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BACKGROUND: BK virus-associated nephropathy (BKVAN) is a relatively common cause of renal dysfunction in the first six months after renal transplantation. It arises from reactivation of the latent and usually harmless BK virus (BK virus) due to immunosuppression and other factors including some that are unique to renal transplantation such as allograft injury. BKVAN is much rarer in non-renal solid organ transplantation, where data regarding diagnosis and management are extremely limited. CASE PRESENTATION: We report a case of a 58-year-old man found to have worsening renal dysfunction nine months after bilateral sequential lung transplantation for chronic obstructive pulmonary disease (COPD). He had required methylprednisolone for acute allograft rejection but achieved good graft function. Urine microscopy and culture and renal ultrasound were normal. BK virus PCR was positive at high levels in urine and blood. Renal biopsy subsequently confirmed BKVAN. The patient progressed to end-stage renal failure requiring haemodialysis despite reduction in immunosuppression, including switching mycophenolate for everolimus, and the administration of intravenous immunoglobulin (IVIG). CONCLUSIONS: This very rare case highlights the challenges presented by BK virus in the non-renal solid organ transplant population. Diagnosis can be difficult, especially given the heterogeneity with which BKV disease has been reported to present in such patients, and the optimal approach to management is unknown. Balancing reduction in immunosuppression against prevention of allograft rejection is delicate. Improved therapeutic options are clearly required.
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Transplante de Pulmão , Infecções por Polyomavirus/diagnóstico , Infecções Tumorais por Vírus/diagnóstico , Vírus BK/genética , Vírus BK/isolamento & purificação , DNA Viral/metabolismo , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim , Transplante de Pulmão/efeitos adversos , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Infecções por Polyomavirus/virologia , Doença Pulmonar Obstrutiva Crônica/terapia , Infecções Tumorais por Vírus/virologiaRESUMO
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by JC virus (JCV). The disease occurs in the setting of significant immunocompromise and has now been reported in many different settings, although only very rarely after lung transplantation. The mortality rate is high and therapeutic options are limited. CASE PRESENTATION: We report a case of a 66-year-old man who presented with non-specific memory disturbance at 19 months after lung transplantation for chronic hypersensitivity pneumonitis. He had required methylprednisolone for acute allograft rejection but achieved good graft function. Physical examination was unremarkable. CT revealed hypodensity in the left frontal lobe. MR demonstrated significant hyperintense white-matter abnormalities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, mainly focused on the periventricular region adjacent the frontal horn of the left lateral ventricle. Brain biopsy confirmed PML. The patient had his immunosuppression reduced but then developed antibody-mediated rejection four months later. Despite re-escalation of immunosuppression, he remains neurologically stable on mirtazapine at eight months post-diagnosis. CONCLUSIONS: This very rare case highlights the challenges presented by PML, especially in the lung transplant population. It reveals the difficult balance between reducing immunosuppression to protect the brain versus prevention of lung allograft rejection. It clearly highlights the need for improved therapeutic modalities.
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Encéfalo/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Transplante de Pulmão/efeitos adversos , Transtornos da Memória/virologia , Adulto , Idoso , Biópsia , Encéfalo/patologia , Encéfalo/virologia , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Transtornos da Memória/diagnóstico , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
Background: Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection. Methods: In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution. Results: Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy. Conclusions: The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease. Clinical Trials Registration: ACTRN12613000981729.
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Transferência Adotiva/métodos , Infecções por Citomegalovirus/terapia , Citomegalovirus/imunologia , Linfócitos T/imunologia , Transplante Autólogo/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Australian data regarding the management of patients with bronchiectasis is scarce. We sought to compare the management of adults with bronchiectasis attending tertiary Australian centres with recent national and international guidelines. METHODS: The Australian Bronchiectasis Registry is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis recruited from 14 tertiary Australian hospitals. We excluded children (<18 years) and those with incomplete data, leaving 589 adults for cross-sectional analyses. We compared the proportion of patients receiving certain therapies, as compared to the proportion eligible for those treatments according to the current guidelines and baseline clinical information available from the registry. RESULTS: Pulmonary rehabilitation was attended by 22%, although it was indicated in 67% of the cohort. Airway clearance was undertaken in 52% of patients, although 71% reported chronic productive cough. Sputum bacterial culture results were available for 59%, and mycobacterial culture results were available for 29% of the cohort. Inhaled antibiotics were used in half of potentially eligible patients. Despite guideline recommendations against routine use, inhaled corticosteroids were used in 48% of patients. Long-term macrolides were used in 28% of participants. CONCLUSIONS: Discrepancies exist between guideline recommendations and real-world treatment of bronchiectasis in Australia, even in tertiary centres. These findings suggest the need for increased patient referral to pulmonary rehabilitation, increased attention to airway clearance, increased collection of sputum samples (especially for mycobacterial culture) and rationalisation of inhaled corticosteroid use. These findings encourage a review of treatment access and will inform ongoing education to promote evidence-based care for people living with bronchiectasis.
