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OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DESIGN: Using an in vivo mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation. RESULTS: FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. CONCLUSION: The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.
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Pneumonia , Doença Pulmonar Obstrutiva Crônica , Humanos , Camundongos , Animais , Doença Pulmonar Obstrutiva Crônica/etiologia , Pulmão/metabolismo , Pulmão/patologia , Pneumonia/etiologia , Inflamação/metabolismo , Carboidratos/farmacologiaRESUMO
OBJECTIVE: People with advanced chronic obstructive pulmonary disease (COPD) have substantial palliative care needs, but uncertainty exists around appropriate identification of patients for palliative care referral.We conducted a Delphi study of international experts to identify consensus referral criteria for specialist outpatient palliative care for people with COPD. METHODS: Clinicians in the fields of respiratory medicine, palliative and primary care from five continents with expertise in respiratory medicine and palliative care rated 81 criteria over three Delphi rounds. Consensus was defined a priori as ≥70% agreement. A criterion was considered 'major' if experts endorsed meeting that criterion alone justified palliative care referral. RESULTS: Response rates from the 57 panellists were 86% (49), 84% (48) and 91% (52) over first, second and third rounds, respectively. Panellists reached consensus on 17 major criteria for specialist outpatient palliative care referral, categorised under: (1) 'Health service use and need for advanced respiratory therapies' (six criteria, eg, need for home non-invasive ventilation); (2) 'Presence of symptoms, psychosocial and decision-making needs' (eight criteria, eg, severe (7-10 on a 10 point scale) chronic breathlessness); and (3) 'Prognostic estimate and performance status' (three criteria, eg, physician-estimated life expectancy of 6 months or less). CONCLUSIONS: International experts evaluated 81 potential referral criteria, reaching consensus on 17 major criteria for referral to specialist outpatient palliative care for people with COPD. Evaluation of the feasibility of these criteria in practice is required to improve standardised palliative care delivery for people with COPD.
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BACKGROUND: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. METHODS: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real-world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5-item Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post-bronchodilator FEV1 ≥80%) or stabilization (post-bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut-offs of ACQ-5/FEV1 scores. The predictors of clinical remission were identified. RESULTS: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. CONCLUSION: Biologic treatment with mepolizumab or omalizumab for severe asthma-induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure.
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Antiasmáticos , Anticorpos Monoclonais Humanizados , Asma , Produtos Biológicos , Humanos , Masculino , Feminino , Omalizumab/uso terapêutico , Antiasmáticos/uso terapêutico , Broncodilatadores/uso terapêutico , Austrália/epidemiologia , Asma/terapia , Produtos Biológicos/uso terapêuticoRESUMO
Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable, with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and subcellular localization were assessed, and cellular proliferation, pAkt/Akt and pERK levels determined. A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80 kDa form (which enhances proliferation) compared with the full-length (180 kDa) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localization pre- and post-epidermal growth factor stimulation; however, epidermal growth factor receptor (EGFR) levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared with wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 min post-stimulation compared with wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic. This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Criança , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa , Células HeLa , Humanos , Neoplasias Pulmonares/genética , Receptor ErbB-2/genética , Receptor ErbB-3/genéticaRESUMO
Low haemoglobin (Hb) concentrations and anaemia in children have adverse effects on development and functioning, some of which may have consequences in later life. Exposure to ambient air pollution is reported to be associated with anaemia, but there is little evidence specific to low- and middle-income countries (LMICs), where childhood anaemia prevalence is greatest. We aimed to determine if long-term ambient fine particulate matter (≤2.5 µm in aerodynamic diameter [PM2.5]) exposure was associated with Hb levels and the prevalence of anaemia in children aged <5 years living in 36 LMICs. We used Demographic and Health Survey data, collected between 2010 and 2019, which included blood Hb measurements. Satellite-derived estimates of annual average PM2.5 was the main exposure variable, which was linked to children's area of residence. Anaemia was defined according to standard World Health Organization guidelines (Hb < 11 g/dL). The association of PM2.5 with Hb levels and anaemia prevalence was examined using multivariable linear and logistic regression models, respectively. We examined whether the effects of ambient PM2.5 were modified by a child's sex and age, household wealth index, and urban/rural place of residence. Models were adjusted for relevant covariates, including other outdoor pollutants and household cooking fuel. The study included 154,443 children, of which 89,904 (58.2%) were anaemic. The country-level prevalence of anaemia ranged from 15.8% to 87.9%. Mean PM2.5 exposure was 33.0 (±21.6) µg/m3. The adjusted model showed that a 10 µg/m3 increase in annual PM2.5 concentration was associated with greater odds of anaemia (OR = 1.098 95% CI: 1.087, 1.109). The same increase in PM2.5 was associated with a decrease in average Hb levels of 0.075 g/dL (95% CI: 0.081, 0.068). There was evidence of effect modification by household wealth index and place of residence, with greater adverse effects in children from lower wealth quintiles and children in rural areas. Exposure to annual PM2.5 was cross-sectionally associated with decreased blood Hb levels, and greater risk of anaemia, in children aged <5 years living in 36 LMICs.
