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1.
Respir Res ; 22(1): 15, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441106

RESUMO

BACKGROUND: Elderly asthmatics represent an important group that is often excluded from clinical studies. In this study we wanted to present characteristics of asthmatics older than 70 years old as compared to younger patients. METHODS: We conducted a retrospective analysis on a series of 758 asthmatics subdivided in three groups: lower than 40, between 40 and 70 and older than 70. All the patients who had a successful sputum induction were included in the study. RESULTS: Older patients had a higher Body Mass Index, had less active smokers and were more often treated with Long Acting anti-Muscarinic Agents. We found a significant increase in sputum neutrophil counts with ageing. There was no significant difference in blood inflammatory cell counts whatever the age group. Forced expiratory volume in one second (FEV1) and FEV1/FVC values were significantly lower in elderly who had lower bronchial hyperresponsiveness and signs of air trapping. We found a lower occurrence of the allergic component in advanced ages. Asthmatics older than 70 years old had later onset of the disease and a significant longer disease duration. CONCLUSION: Our study highlights that asthmatics older than 70 years old have higher bronchial neutrophilic inflammation, a poorer lung function, signs of air trapping and lower airway variability. The role of immunosenescence inducing chronic low-grade inflammation in this asthma subtype remains to be elucidated.


Assuntos
Asma/metabolismo , Volume Expiratório Forçado/fisiologia , Mediadores da Inflamação/metabolismo , Neutrófilos/metabolismo , Testes de Função Respiratória/métodos , Escarro/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/diagnóstico , Asma/imunologia , Feminino , Humanos , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Estudos Retrospectivos , Escarro/imunologia
2.
Ann Allergy Asthma Immunol ; 126(1): 54-60.e1, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553777

RESUMO

BACKGROUND: Eosinophils in induced sputum are not only a useful biomarker for diagnosing asthma but are also associated with severe asthma. However, little is known about the association between eosinophils in spontaneous sputum and asthma severity. OBJECTIVE: To investigate whether spontaneous sputum eosinophils are related to severe asthma in adult patients with asthma. METHODS: We conducted a retrospective cross-sectional study on 86 people with asthma whose spontaneous sputa were successfully collected. Patients were classified into 4 phenotypes according to the eosinophil and neutrophil levels in spontaneous sputum. We determined the association between inflammatory phenotypes and severe asthma. Moreover, we also compared asthma severity among the phenotypes classified according to blood eosinophils and spontaneous sputum eosinophils. RESULTS: Asthma phenotypes were as follows: paucigranulocytic, 30.2%; neutrophilic, 18.6%; eosinophilic, 32.6%; and mixed, 18.6%. People with eosinophilic asthma had the highest blood eosinophils, total immunoglobulin E (IgE), and fractional exhaled nitric oxide among the 4 phenotypes. Significant differences were observed in asthma severity between the phenotypes (P = .019). In particular, 57.2% and 56.2% of patients had severe eosinophilic asthma and mixed asthma, respectively. The logistic regression analysis revealed that spontaneous sputum eosinophilia represented the strongest association with severe asthma among the inflammatory variables. Finally, more patients with severe asthma were included in the phenotype with spontaneous sputum eosinophils greater than 3% and blood eosinophils less than or equal to 300/µL and in the phenotype with spontaneous sputum eosinophils greater than 3% and blood eosinophils greater than 300/µL. CONCLUSION: Spontaneous sputum can provide helpful information on airway inflammatory phenotyping in patients with asthma.


Assuntos
Asma/etiologia , Asma/metabolismo , Fenótipo , Escarro/imunologia , Escarro/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/diagnóstico , Asma/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
3.
BMC Bioinformatics ; 21(1): 457, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059594

RESUMO

BACKGROUND: The pathogenesis of asthma is a complex process involving multiple genes and pathways. Identifying biomarkers from asthma datasets, especially those that include heterogeneous subpopulations, is challenging. Potentially, autoencoders provide ideal frameworks for such tasks as they can embed complex, noisy high-dimensional gene expression data into a low-dimensional latent space in an unsupervised fashion, enabling us to extract distinguishing features from expression data. RESULTS: Here, we developed a framework combining a denoising autoencoder and a supervised learning classifier to identify gene signatures related to asthma severity. Using the trained autoencoder with 50 hidden units, we found that hierarchical clustering on the low-dimensional embedding corresponds well with previously defined and clinically relevant clusters of patients. Moreover, each hidden unit has contributions from each of the genes, and pathway analysis of these contributions shows that the hidden units are significantly enriched in known asthma-related pathways. We then used genes that contribute most to the hidden units to develop a secondary random-forest classifier for directly predicting asthma severity. The feature importance metric from this classifier identified a signature based on 50 key genes, which are associated with severity. Furthermore, we can use these key genes to successfully estimate FEV1/FVC ratios across patients, via support-vector-machine regression. CONCLUSION: We found that the denoising autoencoder framework can extract meaningful patterns corresponding to functional gene groups and patient clusters from the gene expression of asthma patients.


