Association Between FEV1 Decline Rate and Mortality in Long-Term Follow-Up of a 21-Patient Pilot Clinical Trial of Inhaled Liposomal Cyclosporine Plus Standard-of-Care Versus Standard-of-Care Alone for Bronchiolitis Obliterans Syndrome After Lung Transplantation.

BACKGROUND The association between forced expiratory volume in 1 second (FEV1) trajectory and mortality in bronchiolitis obliterans syndrome (BOS) is not well defined. Using long-term data from a prior clinical trial of inhaled liposomal cyclosporine A (L-CsA-I) for lung transplant patients with BOS, this study examined the association between longitudinal FEV1 change and mortality. MATERIAL AND METHODS We analyzed long-term data from a clinical trial which randomized 21 patients with BOS (³20% decrease in FEV1 from personal maximum) to receive L-CsA-I plus standard-of-care (n=11) or standard-of-care (SOC) alone (n=10) for 24 weeks. A joint statistical model, combining a linear mixed model for FEV1 change and Cox regression for mortality, was utilized to examine the overall association between FEV1 trajectory and mortality during follow-up. RESULTS The 21 trial participants (10 single, 11 double lung recipients) had a mean FEV1 of 1.7±0.6 Liters at randomization. Median follow-up post-randomization was 35 months. In joint model analysis, 1 percent FEV1 decline predicted 1.076-fold increased mortality risk (95% confidence interval: -0.998 to 1.160, p=0.058). FEV1 decline was reduced by 2.6% per year in L-CsA-I patients compared to SOC (p=0.210), and overall survival at 1/3/5 years was 91%/64%/27% vs 90%/20%/0% for L-CsA-I versus SOC, respectively (p=0.164). CONCLUSIONS In BOS patients, greater longitudinal FEV1 decline predicts increased mortality. Trends towards prolonged stabilization of FEV1 and improved survival were observed with L-CsA-I receipt. Further analyses will aid in evaluating the utility of FEV1 change as a survival predictor, having implications in BOS management and future trial design.

Relationship between FEV1 decline and mortality in patients with bronchiolitis obliterans syndrome-a systematic literature review.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is one of the most severe complications and the leading cause of late mortality and morbidity after lung transplantation (LT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). No approved treatment for BOS is available. This review aimed to systematically identify and summarise the findings regarding the relationship between FEV1 decline and mortality in patients who developed BOS following LT or allo-HSCT. METHODS: A systematic literature search was performed in the Medline, Embase and Cochrane reviews databases. Of the 501 potential studies identified 25 met inclusion criteria and were analysed. RESULTS: Overall, 13 studies reported a relationship between FEV1 and mortality, and 12 studies reported both mortality and FEV1 results but did not investigate the relationship between them. There was heterogeneity in the analyses, which investigated the relationship between FEV1 decline and mortality across the studies in terms of levels of lung functioning, comparison to a control group, treatment, and statistical methodology; nevertheless, a clear and consistent increase in the risk of death associated with FEV1 decrease was seen in the analysed studies. CONCLUSIONS: The systematic literature review identified studies and findings that support a relationship between FEV1 and mortality, with a decrease in FEV1 being statistically associated with increased risk of death. Knowing that lower FEV1 levels are associated with higher mortality rates may help assess the condition of a patient with BOS and monitor future treatment effectiveness. However, more evidence is needed to further investigate this relationship and to verify its clinical usefulness.

Intensive pulmonary rehabilitation in a pediatric lung transplantation patient: A case report.

BACKGROUND: The pediatric lung transplant is a very important treatment for patients with end-stage lung diseae, and pulmonary rehabilitation (PR) is also an important factor in determining the prognosis. However, there is no much literature available on pulmonary rehabilitation in pediatric patients' post lung transplant. Through this case report, we would like to present our intensive PR program for pediatric patients' post-lung transplant. PATIENT CONCERNS: The 10-year-old boy's breathing before receiving a lung transplant continued to deteriorate and he eventually became dependent on a wheelchair. DIAGNOSIS: He was diagnosed with infantile acute lymphoblastic leukemia at 6 months of age. At the age of one year, he underwent allogeneic bone marrow transplantation, but was diagnosed with post-transplantation bronchiolitis obliterans (PTBO) two months later. He had a lung transplant at the age of 10. INTERVENTIONS: He was hospitalized and received an initial assessment. This assessment included functional, cognitive, and psychological evaluations. He additionally completed PR exercises twice daily for two weeks. After discharge, he continued to participate in an outpatient-based PR program for three months. During the outpatient phase, PR exercises were performed once weekly, in addition to home-based cognitive training. OUTCOMES: Our intensive post-lung PR program improved our patient's exercise capacity, lung function, and quality of life. As a comprehensive rehabilitation service, our program also included a cognitive training component. CONCLUSION: We describe an intensive PR program tailored to pediatric patients' post-lung transplant. The program was feasible and resulted in improvements in functional exercise capacity, lung function, and quality of life. Future research into our method is necessary for continued improvement of this novel program.

