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1.  Quantitative assessment of chronic lung disease of infancy using computed tomography 
The European respiratory journal  2011;39(4):992-999.
The aims of this study were to determine whether infants and toddlers with chronic lung disease of infancy (CLDI) have smaller airways and lower lung density compared with full-term healthy controls.
Multi-slice computed tomography (CT) chest scans were obtained at elevated lung volumes during a brief respiratory pause in sedated infants and toddlers; 38 CLDI were compared with 39 full-term controls. For CLDI subjects, gestational age at birth ranged from 25 to 29 weeks. Airway size was measured for the trachea and the next three to four generations into the right lower lobe; lung volumes and tissue density were also measured.
The relationship between airway size and airway generation differed between the CLDI and full-term groups; the sizes of the first and second airway generations were larger in the shorter CLDI than in the shorter full-term subjects. The increased size in the airways in the CLDI subjects was associated with increasing mechanical ventilation time in the neonatal period. CLDI subjects had a greater heterogeneity of lung density compared with full-term subjects.
Our results indicate that quantitative analysis of multi-slice CT scans at elevated volumes provides important insights into the pulmonary pathology of infants and toddlers with CLDI.
PMCID: PMC4332383  PMID: 22005925
Bronchopulmonary dysplasia; high-resolution computed tomography; lung development; lung volume measurement
3.  Computed tomography score and pulmonary function in infants with chronic lung disease of infancy 
The European respiratory journal  2011;38(4):918-923.
Chronic lung disease of infancy (CLDI) remains a common outcome among infants born extremely prematurely. In older children and adults with lung disease, pulmonary function and computed tomography (CT) scores are used to follow up respiratory disease and assess disease severity. For infants and toddlers, however, these outcomes have been used very infrequently and most often, a dichotomous respiratory outcome (presence or absence of CLDI) is employed.
We evaluated the performance of CT score and pulmonary function to differentiate infants and toddlers with CLDI from a control group.
CT scans, forced expiratory flows and pulmonary diffusing capacity were obtained in 39 CLDI patients and 41 controls (aged 4–33 months). CT scans were quantified using a scoring system, while pulmonary function was expressed as Z-scores. CT score outperformed pulmonary function in identifying those with CLDI. There were no significant correlations between CT score and pulmonary function.
CT score had a better performance than pulmonary function in differentiating individuals with CLDI; however, these outcomes may reflect differing components of the pulmonary pathophysiology of CLDI. This new information on pulmonary outcomes can assist in designing studies with these parameters. Future studies will be required to evaluate which of the outcomes can better detect improvement with therapeutic intervention and/or lung growth.
PMCID: PMC4302386  PMID: 21478219
Bronchopulmonary dysplasia; forced expiratory flows; high-resolution computed tomography; lung function; pulmonary diffusing capacity
4.  [No title available] 
PMCID: PMC4291171  PMID: 25034567
5.  Levels of soluble HLA-G are increased in asthmatic airways 
The European respiratory journal  2010;35(4):925-927.
PMCID: PMC4285585  PMID: 20356990
HLA-G; airway epithelium; bronchoalveolar lavage; asthma
6.  Phenotype of asthmatics with increased airway S-nitrosoglutathione reductase activity 
Study question
S-Nitrosoglutathione is an endogenous airway smooth muscle relaxant. Increased airway S-Nitrosoglutathione breakdown occurs in some asthma patients. We asked whether patients with increased airway catabolism of this molecule had clinical features that distinguished them from other asthma patients.
We measured S-Nitrosoglutathione reductase expression and activity in bronchoscopy samples from 66 subjects in the Severe Asthma Research Program. We also analysed phenotype and genotype data from in the program as a whole.
Airway S-nitrosoglutathione reductase activity was increased in asthma patients (p = 0.032). However, only a subpopulation was affected, and this subpopulation was not defined by a “severe asthma” diagnosis. Subjects with increased activity were younger, had higher Immunoglobulin E and an earlier onset of symptoms. Consistent with a link between S-Nitrosoglutathione biochemistry and atopy, 1) interleukin 13 increased S-Nitrosoglutathione reductase expression, and 2) subjects with an S-Nitrosoglutathione reductase single nucleotide polymorphism (SNP) previously associated asthma had higher Immunoglobulin E than those without this SNP. Expression was higher in airway epithelium than in smooth muscle, and was increased in regions of the asthmatic lung with decreased airflow.
