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Objective: To investigate the related risk factors for bronchiolitis obliterans (BO) in children with mycoplasma pneumonia (MP) bronchiolitis., Method: The clinical data of 227 children with MP bronchiolitis who were admitted to the II Department of Respiratory of Children's Hospital of Hebei Province from January 2018 to June 2020 were retrospectively analyzed. According to the sequelae of BO, they were divided into 32 cases in the BO group and 195 cases in the non-BO group. The univariate analysis was performed on the clinical and laboratory parameters of the two groups, and the multifactor logistic regression was performed further to determine the independent risk factors for the occurrence of BO in MP bronchiolitis, and then, the cut-off value with the maximum diagnostic value of indicators was found through the ROC curve analysis., Results: The results of univariate and multivariate logistic regression analysis showed that the independent risk factors for the occurrence of BO in MP bronchioles were longer duration of moist rales (OR = 1.203, P = 0.003), higher levels of serum lactate dehydrogenase (LDH) (OR = 1.005, P = 0.036), hypoxemia (OR = 7.442, P = 0.035), and pleural effusion (OR = 4.437, P = 0.004). The area under the ROC curve was 78.2%, 72.0%, 68.2%, and 71.0%, respectively ( P < 0.001). The cut-off value of duration of moist rales and levels of serum LDH are 7.5 d and 330 U/L, respectively., Conclusion: Children with MP bronchiolitis with high serum LDH level (≥330 U/L), combined with hypoxemia, pleural effusion, and lung wet rale duration (≥7.5 d), may be more prone to BO, in which lung wet rale duration prediction value is the largest. Among them, duration of pulmonary moist rales has the highest predictive value., Competing Interests: All authors declare that there is no conflict of interest., (Copyright © 2022 KunLing Huang et al.)

Background: Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS., Methods: Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders., Results: A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007)., Conclusions: We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Lung transplantation outcomes remain complicated by bronchiolitis obliterans syndrome (BOS), a major cause of mortality and retransplantation for patients. A variety of factors linking inflammation and BOS have emerged, meriting further exploration of the microbiome as a source of inflammation. In this analysis, we determined features of the pulmonary microbiome associated with BOS susceptibility., Methods: Bronchoalveolar lavage (BAL) samples were collected from 25 patients during standard of care bronchoscopies before BOS onset. Microbial DNA was isolated from BAL fluid and prepared for metagenomics shotgun sequencing. Patient microbiomes were phenotyped using k-means clustering and compared to determine effects on BOS-free survival., Results: Clustering identified 3 microbiome phenotypes: Actinobacteria dominant (AD), mixed, and Proteobacteria dominant. AD microbiomes, distinguished by enrichment with Gram-positive organisms, conferred reduced odds and risks for patients to develop acute rejection and BOS compared with non-AD microbiomes. These findings were independent of treatment models. Microbiome findings were correlated with BAL cell counts and polymorphonuclear cell percentages., Conclusions: In some populations, features of the microbiome may be used to assess BOS susceptibility. Namely, a Gram-positive enriched pulmonary microbiome may predict resilience to BOS., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The characteristics of Mycoplasma pneumonia (M. pneumoniae)-associated bronchiolitis obliterans (BO) are not well known. We retrospectively reviewed 17 patients with M. pneumoniae-associated BO. All patients had M. pneumoniae-associated acute bronchiolitis prior to the development of BO. In the acute bronchiolitis stage, all patients had fever and cough; six patients also had wheezing and dyspnoea. BO was diagnosed approximately 1.5-8 months later based on clinical manifestations and chest high-resolution computed tomography (HRCT) findings. All patients presented with wheezing and/or dyspnoea at the time of diagnosis of BO. HRCT findings included mosaic attenuation, pronounced air trapping, central bronchiectasis and emphysema, according to disease severity. Lung function tests revealed mild to severe airway obstruction. Fourteen of 17 patients had a greater than 12% increase in forced expiratory volume in 1 second values after taking salbutamol. All patients had positive allergy test results and family or personal history of atopic disease. Four patients had a history of asthma before M. pneumonia bronchiolitis. Asthma was diagnosed before, at the time of or after the diagnosis of BO in 11 cases. M. pneumoniae-associated BO may therefore develop following M. pneumonia bronchiolitis and overlap with asthma.

