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1.
Biomolecules ; 11(9)2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34572606

RESUMO

The World Health Organisation reported COPD to be the third leading cause of death globally in 2019, and in 2020, the most common cause of cancer death was lung cancer; when these linked conditions are added together they come near the top of the leading causes of mortality. The cell-biological program termed epithelial-to-mesenchymal transition (EMT) plays an important role in organ development, fibrosis and cancer progression. Over the past decade there has emerged a substantial literature that also links EMT specifically to the pathophysiology of chronic obstructive pulmonary disease (COPD) as primarily an airway fibrosis disease; COPD is a recognised strong independent risk factor for the development of lung cancer, over and above the risks associated with smoking. In this review, our primary focus is to highlight these linkages and alert both the COPD and lung cancer fields to these complex interactions. We emphasise the need for inter-disciplinary attention and research focused on the likely crucial roles of EMT (and potential for its inhibition) with recognition of its strategic place mechanistically in both COPD and lung cancer. As part of this we discuss the future potential directions for novel therapeutic opportunities, including evidence-based strategic repurposing of currently used familiar/approved medications.

2.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445337

RESUMO

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFß2 and IL1ß. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.


Assuntos
Transdiferenciação Celular/genética , Rim/patologia , MicroRNAs/fisiologia , Miocárdio/patologia , Animais , Células Cultivadas , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Fibrose/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Rim/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia
3.
Expert Rev Mol Med ; 23: e10, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34404500

RESUMO

OBJECTIVE: Otitis media (OM) is a common reason for children to be prescribed antibiotics and undergo surgery but a thorough understanding of disease mechanisms is lacking. We evaluate the evidence of a dysregulated immune response in the pathogenesis of OM. METHODS: A comprehensive systematic review of the literature using search terms [otitis media OR glue ear OR AOM OR OME] OR [middle ear AND (infection OR inflammation)] which were run through Medline and Embase via Ovid, including both human and animal studies. In total, 82 955 studies underwent automated filtering followed by manual screening. One hundred studies were included in the review. RESULTS: Most studies were based on in vitro or animal work. Abnormalities in pathogen detection pathways, such as Toll-like receptors, have confirmed roles in OM. The aetiology of OM, its chronic subgroups (chronic OM, persistent OM with effusion) and recurrent acute OM is complex; however, inflammatory signalling mechanisms are frequently implicated. Host epithelium likely plays a crucial role, but the characterisation of human middle ear tissue lags behind that of other anatomical subsites. CONCLUSIONS: Translational research for OM presently falls far behind its clinical importance. This has likely hindered the development of new diagnostic and treatment modalities. Further work is urgently required; particularly to disentangle the respective immune pathologies in the clinically observed phenotypes and thereby work towards more personalised treatments.

4.
Int J STD AIDS ; 32(10): 978-980, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33947276

RESUMO

Recurrence of mucocutaneous herpes simplex virus (HSV) infections is common in immunosuppressed patients. Thymidine kinase mutations conferring resistance to the antiviral agent aciclovir have been observed in such patients. Recommended second-line therapeutic agents against HSV are associated with significant side effects contributing to disease burden. We present a case of aciclovir-resistant herpes simplex virus 2 (HSV-2) in an immunosuppressed (HIV negative) allogenic peripheral blood stem cell transplant (SCT) recipient which was refractory to second-line therapy. Compassionate acquisition of the novel oral helicase-primase inhibitor pritelivir provided both symptomatic and virological control for the duration of its use. We believe this to be the first clinical use of this therapeutic agent in the United Kingdom.


Assuntos
Herpes Simples , Herpesvirus Humano 2 , Aciclovir/uso terapêutico , Idoso , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral , Feminino , Herpes Simples/tratamento farmacológico , Humanos , Piridinas/uso terapêutico , Sulfonamidas , Tiazóis/uso terapêutico
5.
Eur Respir Rev ; 30(160)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34039673

RESUMO

Our starting point is that relatively new findings into the pathogenesis and pathophysiology of airway disease in smokers that lead to chronic obstructive pulmonary disease (COPD) need to be reassessed as a whole and integrated into "mainstream" thinking along with traditional concepts which have stood the test of time. Such a refining of the accepted disease paradigm is urgently needed as thinking on therapeutic targets is currently under active reconsideration. We feel that generalised airway wall "inflammation" is unduly over-emphasised, and highlight the patchy and variable nature of the pathology (with the core being airway remodelling). In addition, we present evidence for airway wall disease in smokers/COPD as including a hypocellular, hypovascular, destructive, fibrotic pathology, with a likely spectrum of epithelial-mesenchymal transition states as significant drivers of this remodelling. Furthermore, we present data from a number of research modalities and integrate this with the aetiology of lung cancer, the role of chronic airway luminal colonisation/infection by a specific group of "respiratory" bacteria in smokers (which results in luminal inflammation) and the central role for oxidative stress on the epithelium. We suggest translation of these insights into more focus on asymptomatic smokers and early COPD, with the potential for fresh preventive and therapeutic approaches.