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Poluentes Atmosféricos , Poluição do Ar , Anemia , Humanos , Criança , Material Particulado/análise , Poluentes Atmosféricos/análise , Estudos Transversais , Exposição Ambiental/análise , Poluição do Ar/análise , Anemia/induzido quimicamente , Anemia/epidemiologia , HemoglobinasRESUMO
BACKGROUND: The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) has been the subject of much uncertainty. COPD clinical guidelines currently recommend selective use of ICS. ICS are not recommended as monotherapy for people with COPD, and are only given in combination with long-acting bronchodilators due to greater efficacy of combination therapy. Incorporating and critiquing newly published placebo-controlled trials into the monotherapy evidence base may help to resolve ongoing uncertainties and conflicting findings about their role in this population. OBJECTIVES: To evaluate the benefits and harms of inhaled corticosteroids, used as monotherapy versus placebo, in people with stable COPD, in terms of objective and subjective outcomes. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was October 2022. SELECTION CRITERIA: We included randomised trials comparing any dose of any type of ICS, given as monotherapy, with a placebo control in people with stable COPD. We excluded studies of less than 12 weeks' duration and studies of populations with known bronchial hyper-responsiveness (BHR) or bronchodilator reversibility. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our a priori primary outcomes were 1. exacerbations of COPD and 2. quality of life. Our secondary outcomes were 3. all-cause mortality, 4. lung function (rate of decline of forced expiratory volume in one second (FEV1)), 5. rescue bronchodilator use, 6. exercise capacity, 7. pneumonia and 8. adverse events including pneumonia. ]. We used GRADE to assess certainty of evidence. MAIN RESULTS: Thirty-six primary studies with 23,139 participants met the inclusion criteria. Mean age ranged from 52 to 67 years, and females were 0% to 46% of participants. Studies recruited across the severities of COPD. Seventeen studies were of duration longer than three months and up to six months and 19 studies were of duration longer than six months. We judged the overall risk of bias as low. Long-term (more than six months) use of ICS as monotherapy reduced the mean rate of exacerbations in those studies where pooling of data was possible (generic inverse variance analysis: rate ratio 0.88 exacerbations per participant per year, 95% confidence interval (CI) 0.82 to 0.94; I2 = 48%, 5 studies, 10,097 participants; moderate-certainty evidence; pooled means analysis: mean difference (MD) -0.05 exacerbations per participant per year, 95% CI -0.07 to -0.02; I2 = 78%, 5 studies, 10,316 participants; moderate-certainty evidence). ICS slowed the rate of decline in quality of life, as measured by the St George's Respiratory Questionnaire (MD -1.22 units/year, 95% CI -1.83 to -0.60; I2 = 0%; 5 studies, 2507 participants; moderate-certainty evidence; minimal clinically importance difference 4 points). There was no evidence of a difference in all-cause mortality in people with COPD (odds ratio (OR) 0.94, 95% CI 0.84 to 1.07; I2 = 0%; 10 studies, 16,636 participants; moderate-certainty evidence). Long-term use of ICS reduced the rate of decline in FEV1 in people with COPD (generic inverse variance analysis: MD 6.31 mL/year benefit, 95% CI 1.76 to 10.85; I2 = 0%; 6 studies, 9829 participants; moderate-certainty evidence; pooled means analysis: 7.28 mL/year, 95% CI 3.21 to 11.35; I2 = 0%; 6 studies, 12,502 participants; moderate-certainty evidence). ADVERSE EVENTS: in the long-term studies, the rate of pneumonia was increased in the ICS group, compared to placebo, in studies that reported pneumonia as an adverse event (OR 1.38, 95% CI 1.02 to 1.88; I2 = 55%; 9 studies, 14,831 participants; low-certainty evidence). There was an increased risk of oropharyngeal candidiasis (OR 2.66, 95% CI 1.91 to 3.68; 5547 participants) and hoarseness (OR 1.98, 95% CI 1.44 to 2.74; 3523 participants). The long-term studies that measured bone effects generally showed no major effect on fractures or bone mineral density over three years. We downgraded the certainty of evidence to moderate for imprecision and low for imprecision and inconsistency. AUTHORS' CONCLUSIONS: This systematic review updates the evidence base for ICS monotherapy with newly published trials to aid the ongoing assessment of their role for people with COPD. Use of ICS alone for COPD likely results in a reduction of exacerbation rates of clinical relevance, probably results in a reduction in the rate of decline of FEV1 of uncertain clinical relevance and likely results in a small improvement in health-related quality of life not meeting the threshold for a minimally clinically important difference. These potential benefits should be weighed up against adverse events (likely to increase local oropharyngeal adverse effects and may increase the risk of pneumonia) and probably no reduction in mortality. Though not recommended as monotherapy, the probable benefits of ICS highlighted in this review support their continued consideration in combination with long-acting bronchodilators. Future research and evidence syntheses should be focused in that area.
