunosuppressive therapy in eight lung transplant recipients (mean age 36 years) with established BOS in an attempt to prevent further decline of the forced expiratory volume in 1 sec (FEV1).. Before the administration of AZI, there was a gradual decline of the FEV1 (-34.4%+/-14.7%) compared with the patients' best postoperative values. Twelve weeks after AZI had been added, there was a significant increase in the FEV1 (+18.3%+/-14.6%, P <0.0001, analysis of variance) with an absolute increase of 328+/-305 mL. This increase persisted in three patients during 9 months of follow-up.. AZI is a promising drug for some patients with BOS after lung transplantation. The exact mechanism of action is unknown at the present time.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Child; Child, Preschool; Forced Expiratory Volume; Humans; Lung Transplantation; Middle Aged; Postoperative Complications; Treatment Outcome

Bronchiolitis obliterans syndrome remains the leading cause of morbidity and mortality in the pulmonary transplant population. Previous studies show that macrolide antibiotics may be efficacious in the treatment of panbronchiolitis and cystic fibrosis. In the latter, azithromycin decreases the number of respiratory exacerbations, improves FEV1, and improves quality of life. We hypothesized that oral azithromycin therapy may improve lung function in patients with bronchiolitis obliterans syndrome. To test this hypothesis, we conducted an open-label pilot trial using maintenance azithromycin therapy in six lung transplant recipients (250 mg orally three times per week for a mean of 13.7 weeks). In this study, five of these six individuals demonstrated significant improvement in pulmonary function, as assessed by FEV1, as compared with their baseline values at the start of azithromycin therapy. The mean increase in the percentage of predicted FEV1 values in these individuals was 17.1% (p

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Bronchiolitis Obliterans; Cystic Fibrosis; Drug Administration Schedule; Follow-Up Studies; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Middle Aged; Pilot Projects; Pulmonary Fibrosis; Quality of Life; Severity of Illness Index; Syndrome; Time Factors; Treatment Outcome

Over the last several decades, the field of lung transplantation has made significant advances. Despite these advancements, morbidity and mortality rates are still high when compared to other solid organ transplants. Clinical trials have a significant role bringing new medications with better effects than their predecessors. Our study is critical in evaluating and tracking clinical trials involving rejection of lung transplant, with a focus on interventional therapeutic trials.. On November 3, 2021, we searched clinicaltrial.gov for interventional clinical trials related to lung transplant rejection. A total of 39 clinical trials are included in this study. Characteristics on each trial were gathered. Linked publications were searched using Medline/PubMed and Embase/Scopus, and their content reviewed and summarized.. The majority of trials were divided into completed (15 out of 39) and recruiting (12 out of 39). 17 trials had between 11 and 50 participants, and 8 had above 100. Only 1 trial lasted >10 years, and the average length of all trials was 3.6 years. The majority of trials were conducted in Europe/UK/Russia and the United States/Canada (17 and 18 trials, respectively). The results were provided in 3 trials, and also published in 3, showing a decrease in the rate of patients reaching an endpoint after chronic rejection with liposomal aerosol cyclosporine, a decrease in their cytokines level, and an increase in their 5-year-survival rate compared to the oral conventional immunosuppressant, the benefit of sirolimus in decreasing the acute rejection rate and severity in comparison to azathioprine, and its efficacy against cytomegalovirus infections. Other trials revealed the benefits of azithromycin in remarkably decreasing airways and systemic inflammation, with a concomitant decline in the risk of both BOS and CLAD; highlighting the deleterious effects of air pollution after transplantation surgery; and using the grading biopsy as a post-transplantation assessment tool.. This study is a descriptive analysis of clinical trials targeting lung transplant rejection. This study shows the low number of trials, lack of variety in location and low publishing rates. Although focus of published trials was mainly towards azithromycin, bronchiolitis obliterans syndrome, air pollution, and biopsy in grading, a remarkable progress was realized concerning therapies, leading to less complications with a delay of chronic rejection onset, and an increase in overall survival. This sheds the light on the need for managing research efforts to fulfill any lack in specific domain, leading to new, effective therapies, and providing thereby much more benefit.

Topics: Azithromycin; Bronchiolitis Obliterans; Clinical Trials as Topic; Graft Rejection; Humans; Immunosuppressive Agents; Lung; Lung Transplantation; Postoperative Complications

We herein report the case of a 20 year-old-man who developed bronchiolitis obliterans after living-donor renal transplantation. The patient presented with dyspnea on exertion and wheezing two years after renal transplantation, and spirometry showed an obstructive pattern. Surgical lung biopsy revealed subepithelial fibrosis that constricted and obstructed the intrabronchiolar space. Based on these findings, the patient was diagnosed with bronchiolitis obliterans. He was prescribed bronchodilators and azithromycin, and he achieved stable respiratory function for two years. The differential diagnosis of respiratory symptoms after renal transplantation includes opportunistic infection and drug-induced lung injury; however, bronchiolitis obliterans should also be considered.

