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.

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.

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.

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.

Características y seguimiento de 38 casos de bronquiolitis obliterante post-infecciosa en Bogotá­Colombia / Characteristics and follow up of 38 Post-Infectious Bronchiolitis Obliterans cases in Bogota­Colombia

Post-infectious bronchiolitis obliterans (PIBO) is a chronic obstructive bronchial disease that develops after a viral respiratory infection, acquired before 2 years of age. In Bogotá, Colombia our group published in 2017 the description and follow-up of 21 cases of this pathology. The purpose of this publication is to describe the evolution of 38 children with PIBO living in Bogotá, Colombia at 2640 m above sea level, with an average of 6.5 years of follow-up. The estimated prevalence of PIBO in the population group in the group studied here was at least 1 case per 10,526 children under 15 years of age. The highest frequency of oxygen dependence and pulmonary hypertension are highlighted in this group of children living at high altitude…

La bronquiolitis obliterante post-infecciosa (BOPI) es una enfermedad bronquial obstructiva crónica, que se desarrolla luego de una infección respiratoria viral, adquirida antes de los 2 años de vida. En Bogotá, Colombia nuestro grupo hizo en al año 2017 la descripción y seguimiento de 21 casos de esta patología. La presente publicación tiene como objetivo describir la evolución de 38 niños con BOPI que viven en la ciudad de Bogotá a 2640 m sobre el nivel del mar, con un segumiento de 6.5 años en promedio. Se calcula que la prevalencia de la enfermedad en el grupo poblacional de donde se refieren estos casos, es de al menos 1 caso por 10.526 menores de 15 años. Se destacan la mayor frecuencia de oxigeno dependencia e hipertensión pulmonar en este grupo de niños que viven a gran altura.

Función pulmonar en bronquiolitis obliterante postinfecciosa / Pulmonary function in post-infectious bronchiolitis obliterans

Bronchiolitis obliterans is a rare and severe chronic lung disease resulting from a lower respiratory tract injury. It may occur after a bone marrow or lung transplantation, infectious diseases, or less frequently after inhaling toxic substances or connective tissue diseases. Pathogenesis and molecular biology, as well as the best treatment of bronchiolitis obliterans, remain the subject of ongoing research. This review discusses our current knowledge of lung function of post-infectious bronchiolitis obliterans.

La bronquiolitis obliterante es una enfermedad pulmonar crónica rara y grave que resulta de una lesión del tracto respiratorio inferior. Puede ocurrir después de un trasplante de médula ósea o pulmón, enfermedades infecciosas, o menos frecuentemente después de inhalar sustancias tóxicas o después de enfermedades del tejido conectivo. La patogénesis y la biología molecular, así como el mejor tratamiento de la bronquiolitis obliterante, siguen siendo objeto de investigación. Esta revisión analiza nuestro conocimiento actual sobre la función pulmonar de los pacientes con bronquiolitis obliterante secundaria a infecciones.

[Lung Function, Lung Clearance Index und Bronchial Inflammation in Children and Adolescents with Bronchiolitis obliterans]. / Lungenfunktion, Lung Clearance Index und bronchiale Entzündung bei Kindern und Jugendlichen mit Bronchiolitis obliterans.

INTRODUCTION: Bronchiolitis obliterans (BO) is a rare and severe pulmonary disease which can occur due to airway infection or as a result of stem cell or lung transplantation. Our goal was to study the lung function and airway inflammation among BO patients. Furthermore, we examined the potential of the lung clearance index (LCI) for BO diagnostics among that group. METHODS: 16 BO patients (age: 16.7; 9.6 - 25.3 years) and 17 healthy controls (age: 16.6; 7.6 - 25.0 years) participated in the study. Lung function parameters (FVC, FEV1, MEF25, RV und RV/TLC) as well as airway reversibility after administration of 400 µg salbutamol was investigated. The lung clearance index was determined using the multiple-breath washout method (MBW). Additionally, induced sputum was analyzed for cytology and cytokine levels (IL-1ß, IL-6, IL-8, TNF-α) using the cytometric bead array (CBA). RESULTS: BO patients had significantly lower FVC, FEV1 and MEF25 but increased RV and RV/TLC. Airway reversibility was observed in 3 patients. The LCI was significantly higher among BO patients compared to the healthy control group (median 10.24 vs. 7.1). Apart from a massive airway inflammation indicated by elevated numbers of total cells and neutrophils, the CBA analysis showed increased levels of IL-6 and IL-8 (p < 0.01). DISCUSSION: In BO patients, lung function in childhood and adolescence is severely impaired. Furthermore, we were able to demonstrate the sensitivity and reproducibility of LCI and its value for the evaluation of small airway obstruction. In induced sputum, a neutrophil-dominated airway inflammation is detectable.