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Pneumonia , Doença Pulmonar Obstrutiva Crônica , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Broncodilatadores/efeitos adversos , Qualidade de Vida , Corticosteroides/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pneumonia/tratamento farmacológico , Progressão da DoençaRESUMO
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease characterised by persistent respiratory symptoms and chronic airflow limitation on spirometry. COPD is highly prevalent and is associated with exacerbations and comorbid conditions. "COPD-X" provides quarterly updates in COPD care and is published by the Lung Foundation Australia and the Thoracic Society of Australia and New Zealand. MAIN RECOMMENDATIONS: The COPD-X guidelines (version 2.65) encompass 26 recommendations addressing: case finding and confirming diagnosis; optimising function; preventing deterioration; developing a plan of care; and managing an exacerbation. CHANGES IN MANAGEMENT AS A RESULT OF THESE GUIDELINES: Both non-pharmacological and pharmacological strategies are included within these recommendations, reflecting the importance of a holistic approach to clinical care for people living with COPD to delay disease progression, optimise quality of life and ensure best practice care in the community and hospital settings when managing exacerbations. Several of the new recommendations, if put into practice in the appropriate circumstances, and notwithstanding known variations in the social determinants of health, could improve quality of life and reduce exacerbations, hospitalisations and mortality for people living with COPD.
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Doença Pulmonar Obstrutiva Crônica , Qualidade de Vida , Humanos , Austrália , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Espirometria , Progressão da DoençaRESUMO
INTRODUCTION: Greenspaces generate several perceived health benefits, including an overall improvement in the quality of life. However, little is known about the effects of greenspaces through pregnancy and early childhood in promoting health-related quality of life (HRQoL) among children. METHOD: Participants were from the Mothers and their Children's Health Study (MatCH), a 2016/17 sub-study of a national prospective study since 1996 known as the Australian Longitudinal Study on Women's Health (ALSWH). Mothers (n=3,048) self-reported on their three youngest children aged under 13 years (n=5,799, mean=7.0 years, s.d=3.2 years) using the Pediatric Quality of Life Inventory (PedsQL) to measure their HRQoL. Since 1996, annual exposure to green and non-green vegetation was measured using two remote sensing indicators: Normalized Difference Vegetation Index (NDVI) and fractional cover of non-photosynthetic vegetation (fNPV), respectively, for 100 m and 500 m buffer zone around maternal residential address. Multiple exposure windows were calculated including during pregnancy, the first year of life and child's lifetime exposure. Generalised estimating equations (GEE) models, adjusting for potential confounders, were used for analyses. RESULTS: A 1 standard deviation increase in NDVI greenness within 500 m buffer around the home at early life and during childhood was positively associated with higher HRQoL in the total scores and psychological health summary scores in the crude model only. No association was found between fNPV (non-green vegetation) at 100 m and 500 m circular buffers and children's HRQoL. The overall findings from our models remained consistent based on a series of sensitivity analyses, including the impact of maternal residential mobility status and geocoding method on the effect estimates. CONCLUSION: Our study revealed that surrounding residential greenspace was not associated with children's HRQoL. Further longitudinal studies are required to better understand the influence of greenspace at different periods of exposure on the health and wellbeing of children.