Aim: We investigated airway function in preschoolers with postinfectious bronchiolitis obliterans (PIBO) using impulse oscillometry (IOS)., Methods: This study enrolled 182 children aged three to five years: 12 with PIBO, 135 with asthma and 35 nonatopic controls. Respiratory resistance and reactance were assessed using IOS., Results: The percentage predicted (% predicted) of prebronchodilator respiratory resistance at 5 Hz was significantly higher in children with PIBO (177.9 ± 118.4%) than the asthma (126.1 ± 30.5%, p = 0.013) or control (121.1 ± 21.8%, p = 0.014) groups. After bronchodilator use, children with PIBO did not reach the values of Rrs5% predicted in the asthma and control groups. Respiratory reactance (Xrs5% predicted) in children with PIBO (337.1 ± 478.5%) was significantly higher than both asthma (130.0 ± 80.0%, p = 0.004) and control (105.1 ± 30.8%, p < 0.001) groups before bronchodilator use and significantly higher than the two groups after bronchodilator use (p = 0.010 and p = 0.004, respectively). The changes in Rrs5 and Xrs5 were not significantly different between the children with PIBO and asthma., Conclusion: Measuring Rrs5 and Xrs5 before and after bronchodilator use may help to discriminate PIBO from asthma in children aged three to five years with chronic or recurrent respiratory symptoms., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Lung transplantation (LTx) is a well-established treatment for end-stage pulmonary disease. However, data regarding microbiology and outcome of patients with non-cystic fibrosis bronchiectasis (NCFB) after lung transplantation are limited., Methods: A retrospective analysis between August 1992 and September 2014 of all patients undergoing lung transplantation at our program of all recipients with a primary diagnosis of bronchiectasis was performed. Microbiology of sputum and bronchoalveolar lavage specimens, lung function and clinical parameters pre- and post-LTx were assessed retrospectively. Overall survival was compared to the total cohort of lung transplant recipients at institution. The survival and development of chronic lung allograft dysfunction (CLAD) was compared in patients with and without chronic Pseudomonas aeruginosa (PSA) infection after LTx., Results: 34 patients were transplanted. Median age at transplantation was 40 (IQR 33-52) years. The most common etiologies of bronchiectasis were idiopathic (41%), chronic obstructive pulmonary disease (COPD) (21%) and post-infectious (15%). The most common organism of pre- and posttransplant chronic airway infection was PSA. One-year Kaplan-Meier survival for patients with bronchiectasis was 85% and 5-year survival was 73% and similar to the entire cohort. All three patients with an associated diagnosis of immunodeficiency died due to infection and sepsis within the first year. Patients with persistent colonization with Pseudomonas aeruginosa after transplantation had worse long-term survival by trend and developed chronic lung allograft dysfunction more frequently., Conclusions: Overall survival of patients with bronchiectasis after LTx is comparable to other underlying diseases. A reduced survival was observed in patients with the underlying diagnosis of immunodeficiency., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Staphylococcus aureus is the most commonly isolated gram-positive bacterium after lung transplantation (LT) and has been associated with poor posttransplant outcomes, but its effect on bronchiolitis obliterans syndrome (BOS) and death in the context of the allograft inflammatory environment has not been studied. A three-state Cox semi-Markovian model was used to determine the influence of allograft S. aureus and the ELR+ CXC chemokines on the survival rates and cause-specific hazards for movement from lung transplant (State 1) to BOS (State 2), from transplant (State 1) to death (State 3), and from BOS (State 2) to death (State 3). Acute rejection, pseudomonas pneumonia, bronchoalveolar lavage fluid (BALF) CXCL5 and its interaction with S. aureus all increased the likelihood of transition from transplant to BOS. Transition to death from transplant was facilitated by pseudomonas infection and single lung transplant. Movement from BOS to death was affected by the interaction between aspergillus, pseudomonas and CXCL5, but not S. aureus. S. aureus isolation had state specific effects after LT and only in concert with elevated BALF CXCL5 concentrations did it augment the risk of BOS. Pseudomonas and elevated BALF concentrations of CXCL5 continued as significant risk factors for BOS and death after BOS in lung transplantation., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The management of bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation presents many challenges, both diagnostically and therapeutically. We developed a computed tomography (CT) voxel-wise methodology termed parametric response mapping (PRM) that quantifies normal parenchyma, functional small airway disease (PRM(fSAD)), emphysema, and parenchymal disease as relative lung volumes. We now investigate the use of PRM as an imaging biomarker in the diagnosis of BOS. PRM was applied to CT data from 4 patient cohorts: acute infection (n = 11), BOS at onset (n = 34), BOS plus infection (n = 9), and age-matched, nontransplant control subjects (n = 23). Pulmonary function tests and bronchoalveolar lavage were used for group classification. Mean values for PRM(fSAD) were significantly greater in patients with BOS (38% ± 2%) when compared with those with infection alone (17% ± 4%, P < .0001) and age-matched control subjects (8.4% ± 1%, P < .0001). Patients with BOS had similar PRM(fSAD) profiles, whether a concurrent infection was present or not. An optimal cut-point for PRM(fSAD) of 28% of the total lung volume was identified, with values >28% highly indicative of BOS occurrence. PRM may provide a major advance in our ability to identify the small airway obstruction that characterizes BOS, even in the presence of concurrent infection., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to describe the clinical characteristics, radiological features and outcomes of 42 children with post-infectious bronchiolitis obliterans (PIBO)., Methods: 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., Results: 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., Conclusions: 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.

Unlabelled: Postinfectious bronchiolitis obliterans (PIBO) is an infrequent chronic lung that causes irreversible obstruction and, or, obliteration of the smaller airways. This review particularly focuses on more than 30 studies from South America., Conclusion: The initial PIBO event occurs in the early years of life and is strongly associated with adenovirus infection and the need for mechanical ventilator support. Treatment requires a multidisciplinary strategy. Multicentre studies are needed to determine progression, optimal management and long-term follow-up., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Multiple independent culture-based studies have identified the presence of Pseudomonas aeruginosa in respiratory samples as a positive risk factor for bronchiolitis obliterans syndrome (BOS). Yet, culture-independent microbiological techniques have identified a negative association between Pseudomonas species and BOS. Our objective was to investigate whether there may be a unifying explanation for these apparently dichotomous results., Methods: We performed bronchoscopies with bronchoalveolar lavage (BAL) on lung transplant recipients (46 procedures in 33 patients) and 26 non-transplant control subjects. We analyzed bacterial communities in the BAL fluid using qPCR and pyrosequencing of 16S rRNA gene amplicons and compared the culture-independent data with the clinical metadata and culture results from these subjects., Findings: Route of bronchoscopy (via nose or via mouth) was not associated with changes in BAL microbiota (p = 0.90). Among the subjects with positive Pseudomonas bacterial culture, P. aeruginosa was also identified by culture-independent methods. In contrast, a distinct Pseudomonas species, P. fluorescens, was often identified in asymptomatic transplant subjects by pyrosequencing but not detected via standard bacterial culture. The subject populations harboring these two distinct pseudomonads differed significantly with respect to associated symptoms, BAL neutrophilia, bacterial DNA burden and microbial diversity. Despite notable differences in culturability, a global database search of UM Hospital Clinical Microbiology Laboratory records indicated that P. fluorescens is commonly isolated from respiratory specimens., Interpretation: We have reported for the first time that two prominent and distinct Pseudomonas species (P. fluorescens and P. aeruginosa) exist within the post-transplant lung microbiome, each with unique genomic and microbiologic features and widely divergent clinical associations, including presence during acute infection.

