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Current pulmonary nodule management guidelines are based on nodule volume doubling time, which assumes exponential growth behaviour. However, this is a theory that has never been validated in vivo in the routine-care target population. This study evaluates growth patterns of untreated solid and subsolid lung cancers of various histologies in a non-screening setting.Growth behaviour of pathology-proven lung cancers from two academic centres that were imaged at least three times before diagnosis (n=60) was analysed using dedicated software. Random-intercept random-slope mixed-models analysis was applied to test which growth pattern most accurately described lung cancer growth. Individual growth curves were plotted per pathology subgroup and nodule type.We confirmed that growth in both subsolid and solid lung cancers is best explained by an exponential model. However, subsolid lesions generally progress slower than solid ones. Baseline lesion volume was not related to growth, indicating that smaller lesions do not grow slower compared to larger ones.By showing that lung cancer conforms to exponential growth we provide the first experimental basis in the routine-care setting for the assumption made in volume doubling time analysis.
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Neoplasias Pulmonares/diagnóstico por imagen , Estadificación de Neoplasias , Nódulo Pulmonar Solitario/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Anciano , Detección Precoz del Cáncer , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Países Bajos , Sistema de Registros , Programas Informáticos , Nódulo Pulmonar Solitario/patologíaRESUMEN
Physical inactivity in patients with chronic obstructive pulmonary disease (COPD) is associated with poor health status and increased disease burden. The present study aims to test the efficacy of a previously developed mobile (m)Health intervention to improve or maintain physical activity in patients with COPD after pulmonary rehabilitation.A randomised controlled trial was performed in 32 physiotherapy practices in the Netherlands. COPD patients were randomised into intervention or usual care groups. The intervention consisted of a smartphone application for the patients and a monitoring website for the physiotherapists. Measurements were performed at 0, 3, 6 and 12â months. Physical activity, functional exercise capacity, lung function, health-related quality of life and body mass index were assessed.157 patients started the study and 121 completed it. There were no significant positive effects of the intervention on physical activity (at 0â months: intervention 5824±3418â steps per weekday, usual care 5717±2870 steps per weekday; at 12â months: intervention 4819±2526 steps per weekday, usual care 4950±2634 steps per weekday; p=0.811) or on the secondary end-points. There was a significant decrease over time in physical activity (p<0.001), lung function (p<0.001) and mastery (p=0.017), but not in functional exercise capacity (p=0.585).Although functional exercise capacity did not deteriorate, our mHealth intervention did not improve or maintain physical activity in patients with COPD after a period of pulmonary rehabilitation.
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Enfermedad Pulmonar Obstructiva Crónica/rehabilitación , Enfermedad Pulmonar Obstructiva Crónica/terapia , Telemedicina/métodos , Anciano , Índice de Masa Corporal , Ejercicio Físico , Tolerancia al Ejercicio , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Monitoreo Ambulatorio , Países Bajos , Modalidades de Fisioterapia , Calidad de Vida , Rehabilitación , Teléfono Inteligente , Resultado del TratamientoRESUMEN
RATIONALE: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. OBJECTIVES: To investigate the genetic component of AWT. METHODS: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. MEASUREMENTS AND MAIN RESULTS: Three significant loci on chromosomes 2q (rs734556; P = 6.2 × 10(-7)) and 10q (rs10794108, P = 8.6 × 10(-8); rs7078439, P = 2.3 × 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10(-8), 7.4 × 10(-8), and 7.5 × 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10(-7)) and rs4796712 in NT5C3B (P = 3.1 × 10(-6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10(-41)). CONCLUSIONS: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.