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Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Bronquiectasia/terapia , Medicina Baseada em Evidências , Fidelidade a Diretrizes/estatística & dados numéricos , Modalidades de Fisioterapia/estatística & dados numéricos , Terapia Respiratória/estatística & dados numéricos , Centros de Atenção Terciária , Administração por Inalação , Idoso , Austrália , Bronquiectasia/complicações , Broncodilatadores/uso terapêutico , Feminino , Infecções por Haemophilus/complicações , Infecções por Haemophilus/tratamento farmacológico , Acessibilidade aos Serviços de Saúde , Humanos , Macrolídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Guias de Prática Clínica como Assunto , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológicoRESUMO
BACKGROUND: There are few cases of multiple bronchial stenoses reported in the literature and none of the severity described here. The case is relevant due to its rareness, the pathophysiological insights derived, the successful interventional pulmonology strategies demonstrated, and as an example of a rare indication for high-risk lung transplantation. CASE PRESENTATION: A 47-year-old man developed multiple recurrent bronchial web-like stenoses five weeks after an episode of severe tracheo-bronchitis presumed secondary to a chemical inhalation injury which initially caused complete bilateral lung collapse necessitating veno-venous extracorporeal membrane oxygenation. The stenoses completely effaced bronchi in many locations causing severe type II respiratory failure requiring mechanical ventilation and bronchoscopic puncture / dilatation then ultimately bilateral lung transplantation. CONCLUSION: This very rare case highlights the morbid sequelae that can arise after catastrophic tracheobronchitis which now, in the era of extracorporeal membrane oxygenation, may be survivable in the short-term.
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Broncopatias/diagnóstico , Constrição Patológica/diagnóstico por imagem , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Traqueia/patologia , Broncopatias/induzido quimicamente , Broncoscopia , Queimaduras Químicas/complicações , Queimaduras por Inalação/complicações , Oxigenação por Membrana Extracorpórea , Humanos , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Radiografia Torácica , Respiração Artificial , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND OBJECTIVE: Immunosuppression therapy following lung transplantation fails to prevent chronic rejection in many patients, which is associated with lack of suppression of cytotoxic mediators and pro-inflammatory cytokines in peripheral blood T and natural killer T (NKT)-like cells. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) upregulate/downregulate pro-inflammatory gene expression, respectively; however, differences in the activity of these enzymes following lung transplant are unknown. We hypothesized decreased HDAC2 expression and increased HAT expression in pro-inflammatory lymphocytes following lung transplant. METHODS: Blood was collected from 18 stable lung transplant patients and 10 healthy age-matched controls. Intracellular pro-inflammatory cytokines and HAT/HDAC2 expression were determined in lymphocyte subsets following culture using flow cytometry. RESULTS: A loss of HDAC2 in cluster of differentiation (CD) 8+ T and NKT-like cells in transplant patients compared with controls was noted (CD8+ T: 28 ± 10 (45 ± 10), CD8+NKT-like: 30 ± 13 (54 ± 16) (mean ± SD transplant) (control)). Loss of HDAC2 was associated with an increased percentage of CD8+ T and NKT-like cells expressing perforin, granzyme b, interferon gamma (IFN-γ) and TNF-α (no change in HAT expression in any lymphocyte subset). There was a negative correlation between loss of HDAC2 expression by CD8+ T cells with cumulative dose of prednisolone and time post-transplant. Treatment with 10 mg/L theophylline + 1 µmol/L prednisolone or 2.5 ng/mL cyclosporine A synergistically upregulated HDAC2 and inhibited IFN-γ and TNF-α production by CD8+ T and NKT-like lymphocytes. CONCLUSION: HDAC2 is decreased in CD8+ T and NKT-like pro-inflammatory lymphocytes following lung transplant. Treatment options that increase HDAC2 may improve graft survival.