We report a 12-year-old boy with progressive bronchiolitis obliterans caused by Achromobacter xylosoxidans (Ax) colonization after liver transplantation, resulting in a steep decline in lung function., (© 2013 Wiley Periodicals, Inc.)

Lung transplantation survival remains significantly impacted by infections and the development of chronic rejection manifesting as bronchiolitis obliterans syndrome (BOS). Traditional microbiologic data has provided insight into the role of infections in BOS. Now, new non-culture-based techniques have been developed to characterize the entire population of microbes resident on the surfaces of the body, also known as the human microbiome. Early studies have identified that lung transplant patients have a different lung microbiome and have demonstrated the important finding that the transplant lung microbiome changes over time. Furthermore, both unique bacterial populations and longitudinal changes in the lung microbiome have now been suggested to play a role in the development of BOS. In the future, this technology will need to be combined with functional assays and assessment of the immune responses in the lung to help further explain the microbiome's role in the failing lung allograft.

In lung transplant recipients (LTRs), severe clinical complications, such as microbial infections of the lung or transplant rejection, may occur. Surfactant protein D (SP-D) is a C-type lectin that is mainly produced in alveolar type II cells. Plasma SP-D levels are usually low, but may increase when the lung-blood barrier is impaired. In this study, we analyzed whether plasma SP-D concentrations reflect rejection or infection of the lung allograft. An enzyme-linked immunosorbent assay was used to measure SP-D levels in plasma samples from 58 LTRs during intervals without pathologic respiratory findings and during episodes of acute cellular rejection (ACR), microbial colonization, and microbial pneumonia. Median plasma SP-D levels were significantly increased during episodes of microbial pneumonia, but not in the absence of pathologic respiratory findings, during microbial colonization, or during ACR up to grade A2-A3 (P < 0.05). During pneumonia, an increased plasma SP-D level was detected in 60% of LTRs and this was further associated with a significantly higher risk for the patients to develop stage III bronchiolitis obliterans syndrome (BOS III) or to die within the subsequent 6 months after pneumonia (P = 0.0093). All patients with a plasma SP-D level of >300 ng/mL during pneumonia developed BOS III and/or died within 6 months of follow-up (P = 0.001). The determination of SP-D levels in plasma during pneumonia in LTRs may be of prognostic value and warrants further evaluation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fungal infections continue to produce morbidity and mortality in lung transplant recipients despite the widespread use of antifungal prophylaxis. There has been a decline in Candida infections but Aspergillus species predominate. Other mold pathogens including Fusarium, Scedosporium, and Zygomycetes also cause infections in lung transplant recipients. Furthermore, the widespread use of antifungal prophylaxis has prompted a delay in onset of Aspergillus infection in lung transplant recipients. Pulmonary parenchymal disease has become the most common manifestation of invasive aspergillosis. Among the risk factors pre- or posttransplant Aspergillus colonization is the most important risk factor reported in several retrospective studies. Recently posttransplant colonization has been implicated in the development of bronchiolitis obliterans syndrome. Other factors that have been reported include preceding cytomegalovirus infections, hypogammaglobulinemia, and single-lung transplantation. The risk factors for other mold infections such as Scedosporium, Fusarium, and Zygomycetes are not well studied. The best antimold prophylaxis strategy and choice of drug remains to be elucidated. Most lung transplant centers use either voriconazole or inhaled amphotericin preparations. However, data have emerged regarding the increased risk of squamous cell cancer in lung transplant recipients on voriconazole prophylaxis. Advances in the diagnosis and treatment of invasive aspergillosis have resulted in a significant decrease in mortality., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Aspergillus colonization after lung transplantation may increase the risk for bronchiolitis obliterans syndrome (BOS), a disease of small airways. We hypothesized that colonization with small conidia Aspergillus species would be associated with a greater risk of BOS, based upon an increased likelihood of deposition in small airways. We studied adult primary lung recipients from two large centers; 298 recipients at University of California, Los Angeles and 482 recipients at Duke University Medical Center. We grouped Aspergillus species by conidia diameter≤3.5 μm. We assessed the relationship of colonization with outcomes in Cox models. Pre-BOS colonization with small conidia Aspergillus species, but not large, was a risk factor for BOS (p=0.002, HR 1.44, 95% CI 1.14-1.82), along with acute rejection, single lung and Pseudomonas. Colonization with small conidia species also associated with risk of death (p=0.03, HR 1.30, 95% CI 1.03-1.64). Although other virulence traits besides conidia size may be important, we have demonstrated in two large independent cohorts that colonization with small conidia Aspergillus species increases the risk of BOS and death. Prospective evaluation of strategies to prevent Aspergillus colonization of small airways is warranted, with the goal of preserving lung allograft function as long as possible., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Rationale: Bronchiolitis obliterans syndrome (BOS) is the primary limiting factor for long-term survival after lung transplantation, and has previously been associated with microbial infections., Objectives: To cross-sectionally and longitudinally characterize microbial communities in allografts from transplant recipients with and without BOS using a culture-independent method based on high-throughput sequencing., Methods: Allografts were sampled by bronchoalveolar lavage, and microbial communities were profiled using 16S rRNA gene amplicon pyrosequencing. Community profiles were compared using the weighted Unifrac metric and the relationship between microbial populations, BOS, and other covariates was explored using PERMANOVA and logistic regression., Measurements and Main Results: Microbial communities in transplant patients fell into two main groups: those dominated by Pseudomonas or those dominated by Streptococcus and Veillonella, which seem to be mutually exclusive lung microbiomes. Aspergillus culture was also negatively correlated with the Pseudomonas-dominated group. The reestablishment of dominant populations present in patients pretransplant, notably Pseudomonas in individuals with cystic fibrosis, was negatively correlated with BOS., Conclusions: Recolonization of the allograft by Pseudomonas in individuals with cystic fibrosis is not associated with BOS. In general, reestablishment of pretransplant lung populations in the allograft seems to have a protective effect against BOS, whereas de novo acquisition of microbial populations often belonging to the same genera may increase the risk of BOS.