6.
Stem Cell Rev Rep ; 17(4): 1503-1504, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33738694
7.
J Psychosoc Oncol ; 39(4): 534-552, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33468039

RESUMO

OBJECTIVES: To establish the demographic, medical, transplant, and lifestyle factors that impact Quality of Life (QoL) in long-term survivors of allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT). DESIGN: Cross-sectional study utilizing self-report measures. SAMPLE/METHODS: In this cross-sectional study of 441 adult survivors of allo-HSCT, participants completed questionnaires assessing QoL, psychological, social, demographic, and clinical variables. FINDINGS: Factors associated with improved QoL post-allo-HSCT included time since transplant, female gender, attendance at outpatient appointments, health screening uptake, exercise, and resumption of travel. Factors significantly associated with impaired QoL included chronic morbidities (GVHD), taking psychotropic medication, failure to resume sexual activity (in men), male gender, psychological distress, low income or decline in work status, transition to non-physical work, and necessity for post-allo-HSCT care from various health professionals. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS: Identification of survivors more likely to experience a reduced QoL following allo-HSCT may enable the targeting of health services to the most vulnerable, and the development of interventions and resources. The data from this study led to the development of HSCT Long-Term Follow Up Clinical Guidelines in New South Wales.

8.
Sex Transm Infect ; 97(1): 5-7, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32366606

RESUMO

OBJECTIVES: Pre-exposure prophylaxis (PrEP) is not commissioned within National Health Service (NHS) England. Individuals can access it privately online or by enrolment into a clinical trial. We established a list of individuals not enrolled in trials, awaiting PrEP. In response to the observation that patients awaiting PrEP trials were being referred with newly diagnosed HIV, we aimed to measure attendance, incident HIV, STI acquisition and missed opportunities for prevention. METHODS: The search was conducted for patients on the list from November 2017 to November 2019. We examined the electronic clinical records of those on the list and extracted demographic information, STI and HIV diagnoses. In addition, for those diagnosed with HIV, we reviewed risk factors including chemsex and prior postexposure prophylaxis. RESULTS: There were 1073 patients on list, and 520 (48.6%) were still awaiting recruitment in a PrEP trial. Eight (0.75%) had an enrolment appointment booked while 200 (18.64%) had been contacted and deemed ineligible according to PrEP trial criteria. 45 (32.15%) had not responded to contact. We identified 15 new HIV infections in patients awaiting PrEP. Of these, 9/15 (60.00%) did not meet eligibility criteria at point of contact, though had been eligible at first referral. CONCLUSION: It is unacceptable that 15 patients acquired HIV while waiting. The individual lifetime cost of treating HIV is estimated at £360 800(1). This equals £5 412 000 for these 15 infections notwithstanding the psychological and physical burden. We advocate the immediate role out of universal PrEP for those who need it on the NHS. While this decision is delayed, harm is coming to those waiting. Wider provision of PrEP may encourage increased attendance, but must consider additional resources to accommodate added visits. We are relieved that at the point of final submission (21 March 2020) NHS England have recently announced funding of PrEP for eligible patients from, further details are pending.


Assuntos
Ensaios Clínicos como Assunto/organização & administração , Definição da Elegibilidade/organização & administração , Infecções por HIV/prevenção & controle , Acesso aos Serviços de Saúde , Profilaxia Pré-Exposição , Adolescente , Adulto , Idoso , Inglaterra/epidemiologia , Feminino , Infecções por HIV/economia , Humanos , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Seleção de Pacientes , Listas de Espera , Adulto Jovem
10.
Am J Physiol Lung Cell Mol Physiol ; 320(2): L288-L300, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296276