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Linfócitos T CD8-Positivos/fisiologia , Histona Desacetilase 2/metabolismo , Transplante de Pulmão , Adulto , Regulação para Baixo , Feminino , Sobrevivência de Enxerto/imunologia , Granzimas/metabolismo , Humanos , Interferon gama/metabolismo , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/métodos , Masculino , Pessoa de Meia-Idade , Perforina/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Chronic lung allograft dysfunction (CLAD), and especially bronchiolitis obliterans syndrome (BOS), remain dominant causes of morbidity and mortality after lung transplantation. Interest is growing in the forced oscillation technique, of which impulse oscillometry (IOS) is a form, as a tool to improve our understanding of these disorders. However, data remain limited and no longitudinal studies have been published, meaning there is no information regarding any capacity IOS may have for the early detection of CLAD. METHODS: We conducted a prospective longitudinal study enrolling a consecutive sample of adult bilateral lung transplant recipients with healthy lung allografts or CLAD and performed ongoing paired IOS and spirometry tests on a clinically determined basis. We assessed for correlations between IOS and spirometry and examined any predictive value either modality may hold for the early detection of BOS. RESULTS: We enrolled 91 patients and conducted testing for 43 mo, collecting 558 analyzable paired IOS and spirometry tests, with a median of 9 tests per subject (interquartile range, 5-12) and a median testing interval of 92 d (interquartile range, 62-161). Statistically significant moderate-to-strong correlations were demonstrated between all IOS parameters and spirometry, except resistance at 20 Hz, which is a proximal airway measure. No predictive value for the early detection of BOS was found for IOS or spirometry. CONCLUSIONS: This study presents the first longitudinal data from IOS after lung transplantation and adds considerably to the growing literature, showing unequivocal correlations with spirometry but failing to demonstrate a predictive value for BOS.
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Síndrome de Bronquiolite Obliterante , Bronquiolite Obliterante , Adulto , Humanos , Oscilometria/métodos , Estudos Prospectivos , Estudos Longitudinais , Transplantados , Pulmão , Espirometria , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Volume Expiratório ForçadoRESUMO
INTRODUCTION: Pulmonary rehabilitation is recommended for people with bronchiectasis. Various education topics are included in these programmes, but the content is largely guided by the needs of people with other respiratory conditions. OBJECTIVES: With the education topics applicable to people with bronchiectasis unclear, we aimed to explore the perspective of adults with this condition on relevant educational topics in a pulmonary rehabilitation context. METHODS: Participants from the Australian Bronchiectasis Registry were invited to undertake a semi-structured interview. Interview transcripts were coded independently, with themes established by consensus (two researchers). RESULTS: Twenty-one people participated. The major themes were greater clarity on the underlying cause of bronchiectasis and prognosis. Most sought knowledge about self-management strategies and treatments to address extra-pulmonary symptoms. Participants requested more information on physiotherapy options and the role of exercise and physical activity outside of pulmonary rehabilitation. Preferences were mixed for the education delivery model. CONCLUSIONS: We have identified unmet educational topics of interest for people with bronchiectasis. Our study provides a framework for education topics desired by adults with bronchiectasis within a pulmonary rehabilitation setting. The topics identified will guide development of an education curriculum for pulmonary rehabilitation that is more fit-for-purpose for people with bronchiectasis.
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Bronquiectasia , Doenças Respiratórias , Adulto , Humanos , Austrália/epidemiologia , Exercício Físico , Modalidades de Fisioterapia , Qualidade de VidaRESUMO
Hepatopulmonary syndrome (HPS) is the triad of liver disease, hypoxia and intrapulmonary shunt. In this case report, we describe an immunocompromised female with a background of common variable immunodeficiency (CVID) who presented with haemoptysis and dyspnoea. Investigations demonstrated significant hypoxaemia and intrapulmonary right-to-left shunting. Further evidence revealed advanced liver cirrhosis, and a diagnosis of HPS was made. This extremely rare association of CVID and HPS is one of the few cases reported in the literature.