Rapid versus gradual lung function decline in bronchiolitis obliterans syndrome after haematopoietic stem cell transplantation is associated with survival outcome.

BACKGROUND AND OBJECTIVE: Bronchiolitis obliterans syndrome (BOS) after haematopoietic stem cell transplantation (HSCT) presents with lung function decline. The pattern of lung function decline after BOS diagnosis could impact prognostication of BOS as a complication after HSCT. The aim of this study was to assess the impact of lung function decline on overall survival (OS) in BOS subjects. METHODS: Subjects with BOS were compared to those without BOS and matched for age, gender, primary diagnoses, conditioning regimes and chronic graft versus host disease. Lung function tests at baseline, at BOS diagnosis and every 3 months after HSCT were evaluated. RESULTS: Of the 1461 subjects undergoing allogeneic HSCT (allo-HSCT) between 1998 and 2015, 95 (6.5%) were diagnosed with BOS. A total of 159 matched HSCT recipients without BOS were identified. A 25% decline in FEV1 within the first 3 months after BOS diagnosis would separate BOS subjects into a subgroup with initial rapid decline and another subgroup with initial gradual decline in lung function. The rapid decline group showed lower subsequent lung function parameters and significantly worse OS compared to the gradual decline group (P = 0.013). CONCLUSION: Post-HSCT BOS subjects with initial rapid lung function decline within 3 months after BOS diagnosis will have significantly poorer lung function and worse OS compared to those with initial gradual decline in lung function after BOS diagnosis. HSCT BOS patients with rapid initial decline in lung function warrant closer monitoring for the development of other post-HSCT complications that could affect their survival.

Constrictive Bronchiolitis in Patients With Primary Sjögren Syndrome.

OBJECTIVE: Constrictive bronchiolitis (CB) is a poorly understood pulmonary manifestation of primary Sjögren syndrome (pSS). We aimed to clarify the presenting clinicoradiologic features and clinical course of pSS-associated CB through a retrospective cohort study. METHODS: We retrospectively identified 11 patients with pSS and CB (defined by mosaic pattern with air trapping on computed tomography) encountered at our institution over 9 years from 2007 to 2015. Presenting clinical features, laboratory results, radiologic findings, and clinical course were analyzed. RESULTS: Our patients were mostly women (91%), with a median age 53 years (range, 31-76 years) at the time of pulmonary symptom (dyspnea or cough) onset. Most (64%) were nonsmokers. Average interval between diagnosis of pSS and the onset of pulmonary symptoms was 4.4 years; in 4 patients (36%), CB was the presenting manifestation of pSS. Chest radiographs were normal (67%) or demonstrated hyperinflation (33%). Pulmonary function testing demonstrated airflow obstruction in 7 patients (63%), and 2 patients (18%) had an isolated reduction in diffusing capacity, whereas the remaining 2 patients manifested mixed physiology or normal results. Surgical lung biopsy was performed in 2 patients and confirmed the diagnosis of CB in both. Treatment was variable among our patients included glucocorticoids, hydroxychloroquine, mycophenolate mofetil, and cyclophosphamide. Among 6 patients with follow-up computed tomography and pulmonary function, the results remained stable or worsened. CONCLUSIONS: Constrictive bronchiolitis is a rare extraglandular manifestation and can sometimes be the presenting manifestation of pSS. This pulmonary manifestation is associated with an indolent clinical course and does not respond well to immunosuppressive therapy.

