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Thorax  2013;69(1):55-62.
The calculation of spirometric Z-scores by Lambda-Mu-Sigma (LMS) rigorously accounts for age-related changes in lung function. Recently, the Global Lung Function Initiative (GLI) expanded the availability of LMS spirometric Z-scores to multiple ethnicities. Hence, in aging populations, the GLI provides an opportunity to rigorously evaluate ethnic differences in respiratory impairment, including spirometric airflow-limitation and restrictive-pattern
Using data from the Third National Health and Nutrition Examination Survey, including participants aged 40-80, we evaluated ethnic differences in GLI-defined respiratory impairment, including prevalence and associations with mortality and respiratory symptoms.
Among 3,506 White-Americans, 1,860 African-Americans, and 1,749 Mexican-Americans, the prevalence of airflow-limitation was 15.1% (13.9, 16.4), 12.4% (10.7, 14.0), and 8.2% (6.7, 9.8), and of restrictive-pattern was 5.6% (4.6, 6.5), 8.0% (6.9, 9.0), and 5.7% (4.5, 6.9), respectively. Airflow-limitation was associated with mortality in White-Americans, African-Americans, and Mexican-Americans — adjusted hazard ratio (aHR) 1.66 (1.23, 2.25), 1.60 (1.09, 2.36), and 1.80 (1.17, 2.76), respectively, but associated with respiratory symptoms only in White-Americans — adjusted odds ratio (aOR) 2.15 (1.70, 2.73). Restrictive-pattern was associated with mortality but only in White-Americans and African-Americans — aHR 2.56 (1.84, 3.55) and 3.23 (2.06, 5.05), and associated with respiratory symptoms but only in White-Americans and Mexican-Americans — aOR 2.16 (1.51, 3.07) and 2.12 (1.45, 3.08), respectively.
In an aging population, we found ethnic differences in GLI-defined respiratory impairment, including prevalence and associations with health outcomes. In particular, African-Americans present a unique public health challenge, with high rates of respiratory impairment being associated with mortality but not respiratory symptoms.
PMCID: PMC3925402  PMID: 23939399
spirometry; mortality; respiratory symptoms; ethnicity
2.  Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD 
Thorax  2014;69(6):516-524.
In models of COPD, environmental stressors induce innate immune responses, inflammasome activation and inflammation. However, the interaction between these responses and their role in driving pulmonary inflammation in stable COPD is unknown.
To investigate the activation of innate immunity and inflammasome pathways in the bronchial mucosa and bronchoalveolar lavage (BAL) of patients with stable COPD of different severity and control healthy smokers and non-smokers.
Innate immune mediators (interleukin (IL)-6, IL-7, IL-10, IL-27, IL-37, thymic stromal lymphopoietin (TSLP), interferon γ and their receptors, STAT1 and pSTAT1) and inflammasome components (NLRP3, NALP7, caspase 1, IL-1β and its receptors, IL-18, IL-33, ST2) were measured in the bronchial mucosa using immunohistochemistry. IL-6, soluble IL-6R, sgp130, IL-7, IL-27, HMGB1, IL-33, IL-37 and soluble ST2 were measured in BAL using ELISA.
In bronchial biopsies IL-27+ and pSTAT1+ cells are increased in patients with severe COPD compared with control healthy smokers. IL-7+ cells are increased in patients with COPD and control smokers compared with control non-smokers. In severe stable COPD IL-7R+, IL-27R+ and TSLPR+ cells are increased in comparison with both control groups. The NALP3 inflammasome is not activated in patients with stable COPD compared with control subjects. The inflammasome inhibitory molecules NALP7 and IL-37 are increased in patients with COPD compared with control smokers. IL-6 levels are increased in BAL from patients with stable COPD compared with control smokers with normal lung function whereas IL-1β and IL-18 were similar across all groups.
Increased expression of IL-27, IL-37 and NALP7 in the bronchial mucosa may be involved in progression of stable COPD.