Assuntos
Algoritmos , Asma/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Escarro/metabolismo , Área Sob a Curva , Asma/patologia , Análise por Conglomerados , Humanos , Anotação de Sequência Molecular , Curva ROC , Índice de Gravidade de Doença , Máquina de Vetores de Suporte
4.
PLoS One ; 15(9): e0238524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915806

RESUMO

BACKGROUND: Markers of lung inflammation measured directly in expectorated sputum have the potential of improving the timing of antibiotic treatment in cystic fibrosis (CF). L-Lactate might be a marker of inflammation, as it is produced from glucose by polymorphonuclear neutrophils (PMNs) in CF lungs. We aimed to investigate changes in and associations between PMNs, glucose and L-lactate in sputum during antibiotic treatment. In addition, the effect of hemoglobin A1c and plasma glucose on these biomarkers were investigated. METHODS: We sampled non-induced sputum at day 0, 7, 14 and 42 in 27 chronically infected CF patients electively treated with 14 days of intravenous antibiotic. To analyze sputum samples, we used flowcytometry to count PMNs and colorimetric assays to estimate lactate and glucose. RESULTS: No changes in levels of PMNs, glucose and lactate were detected in sputum during the antibiotic treatment. Sputum PMNs were positively associated with both glucose (log coefficient = 0.20, p = 0.01) and L-lactate (log coefficient = 0.34, p<0.001). In multivariate analyses, hemoglobin A1c was negatively associated with sputum PMNs (log coefficient = -1.68, p<0.001) and plasma glucose was negatively associated with sputum glucose (log coefficient = -0.09, p = 0.02). CONCLUSIONS: In CF sputum PMNs, glucose and lactate were unchanged during elective antibiotic treatment. However, sputum PMNs were associated with both sputum glucose and sputum lactate. Surprisingly, hyperglycemia seemed to be associated with less PMNs infiltration and less glucose in CF sputum.


Assuntos
Fibrose Cística/sangue , Glucose/metabolismo , Ácido Láctico/metabolismo , Neutrófilos/metabolismo , Escarro/metabolismo , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Biomarcadores/metabolismo , Glicemia/metabolismo , Fibrose Cística/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Injeções Intravenosas , Contagem de Leucócitos , Masculino , Análise Multivariada , Testes de Função Respiratória , Adulto Jovem
5.
PLoS One ; 15(7): e0236496, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702008

RESUMO

BACKGROUND: To improve the quality of diagnosing pulmonary tuberculosis (TB), WHO recommends the use of rapid molecular testing as an alternative to conventional microscopic methods. Loop-mediated isothermal amplification assay (LAMP test) is a practical and cost-effective nucleic amplification technique. We evaluated the pragmatic accuracy of an in-house LAMP assay for the diagnosis of TB in a remote health care setting where an advanced rapid molecular test is not available. METHODS: A prospective diagnostic accuracy study was conducted. Patients with clinical symptoms suggestive of TB were consecutively enrolled from April to August 2016. Sputum samples were collected from each patient and were sent for microscopic examination (both acid-fast stain and fluorescence stain), in-house LAMP test, and TB culture. RESULTS: One hundred and seven patients with TB symptoms were used in the final analysis. This included 50 (46.7%) culture-positive TB patients and 57 (53.3%) culture-negative patients. The overall sensitivity of the in-house LAMP based on culture positivity was 88.8% (95/107) with a 95%CI of 81.2-94.1. The sensitivity was 90.9% (40/44) with a 95%CI of 78.3-97.5 for smear-positive, culture-positive patients, and was 16.7% (1/6) with a 95%CI of 0.4-64.1 for smear-negative, culture-positive patients. The overall sensitivity of the in-house LAMP test compared to smear microscopy methods were not significantly different (p = 0.375). The specificity of the in-house LAMP based on non-TB patients (smear-negative, culture-negative) was 94.7% (54/57) with a 95%CI of 85.4-98.9. CONCLUSIONS: The diagnostic accuracy of the in-house LAMP test in a community hospital was comparable to other previous reports in terms of specificity. The sensitivity of the in-house assay could be improved with better sputum processing and DNA extraction method.