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BACKGROUND: Immunosuppression therapy is ineffective at preventing bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways (SAs). Our previous reports show increased senescent CD28null T and natural killer T (NKT)-like cells in the peripheral blood of patients with BOS and increased cytotoxic, proinflammatory lymphocytes in the SAs. We hypothesized that the cytotoxic, proinflammatory lymphocytes in the SAs would be steroid-resistant senescent CD28null lymphocytes. METHODS: Intracellular cytotoxic mediator granzyme B, interferon (IFN)-γ and tumor necrosis factor (TNF)-α proinflammatory cytokines, and CD28 were measured in the blood, bronchoalveolar lavage, large airway, and SA brushing T and NKT-like cells from 10 patients with BOS, 11 stable lung transplant recipients, and 10 healthy age-matched controls. SA brushings were cultured in the presence of ±1 µmol/liter prednisolone, ±5 mg/liter theophylline, and ±2.5 ng/ml cyclosporine A, and IFN-γ and TNF-α proinflammatory cytokines were assessed using flow cytometry. RESULTS: Increased SA CD28null T and NKT-like cells were identified in patients with BOS compared with that in the controls and stable transplant recipients. Loss of CD28 was associated with increased T and NKT-like cells expressing granzyme B, IFN-γ, and TNF-α. Loss of CD28 expression by CD8+ T cells was significantly associated with forced expiratory volume in 1 sec (Râ¯=â¯0.655, pâ¯=â¯0.006) and with time after transplantation (Râ¯=â¯-0.552, pâ¯=â¯0.041). Treatment with prednisoloneâ¯+â¯theophyllineâ¯+â¯cyclosporin A inhibited IFN-γ and TNF-α production by SA CD28null CD8+ T and NKT-like cells additively. CONCLUSIONS: BOS is associated with the loss of CD28 in SA cytotoxic, proinflammatory senescent T and NKT-like lymphocytes. Treatment options that target the proinflammatory nature of these cells in the SAs may improve graft survival.
Assuntos
Bronquíolos/patologia , Bronquiolite Obliterante/metabolismo , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Células Matadoras Naturais/fisiologia , Transplante de Pulmão , Biomarcadores/metabolismo , Bronquíolos/metabolismo , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/patologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T CD8-Positivos/patologia , Senescência Celular , Progressão da Doença , Feminino , Citometria de Fluxo , Sobrevivência de Enxerto , Humanos , Células Matadoras Naturais/metabolismo , Masculino , SíndromeRESUMO
INTRODUCTION: In adults with bronchiectasis, multicentre data advanced the field including disease characterisation and derivation of phenotypes such as 'frequent exacerbator (FE)' (≥3 exacerbations/year). However, paediatric cohorts are largely limited to single centres and no scientifically derived phenotypes of paediatric bronchiectasis yet exists. Using paediatric data from the Australian Bronchiectasis Registry (ABR), we aimed to: (a) describe the clinical characteristics and compare Indigenous with non-Indigenous children, and (b) determine if a FE phenotype can be identified and if so, its associated factors. METHODS: We retrieved data of children (aged <18-years) with radiologically confirmed bronchiectasis, enrolled between March 2016-March 2020. RESULTS: Across five sites, 540 children [288 Indigenous; median age = 8-years (IQR 6-11)] were included. Baseline characteristics revealed past infection/idiopathic was the commonest (70%) underlying aetiology, most had cylindrical bronchiectasis and normal spirometry. Indigenous children (vs. non-Indigenous) had significantly more environmental tobacco smoke exposure (84% vs 32%, p < 0.0001) and lower birth weight (2797 g vs 3260 g, p < 0.0001). FE phenotype present in 162 (30%) children, was associated with being younger (ORadjusted = 0.85, 95%CI 0.81-0.90), more recent diagnosis of bronchiectasis (ORadjusted = 0.67; 95%CI 0.60-0.75), recent hospitalization (ORadj = 4.51; 95%CI 2.45-8.54) and Pseudomonas aeruginosa (PsA) infection (ORadjusted = 2.43; 95%CI 1.01-5.78). The FE phenotype were less likely to be Indigenous (ORadjusted = 0.14; 95%CI 0.03-0.65). CONCLUSION: Even within a single country, the characteristics of children with bronchiectasis differ among cohorts. A paediatric FE phenotype exists and is characterised by being younger with a more recent diagnosis, PsA infection and previous hospitalization. Prospective data to consolidate our findings characterising childhood bronchiectasis phenotypes are required.