Answer to the question
An early-onset, allergic phenotype characterizes the asthma population with increased S-Nitrosoglutathione reductase activity.
PMCID: PMC4283933  PMID: 25359343
7.  Contributors to diffusion impairment in HIV-infected persons 
The European respiratory journal  2013;43(1):195-203.
Abnormal diffusing capacity is common in HIV-infected individuals including never smokers. Etiologies for diffusing capacity impairment in HIV are not understood, particularly in those without a history of cigarette smoking.
A cross-sectional analysis of 158 HIV-infected individuals without acute respiratory symptoms or infection to determine associations between a DLCO % predicted and participant demographics, pulmonary spirometric measures (FEV1 and FEV1/FVC), radiographic emphysema (fraction of lung voxels <-950 Hounsfield units), pulmonary vascular/cardiovascular disease (echocardiographic tricuspid regurgitant jet velocity [TRV], N-terminal pro-brain natriuretic peptide), and airway inflammation (induced sputum cell counts), stratified by history of smoking.
Mean DLCO was 65.9% predicted, and 55 (34.8%) participants had a significantly reduced DLCO (<60 % predicted). Lower DLCO % predicted in ever smokers was associated with lower post-bronchodilator FEV1 % predicted (p<0.001) and greater radiographic emphysema (p=0.001). In never smokers, mean (standard deviation) DLCO was 72.7% (13.4%) predicted, and DLCO correlated with post-bronchodilator FEV1 (p=0.02), sputum neutrophils (p=0.03), and sputum lymphocytes (p=0.009), but not radiographic emphysema.
Airway obstruction, emphysema, and inflammation influence DLCO in HIV. Never smokers may have a unique phenotype of diffusing capacity impairment. The interaction of multiple factors may account for the pervasive nature of diffusing capacity impairment in HIV infection.
PMCID: PMC4023348  PMID: 23429919
HIV; Pulmonary function; Diffusing capacity; AIDS
8.  Predictors of dyspnea prevalence: Results from the BOLD study 
The European respiratory journal  2013;43(6):1610-1620.
Dyspnea is a cardinal symptom for cardiorespiratory diseases. No study has assessed worldwide variation in dyspnea prevalence or predictors of dyspnea.
We used cross-sectional data from population-based samples in 15 countries of the BOLD study to estimate prevalence of dyspnea in the full sample as well as in an a priori defined low-risk group (few risk factors or dyspnea-associated diseases). Dyspnea was defined by the modified Medical Research Council questions. We used ordered logistic regression analysis to study the association of dyspnea with site, sex, age, education, smoking habits, low/high BMI, self-reported disease, and spirometry results.
Of the 9,484 participants, 27% reported any dyspnea. In the low-risk subsample (N=4,329), 16% reported some dyspnea. In multivariate analyses, all covariates were correlated to dyspnea, but only 13% of dyspnea variation was explained. Women reported more dyspnea than men (odds ratio ≈ 2.1). When forced vital capacity (FVC) fell below 60% of predicted, dyspnea was much more likely.
There was considerable geographical variation in dyspnea, even when we adjusted for known risk factors and spirometry results. We were only able to explain 13% of dyspnea variation.
PMCID: PMC4143752  PMID: 24176991
Dyspnea; Lung function; Epidemiology; Multi-center study
9.  Best lung function equations for the very elderly selected by survival analysis 
The European respiratory journal  2014;43(5):1338-1346.
We evaluated which equations best predicted the lung function of a cohort of nonagenarians based on which best accounted for subsequent survival.
In 1998, we measured lung function, grip strength and dementia score (Mini Mental State Examination (MMSE)) in a population-based sample of 2262 Danes born in 1905. Mortality was registered to 2011 when only five (0.2%) subjects were alive. In half the cohort, we recorded forced expiratory volume in 1 s (FEV1).