Assuntos
Técnicas de Diagnóstico Molecular/normas , Técnicas de Amplificação de Ácido Nucleico/normas , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/genética , Testes Diagnósticos de Rotina/efeitos adversos , Testes Diagnósticos de Rotina/normas , Feminino , Hospitais Comunitários , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Estudos Prospectivos , Escarro/metabolismo , Tailândia/epidemiologia , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/patologia
7.
Cochrane Database Syst Rev ; 4: CD006842, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32352564

RESUMO

BACKGROUND: Chest physiotherapy is widely prescribed to assist the clearance of airway secretions in people with cystic fibrosis. Oscillating devices generate intra- or extra-thoracic oscillations orally or external to the chest wall. Internally they create variable resistances within the airways, generating controlled oscillating positive pressure which mobilises mucus. Extra-thoracic oscillations are generated by forces outside the respiratory system, e.g. high frequency chest wall oscillation. This is an update of a previously published review. OBJECTIVES: To identify whether oscillatory devices, oral or chest wall, are effective for mucociliary clearance and whether they are equivalent or superior to other forms of airway clearance in the successful management of secretions in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. Latest search of the Cystic Fibrosis Trials Register: 29 July 2019. In addition we searched the trials databases ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Latest search of trials databases: 15 August 2019. SELECTION CRITERIA: Randomised controlled studies and controlled clinical studies of oscillating devices compared with any other form of physiotherapy in people with cystic fibrosis. Single-treatment interventions (therapy technique used only once in the comparison) were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria to publications, assessed the quality of the included studies and assessed the evidence using GRADE. MAIN RESULTS: The searches identified 82 studies (330 references); 39 studies (total of 1114 participants) met the inclusion criteria. Studies varied in duration from up to one week to one year; 20 of the studies were cross-over in design. The studies also varied in type of intervention and the outcomes measured, data were not published in sufficient detail in most of these studies, so meta-analysis was limited. Few studies were considered to have a low risk of bias in any domain. It is not possible to blind participants and clinicians to physiotherapy interventions, but 13 studies did blind the outcome assessors. The quality of the evidence across all comparisons ranged from low to very low. Forced expiratory volume in one second was the most frequently measured outcome and while many of the studies reported an improvement in those people using a vibrating device compared to before the study, there were few differences when comparing the different devices to each other or to other airway clearance techniques. One study identified an increase in frequency of exacerbations requiring antibiotics whilst using high frequency chest wall oscillation when compared to positive expiratory pressure (low-quality evidence). There were some small but significant changes in secondary outcome variables such as sputum volume or weight, but not wholly in favour of oscillating devices and due to the low- or very low-quality evidence, it is not clear whether these were due to the particular intervention. Participant satisfaction was reported in 13 studies but again with low- or very low-quality evidence and not consistently in favour of an oscillating device, as some participants preferred breathing techniques or techniques used prior to the study interventions. The results for the remaining outcome measures were not examined or reported in sufficient detail to provide any high-level evidence. AUTHORS' CONCLUSIONS: There was no clear evidence that oscillation was a more or less effective intervention overall than other forms of physiotherapy; furthermore there was no evidence that one device is superior to another. The findings from one study showing an increase in frequency of exacerbations requiring antibiotics whilst using an oscillating device compared to positive expiratory pressure may have significant resource implications. More adequately-powered long-term randomised controlled trials are necessary and outcomes measured should include frequency of exacerbations, individual preference, adherence to therapy and general satisfaction with treatment. Increased adherence to therapy may then lead to improvements in other parameters, such as exercise tolerance and respiratory function. Additional evidence is needed to evaluate whether oscillating devices combined with other forms of airway clearance is efficacious in people with cystic fibrosis.There may also be a requirement to consider the cost implication of devices over other forms of equally advantageous airway clearance techniques. Using the GRADE method to assess the quality of the evidence, we judged this to be low or very low quality, which suggests that further research is very likely to have an impact on confidence in any estimate of effect generated by future interventions.


Assuntos
Oscilação da Parede Torácica/instrumentação , Fibrose Cística/complicações , Pneumopatias Obstrutivas/terapia , Depuração Mucociliar , Muco/metabolismo , Vibração/uso terapêutico , Adolescente , Adulto , Exercícios Respiratórios , Criança , Fibrose Cística/fisiopatologia , Progressão da Doença , Fluxo Expiratório Forçado , Volume Expiratório Forçado , Humanos , Pneumopatias Obstrutivas/etiologia , Pessoa de Meia-Idade , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Escarro/metabolismo
8.
Am J Respir Crit Care Med ; 202(1): 51-64, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32255668

RESUMO

Rationale: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published.Objectives: Identify microRNA and mRNA networks in the sputum of patients with asthma.Methods: We conducted a genome-wide analysis of microRNA and mRNA in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway.Measurements and Main Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for TLR (Toll-like receptor) and T-helper cell type 17 (Th17) signaling and endoplasmic reticulum stress. hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma.Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.