Rationale: Pseudomonas aeruginosa is the most commonly isolated gram-negative bacterium after lung transplantation and has been shown to up-regulate glutamic acid-leucine-arginine-positive (ELR(+)) CXC chemokines associated with bronchiolitis obliterans syndrome (BOS), but the effect of pseudomonas on BOS and death has not been well defined., Objectives: To determine if the influence of pseudomonas isolation and ELR(+) CXC chemokines on the subsequent development of BOS and the occurrence of death is time dependent., Methods: A three-state model was developed to assess the likelihood of transitioning from lung transplant (state 1) to BOS (state 2), from transplant (state 1) to death (state 3), and from BOS (state 2) to death (state 3). This Cox semi-Markovian approach determines state survival rates and cause-specific hazards for movement from one state to another., Measurements and Main Results: The likelihood of transition from transplant to BOS was increased by acute rejection, CXCL5, and the interaction between pseudomonas and CXCL1. The pseudomonas effect in this transition was due to infection rather than colonization. Movement from transplant to death was facilitated by pseudomonas infection and single lung transplant. Transition from BOS to death was affected by the length of time in state 1 and by the interactions between any pseudomonas isolation and CXCL5 and aspergillus, either independently or in combination., Conclusions: Our model demonstrates that common post-transplantation events drive movement from one post-transplantation state to another and influence outcomes differently depending upon when after transplantation they occur. Pseudomonas and the ELR(+) CXC chemokines may interact to negatively influence lung transplant outcomes.

Bacterial airway colonization is frequent among lung transplant recipients. These patients are often treated with antibiotics, which may lead to selection of resistant bacteria. The purpose of this study was to assess whether antibiotic treatment causes acquisition of quinolone-resistant Gram-negative bacteria (QR-GNB), and the effect of such colonization on mortality and on lung rejection. We retrospectively examined data from non-cystic fibrosis, non-bronchiectases lung transplant recipients for antibiotic treatment, GNB in respiratory secretions, bronchiolitis obliterans syndrome (BOS), and mortality. Of 126 patients included, 86 patients had QR-GNB, 22 had quinolone-sensitive bacteria (QS-GNB), and 17 had no growth. Median antibiotic exposure, defined as the fraction of days with antibiotic treatment, was 2.8% in patients without growth, 11.1% in patients with QS-GNB (p=0.012), and 26% in patients with QR-GNB (p<0.0001). Age-adjusted mortality hazard ratio was 9.2 (95% CI 1.272-78.9) for patients with QR-GNB compared with QS-GNB. Age-adjusted hazard ratios for BOS was 3.7 (95% CI 1.33-10.3) for QR-GNB compared with QS-GNB. We found a positive correlation between antibiotic treatment and emergence of QR-GNB. Airway colonization with QR-GNB was significantly associated with mortality and with BOS. Further research is needed to determine whether a change in antibiotic subscription policy is required., (© 2012 John Wiley & Sons A/S.)

Rationale: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers., Objectives: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing., Methods: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover., Measurements and Main Results: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tract microbial richness and diversity. Fungal populations were typically dominated by Candida in both sites or by Aspergillus in BAL but not OW. 16S outlier analysis identified lung-enriched taxa indicating bacteria replicating in the lower respiratory tract. In some cases this confirmed respiratory cultures but in others revealed enrichment by anaerobic organisms or mixed outgrowth of upper respiratory flora and provided quantitative data on relative abundances of bacteria found by culture., Conclusions: Respiratory tract microbial communities in lung transplant recipients differ in structure and composition from healthy subjects. Outlier analysis can identify specific bacteria replicating in lung. These findings provide novel approaches to address the relationship between microbial communities and transplant outcome and aid in assessing lung infections.