Whole-Body Lung Function Test-Derived Outcome Predictors in Allogenic Stem Cell Transplantation.

Despite clinical advances, late onset pulmonary complications in adult recipients of allogenic stem cell transplantation are a major cause of morbidity and mortality. Reported incidence and risk factors in the literature vary broadly and are partly contradictory. Identification of pretransplant factors associated with major complications would be helpful to define individual treatment strategies and early initiation of preventive measures. To evaluate incidence and risk factors of late onset noninfectious pulmonary complications, with special regard to small airways disease (SAD) and bronchiolitis obliterans syndrome (BOS), indicating graft-versus-host disease, following myeloablative versus nonmyeloablative allogenic stem cell transplantation. We reviewed the clinical records and assessed the course of lung function and pulmonary complications in adults who underwent allogenic stem cell transplantation for hematological malignancies between 1999 and 2015 using nonmyeloablative (n = 179) or myeloablative (n = 130) conditioning at the Division of Hematology of the Medical University of Graz. All patients underwent body plethysmography pulmonary function test (PFT), diffusion capacity for carbon monoxide, and arterial blood gas analysis before and repeatedly after transplant. SAD was defined as maximal expiratory flow at 50% and 25% of forced vital capacity <70% predicted. Ventilatory disorders and gas transfer abnormalities were common before and after allogenic stem cell transplantation, independent of conditioning regimen. SAD was common in the nonmyeloablative (34%) and myeloablative (29%) groups. The 100-day post-transplant mortality was significantly associated with reduced pretransplant total lung capacity <80%. Mortality 100 days post-transplant was significantly associated with pretransplant SAD and a pretransplant smoking history. In this subset, a smoking history was independently associated with increased mortality, with a 5-year mortality of 45% compared with 26% in never-smokers. Pretransplant SAD was not predictive for the later development of BOS. Smoking history, pretransplant restrictive PFT, and pre-existing SAD are important risk factors for death following allogenic stem cell transplantation. However, pretransplant SAD is not a predictor of long-term complications, including BOS.

Six-minute walk, lung clearance index, and QOL in bronchiolitis obliterans and cystic fibrosis.

INTRODUCTION: The 6-min walk test (6MWT) predicts outcome in pulmonary hypertension. Recently, its use was reported in both cystic fibrosis (CF) and bronchiolitis obliterans (BO). While the 6MWT is a simple, non-invasive and inexpensive tool, lung clearance index (LCI) measurement requires expensive equipment and expertise. We aimed to evaluate 6MWT in BO and CF, and to compare to MBW (multiple breath washout), pulmonary function tests and quality of life (QOL). METHODS: A prospective single center study assessing 6MWT, MBW, spirometry, whole-body plethysmography and QOL (SF-36 questionnaire) in BO and CF patients and correlations between them. RESULTS: Thirty-three BO patients and 37 CF patients. LCI was significantly higher in BO (12.4 ± 4.2 vs 10.5 ± 3.4, P = 0.044) while FEF 25-75% was significantly lower in BO (43.9 ± 24.4 vs 60.8 ± 30.8, P = 0.014). 6MWD was 474.8 ± 76.3 in BO and 506.6 ± 70 in CF (P > 0.05). There was no correlation between 6MWD and LCI in these small study groups There were few correlation between spirometry prameters and 6MWD. In CF, SF-36 scores correlated with pulmonary functions. CONCLUSIONS: The 6MWT is an easy-to-perform test that may be helpful in chronic lung diseases in regions with limited resources. However,with the current limited data, 6MWT cannot replace LCI or spirometry as a marker of disease progression. Is is suggested that, together with QOL, the 6MWT may provide a global estimation of the physiological and general well-being of these patients. Further larger multi-center studies are warranted to evaluate the correlations of 6MWT with pulmonary physiology parameters in various chronic diseases.