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Remodelación de las Vías Aéreas (Respiratorias)/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , 5'-Nucleotidasa/genética , Proteínas Adaptadoras Transductoras de Señales , Anciano , Proteínas Portadoras/genética , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 2/genética , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Glicoproteínas/genética , Guanilato-Quinasas , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Enfisema Pulmonar/genética , Serpina E2/genética , Tomografía Computarizada por Rayos XRESUMEN
Airway wall thickness and emphysema contribute to airflow limitation. We examined their association with lung function decline and development of airflow limitation in 2021 male smokers with and without airflow limitation. Airway wall thickness and emphysema were quantified on chest computed tomography and expressed as the square root of wall area of a 10-mm lumen perimeter (Pi10) and the 15th percentile method (Perc15), respectively. Baseline and follow-up (median (interquartile range) 3 (2.9-3.1) years) spirometry was available. Pi10 and Perc15 correlated with baseline forced expiratory volume in 1 s (FEV1) (r=â-0.49 and 0.11, respectively (p<0.001)). Multiple linear regression showed that Pi10 and Perc15 at baseline were associated with a lower FEV1 after follow-up (p<0.05). For each sd increase in Pi10 and decrease in Perc15 the FEV1 decreased by 20 mL and 30.2 mL, respectively. The odds ratio for developing airflow limitation after 3 years was 2.45 for a 1-mm higher Pi10 and 1.46 for a 10-HU lower Perc15 (p<0.001). A greater degree of airway wall thickness and emphysema was associated with a higher FEV1 decline and development of airflow limitation after 3 years of follow-up.
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Remodelación de las Vías Aéreas (Respiratorias) , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Fumar , Anciano , Estudios de Seguimiento , Volumen Espiratorio Forzado , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Países Bajos , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/epidemiología , Enfisema Pulmonar/fisiopatología , Fumar/efectos adversos , Fumar/epidemiología , Fumar/fisiopatología , Espirometría/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10(-5)) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value <10(-5) in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10(-6), OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10(-12)). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.
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Moco/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Fumar/efectos adversos , Alelos , Biopsia , Bronquios/patología , Estudios de Cohortes , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Humanos , Pulmón/metabolismo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , ARN Mensajero/metabolismo , Factores de RiesgoRESUMEN
OBJECTIVE: The objective of this study was to investigate the association of spirometry and pulmonary CT biomarkers with cardiovascular events. METHODS: In this lung cancer screening trial 3,080 male participants without a prior cardiovascular event were analysed. Fatal and non-fatal cardiovascular events were included. Spirometry included forced expiratory volume measured in units of one-second percent predicted (FEV1%predicted) and FEV1 divided by forced vital capacity (FVC; FEV1/FVC). CT examinations were quantified for coronary artery calcium volume, pulmonary emphysema (perc15) and bronchial wall thickness (pi10). Data were analysed via a Cox proportional hazard analysis, net reclassification improvement (NRI) and C-indices. RESULTS: 184 participants experienced a cardiovascular event during a median follow-up of 2.9 years. Age, pack-years and smoking status adjusted hazard ratios were 0.992 (95% confidence interval (CI) 0.985-0.999) for FEV1%predicted, 1.000 (95%CI 0.986-1.015) for FEV1/FVC, 1.014 (95%CI 1.005-1.023) for perc15 per 10 HU, and 1.269 (95%CI 1.024-1.573) for pi10 per 1 mm. The incremental C-index (<0.015) and NRI (<2.8%) were minimal. Coronary artery calcium volume had a hazard ratio of 1.046 (95%CI 1.034-1.058) per 100 mm(3), an increase in C-index of 0.076 and an NRI of 16.9% (P < 0.0001). CONCLUSIONS: Pulmonary CT biomarkers and spirometry measurements were significantly associated with cardiovascular events, but did not contain clinically relevant independent prognostic information for cardiovascular events. KEY POINTS: ⢠Pulmonary CT biomarkers and spirometry are associated with cardiovascular events ⢠These pulmonary measurements do not contain clinically relevant independent prognostic information ⢠Only coronary calcium score improved cardiovascular risk prediction above age and smoking.