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Bronquiectasia/fisiopatologia , Exacerbação dos Sintomas , Adolescente , Austrália , Criança , Feminino , Humanos , Masculino , Fenótipo , Sistema de Registros , Fatores de Risco , EspirometriaRESUMO
BACKGROUND: Immunosuppression therapy is ineffective at preventing chronic rejection of lung allografts (bronchiolitis obliterans syndrome [BOS]) and proinflammatory cytokines by steroid-resistant lymphocytes. The class III NAD-sirtuin 1 (SIRT1) is an important negative regulator of inflammation; however, SIRT1 activity following lung transplant has not been studied. We hypothesized that SIRT1 expression is decreased in proinflammatory lymphocytes following lung transplant and that treatment with SIRT1 activators (resveratrol, curcumin) and agents that prevent NAD depletion (theophylline) upregulate SIRT1 and reduce proinflammatory cytokine expression in these cells. METHODS: Intracellular proinflammatory cytokines and SIRT1 were measured in blood T, natural killer T-like cell (NKT-like), and natural killer (NK) cells from patients with BOS (n = 10), stable lung transplant patients (n = 11), and healthy aged-matched controls (n = 10). Blood was cultured in the presence of ±25 µM resveratrol, ±1 µM curcumin, ±5 mg/L theophylline, ±1µM prednisolone and cytokines, and SIRT1 assessed using flow cytometry. RESULTS: There was a loss of SIRT1 in T, NK-like, and NK cells in BOS patients compared with stable patients and controls (%CD8 SIRT1 T cells: 17 ± 10; 37 ± 10; 30 ± 10) (mean ± SEM BOS, stable, control, respectively) (P < 0.05 for all). Loss of SIRT1 was associated with increased T, NKT-like, and NK cells expressing interferon (IFN)γ and tumor necrosis factor (TNF)α. SIRT1 expression by T cells significantly associated with FEV1 (R = 0.655, P = 0.006) and with time posttransplant (R = -0.552, P = 0.041). All treatments upregulated SIRT1 and inhibited IFNγ and TNFα production by T, NK, and NKT-like cells additively. CONCLUSIONS: BOS is associated with decreased SIRT1 in peripheral blood proinflammatory T, NK, and NKT-like lymphocytes following lung transplant. Treatment options that increase SIRT1 may improve graft survival.
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Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/metabolismo , Células Matadoras Naturais/citologia , Linfócitos/citologia , Sirtuína 1/metabolismo , Linfócitos T/citologia , Adulto , Fatores Etários , Carbazóis/farmacologia , Estudos de Casos e Controles , Curcumina/farmacologia , Citocinas/imunologia , Feminino , Sobrevivência de Enxerto/imunologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Imunossupressores/uso terapêutico , Inflamação/imunologia , Interferon gama/imunologia , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prednisolona/farmacologia , Resveratrol/farmacologia , Teofilina/farmacologia , Resultado do TratamentoRESUMO
BACKGROUND: /objective: There are no large, multi-centre studies of Australians with bronchiectasis. The Australian Bronchiectasis Registry (ABR) was established in 2015 to create a longitudinal research platform. We aimed to describe the baseline characteristics of adult ABR participants and assess the impact of disease severity and exacerbation phenotype on quality of life (QoL). METHODS: The ABR is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis. We analysed the baseline data of adult patients (≥18 years). RESULTS: From March 2016-August 2018, 799 adults were enrolled from 14 Australian sites. Baseline data were available for 589 adults predominantly from six tertiary centres (420 female, median age 71 years (interquartile range 64-77), 14% with chronic Pseudomonas aeruginosa infection). Most patients had moderate or severe disease based on the Bronchiectasis Severity Index (BSI) (84%) and FACED (59%) composite scores. Using Global Lung function Initiative-2012 reference equations, the majority of patients (48%) had normal spirometry; only 34% had airflow obstruction (FEV1/FVCâ¯<â¯LLN). Disease severity scores (BSI and FACED) were negatively correlated with QoL-Bronchiectasis domain scores (rs between -0.09 and -0.58). The frequent exacerbator phenotype (≥3 in the preceding year) was identified in 23%; this group had lower scores in all QoL-B domains (pâ¯≤â¯0.001) and more hospitalisations (pâ¯<â¯0.001) than those with <3 exacerbations. CONCLUSIONS: The largest cohort of Australian adults with bronchiectasis has been described. Using contemporary criteria, most patients with bronchiectasis did not have airflow obstruction. The frequent exacerbation trait connotes poorer QoL and greater health-care utilisation.