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; Bronchodilator Agents; Diagnosis, Differential; Fibrosis; Humans; Kidney Transplantation; Living Donors; Lung; Male; Postoperative Complications; Spirometry; Young Adult

Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Until now, no specific biomarkers exist to differentiate between CLAD phenotypes. Therefore, we sought to find suitable cytokines to distinguish between BOS, RAS and Azithromycin Responsive Allograft Dysfunction (ARAD); and reveal potential similarities or differences to end-stage fibrotic diseases. We observed significantly increased Lipocalin-2 serum concentrations in RAS compared to BOS patients. In addition, in RAS patients immunohistochemistry revealed Lipocalin-2 expression in bronchial epithelium and alveolar walls. Patients with ARAD showed significantly lower Activin-A serum concentrations compared to Stable-LTX and BOS patients. Further, increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedom-from-CLAD in Stable-LTX patients. These biomarkers serve as promising serum biomarkers for CLAD prediction and seem suitable for implementation in clinical practice.

Topics: Activins; Adult; Aged; Azithromycin; Biomarkers; Bronchi; Bronchiolitis Obliterans; Cytokines; Female; Humans; Lipocalin-2; Lung Transplantation; Male; Matrix Metalloproteinase 9; Middle Aged; Phenotype; Primary Graft Dysfunction; Transplantation, Homologous

Obliterative bronchiolitis (OB) was a main cause of deterioration of long-term prognosis in lung transplant recipients after the first posttransplant year. Proinflammatory cytokine interleukin-18 (IL-18) strengthened both the natural immunity and acquired immunity and played an important role in organ transplantation. The roles of IL-18 in the occurrence, development, and drug treatment of OB remained unclear.. Small interfering RNA (siRNA) against mouse IL-18 (siRNA-IL-18) was used to silence IL-18 expression. Mouse heterotopic tracheal transplantation model was used to simulate OB. Recipient mice were divided into 5 groups (. The luminal obliteration rates of IL-18 of the siRNA-IL-18 group were significantly lower than those of the negative control group (. IL-18 could be a novel molecular involved in the occurrence, development, and drug treatment of OB.

Topics: Animals; Azithromycin; Basigin; Bronchiolitis Obliterans; Disease Models, Animal; Humans; Interferon-gamma; Interleukin-18; Lung Transplantation; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Mice; RNA, Small Interfering; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

Topics: Azithromycin; Bronchiolitis Obliterans; Hematopoietic Stem Cell Transplantation; Humans; Lung Transplantation; Neoplasms; Retrospective Studies; Transplantation, Homologous

Dysregulated airway epithelial repair following injury is a proposed mechanism driving posttransplant bronchiolitis obliterans (BO), and its clinical correlate bronchiolitis obliterans syndrome (BOS). This study compared gene and cellular characteristics of injury and repair in large (LAEC) and small (SAEC) airway epithelial cells of transplant patients.. Subjects were recruited at the time of routine bronchoscopy posttransplantation and included patients with and without BOS. Airway epithelial cells were obtained from bronchial and bronchiolar brushing performed under radiological guidance from these patients. In addition, bronchial brushings were also obtained from healthy control subjects comprising of adolescents admitted for elective surgery for nonrespiratory-related conditions. Primary cultures were established, monolayers wounded, and repair assessed (±) azithromycin (1 µg/mL). In addition, proliferative capacity as well as markers of injury and dysregulated repair were also assessed.. SAEC had a significantly dysregulated repair process postinjury, despite having a higher proliferative capacity than large airway epithelial cells. Addition of azithromycin significantly induced repair in these cells; however, full restitution was not achieved. Expression of several genes associated with epithelial barrier repair (matrix metalloproteinase 7, matrix metalloproteinase 3, the integrins β6 and β8, and β-catenin) were significantly different in epithelial cells obtained from patients with BOS compared to transplant patients without BOS and controls, suggesting an intrinsic defect.. Chronic airway injury and dysregulated repair programs are evident in airway epithelium obtained from patients with BOS, particularly with SAEC. We also show that azithromycin partially mitigates this pathology.

Topics: Adolescent; Adult; Airway Remodeling; Allografts; Azithromycin; Bronchi; Bronchiolitis Obliterans; Bronchoscopy; Case-Control Studies; Cells, Cultured; Child; Drug Evaluation, Preclinical; Epithelial Cells; Female; Graft Rejection; Humans; Lung Transplantation; Male; Middle Aged; Primary Cell Culture; Regeneration; Transplantation, Homologous; Young Adult

Topics: Azithromycin; Bronchiolitis; Bronchiolitis Obliterans; Humans; Respiratory Sounds

Azithromycin prophylaxis (AP) in lung transplant recipients has been shown to reduce the composite end-point of death or chronic lung allograft dysfunction (CLAD) onset but without a clear effect on overall survival. Our program began using AP in 2010. We sought to evaluate the association between AP and survival and the risk of CLAD and baseline lung allograft dysfunction (BLAD).. We studied double lung recipients transplanted between 2004 and 2016. We defined AP as chronic use of azithromycin initiated before CLAD onset. We analyzed the association between AP and death or retransplant using Cox regression with adjustment for potential confounders. We further used Cox and logistic models to assess the relationship between AP and post-transplant CLAD onset and BLAD, respectively.. A total of 445 patients were included, and 344 (77%) received AP (median time from transplant: 51 days). Patients receiving AP were more likely to receive induction with interleukin-2 receptor antagonists (57% vs 35%; p < 0.001). AP was associated with improved survival (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.42-0.82; p = 0.0020) in our fully adjusted model, with a reduced adjusted risk of BLAD (odds ratio: 0.53; 95% CI: 0.33-0.85; p = 0.0460) but no clear reduction in the adjusted risk of CLAD (HR: 0.69; 95% CI: 0.47-1.03; p = 0.0697).. AP is associated with improved survival after lung transplantation, potentially through improved baseline function. These findings build on prior trial results and suggest that AP is beneficial for lung transplant recipients.