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Enfermedades Cardiovasculares/epidemiología , Detección Precoz del Cáncer , Neoplasias Pulmonares/diagnóstico por imagen , Tamizaje Masivo , Tomografía Computarizada por Rayos X/métodos , Bélgica/epidemiología , Enfermedades Cardiovasculares/etiología , Volumen Espiratorio Forzado , Humanos , Imagenología Tridimensional , Incidencia , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Pronóstico , Factores de Riesgo , Espirometría , Capacidad VitalRESUMEN
RATIONALE: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering. OBJECTIVES: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States. METHODS: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity. MEASUREMENTS AND MAIN RESULTS: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema. CONCLUSIONS: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
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Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Enfisema Pulmonar/genética , Tomografía Computarizada por Rayos X , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Marcadores Genéticos , Técnicas de Genotipaje , Humanos , Masculino , Manosidasas/genética , Persona de Mediana Edad , N-Acetilglucosaminiltransferasas/genética , Proteínas del Tejido Nervioso/genética , Enfisema Pulmonar/diagnóstico por imagen , Enfisema Pulmonar/etnología , ARN Helicasas/genética , Tioléster Hidrolasas/genética , Estados Unidos/epidemiología , alfa-Manosidasa/genética , Proteínas Nucleares snRNP/genéticaRESUMEN
Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background ("Dutch hypothesis"). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κß pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10(-9)). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-κß, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.
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Asma/genética , Estudio de Asociación del Genoma Completo , Enfermedad Pulmonar Obstructiva Crónica/genética , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Adulto JovenRESUMEN
INTRODUCTION: YKL-40 is a novel biomarker in diseases with inflammation, fibrosis and tissue remodelling. Previously, circulating YKL-40 was shown to be elevated in patients with idiopathic pulmonary fibrosis (IPF) and was associated with survival. OBJECTIVE: To compare YKL-40 serum levels between IPF and other interstitial pneumonias such as non-specific interstitial pneumonia (NSIP), smoking-related interstitial lung disease (SR-ILD) and cryptogenic organising pneumonia (COP). MATERIALS AND METHODS: Serum YKL-40 levels were measured in 124 healthy controls and 315 patients. Serial measurements were available in 36 patients with IPF and 6 patients with COP. RESULTS: Serum YKL-40 levels were elevated in all patient groups compared to controls (p < 0.0001), and highest levels were found in the most fibrotic diseases, which showed worst prognosis. CONCLUSION: YKL-40 is highly elevated in fibrotic interstitial pneumonias and may reflect the degree of activity of the fibrogenic process. Remarkably, levels remain high in IPF, but can decrease in other interstitial pneumonias, which appears to be related to a better prognosis.
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Adipoquinas/sangre , Neumonías Intersticiales Idiopáticas/sangre , Neumonías Intersticiales Idiopáticas/diagnóstico , Lectinas/sangre , Adulto , Anciano , Análisis de Varianza , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar , Estudios de Casos y Controles , Proteína 1 Similar a Quitinasa-3 , Neumonía en Organización Criptogénica/sangre , Neumonía en Organización Criptogénica/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Fibrosis Pulmonar Idiopática/sangre , Fibrosis Pulmonar Idiopática/diagnóstico , Modelos Lineales , Masculino , Persona de Mediana Edad , Países Bajos , Valores de Referencia , Estudios RetrospectivosRESUMEN
Emphysema, airway wall thickening and air trapping are associated with chronic obstructive pulmonary disease (COPD). All three can be quantified by computed tomography (CT) of the chest. The goal of the current study is to determine the relative contribution of CT derived parameters on spirometry, lung volume and lung diffusion testing. Emphysema, airway wall thickening and air trapping were quantified automatically on CT in 1,138 male smokers with and without COPD. Emphysema was quantified by the percentage of voxels below -950 Hounsfield Units (HU), airway wall thickness by the square root of wall area for a theoretical airway with 10 mm lumen perimeter (Pi10) and air trapping by the ratio of mean lung density at expiration and inspiration (E/I-ratio). Spirometry, residual volume to total lung capacity (RV/TLC) and diffusion capacity (Kco) were obtained. Standardized regression coefficients (ß) were used to analyze the relative contribution of CT changes to pulmonary function measures. The independent contribution of the three CT measures differed per lung function parameter. For the FEV1 airway wall thickness was the most contributing structural lung change (ß = -0.46), while for the FEV1/FVC this was emphysema (ß = -0.55). For the residual volume (RV) air trapping was most contributing (ß = -0.35). Lung diffusion capacity was most influenced by emphysema (ß = -0.42). In a cohort of smokers with and without COPD the effect of different CT changes varies per lung function measure and therefore emphysema, airway wall thickness and air trapping need to be taken in account.