Complete data were available in 592 subjects with results expressed as standardised residuals (SR) using various prediction equations. Cox proportional hazard regression found lower FEV1SR was a predictor of mortality having controlled for MMSE, grip strength and sex. The US National Health and Nutrition Examination Survey (NHANES) III (1999) equations gave a better spread of median survival by FEV1SR quartile: 3.94, 3.65, 3.51 and 2.61 years with a hazard ratio for death of 1, 1.16, 1.32 and 1.60 respectively, compared with equations derived with the inclusion of elderly subjects.
We conclude that extrapolating from NHANES III equations to predict lung function in nonagenarians gave better survival predictions from spirometry than when employing equations derived using very elderly subjects with possible selection bias. These findings can help inform how future lung function equations for the elderly are derived.
PMCID: PMC4226937  PMID: 24488567
10.  Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis 
The European respiratory journal  2014;44(4):860-872.
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 NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression.
Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, 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 of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution.
PMCID: PMC4217133  PMID: 24993907
11.  Lung Adenocarcinoma Subtypes Based on Expression of Human Airway Basal Cell Genes 
The European respiratory journal  2013;42(5):1332-1344.
Lung cancer, including lung adenocarcinoma (adenoCa), is a heterogeneous disease, which evolves from molecular alterations in the airway epithelium. The study explores whether a subtype of lung adenoCa expresses the unique molecular features of human airway basal cell (BC), and how expression of the airway BC features correlates with the molecular, pathologic and clinical phenotype of lung adenoCa.
Three independent lung adenoCa data sets were analyzed for expression of genes that constitute the airway BC signature. Expression of the BC signature in lung adenoCa was then correlated to clinical and biologic parameters.
Remarkable enrichment of airway BC signature genes was found in lung adenoCa. A subset of lung adenoCa (“BC-high adenoCa”) exhibited high expression of BC signature genes in association with poorer tumor grade, higher frequency of vascular invasion, and shorter survival than adenoCa with lower expression of these genes. At the molecular level, “BC-high adenoCa” displayed higher frequency of KRAS mutations, activation of transcriptional networks and pathways related to cell cycle, extracellular matrix organization, and a distinct differentiation pattern with suppression of ciliated-and Clara cell-related genes.
Activation of the airway BC program is a molecular feature of a distinct, aggressive subtype of lung adenoCa.
PMCID: PMC4124529  PMID: 23645403
Airway basal cell; lung adenocarcinoma; gene expression; cell-of-origin
12.  Targeting EGFR signalling in chronic lung disease: therapeutic challenges and opportunities 
The European respiratory journal  2014;44(2):513-522.
Chronic respiratory diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) and lung cancer, are the second leading cause of death among Europeans. Despite this, there have been only a few therapeutic advances in these conditions over the past 20 years. In this review we provide evidence that targeting the epidermal growth factor receptor (EGFR) signalling pathway may represent a novel therapeutic panacea for treating chronic lung disease. Using evidence from human patient samples, transgenic animal models, and cell and molecular biology studies we highlight the roles of this signalling pathway in lung development, homeostasis, repair, and disease ontogeny. We identify mechanisms underlying lung EGFR pathway regulation and suggest how targeting these mechanisms using new and existing therapies has the potential to improve future lung cancer, COPD and pulmonary fibrosis patient outcomes.
PMCID: PMC4209854  PMID: 24435005
14.  Processed meat consumption and lung function: modification by antioxidants and smoking 
The European respiratory journal  2013;43(4):972-982.
Unhealthy dietary patterns are associated with poorer lung function. It is not known whether this is due to low consumption of antioxidant-rich fruit and vegetables, or is a consequence of higher intakes of harmful dietary constituents such as processed meat.
We examined the individual and combined associations of processed meat, fruit and vegetable consumption and dietary total antioxidant capacity (TAC) with lung function among 1551 men and 1391 women in the Hertfordshire Cohort Study, UK. Diet was assessed by food frequency questionnaire.