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Bronquiectasia , Progressão da Doença , Qualidade de Vida , Sistema de Registros , Índice de Gravidade de Doença , Idoso , Austrália , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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]â¯=â¯0.6, 95% confidence interval [CI]â¯=â¯0.3-1.2, pâ¯=â¯0.12) or small conidia (HRâ¯=â¯0.9, 95% CIâ¯=â¯0.6-1.4, pâ¯=â¯0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HRâ¯=â¯1.4, 95% CIâ¯=â¯1.1-1.8, pâ¯=â¯0.02) and episodes of acute rejection (1-2 episodes, HRâ¯=â¯1.5, 95% CIâ¯=â¯1.1-2.1, pâ¯=â¯0.014; 3-4 episodes, HRâ¯=â¯1.6, 95% CIâ¯=â¯1.0-2.6, pâ¯=â¯0.036; >4 episodes, HRâ¯=â¯2.2, 95% CIâ¯=â¯1.1-4.3, pâ¯=â¯0.02), whereas tacrolimus use was associated with reduced risk of BOS (HRâ¯=â¯0.6, 95% CIâ¯=â¯0.5-0.9, pâ¯=â¯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.
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Aspergillus/isolamento & purificação , Bronquiolite Obliterante/microbiologia , Transplante de Pulmão , Complicações Pós-Operatórias/microbiologia , Adolescente , Adulto , Bronquiolite Obliterante/epidemiologia , Estudos de Coortes , Feminino , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Immunosuppression therapy after lung transplantation fails to prevent bronchiolitis obliterans syndrome (BOS) in many patients, primarily a disease of the small airways. We have reported that BOS is associated with a lack of suppression of cytotoxic mediators, and proinflammatory cytokines, in peripheral blood T, NKT-like (particularly CD8+) and NK cells. We also showed a loss of glucocorticoid receptor (GCR) in proinflammatory lymphocytes after transplant. It is unknown whether these proinflammatory lymphocytes target the small and/or large airways in BOS. METHODS: Blood, bronchoalveolar lavage, large proximal, and small distal airway brushings were collected from patients with BOS (n = 10), stable lung transplant patients (n = 18), and healthy aged-matched controls (n = 10). Intracellular cytotoxic mediators (perforin/granzyme B), proinflammatory cytokines (IFNγ/TNFα), and expression of GCR were determined in lymphocytes subsets from cultured blood using flow cytometry. RESULTS: Increases in CD8 T cells, NKT-like cells, and NK cells were found in the small distal airways in BOS compared with stable patients and controls. An increase in perforin, granzyme B, IFNγ, TNFα, and a loss of GCR from these lymphocyte subsets was also found in BOS. GCR expression by CD8+ T cells from small airways correlated with FEV1 (R = 0.834, P = 0.039). Many of these changes significantly differed from those in the large airways. CONCLUSIONS: BOS is associated with increased cytotoxic/proinflammatory CD8+ T, NKT-like, and NK cells in the small airways. Treatments that increase GCR in these lymphocyte subsets may improve graft survival.