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Pulmón/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfisema Pulmonar/diagnóstico por imagen , Fumar , Anciano , Remodelación de las Vías Aéreas (Respiratorias) , Estudios de Casos y Controles , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Capacidad de Difusión Pulmonar , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/fisiopatología , Volumen Residual , Espirometría , Tomografía Computarizada por Rayos X , Capacidad Pulmonar TotalRESUMEN
Background: In observational studies, high levels of desphospho-uncarboxylated matrix gla protein (dp-ucMGP) that result from vitamin K deficiency were consistently associated with poor clinical outcomes during COVID-19. Vitamin K-activated matrix gla protein (MGP) is required to protect against elastic fibre degradation, and a deficiency may contribute to pathology. However, intervention trials assessing the effects of vitamin K supplementation in COVID-19 are lacking. Methods: This is a single-centre, phase 2, double-blind, randomised, placebo-controlled trial investigating the effects of vitamin K2 supplementation in 40 hospitalised COVID-19 patients requiring supplemental oxygen. Individuals were randomly assigned in a 1:1 ratio to receive 999 mcg of vitamin K2-menaquinone-7 (MK-7)-or a placebo daily until discharge or for a maximum of 14 days. Dp-ucMGP, the rate of elastic fibre degradation quantified by desmosine, and hepatic vitamin K status quantified by PIVKA-II were measured. Grade 3 and 4 adverse events were collected daily. As an exploratory objective, circulating vitamin K2 levels were measured. Results: Vitamin K2 was well tolerated and did not increase the number of adverse events. A linear mixed model analysis showed that dp-ucMGP and PIVKA-II decreased significantly in subjects that received supplementation compared to the controls (p = 0.008 and p = 0.0017, respectively), reflecting improved vitamin K status. The decrease in dp-ucMGP correlated with higher plasma MK-7 levels (p = 0.015). No significant effect on desmosine was found (p = 0.545). Conclusions: These results demonstrate that vitamin K2 supplementation during COVID-19 is safe and decreases dp-ucMGP. However, the current dose of vitamin K2 failed to show a protective effect against elastic fibre degradation.
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Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
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Ancirinas/genética , Factor Nuclear 3-alfa del Hepatocito/genética , Pulmón/fisiopatología , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Adulto , Ancirinas/metabolismo , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 14/genética , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: Increased airway wall thickness (AWT) and parenchymal lung destruction both contribute to airflow limitation. Advances in computed tomography (CT) post-processing imaging allow to quantify these features. The aim of this Dutch population study is to assess the relationships between AWT, lung function, emphysema and respiratory symptoms. METHODS: AWT and emphysema were assessed by low-dose CT in 500 male heavy smokers, randomly selected from a lung cancer screening population. AWT was measured in each lung lobe in cross-sectionally reformatted images with an automated imaging program at locations with an internal diameter of 3.5 mm, and validated in smaller cohorts of patients. The 15th percentile method (Perc15) was used to assess the severity of emphysema. Information about respiratory symptoms and smoking behavior was collected by questionnaires and lung function by spirometry. RESULTS: Median AWT in airways with an internal diameter of 3.5 mm (AWT3.5) was 0.57 (0.44 - 0.74) mm. Median AWT in subjects without symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/or wheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysis only AWT3.5 and emphysema independently explained 31.1%and 9.5%of the variance in FEV1%predicted, respectively, after adjustment for smoking behavior. CONCLUSIONS: Post processing standardization of airway wall measurements provides a reliable and useful method to assess airway wall thickness. Increased airway wall thickness contributes more to airflow limitation than emphysema in a smoking male population even after adjustment for smoking behavior.