Assuntos
Asma/imunologia , Redes Reguladoras de Genes , MicroRNAs/metabolismo , Neutrófilos/metabolismo , Índice de Gravidade de Doença , Escarro/metabolismo , Adulto , Idoso , Asma/diagnóstico , Asma/genética , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Estudo de Associação Genômica Ampla , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , RNA Mensageiro/metabolismo
9.
Respir Res ; 21(1): 72, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197620

RESUMO

BACKGROUND: Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. METHODS: Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 µg and placebo twice daily (BID) in a randomised crossover study. RESULTS: CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 µg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. CONCLUSIONS: Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. TRIAL REGISTRATION: ClinicalTrial.gov, EudraCT, 2015-005550-35. Registered 15 July 2016.


Assuntos
Bronquite Crônica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/administração & dosagem , Escarro/citologia , Administração por Inalação , Idoso , Anti-Inflamatórios/administração & dosagem , Biomarcadores/sangue , Biomarcadores/metabolismo , Bronquite Crônica/metabolismo , Estudos Cross-Over , Feminino , Humanos , Mediadores da Inflamação , Masculino , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Escarro/metabolismo , Sulfonamidas , Transcriptoma , para-Aminobenzoatos
10.
Respir Med ; 162: 105875, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32056673

RESUMO

BACKGROUND: Some patients with asthma present with accelerated lung function decline. This phenomenon is mostly associated with severe exacerbations and with poor asthma control. OBJECTIVE: Our aim was to detect the extent of FEV1 decline in patients with mild asthma and to discriminate clinical, functional and inflammatory factors associated with accelerated FEV1 decline. METHODS: We recruited 50 patients with mild asthma for pulmonary function testing and induced sputum sampling 12-15 years after the initial diagnosis. In 33 patients, from whom sputum of a good quality was obtained, inflammatory cells were counted and concentrations of cytokines IL-2, IL-4, IL-5, IL-8, IL-10, IFN-γ, angiogenin and VEGF in the sputum were measured by cytometric bead array. RESULTS: Eighteen of 33 patients presented with accelerated FEV1 decline of more than 30 ml/year, with a mean (SEM) of 43.2 (3.9) ml/year, compared to 15 control patients with a FEV1 decline of 14.4 (2.1) ml/year. In the accelerated FEV1 decline group, we found elevated sputum levels of IL5 with a median (IQR) of 1.8 (0.4-3.2) pg/ml vs. 0.2 (0.1-1.2) pg/ml, p = 0.04; IL8 with a mean (SEM) of 1503 (194) pg/ml vs. 938 (177) pg/ml, p = 0.04; and eosinophils with a median (IQR) of 223 (41-1020) cells/µl vs. 39 (1-190) cells/µl, p = 0.03. No significant differences in other measured parameters were detected between the two groups. CONCLUSION: Elevated sputum eosinophils, IL5 and IL8, which have a potential to stimulate airway remodelling, might be a useful non-invasive biomarkers and therapeutic targets of accelerated FEV1 decline in asthma patients.


Assuntos
Asma/fisiopatologia , Eosinófilos , Volume Expiratório Forçado , Mediadores da Inflamação/metabolismo , Interleucina-5/metabolismo , Interleucina-8/metabolismo , Escarro/citologia , Escarro/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
11.
Cochrane Database Syst Rev ; 2: CD008816, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32107770