Epithelial-to-mesenchymal transition (EMT) has been implicated in the dysregulated epithelial wound repair that contributes to obliterative bronchiolitis (OB) after lung transplantation. Acquisition of Pseudomonas aeruginosa in the transplanted airway has been shown to be a risk factor for the development of OB. We investigated the potential of P. aeruginosa to drive EMT in primary bronchial epithelial cells (PBECs) isolated from lung transplant recipients. Changes in the expression of epithelial and mesenchymal markers was assessed in cells challenged with clinical isolates of P. aeruginosa or co-cultured with P. aeruginosa-activated monocytic cells (THP-1) in the presence or absence of transforming growth factor (TGF)-β1. P. aeruginosa did not drive or accentuate TGF-β1-driven EMT directly. Co-culturing P. aeruginosa-activated THP-1 cells with PBECs did not drive EMT. However, co-culturing P. aeruginosa-activated THP-1 cells with PBECs significantly accentuated TGF-β1-driven EMT. P. aeruginosa, via the activation of monocytic cells, can accentuate TGF-β1-driven EMT. These in vitro observations may help explain the in vivo clinical observation of a link between acquisition of P. aeruginosa and an increased risk of developing OB.

Lung transplantation is the only therapeutic option for patients with end-stage pulmonary disorders. Despite the improvements in surgical techniques and immunosuppressive therapy, allograft function and long-term survival are limited by the development of chronic lung transplant rejection. In this review, we focus on bronchiolitis obliterans syndrome (BOS) which is the major manifestation of chronic lung allograft rejection. We specifically review the effect of infection, a risk factor for BOS, cytokines/chemokines in the pathogenesis of BOS, and the potential link between the allograft microbiome and immune responses that may mediate the development of BOS. Understanding the allograft microbiome and how it relates to the pathologic mechanisms of BOS may suggest targeted therapies to improve long-term survival post-lung transplantation.

Bronchiolitis obliterans syndrome (BOS) is a major cause of late graft dysfunction in lung transplant recipients. There is increasing evidence that beside alloimmunologic injury also non-alloimmunologic inflammatory conditions may raise the risk of acute and chronic rejection. The oral cavity represents a possible reservoir for pathogenic bacteria due to its close anatomical proximity. In this pilot study, the presence of pathogenic periodontal bacteria in the oral cavity as well as in the lungs of lung transplant recipients was investigated for the first time. Eight lung transplant recipients underwent broncho-alveolar lavage, transbronchial biopsies, and endobronchial biopsies. In addition to routinely performed examinations, pulmonary as well as plaque samples were assessed for Aggregatibacter actinomycetemcomitans (Aa), Tannerella forsythia (Tf), Porphyromonas gingivalis (Pg), and Treponema denticola (Td) with the aid of a hybridization technique. No or only one periodontal pathogen (solitarily Pg) was found in the gingival plaques of five of the eight patients (group A). In three patients, two or more periodontal pathogens were detetectable in the gingival samples (group B). Whereas group A also had not more than one periodontal pathogen in the lungs, group B had more than one species in the lungs. In group B, all patients suffered from BOS, whereas in group A only one patient was affected. This is the first evidence for the presence of periodontal pathogens in the lungs of lung transplant recipients. Further studies with larger cohorts are required to elucidate potential links between periodontal infection, pulmonary colonization, and rejection.

Lung infections caused by the opportunistic pathogen Pseudomonas aeruginosa can present as a spectrum of clinical entities from a rapidly fatal pneumonia in a neutropenic patient to a multi-decade bronchitis in patients with cystic fibrosis. P. aeruginosa is ubiquitous in our environment, and one of the most versatile pathogens studied, capable of infecting a number of diverse life forms and surviving harsh environmental factors. It is also able to quickly adapt to new environments, including the lung, where it orchestrates virulence factors to acquire necessary nutrients, and if necessary, turn them off to prevent immune recognition. Despite these capabilities, P. aeruginosa rarely infects healthy human lungs. This is secondary to a highly evolved host defence mechanism that efficiently removes inhaled or aspirated pseudomonads. Many arms of the respiratory host defence have been elucidated using P. aeruginosa as a model pathogen. Human infections with P. aeruginosa have demonstrated the importance of the mechanical barrier functions including mucus clearance, and the innate immune system, including the critical role of the neutrophilic response. As more models of persistent or biofilm P. aeruginosa infections are developed, the role of the adaptive immune response will likely become more evident. Understanding the pathogenesis of P. aeruginosa, and the respiratory host defence response to it has, and will continue to, lead to novel therapeutic strategies to help patients., (© 2010 The Authors. Respirology © 2010 Asian Pacific Society of Respirology.)

Purpose: Gram-positive (GP) organisms are among the most common cause of infections in early postsurgical and immunocompromised populations. Patients recovering from lung transplantation (LT) are particularly susceptible owing to the physiologic stress imposed by surgery and induction with intense immunosuppression. Sites, types, and timing of GP infections following LT are not well documented. This report describes the clinical spectrum of GP infections and their effects on surgical airway complications (SAC) and bronchiolitis obliterans syndrome (BOS) following LT., Methods and Materials: Data were collected from 202 patients undergoing 208 LT procedures at a single institution between November 1990 and November 2005. Data were retrospectively analyzed according to timing, location, and causative pathogen., Results: In the median follow-up period of 2.7 years (range, 0-13.6 years), 137 GP infections were confirmed in 72 patients. Sites of infection included respiratory tract (42%), blood (27%), skin, wound and catheter (21%), and other (10%). GP pathogens identified were Staphylococcus species (77%), Enterococcus species (12%), Streptococcus species (6%), Pneumococcus (4%), and Eubacterium lentum (1%). The likelihood of SAC and BOS was increased in lung allograft recipients with GP pneumonia as compared with those without (hazard ratio 2.1; 95% confidence interval=1.5-3.1)., Conclusions: GP organisms were responsible for infections in 40% of lung allograft recipients and most commonly isolated from the respiratory tract and blood stream. Staphylococcal species were most frequently identified, 42% of which were methicillin-resistant Staphylococcus aureus (MRSA). Given the strong association of respiratory tract infections with the development of SAC and BOS, empiric antimicrobial strategies after LT should include agents directed against GP organisms, especially MRSA.