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Enfisema Pulmonar/diagnóstico por imagen , Sistema Respiratorio/diagnóstico por imagen , Fumar/efectos adversos , Tomografía Computarizada por Rayos X/métodos , Anatomía Transversal , Interpretación Estadística de Datos , Volumen Espiratorio Forzado , Humanos , Modelos Lineales , Pulmón/patología , Mediciones del Volumen Pulmonar , Masculino , Persona de Mediana Edad , Enfisema Pulmonar/fisiopatología , Pruebas de Función RespiratoriaRESUMEN
BACKGROUND: Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers. METHODS: 3,670 male smokers with mean (SD) 40.8 (17.9) packyears underwent chest CT scans and pulmonary function tests at baseline and after 1 and 3 years follow-up. Smoking status (quitted ≥5, ≥1-<5, <1 years or current smoker) was noted. Rate of progression of emphysema and FEV1-decline after follow-up were assessed by analysis of variance adjusting for age, height, baseline pulmonary function and emphysema severity, packyears, years in study and respiratory symptoms. The quitted ≥5 group was used as reference. RESULTS: Median (Q1-Q3) emphysema severity,<-950 HU, was 8.8 (5.1 - 14.1) and mean (SD) FEV1 was 3.4 (0.73) L or 98.5 (18.5) % of predicted. The group quitted '>5 years' showed significantly lower rates of progression of emphysema compared to current smokers, 1.07% and 1.12% per year, respectively (p<0.001). Current smokers had a yearly FEV1-decline of 69 ml, while subjects quit smoking >5 years had a yearly decline of 57.5 ml (p<0.001). CONCLUSION: Quit smoking >5 years significantly slows the rate of emphysema progression and lung function decline. TRIAL REGISTRATION: Registered at http://www.trialregister.nl with trial number ISRCTN63545820.
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Progresión de la Enfermedad , Enfisema/diagnóstico por imagen , Enfisema/epidemiología , Cese del Hábito de Fumar/estadística & datos numéricos , Fumar/epidemiología , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Comorbilidad , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Prevalencia , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Beyond lung cancer, screening CT contains additional information on other smoking related diseases (e.g. chronic obstructive pulmonary disease, COPD). Since pulmonary function testing is not regularly incorporated in lung cancer screening, imaging biomarkers for COPD are likely to provide important surrogate measures for disease evaluation. Therefore, this study aims to determine the independent diagnostic value of CT emphysema, CT air trapping and CT bronchial wall thickness for COPD in low-dose screening CT scans. METHODS: Prebronchodilator spirometry and volumetric inspiratory and expiratory chest CT were obtained on the same day in 1140 male lung cancer screening participants. Emphysema, air trapping and bronchial wall thickness were automatically quantified in the CT scans. Logistic regression analysis was performed to derivate a model to diagnose COPD. The model was internally validated using bootstrapping techniques. RESULTS: Each of the three CT biomarkers independently contributed diagnostic value for COPD, additional to age, body mass index, smoking history and smoking status. The diagnostic model that included all three CT biomarkers had a sensitivity and specificity of 73.2% and 88.%, respectively. The positive and negative predictive value were 80.2% and 84.2%, respectively. Of all participants, 82.8% was assigned the correct status. The C-statistic was 0.87, and the Net Reclassification Index compared to a model without any CT biomarkers was 44.4%. However, the added value of the expiratory CT data was limited, with an increase in Net Reclassification Index of 4.5% compared to a model with only inspiratory CT data. CONCLUSION: Quantitatively assessed CT emphysema, air trapping and bronchial wall thickness each contain independent diagnostic information for COPD, and these imaging biomarkers might prove useful in the absence of lung function testing and may influence lung cancer screening strategy. Inspiratory CT biomarkers alone may be sufficient to identify patients with COPD in lung cancer screening setting.