RESUMO

BACKGROUND: Inhalation of hypertonic saline improves sputum rheology, accelerates mucociliary clearance and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine whether the timing of hypertonic saline inhalation (in relation to airway clearance techniques or in relation to time of day) has an impact on its clinical efficacy in people with cystic fibrosis. SEARCH METHODS: We identified relevant randomised and quasi-randomised controlled trials from the Cochrane Cystic Fibrosis Trials Register, the Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings. Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register: 28 February 2019. SELECTION CRITERIA: Any trial of hypertonic saline in people with cystic fibrosis where timing of inhalation was the randomised element in the study protocol with either: inhalation up to six hours before airway clearance techniques compared to inhalation during airway clearance techniques compared to inhalation up to six hours after airway clearance techniques; or morning compared to evening inhalation with any definition provided by the author. DATA COLLECTION AND ANALYSIS: Both authors independently assessed the trials identified by the search for potential inclusion in the review. The certainty of the evidence was assessed using GRADE. MAIN RESULTS: The searches identified 104 trial reports which represented 51 trials, of which three cross-over trials (providing data on 77 participants) met our inclusion criteria. We present three comparisons: inhalation before versus during airway clearance techniques; inhalation before versus after airway clearance techniques; and inhalation during versus after airway clearance techniques. One trial (50 participants), given its three-arm design, was eligible for all three comparisons. No trials compared morning versus evening inhalation of hypertonic saline. The evidence from the three trials was judged to be of low quality downgraded for limitations (high risk of bias due to blinding) and indirectness (all participants are adults, and therefore not applicable to children). Intervention periods ranged from one treatment to three treatments in one day. There were no clinically important differences between the timing regimens of inhaling hypertonic saline before, during or after airway clearance techniques in the mean amount of improvement in lung function or symptom scores (77 participants), with the between-group comparisons being non-significant (low-certainty evidence). While there may be little or no difference in the rating of satisfaction when hypertonic saline was inhaled before versus during the airway clearance techniques (64 participants) (with the 95% confidence interval including the possibility of both a higher and lower rating of satisfaction), satisfaction may be lower on a 100-mm scale when inhaled after the airway clearance techniques compared to before: mean difference (MD) 20.38 mm (95% confidence interval (CI) 12.10 to 28.66) and when compared to during the techniques, MD 14.80 mm (95% CI 5.70 to 23.90). Perceived effectiveness showed similar results: little or no difference for inhalation before versus during airway clearance techniques (64 participants); may be lower when inhaled after the airway clearance techniques compared to before, MD 10.62 (95% CI 2.54 to 18.70); and also when compared to during the techniques, MD 15.60 (95% CI 7.55 to 23.65). There were no quality of life or adverse events reported in any of the trials. AUTHORS' CONCLUSIONS: Timing of hypertonic saline inhalation makes little or no difference to lung function (low-certainty evidence). However, inhaling hypertonic saline before or during airway clearance techniques may maximise perceived efficacy and satisfaction. The long-term efficacy of hypertonic saline has only been established for twice-daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available. The identified trials were all of very short intervention periods, so longer-term research could be conducted to establish the effects arising from regular use, which would incorporate the influence of changes in adherence with long-term use, as well as generating data on any adverse effects that occur with long-term use.


Assuntos
Fibrose Cística/tratamento farmacológico , Depuração Mucociliar , Solução Salina Hipertônica/uso terapêutico , Administração por Inalação , Esquema de Medicação , Humanos , Solução Salina Hipertônica/administração & dosagem , Escarro/metabolismo
12.
Respir Res ; 21(1): 21, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931795

RESUMO

BACKGROUND: For still unclear reasons, chronic airway infection often occurs in patients with Chronic Obstructive Pulmonary Disease (COPD), particularly in those with more severe airflow limitation. Fatty-acid binding protein 4 (FABP4) is an adipokine involved in the innate immune response against infection produced by alveolar macrophages (Mɸ). We hypothesized that airway levels of FABP4 may be altered in COPD patients with chronic airway infection. METHODS: In this prospective and controlled study we: (1) compared airway FABP4 levels (ELISA) in induced sputum, bronchoalveolar lavage fluid (BALF) and plasma samples in 52 clinically stable COPD patients (65.2 ± 7.9 years, FEV1 59 ± 16% predicted) and 29 healthy volunteers (55.0 ± 12.3 years, FEV1 97 ± 16% predicted); (2) explored their relationship with the presence of bacterial airway infection, defined by the presence of potentially pathogenic bacteria (PPB) at ≥103 colony-forming units/ml in BALF; (3) investigated their relationship with the quantity and proportion of Mɸ in BALF (flow cytometry); and, (4) studied their relationship with the severity of airflow limitation (FEV1), GOLD grade and level of symptoms (CAT questionnaire). RESULTS: We found that: (1) airway levels of FABP4 (but not plasma ones) were reduced in COPD patients vs. controls [219.2 (96.0-319.6) vs. 273.4 (203.1-426.7) (pg/ml)/protein, p = 0.03 in BALF]; (2) COPD patients with airway infection had lower sputum FABP4 levels [0.73 (0.35-15.3) vs. 15.6 (2.0-29.4) ng/ml, p = 0.02]; (3) in COPD patients, the number and proportion of Mɸ were positively related with FABP4 levels in BALF; (4) BALF and sputum FABP4 levels were positively related with FEV1, negatively with the CAT score, and lowest in GOLD grade D patients. CONCLUSIONS: Airway FABP4 levels are reduced in COPD patients, especially in those with airway infection and more severe disease. The relationship observed between Mɸ and airway FABP4 levels supports a role for FABP4 in the pathogenesis of airway infection and disease severity in COPD.