Bronchiolitis obliterans syndrome (BOS) represents the leading cause of late mortality after lung transplantation (LTx). Cystic fibrosis (CF) patients frequently show airway colonization with gram-negative bacteria (GNB) both before and after LTx. Graft colonization with GNB and its relevance towards BOS development were investigated in a CF population after LTx. Adult CF patients receiving LTx and surviving at least 6 months were included in this prospective observational study between 1/1/2002 and 30/6/2006 in a single center and followed until 31/3/2007. Pre- and post-LTx respiratory culture samples were compared for the presence of identical GNB. BOS-free survival was compared in colonized and non-colonized patients. Fifty-nine adult CF patients with a median age at LTx of 25.5 (18-49) years were included and had a median follow-up of 966 (128-1889) days. Seven patients (15%) demonstrated immediate eradication of GNB in lower respiratory tract samples. A further 18 patients (34%) demonstrated transient colonization. Thirty-four recipients had further positive samples after LTx. Eighteen patients (31%) developed BOS >or=stage 1, 508 (114-1167) days after LTx. Freedom of graft colonization with pseudomonads was independently associated with less frequent development of BOS (p=0.006). Persistent graft colonization with pseudomonads increases the prevalence of BOS after LTx in CF patients. A significant proportion of post-LTx CF patients demonstrates subsequent GNB eradication during later follow-up and this may have a protective role against development of BOS. Strategies to eradicate airway colonization or reduce bacterial load may prevent BOS in CF patients after LTx.

Long-term survival after lung transplantation remains limited by the development of bronchiolitis obliterans syndrome (BOS). Allograft colonization with Pseudomonas aeruginosa is common particularly in recipients with BOS, but a possible etiological relationship remains unexplored. In 155 consecutive lung transplants, the development of allograft colonization with Pseudomonas was strongly associated with the development of BOS within 2 years of transplant (23.4% vs. 7.7% in those colonized and not colonized, respectively, P=0.006). Freedom from BOS was significantly shorter in those patients without any pretransplant bacterial reservoir developing de novo allograft pseudomonal colonization as compared with those remaining free of colonization (Kaplan-Meier log-rank P=0.014). The isolation of Pseudomonas preceded the diagnosis of BOS in 14 of 18 (78%) and by a median of 204 days (95% confidence interval 115-492) in patients developing both these complications. We conclude that de novo colonization of the lung allograft by Pseudomonas is strongly associated with the subsequent development of BOS.

Patients after organ transplantations are at risk for mycobacteriosis development. Frequency of the mycobacterial infection after bone marrow transplantation (BMT) is not as high as one could expect. It ranges from 0.4 to 4.9%. We present a case of a female patient after allogenic BMT as a treatment of chronic myelogenous leucaemia, with bronchiolitis obliterans as a symptom of graft versus host disease (GvHD), treated with corticosteroids and infected with Mycobacterium avium. She was admitted to the hospital with dyspnoea, cough with large amount of sputum production and subfebrile status. She had partial respiratory insufficiency and obturative disturbances of respiration (FEV(1) 0.67 l i.e. 22% of normal) with decline of VC (2.23 l i.e. 64% of normal). The high-resolution computed tomography (HRCT) revealed multifocal infiltrations and bronchiectases in the upper and middle pulmonary fields, which were absent in the previous HRCT taken 3 years earlier. In the bronchial secretion acid-fast bacilli were found by smear and culture. The isolate was classified as Mycobacterium avium complex (MAC) by high performance liquid chromatography (HPLC). The patient was treated with clarithromycin, ciprofloxacin, isoniazide (INH), ethambutol (EMB), amikacin, but M. avium was still present in the sputum after 3 months. Treatment was continued in her parent hospital, where after a few months her sputum became negative for M. avium. But she died over a year later from progressive respiratory insufficiency in the course of bronchiolitis obliterans. The patient was in the group of high risk for mycobacterial infection development and the course of her illness was typical. We decided however to present the case as the topic seems to be quite neglected in the literature.

Mononuclear phagocytes are critical components of the innate host defense of the lung to inhaled bacterial pathogens. The monocyte chemotactic protein CCL2 plays a pivotal role in inflammatory mononuclear phagocyte recruitment. In this study, we tested the hypothesis that increased CCL2-dependent mononuclear phagocyte recruitment would improve lung innate host defense to infection with Streptococcus pneumoniae. CCL2 transgenic mice that overexpress human CCL2 protein in type II alveolar epithelial cells and secrete it into the alveolar air space showed a similar proinflammatory mediator response and neutrophilic alveolitis to challenge with S. pneumoniae as wild-type mice. However, CCL2 overexpressing mice showed an improved pneumococcal clearance and survival compared with wild-type mice that was associated with substantially increased lung mononuclear phagocyte subset accumulations upon pneumococcal challenge. Surprisingly, CCL2 overexpressing mice developed bronchiolitis obliterans upon pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block the CCL2-CCR2 axis in CCL2 overexpressing mice, though completely abrogating bronchiolitis obliterans, led to progressive pneumococcal pneumonia. Collectively, these findings demonstrate the importance of the CCL2-CCR2 axis in the regulation of both the resolution/repair and remodelling processes after bacterial challenge and suggest that overwhelming innate immune responses may trigger bronchiolitis obliterans formation in bacterial lung infections.