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Brônquios/patologia , Bronquiolite Obliterante/imunologia , Linfócitos T CD8-Positivos/patologia , Imunidade Celular , Células Matadoras Naturais/patologia , Transplante de Pulmão/efeitos adversos , Perforina/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Brônquios/imunologia , Brônquios/metabolismo , Bronquiolite Obliterante/metabolismo , Bronquiolite Obliterante/patologia , Líquido da Lavagem Broncoalveolar/química , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Adulto JovemRESUMO
Infections with cytomegalovirus (CMV) can induce severe complications after solid organ transplantation (SOT). The prognosis for ganciclovir-resistant CMV infection and disease is particularly poor. Whereas adoptive transfer of CMV-specific T cells has emerged as a powerful tool in hematopoietic stem cell transplant patients, its translation into the SOT setting remains a significant challenge as underlying immunosuppression inhibits the virus-specific T-cell response in vivo. Here, we demonstrate successful expansion and adoptive transfer of autologous CMV-specific T cells from a seronegative recipient of a seropositive lung allograft with ganciclovir-resistant CMV disease, resulting in the long-term reconstitution of protective anti-viral immunity, CMV infection, disease-free survival and no allograft rejection.
RESUMO
BACKGROUND: Pro-inflammatory cytokines in T and natural killer T (NKT)-like cells increase with time post-transplant in otherwise stable patients, suggesting that some patients become relatively resistant to immunosuppressants such as glucocorticoids (GC). We hypothesized that GC receptor (GCR) would be down-regulated in peripheral blood pro-inflammatory T and NKT-like cells after lung transplantation and loss of GCR would correlate with time post-transplant. METHODS: Blood was collected from 17 stable lung transplant patients and 17 healthy, aged-matched controls. Intracellular GCR expression and pro-inflammatory cytokines were determined using flow cytometry. RESULTS: There was a loss of GCR in CD8(+) and CD8(-) T and NKT-like cells in transplant patients compared with control subjects (transplants 37 ± 9%, controls 47 ± 12%; GCR(+)CD8(+) and CD8(-) T cells: transplants 39 ± 13%, controls 58 ± 13%). Loss of GCR was associated with a greater percentage of T cells producing interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) but not NKT-like cells. There was a correlation between the percentage of GCR-negative T cells with months post-transplant (R = 0.519, p = 0.033) and dose of prednisolone (R = 0.775, p = 0.038). CONCLUSIONS: Time post-transplant and prednisolone dose correlate with loss of GCR in pro-inflammatory T cells in stable transplant patients, suggesting the need for reassessment of the long-term use of steroids after lung transplant in view of their attendant significant side effects.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Inflamação/metabolismo , Pneumopatias/cirurgia , Transplante de Pulmão , Células T Matadoras Naturais/metabolismo , Receptores de Glucocorticoides/metabolismo , Adulto , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Regulação para Baixo , Glucocorticoides/uso terapêutico , Humanos , Interferon gama/metabolismo , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia , Período Pós-Operatório , Prednisolona/uso terapêutico , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: We previously showed that bronchiolitis obliterans syndrome (BOS) is associated with lack of immunosuppression of T-cell pro-inflammatory cytokines and granzyme B. We recently showed that natural killer (NK) T (NKT)-like cells are a major source of pro-inflammatory cytokines and granzymes in the blood of stable lung transplant patients. NK cells also produce these pro-inflammatory mediators, and we hypothesized that BOS may be associated with lack of immunosuppression of these pro-inflammatory mediators in NK and NKT-like cells. METHOD: Granzyme, perforin, and intracellular cytokine profiles from stable transplant recipients, patients with evidence of BOS, and healthy controls were determined using multiparameter flow cytometry. RESULTS: The percentage of NK cells expressing granzymes and perforin was significantly increased in BOS patients compared with stable patients and in stable patients compared with controls (89% ± 13%, 69% ± 12%, 33% ± 14% for NK and 35% ± 19%, 12% ± 15%, and 2% ± 3% for NKT-like granzyme B producing cells for BOS, stable patients and controls, respectively). There was an increase in the percentage of NK and NKT-like cells producing interferon (IFN)-γ and tumor necrosis factor (TNF)-α in BOS compared with stable patients (36% ± 16% and 10% ± 4% for NK and 32% ± 13% and 17% ± 8% for NKT-like IFN-γ producing cells for BOS and stable patients, respectively). There was a significant correlation between increased NK IFN-γ and TNF-α and values of forced expiratory volume in 1 second. CONCLUSIONS: BOS is associated with increased peripheral blood NK and NKT-like cells expressing granzymes, perforin, and Th1 pro-inflammatory cytokines. These cells may migrate to the lungs and have an impact in airway damage in BOS. Therapeutic targeting of these pro-inflammatory mediators and monitoring response longitudinally using this assay may reduce BOS.