Childhood bronchiolitis obliterans in Hong Kong-case series over a 20-year period.

BACKGROUND AND OBJECTIVE: Bronchiolitis obliterans (BO) is a rare but serious condition. The natural history and outcomes remain poorly understood. In this clinical review, we aimed to describe the clinical characteristics and outcomes of children diagnosed with BO in Hong Kong (HK). METHODS: This was a retrospective study of pediatric patients with BO under the care of six respiratory units in HK from January 1996 to December 2015. Information was retrieved from medical records. RESULTS: Fifty-six patients were included with a male predominance (67.9%). The median age at diagnosis was 1.98 years (interquartile range [IQR]: 0.84-4.99 years). Postinfectious BO (PIBO) was the commonest cause (64.3%) followed by posthematopoietic stem-cell transplant (21.4%). Adenovirus (63.2%) was the commonest causative pathogen among PIBO. The median follow-up duration was 9.7 years (IQR: 2.9-14.3 years). Twenty-five patients (44.6%) could achieve symptom-free recovery at the time of follow-up. Five (8.9%) and three (5.4%) were oxygen or ventilator dependent, respectively. There were two deaths, both had posttransplant BO. Patients who developed BO after transplant had significantly worse lung function than those with PIBO. There were no risk factors significantly associated with worse clinical outcomes (oxygen/ventilator dependence or death) by logistic regression. Among patients with PIBO, coinfection at presentation was significantly associated with persistent symptoms at follow-up (p = .028). CONCLUSIONS: The most common cause of childhood BO in HK is postinfectious and coinfection at presentation was associated with persistent symptoms at follow-up. Further studies are needed to better elucidate disease progression, treatment options and long term outcomes.

Respiratory muscle impairment evaluated with mep/mip ratio in children and adolescents with chronic respiratory disease / Fraqueza muscular respiratória avaliada por meio da relação pemax/pimax em crianças com doença respiratória crônica

ABSTRACT Objective: To evaluate the strength of respiratory muscles and to compare maximum inspiratory (MIP) and expiratory (MEP) pressure and MEP/MIP ratio between patients with chronic respiratory diseases and healthy individuals. Methods: Case-control study. Individuals with neuromuscular disease and post-infectious bronchiolitis obliterans were considered. In addition, they were also matched according to anthropometric and demographic characteristics with healthy children and adolescents. MIP, MEP in the three groups, and pulmonary function only in patients with chronic respiratory diseases were recorded. Results: A total of 52 subjects with CRD (25 with neuromuscular disease, and 27 with post-infectious bronchiolitis obliterans) and 85 healthy individuals were included, with an average age of 11.3±2.1 years. Patients with neuromuscular disease and post-infectious bronchiolitis obliterans presented lower MIP and MEP when compared with healthy individuals, although MEP/MIP ratio was lower in patients with neuromuscular disease (0.87±0.3) and higher in patients with post-infectious bronchiolitis obliterans (1.1±0.3) compared to the healthy group (0.97±0.2). Only in patients with neuromuscular disease a negative correlation was observed between MEP/MIP ratio and age (r=-0.50; p=0.01). Conclusions: Differences in the pattern of muscular weakness between patients with chronic respiratory diseases were observed. In patients with neuromuscular disease, a decrease in the MEP/MIP ratio depending on MIP was verified; and in those patients with post-infectious bronchiolitis obliterans, an increase in the MEP/MIP ratio depending on MIP was also observed.

RESUMO Objetivo: Avaliar a força dos músculos respiratórios e comparar a relação entre a pressão expiratória máxima (PEmáx) e a pressão inspiratória máxima (PImáx) em pacientes com doença respiratória crônica (DRC) e crianças saudáveis. Métodos: Estudo caso-controle. Foram selecionados indivíduos com doença neuromuscular e bronquiolite obliterante pós-infecciosa. Ademais, os grupos foram pareados com crianças e adolescentes saudáveis, considerando características antropométricas e demográficas. Foram registradas a PImáx e a PEmáx nos três grupos e a função pulmonar apenas em pacientes com doença respiratória crônica. Resultados: Foram incluídos 52 indivíduos com DRC (25 com doença neuromuscular e 27 com bronquiolite obliterante pós-infecciosa) e 85 indivíduos saudáveis, com idade média de 11,3±2,1 anos. Pacientes com doença neuromuscular e bronquiolite obliterante pós-infecciosa apresentaram menor PImáx e PEmáx em comparação aos indivíduos saudáveis, embora a relação PEmáx/PImáx tenha sido menor nos pacientes com doença neuromuscular (0,87±0,3) e maior nos pacientes com bronquiolite obliterante pós-infecciosa (1,1±0,3) em comparação ao grupo saudável (0,97±0,2). Somente em pacientes com doença neuromuscular foi observada uma correlação negativa entre a razão PEmáx/PImáx e a idade (r=-0,50; p=0,01). Conclusões: Foram observadas diferenças no padrão de fraqueza muscular em pacientes com doença respiratória crônica. Nos pacientes com doença neuromuscular, verificou-se diminuição na relação PEmáx/PImáx dependendo da PImáx; em pacientes com bronquiolite obliterante pós-infecciosa, foi observado aumento na relação dependendo da PImáx.