Topics: Allografts; Anti-Bacterial Agents; Azithromycin; Biopsy; Bronchiolitis Obliterans; Chronic Disease; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Lung Transplantation; Male; Middle Aged; Postoperative Care; Primary Graft Dysfunction; Retrospective Studies; Risk Factors; Transplant Recipients; Treatment Outcome

Identification of disease phenotypes might improve the understanding of patients with chronic lung allograft dysfunction (CLAD). The aim of the study was to assess the impact of pulmonary restriction and air trapping by lung volume measurements at the onset of CLAD.A total of 396 bilateral lung transplant recipients were analysed. At onset, CLAD was further categorised based on plethysmography. A restrictive CLAD (R-CLAD) was defined as a loss of total lung capacity from baseline. CLAD with air trapping (AT-CLAD) was defined as an increased ratio of residual volume to total lung capacity. Outcome was survival after CLAD onset. Patients with insufficient clinical information were excluded (n=95).Of 301 lung transplant recipients, 94 (31.2%) developed CLAD. Patients with R-CLAD (n=20) and AT-CLAD (n=21), respectively, had a significantly worse survival (p<0.001) than patients with non-R/AT-CLAD. Both R-CLAD and AT-CLAD were associated with increased mortality when controlling for multiple confounding variables (hazard ratio (HR) 3.57, 95% CI 1.39-9.18; p=0.008; and HR 2.65, 95% CI 1.05-6.68; p=0.039). Furthermore, measurement of lung volumes was useful to identify patients with combined phenotypes.Measurement of lung volumes in the long-term follow-up of lung transplant recipients allows the identification of patients who are at risk for worse outcome and warrant special consideration.

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; Chronic Disease; Female; Germany; Humans; Lung; Lung Transplantation; Male; Middle Aged; Primary Graft Dysfunction; Retrospective Studies; Risk Factors; Survival Analysis; Tidal Volume; Transplantation, Homologous

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Bronchiolitis; Bronchiolitis Obliterans; Haemophilus Infections; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections

To evaluate the safety and effectiveness of a novel therapeutic regimen for bronchiolitis obliterans sydrome (BOS) affter hematopoietic stem cell transplantation (HSCT).. Seven patients who had received HSCT and had been diagnosed as BOS were enrolled in this study. They received weekly intravenous injection of umbilical cord-derived mesenchymal stem cells (MSC) at a dose of 1 × 10(6)/kg for 4 weeks. Budesonide was given orally at a daily dose of 0.25 g, and salmeterol was inhaled at a dose of 4.5 µg for 3 times per day. Methylprednisolone was given at a dose of 1 mg/(kg·d) for 2 weeks when respiratory failure occured. The dose of methylprednisolone was tapered to 0.25 mg/(kg·d) after 4 weeks and was adjusted according to the occurrence and severity of chronic graft-versus-host disease (cGVHD).. The therapy was generally safe and no severe acute toxicity was observed. One patient died of heart failure during the treatment, the other 6 patients were alive and the pulmonary function parameters including FEV1, FEV1/FVC, PaO2 and AaDO2 were significantly improved after 6 months as compared with the baseline parameters (P < 0.05).. MSC combined with budesonide, almeterol and azithromycin has been confirmed to be generally safe and can reduce the dose of glucocorticoid in treatment of BOS after HSCT.

Topics: Azithromycin; Bronchiolitis Obliterans; Budesonide; Combined Modality Therapy; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Mesenchymal Stem Cell Transplantation; Methylprednisolone; Salmeterol Xinafoate

Topics: Anti-Bacterial Agents; Azithromycin; Biopsy; Bronchiolitis Obliterans; Bronchodilator Agents; Diagnosis, Differential; Drug Resistance; Dyspnea; Glucocorticoids; Humans; Lung; Male; Middle Aged; Respiratory Function Tests; Tomography, X-Ray Computed; Treatment Outcome

The natural history of lung function in patients with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant is poorly characterized. Understanding the trajectory of lung function is necessary for prompt clinical recognition and treatment and also for the rational design of prospective studies.. To describe the longitudinal trajectory of lung function parameters, including FEV. Subjects with BOS defined by National Institutes of Health consensus guidelines criteria from a recent multicenter prospective trial of combination treatment with fluticasone, azithromycin and montelukast and a retrospective cohort from Fred Hutchinson Cancer Research Center were included. Longitudinal change in FEV. The FEV