Bronchiolitis obliterans (OB) or bronchiolitis obliterans syndrome (BOS) remains a major hurdle in the long-term survival of lung transplant recipients. The pathogenesis of OB or BOS remains to be fully discerned, but it is hypothesized that allogenic or nonallogenic insults result in the release of chemokines and T lymphocytes propagating the injury and ultimately recruiting fibroblasts culminating in intraluminal proliferation. Infectious agents, with or without other exogenous factors, have been proposed to have a contributory role in the development of OB or BOS. Cytomegalovirus (CMV) is an immunomodulating virus that may lead to persistent stimulation of T cells with the release of chemokines that may promote OB. Animal studies have correlated the development of OB with CMV infection. However, assessment of CMV as a risk factor for the development of OB or BOS in clinical studies has yielded conflicting results. CMV infection was noted to have a hazard ratio of 1.62 in one study, whereas CMV pneumonitis was associated with relative risk of 2.3. Additional studies did not find a higher risk for developing OB or BOS with CMV. Other viruses including respiratory syncytial virus and parainfluenza viruses can promote epithelial damage and act synergistically with chronic rejection in the development of OB. A higher (47%) incidence of BOS has been noted during the respiratory virus season. The evidence of Pneumocystis carinii pneumonia or other infectious episodes causing OB is lacking. Thus, although the role of infectious agents in the development of OB or BOS is biologically plausible, an incontrovertible association between infection and OB or BOS has not been documented. This is a US government work. There are no restrictions on its use.

Objective: To assess the incidence of pseudomonal infection, colonization, and inflammation in the allograft of lung transplant recipients with cystic fibrosis (CF) as compared with recipients with other end-stage lung disease., Design: Retrospective review., Setting: University medical center transplant service., Patients: All patients with CF and chronic pseudomonal infection (n=62) and patients with nonseptic end-stage lung disease (n=52) receiving a double lung transplant between October 1983 and March 1996., Results: Fifty lung transplant recipients with CF survived beyond postoperative day (POD) 15 and were subject to sequential bronchoscopy with BAL. Forty-four CF lung transplant recipients had Pseudomonas isolated from the allograft by median POD 15 as compared with 21 non-CF lung transplant recipients (p<0.001) with isolation at median POD 158 (p<0.0001). Thirteen CF lung transplant recipients had histologic evidence of infection when Pseudomonas was isolated as compared with only three of the non-CF lung transplant recipients (p<0.01). These infections occurred earlier in the CF lung transplant recipients (median POD 10 vs 261) (p<0.01). When compared with non-CF lung transplant recipients, CF lung transplant recipients with Pseudomonas isolated but without concomitant histologic infection (colonized) were demonstrated to have increased number of polymorphonuclear cells (PMNs) in the BAL fluid recovered from the allograft (17.66+/-24.94 x 10(6) cells vs 3.46+/-4.73 x 10(6)) (p<0.05). Non-CF lung transplant recipients who became colonized with Pseudomonas also had a greater number of PMNs recovered when compared with non-CF lung transplant recipients who did not have Pseudomonas (22.32+/-34.00 x 10(6) cells vs 0.21+/-0.18 x 10(6)) (p<0.01). Nine of 32 (28%) lung transplant recipients with CF have died from pseudomonal allograft infections, but this is no greater than 4 of 21 (19%) deaths related to Pseudomonas infection in recipients without CF (p=0.34)., Conclusions: Isolation of Pseudomonas from the lung allograft occurs more frequently and earlier after transplantation in recipients with CF. While infections related to Pseudomonas also occur more frequently in recipients with CF, there is no increase in mortality. There is an intense inflammatory response in the lung allograft associated with the isolation of Pseudomonas in recipients with and without CF.

We identified eight patients with bronchiolitis obliterans (BO) in the autopsies of 81 bone marrow transplant (BMT) recipients. Rapidly progressive dyspnoea and cough were the main presenting symptoms in all eight patients, associated with overinflation and/or infiltrative opacity seen on chest X-ray and obstructive disorder revealed by pulmonary function tests. Early lesions were characterized by epithelial loss and an inflammatory infiltrate containing foamy histiocytes with mild luminal narrowing. Partial or total occlusion of the bronchiolar lumina by fibrous connective tissue was the feature of late lesions. Both changes were coexistent in all cases. In one case, small bronchi with cartilage were also affected by the obstructive process, showing bronchitis obliterans. All eight patients showed non-obstructive broncho-bronchiolitis characterized by denuding of respiratory epithelium, mural oedema and an inflammatory infiltrate in addition to BO, and these changes were also seen in 18 patients without BO. The submucosal glands of large bronchi and the trachea showed mucous retention and a mild inflammatory infiltrate in four of the eight patients. Coexistent infectious processes were seen in all cases, cytomegalovirus and Aspergillus being the most frequent organisms. BO probably develops as an immunopathological event related to graft-versus-host disease (GVHD) during the impaired immune status phase of the post-BMT period, possibly initiated by infection. Bronchial gland involvement in chronic GVHD is one of the factors responsible for this abnormal immune status.