After controlling for confounders, processed meat consumption was negatively associated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in men and women, while fruit and vegetable consumption and dietary TAC were positively associated with FEV1 and FVC, but not FEV1/FVC. In men the negative association between processed meat consumption and FEV1 was more marked in those who had low fruit and vegetable consumption (Pinteraction=0.035), and low dietary TAC (Pinteraction=0.025). The deficit in FEV1/FVC associated with processed meat consumption was larger in men who smoked (Pinteraction=0.022).
Higher processed meat consumption is associated with poorer lung function, especially in men who have lower fruit and vegetable consumption or dietary TAC, and among current smokers.
PMCID: PMC3956622  PMID: 24176995
Dietary balance; total antioxidant capacity; fruit and vegetables; processed meat; lung function
16.  Bronchoalveolar lavage neuregulin-1 is elevated in acute lung injury and correlates with inflammation 
The European respiratory journal  2012;41(2):396-401.
Shedding of neuregulin (NRG)-1 from the pulmonary epithelium leads to activation of the epithelial human epidermal growth factor receptor (HER)2 receptor, increased pulmonary epithelial permeability and acute lung injury (ALI). We sought to determine whether NRG-1 was detectable and elevated in bronchoalveolar lavage (BAL) and plasma from patients with ALI compared with controls and to determine whether a correlation exists between NRG-1 and inflammation and outcome in ALI.
Matched BAL and plasma samples were obtained from 23 ALI patients requiring intubation and mechanical ventilation. Control patients (n=5) included healthy volunteers. NRG-1 and indices of inflammation were measured in BAL and plasma via ELISA.
The mean±sd BAL NRG-1 concentration in ALI patients was 187.0±21.35 pg·mL−1 compared with 85.50±9.2 pg·mL−1 in controls (p=0.001). Increased BAL NRG-1 was associated with markers of inflammation, and inversely correlated with ventilator-free days (VFDs; r= −0.51, p=0.015). Plasma NRG-1 was elevated in ALI patients compared with controls (611.7±354.2 versus 25.17±19.33 pg·mL−1, p<0.001) and inversely correlated with VFDs (r= −0.51, p=0.04).
These results confirm shedding of NRG-1 in ALI and suggest that the NRG-1–HER2 pathway is active in patients with ALI.
PMCID: PMC4140244  PMID: 22599357
Acute respiratory failure; alveolar epithelium; biomarkers; inflammatory mediators
17.  Pulmonary Function Measures Predict Mortality Differently in Idiopathic Pulmonary Fibrosis versus Combined Pulmonary Fibrosis and Emphysema 
The European respiratory journal  2010;38(1):176-183.
The composite physiologic index(CPI) was derived to represent the extent of fibrosis on high resolution computed tomography, adjusting for emphysema in patients with idiopathic pulmonary fibrosis(IPF). We hypothesized longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 second(FEV1), forced vital capacity(FVC), or diffusing capacity for carbon monoxide(DLCO) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema(CPFE).
Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n=321), 6 months (n=211) and 12 months (n=144). Presence of CPFE was determined by high resolution computed tomography.
A 5 point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p=0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in DLCO or an absolute increase in CPI of 5 points all discriminated median survival by 2.1 to 2.2 years versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV1 predicted mortality (HR 3.7, p=0.046).
In IPF, a 5 point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in DLCO. For CPFE patients, change in FEV1 was the best predictor of mortality.
PMCID: PMC4084829  PMID: 21148225
Chronic Obstructive Pulmonary Disease; Idiopathic Pulmonary Fibrosis; Prognosis; Pulmonary Function; Survival
21.  Prior cardiovascular disease increases long-term mortality in COPD patients with pneumonia 
There is controversy regarding the impact of chronic obstructive pulmonary disease (COPD) in clinical outcomes in elderly patients with pneumonia. Comorbidities such as cardiovascular disease have been reported to play an important role in patients with acute exacerbations of COPD. However, limited data are available regarding the impact of cardiovascular disease in elderly COPD patients who require hospitalisation for pneumonia.