Topics: Acetates; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Cyclopropanes; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Linear Models; Lung; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Prospective Studies; Quinolines; Retrospective Studies; Sulfides; Survival Rate; United States; Young Adult

Azithromycin has become a standard of care in therapy of bronchiolitis obliterans following lung transplantation. Matrix metalloprotease-9 broncho-alveolar lavage levels increase in airway neutrophilia and bronchiolitis obliterans. Interleukin-17 may play a role in lung allograft rejection, and interleukin-12 is downregulated in bronchiolitis obliterans. Whether these mechanisms can be targeted by azithromycin remains unclear.. Bronchiolitis obliterans was induced by transplantation of Fischer F344 rat left lungs to Wistar Kyoto rats. Allografts with azithromycin therapy from day 1 to 28 or 56 and mono- or combination therapy with the broad-spectrum matrix metalloprotease inhibitor tanomastat from day 1 to 56 were compared to control allografts and isografts. Graft histology was assessed, and tissue cytokine expression studied using Western blotting and immunofluorescence.. The chronic airway rejection score in the azithromycin group did not change between 4 and 8 weeks after transplantation, whereas it significantly worsened in control allografts (P = .041). Azithromycin+tanomastat prevented complete allograft fibrosis, which occurred in 40% of control allografts. Azithromycin reduced interleukin-17 expression (P = .049) and the number of IL-17(+)/CD8(+) lymphocytes at 4 weeks, and active matrix metalloprotease-9 at 8 weeks (P = .017), and increased interleukin-12 expression (P = .025) at 8 weeks following transplantation versus control allografts.. The expression of interleukin-17 and matrix metalloprotease-9 in bronchiolitis obliterans may be attenuated by azithromycin, and the decrease in interleukin-12 expression was prevented by azithromycin. Combination of azithromycin with a matrix metalloprotease inhibitor is worth studying further because it prevented complete allograft fibrosis in this study.

Topics: Animals; Azithromycin; Biphenyl Compounds; Bronchiolitis Obliterans; Disease Models, Animal; Drug Therapy, Combination; Fibrosis; Graft Survival; Interleukin-12; Interleukin-17; Lung; Lung Transplantation; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Phenylbutyrates; Rats, Inbred F344; Rats, Inbred WKY; Time Factors

Topics: Animals; Azithromycin; Biphenyl Compounds; Bronchiolitis Obliterans; Lung; Male; Matrix Metalloproteinase Inhibitors; Phenylbutyrates

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Asthma; Azithromycin; Bronchiolitis Obliterans; Chlamydophila Infections; Clarithromycin; Female; Haemophilus Infections; Humans; Lung Transplantation; Male

Although survival after lung transplantation has improved significantly during the last decade, chronic rejection is thought to be the major cause of late mortality. The physiologic hallmark of chronic rejection has been a persistent fall in forced expiratory volume in 1 second associated with an obstructive ventilatory defect, for which the term bronchiolitis obliterans syndrome (BOS) was defined to allow a uniformity of description and grading of severity throughout the world. Although BOS was generally thought to be irreversible, recent evidence suggests that some patients with BOS may respond to azithromycin with > 10% improvement in their forced expiratory volume in 1 second. In addition, a restrictive form of chronic rejection has recently been described that does not fit the strict definition of BOS as an obstructive defect. Hence, the term chronic lung allograft dysfunction (CLAD) has been introduced to cover all forms of graft dysfunction, but CLAD has yet to be defined. We propose a definition of CLAD and a flow chart that may facilitate recognition of the different phenotypes of CLAD that can complicate the clinical course of lung transplant recipients.

Topics: Allografts; Azithromycin; Bronchiolitis Obliterans; Chronic Disease; Forced Expiratory Volume; Graft Rejection; Humans; Lung; Lung Transplantation; Phenotype; Terminology as Topic

To evaluate the utility of home spirometry (HS) versus office spirometry (OS) in assessing treatment response to azithromycin in bronchiolitis obliterans syndrome (BOS).. 239 Lung transplant recipients were retrospectively studied. ΔFEV1 ± 10% from FEV1 at azithromycin initiation for ≥7 consecutive days in HS or ≥2 measures in OS were taken as cut-off for response or progression.. Based upon HS, 161/239 (67%) patients were progressive despite macrolide, 19 of who exhibited transient improvement in FEV1 (11%). Time to progression was 29 (13-96) days earlier with HS than in OS. Forty-six (19%) recipients responded in HS after median 81 (22-343) days, whilst 22% remained stable. Concordance in azithromycin treatment response between OS and HS was observed in 210 of 239 patients (88%). Response or stabilization conferred significant improvement in survival (p = 0.005). Transient azithromycin responders demonstrated improved survival when compared to azithromycin refractory patients (p = 0.034).. HS identified azithromycin refractory patients significantly earlier than OS, possibly facilitating aggressive treatment escalation that may improve long-term outcome. Treatment response to azithromycin should be assessed 4 weeks after initiation. Responders demonstrated best survival, with even transient response conferring benefit. Macrolide-refractory BOS carried the worst prognosis.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Disease Progression; Drug Resistance, Bacterial; Early Diagnosis; Female; Forced Expiratory Volume; Home Care Services; Humans; Lung Transplantation; Male; Middle Aged; Retrospective Studies; Spirometry; Survival Analysis; Treatment Outcome