Pathological and bacteriological observations were made on 100 (0.98%) pneumonic lungs of 10140 slaughtered beef calves during March 1995-June 1996 period. Gross lesions were mainly lobular and occasionally lobar pattern and, were frequently observed in the pars cranialis of lobus cranialis dexter. In histological examination, proliferative-exudative pneumonia was observed in 79 cases, and proliferative pneumonia alone in 21 cases. In bacteriological examination, Pasteurella haemolytica. Pasteurella multocida and Haemophilus somnus were isolated from 42.8 and 10 of pneumonic lungs respectively. In 7 cases, P. haemolytica and H. somnus were isolated from the same sample P. haemolytica and P. multocida were also found in the same sample in 2 cases. There was a close relation among these organisms and exudative inflammation (P < 0.01).

Airway damage resulting in bronchiolitis obliterans occurs frequently in patients after heart-lung and lung transplantation. Generally, chronic rejection is assumed to be the most important cause of bronchiolitis obliterans. However, viral infections might also be potential causes of airway damage after lung transplantation. In the present study, we investigated whether viral infections could induce airway damage in rat lung transplants in the absence or presence of chronic rejection. We compared the histopathology of the airways in 3 groups of rats: (1) nontransplanted LEW lungs, (2) LEW-to-LEW syngeneic lung transplants, and (3) BN-to-LEW allogeneic lung transplants. Nontransplanted and transplanted rats were treated with CsA to induce permanent graft acceptance of the allografts. Six months after transplantation, 4 noninfected rats of each group were killed for histological investigation (another 4 noninfected allografted rats were killed 56 days later). The remaining 16 rats in each group were infected with Sendai virus (parainfluenza type 1) intratracheally. These rats were killed for histological investigation 4, 7, 21, and 56 days after infection. In the lungs of the noninfected rats of the nontransplanted and syngeneically transplanted groups, airway changes were absent. After viral infection in these lungs, mild inflammation developed in the airways that was transient and completely resolved by day 56 after infection. In contrast, in the allogeneically transplanted lungs the viral infection caused severe and permanent damage of the airways. In the bronchioles and the large airways throughout the allogeneic lung transplants, inflammation with epithelial necrosis and formation of granulation tissue was present. On day 56 after infection, the bronchioles showed scarring in the submucosa and obliteration of the lumen, typical features of bronchiolitis obliterans. This study shows that a respiratory viral infection aggravates the airway damage in rat lung allografts with chronic rejection. The findings suggest that viral infections and chronic rejection play a synergistic role in the development of bronchiolitis obliterans after human heart-lung and lung transplantation: the virus infection may stimulate chronic rejection and rejection may hamper the local defense against the virus.

We report two cases of necrotizing bronchiolitis and bronchiolitis obliterans associated with the finding of the fungus aspergillus. One of the cases also showed bronchiolocentric granulomas and mucoid impaction of a segmental bronchus. Both patients were immunocompromised and had presented with dyspnea, cough, fever, and pulmonary infiltrates. Systemic antifungal therapy led to symptomatic and radiologic resolution. We surmise that these cases represent unusual examples of chronic necrotizing aspergillosis. The spectrum of pulmonary aspergillus diseases is reviewed.

Since its recognition as a clinical entity in the 1940s, our knowledge of bronchiolitis has grown with respect to the breadth of disease, epidemiology, treatment, and long-term effects. Bronchiolitis occurs most commonly in infants and children in association with a predictably small number of respiratory pathogens. Our knowledge of the association of bronchiolitis to subsequent wheezing is in a state of evolution. Rarely, bronchiolitis may progress to a chronic obstructive process, bronchiolitis obliterans, seen most often following adenovirus infection. The diagnosis of bronchiolitis in adults is relatively rare and although specific information on etiologic agents is lacking, it is not unlikely that the implicated infectious agents in infant bronchiolitis may play a role in the adult form of the disease. Bronchiolitis obliterans in adults occurs as a result of many possible causes, including infection. Although infection probably contributes to the pathogenesis of bronchiolitis obliterans in the post-organ-transplant population, this process appears to be a complex interaction centering around graft rejection.

Lung transplantation has become a realistic treatment in some patients with severe respiratory impairment or severe pulmonary arterial hypertension. Immunosuppression therapy is about the same in all transplantation units and includes cyclosporin, corticosteroids and azathioprine. The diagnosis of acute rejection episodes has been greatly facilitated by the histological study of transbronchial biopsies obtained by endoscopy. Improvements in the short-term prognosis of these patients have made it possible to individualize an unusual and delayed complication: bronchiolitis obliterans. This progressive and diffuse obstruction followed by destruction of the transplant's bronchioles is interpreted as a consequence of chronic rejection. The diagnosis of bronchiolitis obliterans is difficult and rests essentially on degradation of the respiratory function resisting to increased immunosuppression. Some viral infections perhaps contribute to its development, and it may be so severe as to require another lung transplantation.

This report describes a 28-year-old patient with an acute onset of respiratory symptoms associated with clinical and roentgenographic features of an interstitial lung disease which proved fatal. The entity of bronchiolitis obliterans, which was diagnosed on transbronchial biopsy, is discussed, with particular emphasis on the postinfectious type.

This report describes a patient with right lower lung (RLL) pneumonia of a subacute nature. Sputum and bronchial washings both grew N asteroides. Open lung biopsy showed bronchiolitis obliterans. Both the clinical and radiologic picture dramatically improved during three weeks of treatment with trimethoprim and sulfamethoxazole (TMP - SMX), indicating the possibility that N asteroides infection contributed to bronchiolitis obliterans pneumonia in this patient.