RESUMO

Cystic fibrosis (CF) arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in progressive and life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterized. Our aims were to describe the clinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individuals harboring R751L (2 patients with G551D/R751L and 1 with F508del/R751L). Assessment of R751L-CFTR function was made in primary human bronchial epithelial cultures (HBEs) and Xenopus oocytes. Molecular properties of R751L-CFTR were investigated in the presence of known CFTR modulators. Although sweat chloride was elevated in all three patients, the clinical phenotype associated with R751L was mild. Chloride secretion in F508del/R751L HBEs was reduced compared with non-CF HBEs and associated with a reduction in sodium absorption by the epithelial sodium channel (ENaC). However, R751L-CFTR function in Xenopus oocytes, together with folding and cell surface transport of R751L-CFTR, was not different from wild-type CFTR. Overall, R751L-CFTR was associated with reduced sodium chloride absorption but had functional properties similar to wild-type CFTR. This is the first report of R751L-CFTR that combines clinical phenotype with characterization of functional and biological properties of the mutant channel. Our work will build upon existing knowledge of mutations within this region of CFTR and, importantly, inform approaches for clinical management. Elevated sweat chloride and reduced chloride secretion in HBEs may be due to alternative non-CFTR factors, which require further investigation.


Assuntos
Brônquios , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Células Epiteliais , Mutação de Sentido Incorreto , Cloreto de Sódio/metabolismo , Substituição de Aminoácidos , Animais , Brônquios/metabolismo , Brônquios/patologia , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Xenopus laevis
12.
JCI Insight ; 5(16)2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32814718

RESUMO

Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.


Assuntos
Inflamação/fisiopatologia , Cinurenina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Arginina/metabolismo , Doença Crônica , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Idoso Fragilizado , Humanos , Inflamação/metabolismo , Interleucina-10/genética , Cinurenina/sangue , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Junção Neuromuscular/metabolismo , Junção Neuromuscular/fisiopatologia , Serotonina/sangue , Triptofano/sangue , Velocidade de Caminhada , Adulto Jovem
13.
Stem Cells ; 38(10): 1292-1306, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32621788

RESUMO

Inhibition of E-cad in mouse embryonic stem cells (mESCs) leads to a switch from LIF-BMP to Activin/Nodal-dependent pluripotency, consistent with transition from a naïve to primed pluripotent phenotype. We have used both genetic ablation and steric inhibition of E-cad function in mESCs to assess alterations to phenotype using quantitative mass spectrometry analysis, network models, and functional assays. Proteomic analyses revealed that one third of detected proteins were altered in E-cad null mESCs (Ecad-/- mESCs) compared to wild type (624 proteins were downregulated and 705 were proteins upregulated). Network pathway analysis and subsequent cellular flux assays confirmed a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, specifically through mitochondrial complex III downregulation and hypoxia inducible factor 1a target upregulation. Central to this was the transcriptional coactivator EP300. E-cad is a well-known tumor suppressor, its downregulation during cancer initiation and metastasis can be linked to the metabolic switch known as Warburg effect. This study highlights a phenomena found in both primed pluripotent state and cancer stemness and links it to loss of E-cad. Data are available via ProteomeXchange with identifier PXD012679.

15.
Arthritis Res Ther ; 22(1): 106, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381123

RESUMO

BACKGROUND: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. METHODS: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. RESULTS: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. CONCLUSIONS: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Humanos , Metotrexato/uso terapêutico , Camundongos , Líquido Sinovial , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Fator de Necrose Tumoral alfa
16.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1158-L1164, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267720

RESUMO

Shifts in cellular metabolic phenotypes have the potential to cause disease-driving processes in respiratory disease. The respiratory epithelium is particularly susceptible to metabolic shifts in disease, but our understanding of these processes is limited by the incompatibility of the technology required to measure metabolism in real-time with the cell culture platforms used to generate differentiated respiratory epithelial cell types. Thus, to date, our understanding of respiratory epithelial metabolism has been restricted to that of basal epithelial cells in submerged culture, or via indirect end point metabolomics readouts in lung tissue. Here we present a novel methodology using the widely available Seahorse Analyzer platform to monitor real-time changes in the cellular metabolism of fully differentiated primary human airway epithelial cells grown at air-liquid interface (ALI). We show increased glycolytic, but not mitochondrial, ATP production rates in response to physiologically relevant increases in glucose availability. We also show that pharmacological inhibition of lactate dehydrogenase is able to reduce glucose-induced shifts toward aerobic glycolysis. This method is timely given the recent advances in our understanding of new respiratory epithelial subtypes that can only be observed in vitro through culture at ALI and will open new avenues to measure real-time metabolic changes in healthy and diseased respiratory epithelium, and in turn the potential for the development of novel therapeutics targeting metabolic-driven disease phenotypes.