RESPIRATORY MUSCLE IMPAIRMENT EVALUATED WITH MEP/MIP RATIO IN CHILDREN AND ADOLESCENTS WITH CHRONIC RESPIRATORY DISEASE.

OBJECTIVE: To evaluate the strength of respiratory muscles and to compare maximum inspiratory (MIP) and expiratory (MEP) pressure and MEP/MIP ratio between patients with chronic respiratory diseases and healthy individuals. METHODS: Case-control study. Individuals with neuromuscular disease and post-infectious bronchiolitis obliterans were considered. In addition, they were also matched according to anthropometric and demographic characteristics with healthy children and adolescents. MIP, MEP in the three groups, and pulmonary function only in patients with chronic respiratory diseases were recorded. RESULTS: A total of 52 subjects with CRD (25 with neuromuscular disease, and 27 with post-infectious bronchiolitis obliterans) and 85 healthy individuals were included, with an average age of 11.3±2.1 years. Patients with neuromuscular disease and post-infectious bronchiolitis obliterans presented lower MIP and MEP when compared with healthy individuals, although MEP/MIP ratio was lower in patients with neuromuscular disease (0.87±0.3) and higher in patients with post-infectious bronchiolitis obliterans (1.1±0.3) compared to the healthy group (0.97±0.2). Only in patients with neuromuscular disease a negative correlation was observed between MEP/MIP ratio and age (r=-0.50; p=0.01). CONCLUSIONS: Differences in the pattern of muscular weakness between patients with chronic respiratory diseases were observed. In patients with neuromuscular disease, a decrease in the MEP/MIP ratio depending on MIP was verified; and in those patients with post-infectious bronchiolitis obliterans, an increase in the MEP/MIP ratio depending on MIP was also observed.

Bronchoalveolar lavage T cell cytokine profiles and their association with lung function in children with Mycoplasma pneumoniae -associated bronchiolitis obliterans.

BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) infection may progress to bronchiolitis obliterans (BO), with an underlying chronic inflammatory process. The aim of this study was to investigate the cytokine profiles in pulmonary T-lymphocytes and their associations with lung function in patients with BO following M. pneumoniae infection. METHODS: Bronchoalveolar lavage (BAL) samples were obtained from 10 controls and 18 children with M. pneumoniae-associated BO. We analyzed the BAL T cells for interferon (IFN)-γ, interleukin (IL)-4, IL-9, IL-17, CD25, and Foxp3 by intercellular flow cytometry. The associations with T-cell subpopulations and lung function parameters were determined. RESULTS: In BAL fluid, significantly increased proportions of T-helper 1 (Th1), Th17, and Tc1 cells were found in M. pneumoniae-associated BO patients when compared with controls. The percentages of Th17 cells showed correlations with forced expiratory volume in 1 second % predicted value (r = -0585; P < .05) and forced expiratory flow at 25% to 75% (FEF25%-75% ) % predicted value (r = -.618; P < .01). Higher proportions of Tc1 (r = -.488; P < .05) and Tc17 (r = -.542; P < .05) were significantly correlated with a reduced FEF25%-75% % predicted value in M. pneumoniae-associated BO patients. CONCLUSIONS: Our comprehensive cytokines analysis of BAL T cells revealed correlations of IL-17-producing and IFN-γ-producing T cells with lung function, suggesting that increased T-cell subpopulations may play a role in M. pneumoniae-associated BO progression.

Health-related quality of life in patients with bronchiolitis obliterans.