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Saúde Mental , Qualidade de Vida , Austrália , Criança , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Gravidez , Estudos ProspectivosRESUMO
Add-on azithromycin (AZM) significantly reduces exacerbations in poorly controlled asthma irrespective of disease phenotype. In a predefined substudy of the original AMAZES protocol (500 mg, three times a week for 48 weeks), we report that AZM treatment reduces key sputum inflammatory proteins (interleukin (IL)-6, IL-1ß and extracellular DNA), which is more evident in non-eosinophilic asthma (NEA). Moreover, AZM reduced Haemophilus influenzae load only in NEA. Our data support the anti-inflammatory effects of AZM in poorly controlled asthma. Prospective studies are required to identify patients that derive greatest benefit from AZM add-on therapy.
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Asma/tratamento farmacológico , Azitromicina/administração & dosagem , Citocinas/metabolismo , Escarro/metabolismo , Antibacterianos/uso terapêutico , Asma/metabolismo , Humanos , Estudos ProspectivosRESUMO
AIMS: Advanced nonmalignant respiratory diseases are associated with significant patient morbidity, yet access to palliative care occurs late, if at all. Our aim was to examine referral criteria for palliative care among patients with advanced nonmalignant respiratory disease, with a view to developing a standardised set of referral criteria. METHODS: We performed a systematic review of all studies reporting on referral criteria to palliative care in advanced nonmalignant respiratory disease, with a focus on chronic obstructive pulmonary disease and interstitial lung disease. The systematic review was conducted and reported according to the PRISMA guidelines, and was undertaken using electronic databases (Ovid, MEDLINE, Ovid Embase and PubMed). RESULTS: Searches yielded 2052 unique titles, which were screened for eligibility and resulted in 62 studies addressing referral criteria to palliative care in advanced nonmalignant respiratory disease. Of 18 categories put forward for referral to palliative care, the most commonly discussed factors were hospital use (69% of papers), indicators of poor respiratory status (47%), physical and emotional symptoms (37%), functional decline (29%), need for advanced respiratory therapies (27%), and disease progression (26%). CONCLUSION: Clinicians consider referral to specialist palliative care for a wide range of disease- and needs-based criteria. Our findings highlight the need to standardise palliative care access by developing consensus referral criteria for patients with advanced nonmalignant respiratory illnesses.