This study aimed to describe the clinical characteristics, radiological features and outcomes of 42 children with post-infectious bronchiolitis obliterans (PIBO).. Forty-two children diagnosed with PIBO were prospectively studied at the First Hospital of Jilin University in northern China between January, 2008 and January, 2013. Their clinical characteristics, lung high resolution computed tomography (HRCT) findings and pulmonary function tests were reported.. In children with PIBO, adenovirus was the most common etiologic agent (21/42), followed by Mycoplasma pneumoniae (M. pneumoniae). All of the patients presented with repeated wheezing and tachypnea. In addition, 22 patients required intensive management, while six patients required home oxygen therapy. HRCT findings were consistent with the PIBO diagnosis in all of the patients. Pulmonary function testing was useful in evaluating therapeutic responses. Systemic steroids combined with azithromycin were effective for PIBO treatment.. Severe adenovirus bronchiolitis and M. pneumoniae infections have a higher risk of development for PIBO. HRCT and pulmonary function testing are useful in the diagnosis of PIBO. The degree of airway obstruction did not differ significantly between adenovirus and M. pneumoniae. A combination of steroids and azithromycin offers some benefit in treating these patients.

Topics: Adenovirus Infections, Human; Adolescent; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Child; Child, Preschool; Combined Modality Therapy; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Oxygen Inhalation Therapy; Pneumonia, Mycoplasma; Prednisone; Prospective Studies; Respiratory Function Tests; Tomography, X-Ray Computed; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Azithromycin; Biopsy; Bronchiolitis Obliterans; Cyclosporine; Disease Management; Forced Expiratory Volume; Gastroesophageal Reflux; Graft Rejection; Humans; Immunosuppressive Agents; Lung; Lung Transplantation; Reoperation; Risk Factors; Tacrolimus; Tomography, X-Ray Computed

Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality in lung transplant recipients after the first year. Treatment remains limited and unpredictable. Existing data suggests extracorporeal photopheresis (ECP) may be beneficial. This study aimed to identify factors predicting treatment response and the prognostic implications. A single center retrospective analysis of all patients commencing ECP for CLAD between November 1, 2007 and September 1, 2011 was performed. In total 65 patients were included, 64 of whom had deteriorated under azithromycin. Median follow-up after commencing ECP was 503 days. Upon commencing ECP, all patients were classified using proposed criteria for emerging clinical phenotypes, including "restrictive allograft syndrome (RAS)", "neutrophilic CLAD (nCLAD)" and "rapid decliners". At follow-up, 8 patients demonstrated ≥10% improvement in FEV1 , 27 patients had stabilized and 30 patients exhibited ≥10% decline in FEV1 . Patients fulfilling criteria for "rapid decliners" (n=21, p=0.005), RAS (n=22, p=0.002) and those not exhibiting neutrophilia in bronchoalveolar lavage (n=44, p=0.01) exhibited poorer outcomes. ECP appears an effective second line treatment in CLAD patients progressing under azithromycin. ECP responders demonstrated improved progression-free survival (median 401 vs. 133 days). Proposed CLAD phenotypes require refinement, but appear to predict the likelihood of ECP response.

Topics: Adult; Algorithms; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Disease-Free Survival; Female; Forced Expiratory Volume; Humans; Light; Lung; Lung Transplantation; Male; Middle Aged; Neutrophils; Phenotype; Photopheresis; Primary Graft Dysfunction; Retrospective Studies; Transplantation, Homologous; Treatment Outcome

Chronic rejection is the major problem hampering long-term survival after lung transplantation. Recently, it became clear that patients may develop an obstructive (bronchiolitis obliterans syndrome [BOS]) or a restrictive lung function defect (restrictive allograft syndrome [RAS]), for which specific risk factors are unknown.. A retrospective analysis of our lung transplantation cohort was performed (n=380). Patients with an irreversible decline in forced expiratory volume in 1 second were identified and classified as BOS or RAS. Patient characteristics, bronchoalveolar lavage (BAL) cellularity, rates of respiratory tract infection, colonization, acute rejection, and lymphocytic bronchiolitis were compared between BOS, RAS, and stable patients.. There were 103 patients suffering from chronic rejection, of which 79 had BOS and 24 were diagnosed with RAS. There were more patients with infection and pseudomonal colonizations in BOS and RAS compared with control (P=0.0090 and P=0.0034, respectively). More patients ever experienced acute and severe acute rejections (A≥2; both P<0.0001) and lymphocytic bronchiolitis (P=0.0006) in BOS and RAS versus control. There were more patients experiencing severe lymphocytic bronchiolitis in RAS compared with BOS (P=0.031). BAL neutrophilia in BOS and RAS were elevated at days 360, 540, and 720 versus control. BOS, but especially RAS patients, experienced more frequent episodes of increased BAL eosinophilia (≥2%; P<0.0001).. Acute rejection, lymphocytic bronchiolitis, colonization with pseudomonas, infection, and BAL eosinophilia and neutrophilia are risk factors for the later development not only of RAS but also of BOS.