INTRODUCTION: Bronchiolitis obliterans (BO) is mainly caused by infections and hematopoietic stem cell transplantation (HSCT). This study aimed to investigate the health-related quality of life (HRQOL) of children with BO compared to the healthy children and also to assess the HRQOL according to the etiology. METHODS: Postinfectious (group 1) and post-HSCT BO (group 2) patients and healthy children were included in the study. HRQOL was assessed by the Short Form-36 (SF-36) and St George's Respiratory Questionnaire (SGRQ). Correlations between demographic and clinical characteristics, pulmonary function tests, high-resolution chest tomography scores, and HRQOL were assessed. RESULTS: Thirty-seven postinfectious and post-HSCT BO patients and 34 healthy children were included in the study. Mean age was 13.8 ± 0.7 years. Mean forced vital capacity and forced expiratory volume1 were 60.7 ± 2.7% predicted, and 49.8 ± 3.1% predicted, respectively. The SF-36 scores were lower in BO patients compared to healthy children (P < .01). Patients with better lung functions had higher SF-36 scores, but lower SGRQ. The number of inhaled therapies, acute exacerbations, hospitalizations were inversely correlated with SF-36. A positive correlation was found between these parameters and total SGRQ scores (r = .507, P = .02; r = .409, P = .12; r = .326, P = .049, respectively). SF-36 scores were better in group 1 for subscales of physical role functioning and social role functioning compared to group 2. (P = .01, P = .01, respectively). CONCLUSION: The HRQOL of patients with BO measured by SF-36 was low compared to healthy children. SF-36 scores were more affected in post-HSCT BO patients. HRQOL of children with chronic lung disease should be taken into consideration in the management of these patients.

Long-term pulmonary function testing in pediatric bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

RATIONALE: Bronchiolitis obliterans syndrome (BOS) is a severe, chronic inflammation of the airways leading to an obstruction of the bronchioles. So far, there are only a few studies looking at the long-term development of pulmonary impairment in children with BOS. OBJECTIVE: The objective of this study was to investigate the incidence and long-term outcome of BOS in children who underwent allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Medical charts of 526 children undergoing HSCT in Frankfurt/Main, Germany between 2000 and 2017 were analyzed retrospectively and as a result, 14 patients with BOS were identified. A total of 271 lung functions (spirometry and body plethysmography), 26 lung clearance indices (LCI), and 46 chest high-resolution computed tomography (HRCT) of these 14 patients with BOS were evaluated. RESULTS: Fourteen patients suffered from BOS after HSCT (2.7%), whereby three distinctive patterns of lung function impairment were observed: three out of 14 patients showed a progressive lung function decline; two died and one received a lung transplant. In five out of 14 patients with BOS persisted with a severe obstructive and secondarily restrictive pattern in lung function (forced vital capacity [FVC] < 60%, forced expiratory volume in 1 second [FEV1] < 50%, and FEV1/FVC < 0.7) and increased LCI (11.67-20.9), six out of 14 patients recovered completely after moderate lung function impairment and signs of BOS on HRCT. Long-term FVC in absolute numbers was increased indicating that the children still have lung growth. CONCLUSION: Our results showed that the incidence of BOS in children is low. BOS was associated with high mortality and may lead to persistent obstructive lung disease; although, lung growth continued to exist.

Lung Transplant Patients Show a Dissimilar Peripheral B-Cell Subset Ratio Compared With Healthy Controls.

OBJECTIVES: Lung transplant is a last treatment option for patients with end-stage pulmonary disease. Chronic lung allograft dysfunction, which generally manifests as bronchiolitis obliterans syndrome, is a major long-term survival limitation. Bronchiolitis obliterans syndrome is diagnosed when forced expiratory volume in 1 second declines > 20% in the absence of known causes. B cells can either contribute or restrain the development of bronchiolitis obliterans syndrome (eg, via induction of alloimmune antibodies, regulation of cellular immunity, and induction of tolerance). Here, we explored how peripheral B-cell subsets were altered in lung transplant recipients with bronchiolitis obliterans syndrome. MATERIALS AND METHODS: Fresh whole blood samples were analyzed from 42 lung transplant recipients, including 17 with bronchiolitis obliterans syndrome; samples from these groups were compared with 10 age-matched healthy control samples. B-cell subsets were analyzed using flow cytometry, and relative distributions of subsets were compared. Changes in forced expiratory volume in 1 second were also determined. RESULTS: Absolute B-cell count was significantly increased in transplant recipients with bronchiolitis obliterans syndrome. Transitional (CD24+CD38+) and naïve (CD27-IgD+) B cells were decreased in lung transplant patients, with transitional B cells almost absent in those with bronchiolitis obliterans syndrome. Double-negative (CD27-IgD-) memory B cells were significantly increased (P < .001). No differences were found for plasmablasts (CD38+CD24-) and switched (CD27+IgD-) and non-switched (CD27+IgD+) memory B cells. Correlation analyses showed positive correlations between lung function and naïve B cells in transplant recipients (P = .0245; r = -0.458). CONCLUSIONS: Peripheral B-cell count and subset distribution were altered in lung transplant recipients with and without bronchiolitis obliterans syndrome compared with healthy controls. Transitional and naïve B-cell decreases may be caused by differentiation toward double-negative B-cells, which were increased. The correlation between forced expiratory volume and naïve B cells during follow-up care may be clinically interesting to investigate.

Quantitative CT analysis for bronchiolitis obliterans in perinatally HIV-infected adolescents-comparison with controls and lung function data.