Assuntos
Proteínas de Ligação a Ácido Graxo/metabolismo , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Infecções Respiratórias/metabolismo , Índice de Gravidade de Doença , Adulto , Idoso , Líquido da Lavagem Broncoalveolar , Estudos Transversais , Feminino , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Testes de Função Respiratória/métodos , Infecções Respiratórias/diagnóstico , Escarro/metabolismo
13.
Acta Cytol ; 64(1-2): 16-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30878997

RESUMO

Pulmonary cytology is a challenging diagnostic tool, and it is usually evaluated considering medical history and radiological findings in order to reach an accurate diagnosis. Since the majority of lung cancer patients have an advanced stage at diagnosis, a cytological specimen is frequently the only material available for diagnosis and further prognostic/predictive marker determination. Several types of specimens can be obtained from the respiratory system (including sputum, bronchoalveolar lavage, bronchial brushing, fine needle aspiration, and pleural fluid) with different technical preclinical management protocols and different diagnostic yields. Immunocytochemistry (ICC) has a pivotal role in the determination of diagnostic, prognostic, and predictive markers. Therefore, limited cytology samples are to be used with a cell-sparing approach, to allow both diagnostic ICC evaluation as well as predictive marker assessment by ICC or specific molecular assays. In this review, we describe the most common ICC markers used for the diagnosis and prognostic/predictive characterization of thoracic tumors in different cytological specimens.


Assuntos
Biomarcadores Tumorais/metabolismo , Citodiagnóstico/métodos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Biópsia por Agulha Fina/métodos , Lavagem Broncoalveolar/métodos , Broncoscopia/métodos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Escarro/metabolismo
14.
Clin Drug Investig ; 40(2): 105-117, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31721070

RESUMO

BACKGROUND: Among the many consequences of loss of CFTR protein function, a significant reduction of the secretion of bicarbonate (HCO3-) in cystic fibrosis (CF) is a major pathogenic feature. Loss of HCO3- leads to abnormally low pH and impaired mucus clearance in airways and other exocrine organs, which suggests that NaHCO3 inhalation may be a low-cost, easily accessible therapy for CF. OBJECTIVE: To evaluate the safety, tolerability, and effects of inhaled aerosols of NaHCO3 solutions (4.2% and 8.4%). METHODS: An experimental, prospective, open-label, pilot, clinical study was conducted with 12 CF volunteer participants over 18 years of age with bronchiectasis and pulmonary functions classified as mildly to severely depressed. Sputum rheology, pH, and microbiology were examined as well as spirometry, exercise performance, quality-of-life assessments, dyspnea, blood count, and venous blood gas levels. RESULTS: Sputum pH increased immediately after inhalation of NaHCO3 at each clinical visit and was inversely correlated with rheology when all parameters were evaluated: [G' (elasticity of the mucus) = - 0.241; G″ (viscosity of the mucus) = - 0.287; G* (viscoelasticity of the mucus) = - 0.275]. G* and G' were slightly correlated with peak flow, forced expiratory volume in 1 s (FEV1), and quality of life; G″ was correlated with quality of life; sputum pH was correlated with oxygen consumption (VO2) and vitality score in quality of life. No changes were observed in blood count, venous blood gas, respiratory rate, heart rate, peripheral oxygen saturation of hemoglobin (SpO2), body temperature, or incidence of dyspnea. No adverse events associated with the study were observed. CONCLUSION: Nebulized NaHCO3 inhalation appears to be a safe and well tolerated potential therapeutic agent in the management of CF. Nebulized NaHCO3 inhalation temporarily elevates airway liquid pH and reduces sputum viscosity and viscoelasticity.


Assuntos
Fibrose Cística/tratamento farmacológico , Bicarbonato de Sódio/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Fibrose Cística/fisiopatologia , Fibrose Cística/psicologia , Elasticidade , Feminino , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos , Qualidade de Vida , Bicarbonato de Sódio/efeitos adversos , Escarro/metabolismo , Viscosidade
15.
Genet Test Mol Biomarkers ; 24(1): 10-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31880470

RESUMO

Aims: To investigate the expression levels of serum interleukin-17 (IL-17) and interleukin-27 (IL-27) in children with bronchial asthma and to correlate these expression levels with lung function indicators. Methods: A total of 106 children with bronchial asthma (observation group: 76 in the acute attack phase, 30 in remission) and 60 healthy children (control group) aged 1-10 years were enrolled. Results: Levels of IL-17, IL-27, and fractional exhaled nitric oxide (FeNO) in the peripheral blood of children with bronchial asthma were higher compared to the control group. In addition, blood IL-17, IL-27, and FeNO levels in the children in the acute stage of bronchial asthma were higher compared with those in remission. The respiratory rate of children in the remission stage was lower compared with those in the acute stage, however, the other indicators were higher. IL-17, IL-27, and FeNO levels positively correlated with the respiratory rate and were negatively correlated with inspiratory time, expiratory time, peak time, and time to reach peak tidal expiratory flow/total expiratory time (TPTEF/TE; all p < 0.05). Conclusion: IL-17 and IL-27 levels are associated with the incidence and the development of bronchial asthma in children, and could be useful diagnostic markers. They may also effectively improve the specificity of FeNO for diagnosing the extent of lung injury in children.