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Doenças Pulmonares Intersticiais , Doença Pulmonar Obstrutiva Crônica , Atenção à Saúde , Humanos , Cuidados Paliativos , Doença Pulmonar Obstrutiva Crônica/terapia , Encaminhamento e ConsultaRESUMO
Add-on azithromycin (AZM) results in a significant reduction in exacerbations among adults with persistent uncontrolled asthma. The aim of this study was to assess the cost-effectiveness of add-on AZM in terms of healthcare and societal costs.The AMAZES trial randomly assigned 420 participants to AZM or placebo. Healthcare use and asthma exacerbations were measured during the treatment period. Healthcare use included all prescribed medicine and healthcare contacts. Costs of antimicrobial resistance (AMR) were estimated based on overall consumption and published estimates of costs. The value of an avoided exacerbation was based on published references. Differences in cost between the two groups were related to differences in exacerbations in a series of net monetary benefit estimates. Societal costs included lost productivity, over the counter medicines, steroid induced morbidity and AMR costs.Add-on AZM resulted in a reduction in healthcare costs (mean (95% CI)) including nights in hospital (AUD 433.70 (AUD 48.59-818.81) or EUR 260.22 (EUR 29.15-491.29)), unplanned healthcare visits (AUD 20.25 (AUD 5.23-35.27) or EUR 12.15 (EUR 3.14-21.16)), antibiotic costs (AUD 14.88 (AUD 7.55-22.21) or EUR 8.93 (EUR 4.53-13.33)) and oral corticosteroid costs (AUD 4.73 (AUD 0.82-8.64) or EUR 2.84 (EUR 0.49-5.18)); all p<0.05. Overall healthcare and societal costs were lower (AUD 77.30 (EUR 46.38) and AUD 256.22 (EUR 153.73) respectively) albeit not statistically significant. The net monetary benefit of add-on AZM was estimated to be AUD 2072.30 (95% CI AUD 1348.55-2805.23) or (EUR 1243.38 (EUR 809.13-1683.14) assuming a willingness to pay per exacerbation avoided of AUD 2651 (EUR 1590.60). Irrespective of the sensitivity analysis applied, the net monetary benefit for total, moderate and severe exacerbations remained positive and significant.Add-on AZM therapy in poorly controlled asthma was a cost-effective therapy. Costs associated with AMR did not influence estimated cost-effectiveness.
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Asma , Azitromicina , Corticosteroides/uso terapêutico , Adulto , Antibacterianos/uso terapêutico , Asma/tratamento farmacológico , Azitromicina/uso terapêutico , Análise Custo-Benefício , HumanosRESUMO
BACKGROUND: The AMAZES randomized controlled trial demonstrated that long-term low-dose azithromycin treatment reduces exacerbations of poorly controlled asthma, but the therapeutic mechanisms remain unclear. Dysregulation of the inflammatory tumour necrosis factor (TNF) pathway is implicated in asthma and could be suppressed by azithromycin. We aimed to determine the inflammatory and clinical associations of soluble TNF signalling proteins (TNF receptors [TNFR] 1 and 2, TNF) in sputum and serum, and to test the effect of 48 weeks of azithromycin vs placebo on TNF markers. METHODS: Sputum supernatant and serum TNFR1, TNFR2 (n = 142; 75 azithromycin-treated, 67 placebo-treated) and TNF (n = 48; 22 azithromycin-treated, 26 placebo-treated) were measured by ELISA in an AMAZES trial sub-population at baseline and end of treatment. Baseline levels were compared between sputum inflammatory phenotypes, severe/non-severe asthma and frequent/non-frequent exacerbators. Effect of azithromycin on markers was tested using linear mixed models. RESULTS: Baseline sputum TNFR1 and TNFR2 were significantly increased in neutrophilic vs non-neutrophilic asthma phenotypes, while serum markers did not differ. Sputum TNFR1 and TNFR2 were increased in severe asthma and correlated with poorer lung function, worse asthma control and increasing age. Serum TNFR1 was also increased in severe asthma. Sputum and serum TNFR2 were increased in frequent exacerbators. Azithromycin treatment significantly reduced sputum TNFR2 and TNF relative to placebo, specifically in non-eosinophilic participants. CONCLUSIONS: We demonstrate dysregulation of TNF markers, particularly in the airways, that relates to clinically important phenotypes of asthma including neutrophilic and severe asthma. Suppression of dysregulated TNF signalling by azithromycin could contribute to its therapeutic mechanism.
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Asma , Azitromicina , Antibacterianos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Azitromicina/uso terapêutico , Biomarcadores , Humanos , Escarro , Fator de Necrose Tumoral alfaRESUMO
The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly noncommunicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a "poor" diet or protection against disease with a "healthy" diet. In addition, many mucosa-associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host-microbiome and inter-microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract) and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.