OBJECTIVE: To compare quantitative chest CT parameters in perinatally HIV-infected adolescents with and without bronchiolitis obliterans compared with HIV-uninfected controls and their association with lung function measurements. MATERIALS AND METHODS: Seventy-eight (41 girls) HIV-infected adolescents with a mean age of 13.8 ± 1.65 years and abnormal pulmonary function tests in the prospective Cape Town Adolescent Antiretroviral Cohort underwent contrast-enhanced chest CT on inspiration and expiration. Sixteen age-, sex-, and height-matched non-infected controls were identified retrospectively. Fifty-one HIV-infected adolescents (28 girls) displayed mosaic attenuation on expiration suggesting bronchiolitis obliterans. Pulmonary function tests were collected. The following parameters were obtained: low- and high-attenuation areas, mean lung density, kurtosis, skewness, ventilation heterogeneity, lung mass, and volume. RESULTS: HIV-infected adolescents showed a significantly higher mean lung density, ventilation heterogeneity, mass, and high- and low-attenuation areas compared with non-infected individuals. Kurtosis and skewness were significantly lower as well. HIV-infected adolescents with bronchiolitis obliterans had a significantly lower kurtosis and skewness compared with those without bronchiolitis obliterans. Lung mass and volume showed the strongest correlations with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and alveolar volume. Low-attenuation areas below - 950 HU and ventilation heterogeneity showed the strongest correlation with FEV1/FVC (range, - 0.51 to - 0.34) and forced expiratory flow between 25 and 75% of FVC (range, - 0.50 to - 0.35). CONCLUSION: Quantitative chest CT on inspiration is a feasible technique to differentiate perinatally HIV-infected adolescents with and without bronchiolitis obliterans. Quantitative CT parameters correlate with spirometric measurements of small-airway disease. KEY POINTS: • Perinatally HIV-infected adolescents showed a more heterogeneous attenuation of the lung parenchyma with a higher percentage of low- and high-attenuation areas compared with non-infected patients. • Kurtosis and skewness are able to differentiate between HIV-infected adolescents with and without bronchiolitis obliterans using an inspiratory chest CT. • Quantitative CT parameters of the chest correlate significantly with pulmonary function test. Low-attenuation areas and ventilation heterogeneity are particularly associated with spirometric parameters related to airway obstruction.

Postinfectious bronchiolitis obliterans masked by misdiagnosis as asthma.

OBJECTIVES: Asthma and postinfectious bronchiolitis obliterans (PIBO) have similar clinical findings, and PIBO may be misdiagnosed with asthma. This study aimed to determine the clinical features of PIBO in children and the causes of delay in its diagnosis. METHODS: We retrospectively evaluated all patients diagnosed with PIBO in four pediatric pulmonology centers between 2007 and 2018. In total, 64 PIBO patients were retrospectively reviewed. We compared the clinical and laboratory differences between PIBO patients who had initially been misdiagnosed with asthma and correctly diagnosed with PIBO. RESULTS: Of the 64 patients, 22 (34.4%) had initially been misdiagnosed with asthma. Adenovirus was the most common infectious agent in children. The age upon diagnosis was older, and the symptom duration was significantly longer in patients misdiagnosed with asthma (P < .05). There were no statistical differences in terms of sex, history of prematurity, duration of hospitalization, treatment, history of oxygen or mechanical ventilation support, pulmonary function test (PFT) results and asthma-predisposing findings between the two groups (P > .05). CONCLUSIONS: Patients with PIBO who had initially been misdiagnosed with asthma were correctly diagnosed at older ages and had longer symptom duration. Asthma may mask PIBO diagnosis by the similarity of symptoms and the clinical response to inhaled ß2-agonist or steroid treatment. PFTs may not help clinicians because of the age of children. The delay in the diagnosis of PIBO is probably attributable to the fact that some clinicians fail to include PIBO in the differential diagnosis when there is no clinical response to asthma medication.

Hydrogen water alleviates obliterative airway disease in mice.

OBJECTIVE: Bronchiolitis obliterans syndrome arising from chronic airway inflammation is a leading cause of death following lung transplantation. Several studies have suggested that inhaled hydrogen can protect lung grafts from ischemia-reperfusion injury via anti-inflammatory and -oxidative mechanisms. We investigated whether molecular hydrogen-saturated water can preserve lung allograft function in a heterotopic tracheal allograft mouse model of obliterative airway disease METHODS: Obliterative airway disease was induced by heterotopically transplanting tracheal allografts from BALB/c donor mice into C57BL/6 recipient mice, which were subsequently administered hydrogen water (10 ppm) or tap water (control group) (n = 6 each) daily without any immunosuppressive treatment. Histological and immunohistochemical analyses were performed on days 7, 14, and 21. RESULTS: Hydrogen water decreased airway occlusion on day 14. No significant histological differences were observed on days 7 or 21. The cluster of differentiation 4/cluster of differentiation 3 ratio in tracheal allografts on day 14 was higher in the hydrogen water group than in control mice. Enzyme-linked immunosorbent assay performed on day 7 revealed that hydrogen water reduced the level of the pro-inflammatory cytokine interleukin-6 and increased that of forkhead box P3 transcription factor, suggesting an enhancement of regulatory T cell activity. CONCLUSIONS: Hydrogen water suppressed the development of mid-term obliterative airway disease in a mouse tracheal allograft model via anti-oxidant and -inflammatory mechanisms and through the activation of Tregs. Thus, hydrogen water is a potential treatment strategy for BOS that can improve the outcome of lung transplant patients.