Assuntos
Asma/imunologia , Interleucina-17/genética , Interleucinas/genética , Asma/genética , Asma/metabolismo , Criança , Pré-Escolar , China , Feminino , Volume Expiratório Forçado , Expressão Gênica/genética , Humanos , Lactente , Interleucina-17/análise , Interleucina-17/sangue , Interleucinas/análise , Interleucinas/sangue , Masculino , Óxido Nítrico/análise , Óxido Nítrico/sangue , Testes de Função Respiratória/métodos , Escarro/metabolismo
16.
PLoS One ; 14(12): e0226578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851705

RESUMO

The bacterial growth environment within cystic fibrosis (CF) sputum is complex, dynamic, and shaped by both host and microbial processes. Characterization of the chemical parameters within sputum that stimulate the in vivo growth of airway pathogens (e.g. Pseudomonas aeruginosa) and their associated virulence factors may lead to improved CF treatment strategies. Motivated by conflicting reports of the prevalence and abundance of P. aeruginosa-derived metabolites known as phenazines within CF airway secretions, we sought to quantify these metabolites in sputum using quadrupole time-of-flight mass spectrometry. In contrast to our previous work, all phenazines tested (pyocyanin (PYO), phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide, and 1-hydroxyphenazine) were below detection limits of the instrument (0.1 µM). Instead, we identified a late-eluting compound that shared retention time and absorbance characteristics with PCA, yet generated mass spectra and a fragmentation pattern consistent with ferriprotoporphyrin IX, otherwise known as heme B. These data suggested that UV-vis chromatographic peaks previously attributed to PCA and PYO in sputum were mis-assigned. Indeed, retrospective analysis of raw data from our prior study found that the heme B peak closely matched the peaks assigned to PCA, indicating that the previous study likely uncovered a positive correlation between pulmonary function (percent predicted forced expiratory volume in 1 second, or ppFEV1) and heme B, not PCA or any other phenazine. To independently test this observation, we performed a new tandem mass-spectrometry analysis of 71 additional samples provided by the Mountain West CF Consortium Sputum Biomarker study and revealed a positive correlation (ρ = -0.47, p<0.001) between sputum heme concentrations and ppFEV1. Given that hemoptysis is strongly associated with airway inflammation, pulmonary exacerbations and impaired lung function, these new data suggest that heme B may be a useful biomarker of CF pathophysiology.


Assuntos
Fibrose Cística/metabolismo , Heme/metabolismo , Pulmão/fisiopatologia , Escarro/metabolismo , Adulto , Feminino , Humanos , Masculino
17.
Sci Rep ; 9(1): 19241, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848359

RESUMO

Asthma-COPD overlap (ACO) has been under intensive focus; however, the levels of damage-associated molecular patterns (DAMPs) that can activate the innate and adaptive immune responses of ACO are unknown. The present study aimed to examine the levels of some DAMPs in asthma, COPD, and ACO and to identify the associations between clinical characteristics and DAMPs in ACO. Sputum from subjects with asthma (n = 87) or COPD (n = 73) and ACO (n = 68) or from smokers (n = 62) and never-smokers (n = 62) was analyzed for high mobility group protein B1 (HMGB1), heat shock protein 70 (HSP70), LL-37, S100A8, and galectin-3 (Gal-3). The concentration of HMGB1, HSP70, LL-37, and S100A8 proteins in sputum from ACO patients was significantly elevated, whereas that of Gal-3 was reduced, compared to that of smokers and never-smokers. The levels of HMGB1 and Gal-3 proteins in ACO patients were elevated compared to those in asthma patients. The sputum from ACO patients showed an increase in the levels of LL-37 and S100A8 proteins compared to that of asthma patients, whereas the levels decreased compared to those of COPD patients. The concentrations of HMGB1, HSP70, LL-37, and S100A8 proteins in the sputum of 352 participants were negatively correlated, whereas the levels of Gal-3 were positively correlated, with FEV1, FEV1%pred, and FEV1/FVC. Sputum HMGB1 had a high AUC of the ROC curve while distinguishing ACO patients from asthma patients. Meanwhile, sputum LL-37 had a high AUC of the ROC curve in differentiating asthma and COPD. The release of sputum DAMPs in ACO may be involved in chronic airway inflammation in ACO; the sputum HMGB1 level might serve as a valuable biomarker for distinguishing ACO from asthma, and the sputum LL-37 level might be a biomarker for differentiating asthma and COPD.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Asma/metabolismo , Calgranulina A/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumar/metabolismo , Escarro/metabolismo , Idoso , Asma/complicações , Asma/patologia , Biomarcadores/metabolismo , Feminino , Galectina 3/metabolismo , Proteína HMGB1/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Fumar/efeitos adversos , Fumar/patologia
18.
Respir Res ; 20(1): 252, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718667