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Microbioma Gastrointestinal , Doenças do Sistema Imunitário , Microbiota , Dieta , Trato Gastrointestinal , HumanosRESUMO
Lung cancer remains the leading cause of cancer related mortality worldwide. We aimed to test whether a simple blood biomarker (extracellular vesicle miRNAs) can discriminate between cases with and without lung cancer. METHODS: plasma extracellular vesicles (EVs) were isolated from four cohorts (n = 20 in each): healthy non-smokers, healthy smokers, lung cancer, and stable COPD participants. EV miRNA expression was evaluated using the miRCURY LNA miRNA Serum/Plasma assay for 179 specific targets. Significantly dysregulated miRNAs were assessed for discriminatory power using ROC curve analysis. RESULTS: 15 miRNAs were differentially expressed between lung cancer and healthy non-smoking participants, with the greatest single miRNA being miR-205-5p (AUC 0.850), improving to AUC 0.993 in combination with miR-199a-5p. Moreover, 26 miRNAs were significantly dysregulated between lung cancer and healthy smoking participants, with the greatest single miRNA being miR-497-5p (AUC 0.873), improving to AUC 0.953 in combination with miR-22-5p; 14 miRNAs were significantly dysregulated between lung cancer and stable COPD participants, with the greatest single miRNA being miR-27a-3p (AUC 0.803), with two other miRNAs (miR-106b-3p and miR-361-5p) further improving discriminatory power (AUC 0.870). CONCLUSION: this case control study suggests miRNAs in EVs from plasma holds key biological information specific for lung cancer and warrants further prospective assessment.
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Biomarcadores Tumorais/genética , Vesículas Extracelulares/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Idoso , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Curva ROCRESUMO
AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD-related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD-related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non-pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.
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Doença Pulmonar Obstrutiva Crônica/terapia , Enfisema Pulmonar/terapia , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/uso terapêutico , Austrália , Progressão da Doença , Humanos , Transplante de Pulmão , Nova Zelândia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/etiologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/etiologia , Procedimentos de Cirurgia Plástica , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
Rationale: The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.Objectives: To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.Methods: 16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.Measurements and Main Results: Paired sputum samples were available from 61 patients (n = 34 placebo, n = 27 azithromycin). Azithromycin did not affect bacterial load (P = 0.37) but did significantly decrease Faith's phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.Conclusions: In patients with persistent uncontrolled asthma, azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.
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Antibacterianos/administração & dosagem , Asma/microbiologia , Azitromicina/administração & dosagem , Farmacorresistência Bacteriana/efeitos dos fármacos , Haemophilus influenzae/isolamento & purificação , Adulto , Idoso , Carga Bacteriana , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moraxella catarrhalis/isolamento & purificação , Pseudomonas aeruginosa/isolamento & purificação , Escarro/microbiologia , Staphylococcus aureus/isolamento & purificação , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
BACKGROUND: Telemonitoring studies in chronic heart failure are characterized by mixed mortality and hospitalization outcomes, which have deterred the uptake of telemonitoring in clinical practice. These mixed outcomes may reflect the diverse range of patient management strategies incorporated in telemonitoring. To address this, we compared the effects of different telemonitoring strategies on clinical outcomes. OBJECTIVE: The aim of this systematic review and subgroup meta-analysis was to identify noninvasive telemonitoring strategies attributing to improvements in all-cause mortality or hospitalization outcomes for patients with chronic heart failure. METHODS: We reviewed and analyzed telemonitoring strategies from randomized controlled trials (RCTs) comparing telemonitoring intervention with usual care. For each strategy, we examined whether RCTs that applied the strategy in the telemonitoring intervention (subgroup 1) resulted in a significantly lower risk ratio (RR) of all-cause mortality or incidence rate ratio (IRR) of all-cause hospitalization compared with RCTs that did not apply this strategy (subgroup 2). RESULTS: We included 26 RCTs (N=11,450) incorporating 18 different telemonitoring strategies. RCTs that provided medication support were found to be associated with a significantly lower IRR value than RCTs that did not provide this type of support (P=.01; subgroup 1 IRR=0.83, 95% CI 0.72-0.95 vs subgroup 2 IRR=1.02, 95% CI 0.93-1.12). RCTs that applied mobile health were associated with a significantly lower IRR (P=.03; IRR=0.79, 95% CI 0.64-0.96 vs IRR=1.00, 95% CI 0.94-1.06) and RR (P=.01; RR=0.67, 95% CI 0.53-0.85 vs RR=0.95, 95% CI 0.84-1.07). CONCLUSIONS: Telemonitoring strategies involving medication support and mobile health were associated with improvements in all-cause mortality or hospitalization outcomes. These strategies should be prioritized in telemonitoring interventions for the management of patients with chronic heart failure.