Long-term effect of azithromycin in bronchiolitis obliterans syndrome.

Introduction: Azithromycin stabilises and improves lung function forced expiratory volume in one second (FEV1) in lung transplantation patients with bronchiolitis obliterans syndrome (BOS). A post hoc analysis was performed to assess the long-term effect of azithromycin on FEV1, BOS progression and survival . Methods: 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 FEV1, BOS free progression and overall survival. Results: FEV1 in the placebo group improved after open-label azithromycin and was comparable with the treatment group by 6 months. FEV1 decreased after 1 and 5 years and was not different between groups. Patients (n=18) with rapid progression of BOS underwent total lymphoid irradiation (TLI). Progression-free survival (log-rank test p=0.40) and overall survival (log-rank test p=0.28) were comparable. Survival of patients with early BOS was similar to late-onset BOS (log-rank test p=0.74). Discussion: Long-term treatment with azithromycin slows down the progression of BOS, although the effect of TLI may affect the observed attenuation of FEV1 decline. BOS progression and long-term survival were not affected by randomisation to the placebo group, given the early cross-over to azithromycin and possibly due to TLI in case of further progression. Performing randomised placebo-controlled trials in lung transplantation patients with BOS with a blinded trial duration is feasible, effective and safe.

The efficacy of mesenchymal stem cells in bronchiolitis obliterans syndrome after allogeneic HSCT: A multicenter prospective cohort study.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) after allo-HSCT is a devastating complication with limited therapeutic options. We aimed to assess the efficacy and safety of mesenchymal stem cells (MSCs) in BOS after allo-HSCT. METHODS: This multicenter prospective cohort study enrolled 81 allo-HSCT recipients whose BOS were diagnosed within 6 months. The choice of prednisone and azithromycin combined with or without MSCs was based on patient preferences (MSC n = 49, non-MSC n = 32). The primary endpoint was response rate at 3 months, defined as the proportion of patients achieving FEV1 improvement or steroid sparing. The trial was registered at ClinicalTrials.gov (NCT02543073). FINDINGS: Response rate was 35/49 patients (71%, 95% CI 59 to 84%) and 14/32 (44%, 27 to 61%) in MSC and non-MSC group, respectively (p = 0.013). The addition of MSCs was associated with a better difference for change in FEV1 rate of decline, compared to non-MSC group (53 mL/months, 2 to 103; p = 0.040). The 3-year overall survival post-diagnosis was 70.6% (55.9 to 85.3%) and 58.2% (36.1 to 78.5%) in MSC and non-MSC group, respectively (p = 0.21). Clinical improvement was accompanied by a significant increase of interleukin (IL)-10-producing CD5+B cells. There was no statistical difference in the rates of infections and leukemia relapse between the two groups. MSCs were well-tolerated with no serious adverse events. INTERPRETATION: MSCs offer an effective and safe therapeutic option for BOS after allo-HSCT. Our study strengthens evidence for clinical use of MSC therapy in BOS. These data also provide novel insight into potential biological mechanisms of MSC treatment and support further investigation in larger randomized controlled trials. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, Health Collaborative Innovation Major Projects of Guangzhou City, Science and Technology Planning Project of Guangdong Province.

Health-related quality of life in post-infectious bronchiolitis obliterans: agreement between children and their proxy / Qualidade de vida relacionada à saúde na bronquiolite obliterante pós-infecciosa: concordância entre as crianças e seus cuidadores

Abstract Objective: To assess the level of agreement in health-related quality of life between children with Post-infectious Bronchiolitis Obliterans and their parent (so-called proxy). Methods: Participants aged between 8and 17 years who had been previously diagnosed with Post-infectious Bronchiolitis Obliterans were regularly followed up at a pediatric pulmonology outpatient clinic. Parents or legal guardians (caregivers) of these patients were also recruited for the study. A validated and age-appropriate version of the Pediatric Quality of Life Inventory 4.0 was used for the assessment of health-related quality of life. Caregivers completed the corresponding proxy versions of the questionnaire. The correlation between self and proxy reports of health-related quality of life was determined by intra-class correlation coefficient and dependent t-tests. Results: The majority of participants were males (79.4%), and the average age was 11.8 years. Intra-class correlations between each of the Pediatric Quality of Life Inventory 4.0 domains and the total score were all lower than 0.6, with a range between 0.267 (poor) and 0.530 (fair). When the means of each domain and the total score of the questionnaires were compared, caregivers were observed to have a significantly lower health-related quality of life score than children, with the exception of the social domain in which the difference was not significant. However, the differences in score exceeded the critical threshold difference of four points in all other domains. Conclusion: Proxies of children and adolescents with Post-infectious Bronchiolitis Obliterans appear to consistently perceive their children as having lower health-related quality of life than how the patients perceive themselves.