RESUMO

BACKGROUND: Endotoxin is a component of particulate matter linked to respiratory disease. Our group has shown that experimental endotoxin inhalation challenge reproducibly triggers neutrophilic inflammation in the airways and in peripheral blood. Sputum induction is currently the only available method for assessing airway neutrophilia but is laborious and time-consuming. This analysis examined the correlation between systemic and airway inflammatory responses to endotoxin to determine if peripheral blood could serve as a surrogate marker for neutrophilic airway inflammation. METHODS: We conducted a retrospective study of 124 inhaled endotoxin challenges conducted at our center using 20,000 endotoxin units (EU) of Clinical Center Reference Endotoxin (CCRE). Venipuncture and induced sputum samples were obtained at baseline and 6 hours after completion of endotoxin challenge. The relationship between change in sputum neutrophils (post-challenge - baseline) and change in peripheral blood neutrophils (post-challenge - baseline) was assessed using Spearman's correlation analyses. RESULTS: Inhaled endotoxin induced a significant increase in mean sputum percent neutrophils and peripheral blood absolute neutrophil counts in healthy adults with or without mild asthma, but no significant correlation was found between airway and systemic neutrophilia (r = 0.13, p = 0.18). Stratification by degree of airway neutrophil response and by atopic or asthmatic status did not change the results. CONCLUSIONS: Inhalation challenge with endotoxin safely and effectively induces airway neutrophilic inflammation in most individuals. Increases in endotoxin-induced peripheral blood neutrophils do not correlate well with airway responses and should not be used as a surrogate marker of airway inflammation.


Assuntos
Endotoxinas/administração & dosagem , Mediadores da Inflamação/sangue , Neutrófilos/metabolismo , Escarro/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Administração por Inalação , Adulto , Endotoxinas/efeitos adversos , Feminino , Humanos , Mediadores da Inflamação/análise , Masculino , Pessoa de Meia-Idade , Neutrófilos/química , Estudos Retrospectivos , Escarro/química , Adulto Jovem
19.
Respir Res ; 20(1): 254, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718676

RESUMO

BACKGROUND: Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD. METHODS: Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation. RESULTS: The 182 COPD participants in the analysis were 66 ± 8 years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61 ± 1.89 ng/mL (mean ± SD) in sputum and 0.60 ± 1.13 ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV1/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk. CONCLUSIONS: In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS).


Assuntos
Glicina/sangue , Prolina/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Espirometria/métodos , Escarro/metabolismo , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escarro/química
20.
COPD ; 16(5-6): 354-361, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31631716

RESUMO

Blood eosinophilia has been proposed as a surrogate marker for airway eosinophilia and as a predictor of treatment response in chronic obstructive pulmonary disease (COPD). The aim of the study was to assess the relationship between blood and sputum eosinophils and to investigate the association between blood and sputum eosinophil count and clinical features of mild-to-moderate COPD. We performed a retrospective analysis of blood and sputum eosinophil count, as well as demographic and lung function data in a cohort of 90 stable, steroid-naive (Global Initiative for Chronic Obstructive Lung Disease 1 or 2) COPD patients and 20 control subjects. Blood and sputum eosinophil count did not correlate both in patients with COPD (r = -0.04 p = 0.705) and in controls (r = 0.05, p = 0.838). Sputum eosinophilia (≥3%) was present in 40% of COPD patients. The median blood eosinophil count in patients with COPD was 180 (interquartile range 90-270)/µL; patients with low blood eosinophils (<180/µL) did not differ from those with high blood eosinophils (≥180/µL) in terms of forced expiratory volume in 1 second, bronchial reversibility or hyperresponsiveness. This was also the case when COPD patients with and without sputum eosinophilia were compared. At the same time, positive bronchial reversibility and positive bronchial hyperresponsiveness were observed in 2 (11%) COPD patients with high blood eosinophils and in 1 (5%) patient with sputum eosinophilia. There was a weak, albeit significant correlation (r = 0.22 p = 0.041) between blood eosinophil count and age in patients with COPD. Peripheral eosinophil count poorly reflects sputum eosinophils and lung function in stable steroid-naive mild-to-moderate COPD patients.


Assuntos
Hiper-Reatividade Brônquica/etiologia , Eosinofilia/etiologia , Eosinófilos/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Adulto , Idoso , Hiper-Reatividade Brônquica/diagnóstico , Estudos de Casos e Controles , Eosinofilia/diagnóstico , Eosinofilia/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Testes de Função Respiratória , Estudos Retrospectivos , Índice de Gravidade de Doença , Escarro/metabolismo
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