Assuntos
Insuficiência Cardíaca/terapia , Telemedicina/métodos , Doença Crônica , Insuficiência Cardíaca/mortalidade , HumanosRESUMO
BACKGROUND: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). OBJECTIVES: We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. METHODS: One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. RESULTS: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. CONCLUSION: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.
Assuntos
Asma/genética , Índice de Gravidade de Doença , Escarro , Transcriptoma , Idoso , Antibacterianos/uso terapêutico , Asma/tratamento farmacológico , Asma/imunologia , Azitromicina/uso terapêutico , Método Duplo-Cego , Eosinófilos/imunologia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Fenótipo , Escarro/imunologiaRESUMO
Pleural mesothelioma is a cancer of serosal surfaces caused by environmental exposure to asbestos. Clinical outcome remains poor and while trials of new treatments are ongoing it remains an understudied cancer. Mesothelioma cell lines can readily be grown from primary tumour and from tumour cells shed into pleural effusion with the latter representing a particularly valuable source of DNA in clinical settings, procurable without the need for additional invasive procedures. However, it is not well understood how accurately patient-derived cultured tumour cells represent the molecular characteristics of their primary tumour. We used whole-genome sequencing of primary tumour and matched cultured cells to comprehensively characterize mutations and structural alterations. Most cases had complex rearranged genomes with evidence of chromoanagenesis and rearrangements reminiscent of chromoplexy. Many of the identified driver mutations were structural, indicating that mesothelioma is often caused by structural alterations and catastrophic genomic events, rather than point mutations. Because the majority of genomic changes detected in tumours were also displayed by the genomes of cultured tumour cells, we conclude that low-passage cultured tumour cells are generally suitable for molecular characterization of mesothelioma and may be particularly useful where tissue samples with high tumour cell content are not available. However, the subclonal compositions of the cell lines did not fully recapitulate the subclonal diversity of the primary tumours. Furthermore, longitudinal acquisition of major alterations in subclonal cell populations was observed after long-term passaging. These two factors define limitations of tumour-derived cell lines as genomic substrate for clinical purposes.
Assuntos
Mesotelioma/genética , Neoplasias Pleurais/genética , Sequenciamento Completo do Genoma , Linhagem Celular Tumoral , Humanos , Mesotelioma/patologia , Mutação , Neoplasias Pleurais/patologiaRESUMO
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death world-wide by 2020. Prolonged exposure to particulate matter is associated with COPD progression and mortality. Diesel emissions are a major contributor to particulate matter pollution. In this study we test a therapeutic antioxidant, N-acetylcysteine (NAC), for its ability to protect bronchial epithelial cells (pHBECs) from patients with COPD from adverse effects of diesel emission exposure. METHODS: pHBECs from patients with or without COPD were cultured at air-liquid interface (ALI). Cells were exposed to diesel emissions for 30â¯min with or without 3-h post-exposure treatment with 5â¯mM N-acetylcysteine (NAC). Filtered laboratory air was tested as a negative control. Cell responses (cell viability, inflammation and oxidative stress) and gene expression profiles for intracellular and immune signaling were assessed. RESULTS: Diesel emissions exposure increased IL-8 secretion and production, antioxidant production, and cytochrome P450 1a1 (CYP1a1) mRNA expression and suppressed superoxide dismutase-1 (SOD1) mRNA expression in bronchial epithelial cells from COPD patients. Treatment with N-acetyl cysteine attenuated the suppression of SOD1. Nanostring gene expression profiling of the filtered air controls showed COPD epithelial cells have increased expression of MHC class II and an interferon signaling profile. CONCLUSIONS: This study indicates that bronchial epithelial cells from COPD patients may be vulnerable to diesel emission exposure due to reduced antioxidant capacity, and elevated CYP1a1 mRNA expression. NAC did not appear to offer protection. Future research will be needed to explore other means of recovering oxidant capacity in COPD airways.