Resumo: Objetivo: Avaliar o nível de concordância a respeito da qualidade de vida relacionada à saúde entre crianças com bronquiolite obliterante pós-infecciosa e seus pais (responsáveis). Métodos: Os participantes entre 8-17 anos, anteriormente diagnosticados com bronquiolite obliterante pós-infecciosa, foram acompanhados regularmente no ambulatório de pneumologia pediátrica. Os pais ou responsáveis legais (cuidadores) desses pacientes também foram convidados a participar do estudo. Uma versão validada e adequada para a idade do Inventário Pediátrico de Qualidade de Vida, versão 4.0, foi utilizada para a avaliação da qualidade de vida relacionada à saúde. Os cuidadores concluíram as versões do questionário correspondentes aos responsáveis. A correlação entre os autorrelatos e os relatos dos responsáveis da qualidade de vida relacionada à saúde foi determinada pelo coeficiente de correlação intraclasse e pelos testes t dependentes. Resultados: A maior parte dos participantes era do sexo masculino (79,4%) e a idade média foi 11,8 anos. As correlações intraclasse entre cada um dos domínios do Inventário Pediátrico de Qualidade de Vida e o escore total foram todas inferiores a 0,6, com intervalo entre 0,267 (baixo) e 0,530 (justo). Quando as médias de cada domínio e o escore total dos questionários foram comparados, observamos que os cuidadores apresentaram qualidade de vida relacionada à saúde significativamente menor em comparação com as crianças, com exceção do domínio social, no qual a diferença não foi significativa. Contudo, as diferenças no escore ultrapassaram o limite de diferença essencial de 4 pontos em todos os outros domínios. Conclusão: Os responsáveis pelas crianças e adolescentes com bronquiolite obliterante pós-infecciosa parecem perceber de forma consistente que suas crianças possuem qualidade de vida relacionada à saúde menor que os próprios pacientes.

Health-related quality of life in post-infectious bronchiolitis obliterans: agreement between children and their proxy.

OBJECTIVE: To assess the level of agreement in health-related quality of life between children with Post-infectious Bronchiolitis Obliterans and their parent (so-called proxy). METHODS: Participants aged between 8and 17 years who had been previously diagnosed with Post-infectious Bronchiolitis Obliterans were regularly followed up at a pediatric pulmonology outpatient clinic. Parents or legal guardians (caregivers) of these patients were also recruited for the study. A validated and age-appropriate version of the Pediatric Quality of Life Inventory 4.0 was used for the assessment of health-related quality of life. Caregivers completed the corresponding proxy versions of the questionnaire. The correlation between self and proxy reports of health-related quality of life was determined by intra-class correlation coefficient and dependent t-tests. RESULTS: The majority of participants were males (79.4%), and the average age was 11.8 years. Intra-class correlations between each of the Pediatric Quality of Life Inventory 4.0 domains and the total score were all lower than 0.6, with a range between 0.267 (poor) and 0.530 (fair). When the means of each domain and the total score of the questionnaires were compared, caregivers were observed to have a significantly lower health-related quality of life score than children, with the exception of the social domain in which the difference was not significant. However, the differences in score exceeded the critical threshold difference of four points in all other domains. CONCLUSION: Proxies of children and adolescents with Post-infectious Bronchiolitis Obliterans appear to consistently perceive their children as having lower health-related quality of life than how the patients perceive themselves.

Evolution of Functional Exercise Capacity in Lung Transplant Patients With and Without Bronchiolitis Obliterans Syndrome: A Longitudinal Case-Control Study / Evolución de la capacidad funcional al ejercicio en pacientes con trasplante pulmonar con y sin síndrome de bronqueolitis obliterante: estudio longitudinal de casos-control