Topics: Adult; Azithromycin; Bronchiolitis Obliterans; C-Reactive Protein; Female; Graft Rejection; Humans; Immunosuppressive Agents; Interleukin-8; Lung Diseases; Lung Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Transplantation, Homologous

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male

Bronchiolitis obliterans syndrome (BOS) is a devastating pulmonary complication affecting long-term survivors of allogeneic hematopoietic cell transplantation. Treatment of BOS with prolonged courses of high dose corticosteroids is often associated with significant morbidity. Reducing the exposure to corticosteroids may reduce treatment-related morbidity. Our institution has recently begun to treat patients with emerging therapies in an effort to diminish corticosteroid exposure. We retrospectively reviewed the 6-month corticosteroid exposure, lung function and failure rates in eight patients with newly diagnosed BOS who were treated with a combination of fluticasone, azithromycin and montelukast (FAM) and a rapid corticosteroid taper. These patients were compared with 14 matched historical patients who received high-dose corticosteroids, followed by a standard taper. The median 6-month prednisone exposure in FAM-treated patients was 1819 mg (0-4036 mg) compared with 7163 mg (6551-7829 mg) in the control group (P=0.002). The median forced expiratory volume in 1 s (FEV(1)) change in FAM-treated patients was 2% (-3 to 4%] compared with 1% (-4 to 5%) in the control group (P=1.0). Prednisone exposure in FAM patients was one quarter that of a retrospective-matched group of patients, with minimal change in median FEV(1), suggesting that BOS may be spared of the morbidities associated with long-term corticosteroid use by using alternative agents with less side effects.

Topics: Acetates; Adrenal Cortex Hormones; Adult; Androstadienes; Azithromycin; Bronchiolitis Obliterans; Cyclopropanes; Female; Fluticasone; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Quinolines; Retrospective Studies; Sulfides; Transplantation, Homologous; Young Adult

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Humans; Inflammation; Lung Diseases; Lung Transplantation; Placebos; Retrospective Studies

Azithromycin (AZM) improved bronchiolitis obliterans syndrome (BOS) and reduced aspiration in lung transplant (LTx) recipients. We hypothesize that AZM could improve graft and overall survival more efficiently in LTx patients with BOS who have bile acid (BA) aspiration by protecting against the aspiration-induced progression of BOS. The goal was to compare FEV(1) (% baseline), BOS progression and overall survival in LTx recipients treated with AZM for BOS, both with versus without BA aspiration. Therefore, LTx recipients treated with AZM for BOS were recruited and broncho-alveolar lavage (BAL) samples were analyzed for the presence of BA and neutrophilia before the start of AZM treatment. Short-term effect of AZM on FEV(1) and BAL neutrophilia was assessed, progression of BOS and survival were followed-up for 3 years and results were compared between patients with/without BA aspiration. 19/37 LTx patients had BA in BAL. BA aspiration predisposed to a significantly worse outcome, in terms of decline in FEV(1) , progression of BOS ≥ 1 and survival. AZM does not seem to protect against the long-term allograft dysfunction caused by gastroesophageal reflux (GER) and aspiration and an additional treatment targeting aspiration may be indicated in those LTx patients.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bile Acids and Salts; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Cohort Studies; Disease Progression; Female; Forced Expiratory Volume; Gastroesophageal Reflux; Humans; Kaplan-Meier Estimate; Lung Transplantation; Male; Middle Aged; Neutrophils; Respiratory Aspiration

Chronic lung allograft dysfunction (CLAD) remains a major risk factor for death after lung transplantation. Previous data suggested that within CLAD at least 2 phenotypes are present: a neutrophilic type (nCLAD or neutrophilic reversible allograft dysfunction [NRAD]), reversible with azithromycin therapy, vs a low neutrophilic type, non-responsive to azithromycin (fibrotic bronchiolitis obliterans syndrome [fBOS]). We aimed to further characterize this dichotomy by measuring multiple proteins in the bronchoalveolar lavage (BAL) fluid of 28 lung recipients.. Patients were retrospectively subdivided by the absence or presence of CLAD and subsequently by their response to azithromycin, resulting in 3 groups: 10 stable, 9 responsive (nCLAD/NRAD), and 9 non-responsive (fBOS). Enzyme-linked immunosorbent assay was used to measure 32 different proteins.. Protein variations were predominantly present in the nCLAD/NRAD group, whereas no differences were observed in the fBOS group compared with control. MCP-1 (p < 0.01), RANTES (p < 0.05), IL-1β (p < 0.01), IL-8 (p < 0.01), TIMP-1 (p < 0.01), MMP-8 (p < 0.01), MMP-9 (p < 0.01), HGF (p < 0.001), MPO (p < 0.01), and bile acid (p < 0.05) concentrations were upregulated in nCLAD/NRAD compared with fBOS, whereas PDGF-AA (p < 0.05) was downregulated.. These data provide further evidence that within CLAD there is a heterogeneity of phenotypes with different mechanisms involved. Further investigation is warranted to unravel the pathophysiology of both phenotypes.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bile Acids and Salts; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemokine CCL5; Female; Hepatocyte Growth Factor; Humans; Interleukin-1beta; Interleukin-8; Lung Transplantation; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Middle Aged; Peroxidase; Phenotype; Primary Graft Dysfunction; Proteins; Retrospective Studies; Risk Factors; Tissue Inhibitor of Metalloproteinase-1; Transplantation, Homologous; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) remains the major hurdle to improve long-term survival after lung transplantation, as its treatment remains troublesome. In this pilot study, we investigated the effect of montelukast (a leukotriene receptor antagonist) on the FEV(1) decline after diagnosis of BOS and compared this with a control group. In both groups, 11 patients were included with BOS stage <3 and bronchoalveolar lavage (BAL) neutrophilia <15%, already being treated or concurrently being started on azithromycin. Control patients were selected retrospectively. After adding montelukast (10 mg/day) to the immunosuppressive regimen, the FEV(1) decline significantly decreased from 112 ± 26 ml/month before BOS diagnosis to 13 ± 13 ml/month after 6 months of montelukast therapy (P = 0.001). In the control group, there was no significant change in the rate of FEV(1) decline: 103 ± 20 ml/month before BOS diagnosis to 114 ± 27 ml/month (P = 0.55). Adding montelukast may be a promising treatment option in patients with low neutrophilic (<15%) BOS after lung transplantation, already or concurrently being treated with azithromycin.