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Enfisema/diagnóstico , Enfisema/epidemiología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Anciano , Broncografía/estadística & datos numéricos , Comorbilidad , Detección Precoz del Cáncer , Humanos , Incidencia , Masculino , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Países Bajos/epidemiología , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria/estadística & datos numéricos , Factores de Riesgo , Sensibilidad y Especificidad , Fumar/epidemiologíaRESUMEN
The aim of this study was to investigate the effect of iontophoresis combined with local psoralen plus ultraviolet A (PUVA) therapy in chronic foot eczema. A randomized, observer-blinded, multi-centre study was conducted in 48 patients with chronic moderate-to-severe foot eczema randomized to one of 3 groups: In the iontophoresis group local bath-PUVA was preceded by iontophoresis. In the PUVA group only local PUVA was given. The corticosteroid group was treated with fluticasone. All treatments were given for 8 weeks, with an 8-week follow-up period. The primary efficacy parameter was eczema score described by Rosén et al. Secondary efficacy parameters were a global impression by the patient, and the Dermatology Life Quality Index (DLQI). The eczema score and the DLQI decreased significantly over time. There were no significant differences in the decrease in eczema score (p=0.053) and DLQI values (p=0.563) between the 3 treatments. The DLQI values in our chronic foot eczema patients were high. There was no obvious advantage of local bath-PUVA with or with-out iontophoresis over local steroid therapy.
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Eccema/terapia , Ficusina/administración & dosificación , Dermatosis del Pie/terapia , Iontoforesis , Terapia PUVA , Fármacos Fotosensibilizantes/administración & dosificación , Administración Cutánea , Corticoesteroides/administración & dosificación , Adulto , Androstadienos/administración & dosificación , Terapia Combinada , Eccema/diagnóstico , Eccema/psicología , Femenino , Fluticasona , Dermatosis del Pie/diagnóstico , Dermatosis del Pie/psicología , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Calidad de Vida , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: Classification of COPD is currently based on the presence and severity of airways obstruction. However, this may not fully reflect the phenotypic heterogeneity of COPD in the (ex-) smoking community. We hypothesized that factor analysis followed by cluster analysis of functional, clinical, radiological and exhaled breath metabolomic features identifies subphenotypes of COPD in a community-based population of heavy (ex-) smokers. METHODS: Adults between 50-75 years with a smoking history of at least 15 pack-years derived from a random population-based survey as part of the NELSON study underwent detailed assessment of pulmonary function, chest CT scanning, questionnaires and exhaled breath molecular profiling using an electronic nose. Factor and cluster analyses were performed on the subgroup of subjects fulfilling the GOLD criteria for COPD (post-BD FEV1/FVC < 0.70). RESULTS: Three hundred subjects were recruited, of which 157 fulfilled the criteria for COPD and were included in the factor and cluster analysis. Four clusters were identified: cluster 1 (n = 35; 22%): mild COPD, limited symptoms and good quality of life. Cluster 2 (n = 48; 31%): low lung function, combined emphysema and chronic bronchitis and a distinct breath molecular profile. Cluster 3 (n = 60; 38%): emphysema predominant COPD with preserved lung function. Cluster 4 (n = 14; 9%): highly symptomatic COPD with mildly impaired lung function. In a leave-one-out validation analysis an accuracy of 97.4% was reached. CONCLUSIONS: This unbiased taxonomy for mild to moderate COPD reinforces clusters found in previous studies and thereby allows better phenotyping of COPD in the general (ex-) smoking population.