Introduction: Bronchiolitis Obliterans Syndrome (BOS) is a debilitating disease with limited treatment options that threatens both the quality of life and long-term survival of lung transplant (LTx) recipients. This retrospective longitudinal case-control study was performed to compare the long-term functional evolution of LTx recipients with and without BOS. Methods: Twenty-four LTx recipients with BOS (BOS=Cases) and 24 without BOS (NON-BOS=Controls) were selected and individually matched according to age, gender, diagnosis and LTx characteristics. Measurements of 6-minute walking distance (6MWD), symptoms of dyspnea (BORG CR-10 scale), and comprehensive pulmonary function testing were performed before LTx and at annual follow-up assessments after LTx. Results: Peak FEV1 after LTx was similar in both groups [FEV1 (% predicted) 101 ± 25 vs. 101 ± 31, p = 0.96] and BOS diagnosis in cases was established 3.6 ± 2.5 years after LTx. At the final follow-up assessment (6.5 ± 3.2 years after LTx) FEV1 (% predicted) was 86 ± 34 in NON-BOS vs. 44 ± 17 in BOS (p < 0.001). Evolution of 6MWD was different between groups (group by time interaction: p = 0.002). Borg dyspnea scores were also significantly different between groups at the final evaluation (NON-BOS 3.3 ± 1.7 vs. BOS 5.0 ± 2.2; p = 0.024). Conclusions: We observed gradual reductions in functional exercise capacity and increasing symptoms of dyspnea in patients who developed BOS after LTx. As such, prospective studies seem warranted to explore whether rehabilitative interventions might be useful to improve symptoms and slow down deterioration of exercise capacity in these patients from the onset of BOS

Introducción: El síndrome de bronquiolitis obliterante (BOS) es una enfermedad debilitante con opciones de tratamiento limitadas que amenaza tanto la calidad de vida como la supervivencia a largo plazo de los trasplantados pulmonares (LTx). Este estudio longitudinal retrospectivo de casos-controles se realizó para comparar la evolución functional de los LTx con y sin BOS a largo plazo. Métodos: Se seleccionaron 24 LTx con BOS (BOS = casos) y 24 sin BOS (NON-BOS = controles). Los casos y controles se emparejaron individualmente atendiendo a la edad, el sexo, el diagnóstico y las características del trasplante. Las mediciones incluyeron: la distancia recorrida en la prueba de 6min marcha (6MWD), la disnea (BORG CR-10) y la función pulmonar, antes del LTx y anualmente en el post-LTx. Resultados: El FEV1 pico post-LTx fue similar en ambos grupos (FEV1 [% predicho] 101 ± 25 vs. 101 ± 31; p = 0,96) y el diagnóstico de BOS en los casos se estableció a los 3,6 ± 2,5 años del LTx. En la evaluación del seguimiento final (6,5 ± 3,2 años tras el LTx) el FEV1 (% predicho) fue del 86±34 en los NON-BOS vs. 44 ± 17 en los BOS (p < 0,001). La evolución del 6MWD fue diferente entre grupos (interacción tiempo por grupo: p = 0,002). La puntuación de disnea en la evaluación final también fue diferente significativamente entre grupos (NON-BOS 3,3 ± 1,7 vs. BOS 5,0 ± 2,2; p = 0,024). Conclusiones: Se ha observado una reducción gradual de la capacidad funcional de ejercicio y un incremento de la disnea en los pacientes con BOS tras el LTx. Así pues, parecen pertinentes estudios prospectivos para examinar si la rehabilitación puede mejorar la sintomatología y enlentecer el deterioro de la capacidad de ejercicio en los pacientes que desarrollan el BOS tras el trasplante

Diagnostic value of ventilation/perfusion single-photon emission computed tomography/computed tomography for bronchiolitis obliterans syndrome in patients after lung transplantation.

OBJECTIVE: To evaluate the diagnostic value of function volume/morphological volume ratio calculated from ventilation/perfusion single-photon emission computed tomography/computed tomography in distinguishing the lungs with bronchiolitis obliterans syndrome (BOS) from the lungs without this syndrome after lung transplantation and to assess its relationship with spirometry parameters. MATERIALS AND METHODS: We retrospectively identified 84 consecutive lung transplant recipients and 13 donors who underwent ventilation/perfusion single-photon emission computed tomography/computed tomography. Differences in the function volume/morphological volume ratio of unilateral lungs were tested for significance between the lungs with and without BOS. Receiver operating characteristics and correlations between function volume/morphological volume ratios of bilateral lungs and forced expiratory volume in 1 s, forced vital capacity, and total lung capacity were analyzed. RESULTS: The function volume/morphological volume ratios of ventilation and perfusion images of unilateral lungs were significantly lower in lungs with BOS (each P<0.0001). The area under the curve values of ventilation and perfusion images were 0.97 and 0.99, respectively. Significant correlations were identified between the function volume/morphological volume ratios of ventilation and perfusion images and forced expiratory volume in 1 s (r=0.54, P<0.0001 and r=0.45, P<0.0001, respectively). The function volume/morphological volume ratio of ventilation image had a significantly weak correlation with forced vital capacity. CONCLUSION: The function volume/morphological volume ratio enables a semiquantitative assessment of ventilation and perfusion lung functions and is useful for diagnosing BOS after lung transplantation.