We examined a cohort of subjects with pneumonia and pre-existing COPD. Prior cardiovascular disease was defined as history of myocardial infarction, congestive heart failure, cardiac arrhythmia, unstable angina or stroke. Outcomes examined included 30-day, 90-day, 6-month and 1-year mortality.
We included 17 140 elderly COPD patients who were hospitalised for pneumonia. Prior cardiovascular disease was present in 10 240 (59.7%) patients. Prior cardiovascular disease was independently associated with 90-day mortality (21.3% versus 19.4%; hazard ratio (HR) 1.29, 95% CI 1.02–1.17), 6-month mortality (29.0% versus 26.1%; HR 1.28, 95% CI 1.07–1.50) and 12-month mortality (39.2% versus 34.5%; HR 1.33, 95% CI 1.15–1.54) when compared to no prior cardiovascular disease. The temporal differential effect between groups increases from 1.0% at 30 days to 4.7% at 1 year.
Prior cardiovascular disease is associated with increased long-term mortality in elderly COPD patients with pneumonia. Differences in mortality rates increased over time.
PMCID: PMC4066656  PMID: 23598950
22.  Pulmonary MMP-9 Activity in Mechanically Ventilated Children with RSV Disease 
The European respiratory journal  2013;43(4):1086-1096.
RSV infection is a potent stimulus for airway epithelial expression of MMP-9, and MMP-9 activity in vivo is a predictor of disease severity in children with RSV-induced respiratory failure (RSV-RF).
Human airway epithelial cells were infected with RSV A2 strain, and analyzed for MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1, a natural inhibitor of MMP-9) release. In addition, endotracheal samples from children with RSV-RF and controls (non-RSV pneumonia and non-lung disease controls) were analyzed for MMP-9, TIMP-1, human neutrophil elastase (HNE) and myeloperoxidase (MPO) activity.
RSV infection of airway epithelia was sufficient to rapidly induce MMP-9 transcription and protein release. Pulmonary MMP-9 activity peaked at 48 hours in infants with RSV-RF compared to controls. In the RSV group, MMP-9 activity and MMP-9:TIMP-1 ratio imbalance predicted higher oxygen requirement and worse Pediatric Risk of Mortality scores. Highest levels of HNE and MPO were measured in the RSV cohort but unlike MMP-9, these neutrophil markers failed to predict disease severity.
These results support the hypothesis that RSV is a potent stimulus for MMP-9 expression and release from human airway epithelium, and that MMP-9 is an important biomarker of disease severity in mechanically ventilated children with RSV lung infection.
PMCID: PMC4059407  PMID: 24311764
23.  APOM and High-Density Lipoprotein are associated with Lung Function and Percent Emphysema 
The European respiratory journal  2013;43(4):1003-1017.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.
We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.
We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.
These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
PMCID: PMC4041087  PMID: 23900982
Apolipoproteins; Cholesterol; Percent Emphysema; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
24.  Apoptotic cell clearance and fibrotic lung disease 
The European respiratory journal  2012;40(2):289-290.
PMCID: PMC4036233  PMID: 22855466
25.  The role of matrix metalloproteases in cystic fibrosis lung disease 
The European respiratory journal  2011;38(3):721-727.
Significant airway remodeling is a major component of the increased morbidity and mortality observed in cystic fibrosis (CF) patients. These airways feature ongoing leukocytic inflammation and unrelenting bacterial infection. In contrast to acute bacterial pneumonia, CF infection is not cleared efficiently and the ensuing inflammatory response causes tissue damage. This structural damage is mainly a result of free proteolytic activity released by infiltrated neutrophils and macrophages. Major proteases in this disease are serine and matrix metalloproteases (MMPs). While the role of serine proteases, such as elastase, has been characterized in detail, there is emerging evidence that MMPs could play a key role in the pathogenesis of CF lung disease. This review summarizes studies linking MMPs with CF lung disease and discusses the potential value of MMPs as future therapeutic targets in CF and other chronic lung diseases.
PMCID: PMC4036453  PMID: 21233269
Cystic fibrosis; lung disease; elastase; neutrophil; proteases; antiproteases

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