Assuntos
Ar , Diferenciação Celular , Sistemas Computacionais , Metabolismo Energético , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Nariz/citologia , Ácidos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Glucose/farmacologia , Humanos , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Metabolômica
17.
J Physiol ; 598(7): 1327-1338, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582750

RESUMO

KEY POINTS: Our group previously discovered and characterized the microtubule mechanotransduction pathway linking diastolic stretch to NADPH oxidase 2-derived reactive oxygen species signals that regulate calcium sparks and calcium influx pathways. Here we used focused experimental tests to constrain and expand our existing computational models of calcium signalling in heart. Mechanistic and quantitative modelling revealed new insights in disease including: changes in microtubule network density and properties, elevated NOX2 expression, altered calcium release dynamics, how NADPH oxidase 2 is activated by and responds to stretch, and finally the degree to which normalizing mechano-activated reactive oxygen species signals can prevent calcium-dependent arrhythmias. ABSTRACT: Microtubule (MT) mechanotransduction links diastolic stretch to generation of NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS), signals we term X-ROS. While stretch-elicited X-ROS primes intracellular calcium (Ca2+ ) channels for synchronized activation in the healthy heart, the dysregulated excess in this pathway underscores asynchronous Ca2+ release and arrhythmia. Here, we expanded our existing computational models of Ca2+ signalling in heart to include MT-dependent mechanotransduction through X-ROS. Informed by new focused experimental tests to properly constrain our model, we quantify the role of X-ROS on excitation-contraction coupling in healthy and pathological conditions. This approach allowed for a mechanistic investigation that revealed new insights into X-ROS signalling in disease including changes in MT network density and post-translational modifications (PTMs), elevated NOX2 expression, altered Ca2+ release dynamics (i.e. Ca2+ sparks and Ca2+ waves), how NOX2 is activated by and responds to stretch, and finally the degree to which normalizing X-ROS can prevent Ca2+ -dependent arrhythmias.


Assuntos
Sinalização do Cálcio , Mecanotransdução Celular , Arritmias Cardíacas/metabolismo , Cálcio/metabolismo , Humanos , Microtúbulos/metabolismo , Miócitos Cardíacos/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Allergy ; 75(5): 1146-1154, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31605638

RESUMO

BACKGROUND: It is suggested that airway fungi, in particular Aspergillus may impinge on clinical phenotype in asthma. Indeed, the term severe asthma with fungal sensitization (SAFS) has been coined. We aimed to ascertain whether the presence of fungi, in particular Aspergillus fumigatus, in the airway correlated with asthma severity and control. Furthermore, we aimed to determine whether traditional markers of Aspergillus sensitization related to the presence of Aspergillus within the airway. METHODS: Sixty-nine patients characterized by asthma severity (GINA) and level of control (ACQ-7) underwent bronchoscopy and bronchoalveolar lavage (BAL). Serum was assessed for A fumigatus-specific IgE and total IgE. Galactomannan and relevant cytokine levels were assessed in serum, plasma and BAL. BAL was analyzed for the presence of A fumigatus. RESULTS: In BAL, fungi were visible by microscopy in 70% and present by qPCR in 86% of patients, while A fumigatus was detectable by qPCR in 46%. Plasma and BAL IL-4, IL-6, IL-10, IL-13 and TNF-α correlated with BAL fungal presence, while plasma IL-17 correlated with BAL fungal presence. Aspergillus positive BAL correlated with increased plasma and BAL IL-6 and BAL IL-13. There was no relationship between fungal airway presence and steroid dose, asthma severity or control. The presence of Aspergillus within the airway did not relate to serum IgE positivity for Aspergillus. CONCLUSIONS: Fungi were present in a large proportion of our asthmatic patients' airways, but their presence was not predicted by traditional markers of sensitization, nor did it appear to be related to measures of disease severity or control.


Assuntos
Aspergilose Broncopulmonar Alérgica , Asma , Aspergillus fumigatus , Asma/diagnóstico , Líquido da Lavagem Broncoalveolar , Humanos , Imunoglobulina E , Índice de Gravidade de Doença
20.
BMJ Open Respir Res ; 6(1): e000465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673366

RESUMO

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.


Assuntos
Azitromicina/uso terapêutico , Bronquiolite Obliterante/tratamento farmacológico , Adulto , Azitromicina/farmacologia , Bronquiolite Obliterante/mortalidade , Bronquiolite Obliterante/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Síndrome , Fatores de Tempo , Resultado do Tratamento
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