Topics: Acetates; Azithromycin; Bronchiolitis Obliterans; Cyclopropanes; Female; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Lung Transplantation; Male; Middle Aged; Pilot Projects; Quinolines; Sulfides; Treatment Outcome

Topics: Azithromycin; Bronchiolitis Obliterans; Humans; Lung Transplantation; Postoperative Complications

Recently a novel subgroup of bronchiolitis obliterans syndrome (BOS) has been described in patients after lung transplantation with high neutrophil counts in broncho-alveolar lavage and recovery of lung functional decline with azithromycin treatment. We aimed to describe the thin-section computed tomography (CT) findings of these neutrophilic reversible allograft dysfunction (NRAD) patients before and after azithromycin.. A cohort of 100 lung transplant recipients with BOS were treated with azithromycin and underwent lung function testing, broncho-alveolar lavage and CT before azithromycin treatment and during follow-up. The 200 CT data sets were scored for bronchial dilatation, mucus plugging, centrilobular abnormalities, airway wall thickening, consolidation, ground glass and end-expiratory air trapping.. NRAD was characterized by more centrilobular abnormalities on CT (p = 0.03 for prevalence and p = 0.06 for severity) compared to non-responders. At follow-up NRAD patients showed improvement in all CT abnormalities including air trapping, but the degree of improvement in all CT abnormalities was significantly different between responders and non-responders (who showed progression of bronchus dilatation, consolidation and air trapping).. Within BOS patients those with NRAD differ from azithromycin non-responders by more centrilobular abnormalities on CT before azithromycin and improvement in bronchus dilatation, consolidation and air trapping during treatment.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Cohort Studies; Female; Humans; Leukocyte Count; Lung Transplantation; Male; Middle Aged; Neutrophils; Respiratory Function Tests; Retrospective Studies; Tomography, X-Ray Computed

Extracorporeal photopheresis (ECP) has been used to treat acute and chronic rejection after solid organ transplantation. However, data supporting the use of ECP for bronchiolitis obliterans syndrome (BOS) after lung transplantation are limited.. We retrospectively analyzed the efficacy and safety of ECP for progressive BOS at our institution. Between January 1, 2000, and December 31, 2007, 60 lung allograft recipients were treated with ECP for progressive BOS.. During the 6-month period before the initiation of ECP, the average rate of decline in forced expiratory volume in 1 second (FEV(1)) was -116.0 ml/month, but the slope decreased to -28.9 ml/month during the 6-month period after the initiation of ECP, and the mean difference in the rate of decline was 87.1 ml/month (95% confidence interval, 57.3-116.9; p < 0.0001). The FEV(1) improved in 25.0% of patients after the initiation of ECP, with a mean increase of 20.1 ml/month.. ECP is associated with a reduction in the rate of decline in lung function associated with progressive BOS.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Combined Modality Therapy; Disease Progression; Female; Forced Expiratory Volume; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Lung; Lung Transplantation; Male; Middle Aged; Photopheresis; Retrospective Studies; Treatment Outcome