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Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Anciano , Pruebas Respiratorias , Análisis por Conglomerados , Estudios Transversales , Análisis Factorial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Índice de Severidad de la Enfermedad , Cese del Hábito de Fumar , Encuestas y Cuestionarios , Tomografía Computarizada por Rayos XRESUMEN
Genome-wide association studies (GWAS) for Crohn's disease (CD) have identified loci explaining approximately 20% of the total genetic risk of CD. Part of the other genetic risk loci is probably partly hidden among signals discarded by the multiple testing correction needed in the analysis of GWAS data. Strategies for finding these hidden loci require large replication cohorts and are costly to perform. We adopted a strategy of selecting SNPs for follow-up that showed a correlation to gene expression [cis-expression quantitative trait loci (eQTLs)] since these have been shown more likely to be trait-associated. First we show that there is an overrepresentation of cis-eQTLs in the known CD-associated loci. Then SNPs were selected for follow-up by screening the top 500 SNP hits from a CD GWAS data set. We identified 10 cis-eQTL SNPs. These 10 SNPs were tested for association with CD in two independent cohorts of Dutch CD patients (1539) and healthy controls (2648). In a combined analysis, we identified two cis-eQTL SNPs that were associated with CD rs2298428 in UBE2L3 (P=5.22x10(-5)) and rs2927488 in BCL3 (P=2.94x10(-4)). After adding additional publicly available data from a previously reported meta-analysis, the association with rs2298428 almost reached genome-wide significance (P=2.40x10(-7)) and the association with rs2927488 was corroborated (P=6.46x10(-4)). We have identified UBE2L3 and BCL3 as likely novel risk genes for CD. UBE2L3 is also associated with other immune-mediated diseases. These results show that eQTL-based pre-selection for follow-up is a useful approach for identifying risk loci from a moderately sized GWAS.
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Enfermedad de Crohn/genética , Expresión Génica , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Enzimas Ubiquitina-Conjugadoras/genética , Proteínas del Linfoma 3 de Células B , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Población Blanca/genéticaRESUMEN
Emphysema distribution is associated with chronic obstructive pulmonary disease. It is, however, unknown whether computed tomography (CT)-quantified emphysema distribution (upper/lower lobe) is associated with lung function decline in heavy (former) smokers. 587 male participants underwent lung CT and pulmonary function testing at baseline and after a median (interquartile range) follow-up of 2.9 (2.8-3.0) yrs. The lungs were automatically segmented based on anatomically defined lung lobes. Severity of emphysema was automatically quantified per anatomical lung lobe and was expressed as the 15th percentile (Hounsfield unit point below which 15% of the low-attenuation voxels are distributed (Perc15)). The CT-quantified emphysema distribution was based on principal component analysis. Linear mixed models were used to assess the association of emphysema distribution with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC), FEV(1) and FVC decline. Mean ± SD age was 60.2 ± 5.4 yrs, mean baseline FEV(1)/FVC was 71.6 ± 9.0% and overall mean Perc15 was -908.5 ± 20.9 HU. Participants with upper lobe-predominant CT-quantified emphysema had a lower FEV(1)/FVC, FEV(1) and FVC after follow-up compared with participants with lower lobe-predominant CT-quantified emphysema (p=0.001), independent of the total extent of CT-quantified emphysema. Heavy (former) smokers with upper lobe-predominant CT-quantified emphysema have a more rapid decrease in lung function than those with lower lobe-predominant CT-quantified emphysema.
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Pulmón , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/fisiopatología , Tomografía Computarizada por Rayos X , Anciano , Progresión de la Enfermedad , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfisema Pulmonar/diagnóstico por imagen , Enfisema Pulmonar/etiología , Fumar/efectos adversos , EspirometríaRESUMEN
BACKGROUND: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Age-dependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. METHODS: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. RESULTS: Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. CONCLUSIONS: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.