Previous studies have suggested that azithromycin improves lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, these studies did not include a non-treated BOS control cohort or perform survival analysis. This study was undertaken to estimate the effect of azithromycin treatment on survival in lung transplant recipients with BOS.. We conducted a retrospective cohort study of consecutive lung transplant recipients who developed BOS between 1999 and 2007. An association between azithromycin treatment and death was assessed using univariate and multivariate time-dependent Cox regression analysis.. Of the 178 recipients who developed BOS in our study, 78 did so after 2003 and were treated with azithromycin. The azithromycin-treated and untreated cohorts had similar baseline characteristics. Univariate analysis demonstrated that azithromycin treatment was associated with a survival advantage and this beneficial treatment effect was more pronounced when treatment was initiated during BOS Stage 1. Multivariate analysis demonstrated azithromycin treatment during BOS Stage 1 (adjusted hazard ratio = 0.23, p = 0.01) and absolute forced expiratory volume in 1 second (FEV(1)) at the time of BOS Stage 1 (adjusted hazard ratio = 0.52, p = 0.003) were both associated with a decreased risk of death.. In lung transplant recipients with BOS Stage 1, azithromycin treatment initiated before BOS Stage 2 was independently associated with a significant reduction in the risk of death. This finding supports the need for a randomized, controlled trial to confirm the impact of azithromycin on survival in lung transplant recipients.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Cause of Death; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Lung Transplantation; Male; Middle Aged; Opportunistic Infections; Postoperative Complications; Proportional Hazards Models; Pseudomonas Infections; Retrospective Studies; Risk Factors; Survival Analysis

Azithromycin may reverse or halt the decline of pulmonary function (FEV(1)) in bronchiolitis obliterans syndrome (BOS). In this study we investigated the effects of long-term azithromycin treatment in lung transplant recipients with BOS.. A retrospective, observational, cohort study was performed on 107 patients with BOS (Stages 0p/1/2/3, n = 23/62/20/2), who were treated with azithromycin for 3.1 ± 1.9 years. Patients were evaluated 6.3 ± 3.8 years after transplantation and assessed for evolution of FEV(1), bronchoalveolar lavage neutrophilia and overall survival after initiation of azithromycin. Survival curves were analyzed using the log-rank test. Cox proportional hazard survival regression analysis was performed to estimate hazard ratios of clinical variables predicting outcome.. FEV(1) increased ≥ 10% after 3 to 6 months of treatment in 40% of patients, of whom 33% later redeveloped BOS. FEV(1) further declined in 78% and stabilized in 22% of the remaining non-responders. Pre-treatment neutrophilia was higher in responders: 29.3% (9.3% to 69.7%) vs 11.5% (2.9% to 43.8%) (p = 0.025), in whom it significantly decreased to 4.2% (1.8% to 17.6%) (p = 0.041) after 3 to 6 months of azithromycin. Responders demonstrated better survival compared with non-responders (p = 0.050), with 6 and 21 patients, respectively, dying during follow-up (p = 0.027). Multivariate analysis identified initial azithromycin response and earlier post-transplant initiation of azithromycin to be protective for both BOS progression/relapse (hazard ratio [HR] = 0.12 [95% confidence interval 0.05 to 0.28], p < 0.0001; and HR = 0.98 [95% confidence interval 0.97 to 0.98], p < 0.0001, respectively) and retransplantation/death during follow-up (HR 0.10 [95% confidence interval 0.02 to 0.48], p = 0.004; and HR 0.96 [95% confidence interval 0.95 to 0.98], p < 0.0001, respectively).. Long-term azithromycin benefits pulmonary function and survival in BOS, particularly in patients with increased lavage neutrophilia.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Lung; Lung Transplantation; Male; Middle Aged; Respiratory Function Tests; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome

Bronchiolitis obliterans syndrome (BOS) remains a major problem after lung transplantation. Azithromycin seems to be beneficial in some patients with established BOS. We investigated the efficacy of total lymphoid irradiation (TLI) in 6 BOS patients with a continuous decline in FEV(1), despite treatment with azithromycin for a mean of 12 +/- 13 (range, 1-35) months. A historical control group consisted of 5 patients with declining FEV(1), also nonresponders to azithromycin and those not treated with TLI. All 6 TLI patients received the total dose of 8 Gy in 10 sessions. There was a significant change in the decline of the FEV(1) after TLI treatment (from 221 +/- 107 to 94 +/- 79 mL/mo; P = .041). Three patients died, due to BOS progression, overwhelming pneumonia, and sudden cardiac arrest, respectively, 3.5, 11, and 26 months after TLI; two patients underwent retransplantation at 6 and 19 months after TLI, respectively. The sixth patient remains stable in BOS stage 3 after a follow-up period of 24 months. In the control group, there was no significant change in FEV(1) decline (209 +/- 97 mL/mo before versus 193 +/- 81 mL/mo after starting azithromycin; P = not significant). Two patients remain stable in BOS stage 3, 1 died of BOS progression, and the 5th patient is scheduled for retransplantation. We conclude that patients who do not or no longer respond to azithromycin may benefit from TLI, as suggested by a decreased rate in decline of the FEV(1).

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Forced Expiratory Volume; Humans; Lung Transplantation; Lymphatic Irradiation

Topics: Azithromycin; Bronchiolitis Obliterans; Evidence-Based Medicine; Humans; Treatment Failure

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.. 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.. 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.. 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).. 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.

Topics: Adult; Airway Obstruction; Anti-Bacterial Agents; Azithromycin; Bronchiolitis Obliterans; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Retrospective Studies; Syndrome; Treatment Outcome

Topics: Anti-Inflammatory Agents; Azithromycin; Bronchiolitis Obliterans; Bronchoscopy; CD4 Antigens; Humans; Interleukin-6; Lung Transplantation; Lymphocyte Activation; Monocytes; Treatment Outcome