PMCID: PMC4219154  PMID: 24430176
COPD Pathology; Innate Immunity
3.  Comparison of spirometric thresholds in diagnosing smoking related airflow obstruction 
Thorax  2013;69(5):409-414.
The diagnosis of chronic obstructive pulmonary disease (COPD) is based on detection of airflow obstruction on spirometry. There is no consensus regarding using a fixed threshold to define airflow obstruction versus using the lower limit of normal (LLN) adjusted for age. We compared the accuracy and discrimination of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommended Fixed ratio of FEV1/FVC<0.70 with LLN in diagnosing smoking related airflow obstruction using computed tomography defined emphysema and gas trapping as the disease gold standard.
Data from a large multicenter study (COPDGene), which included current and former smokers (age range 45 to 80 years) with and without airflow obstruction, was analyzed. Concordance between spirometric thresholds was measured. The accuracy of the thresholds in diagnosing emphysema and gas trapping was assessed using quantitative CT as gold standard.
7743 subjects were included. There was very good agreement between the two spirometric cut-offs (kappa = 0.85; 95%CI=0.83–0.86, p<0.001). 7.3% were discordant. Subjects with airflow obstruction by Fixed ratio only had a greater degree of emphysema (4.1% vs 1.2%, p<0.001) and gas trapping (19.8% vs 7.5%, p<0.001) than those positive by LLN only, and also smoking controls without airflow obstruction (4.1% vs 1.9%, and 19.8% vs 10.9% respectively, p<0.001). On follow up, the Fixed ratio only group had more exacerbations than smoking controls.
As compared to the Fixed ratio, the use of LLN will fail to identify a number of patients with significant pulmonary pathology and respiratory morbidity.
PMCID: PMC4146523  PMID: 23525095
Fixed ratio; Lower Limit of Normal; Spirometry; COPD
4.  Comparison of Spatially Matched Airways Reveals Thinner Airway Walls in COPD. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study and the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) 
Thorax  2014;69(11):987-996.
COPD is characterized by reduced airway lumen dimensions and fewer peripheral airways. Most studies of airway properties sample airways based upon lumen dimension or at random, which may bias comparisons given reduced airway lumen dimensions and number in COPD. We sought to compare central airway wall dimensions on computed tomography (CT) in COPD and controls using spatially matched airways, thereby avoiding selection bias of airways in the lung.
The MESA COPD Study and SPIROMICS recruited smokers with COPD and controls aged 50–79 years and 40–80 years, respectively. COPD was defined by current guidelines. Using CT image data, airway dimensions were measured for all central airway segments (generations 0–6) following 5 standardized paths into the lungs. Case-control airway comparisons were spatially matched by generation and adjusted for demographics, body size, smoking, CT dose, percent emphysema, airway length, and lung volume.
Among 311 MESA COPD participants, airway wall areas at generations 3–6 were smaller in COPD compared to controls(all p<0.001). Among 1248 SPIROMICS participants, airway wall areas at generations 1–6 were smaller(all p<0.001), and this reduction was monotonic with increasing COPD severity(P<0.001). In both studies, sampling airways by lumen diameter or randomly resulted in a comparison of more proximal airways in COPD to more peripheral airways in controls(p<0.001) resulting in the appearance of thicker walls in COPD(p<0.02).
Airway walls are thinner in COPD when comparing spatially matched central airways. Other approaches to airway sampling result in comparisons of more proximal to more distal airways and potentially biased assessment of airway properties in COPD.
PMCID: PMC4198462  PMID: 24928812
Chronic obstructive pulmonary disease; computed tomography; airways; walls
5.  Lesson of the month: extrinsic allergic (bronchiolo)alveolitis and metal working fluids 
Thorax  2014;69(11):1059-1060.
PMCID: PMC4215265  PMID: 25005567
Occupational Lung Disease; Hypersensitivity pneumonitis
6.  Cochrane corner: is integrated disease management for patients with COPD effective? 
Thorax  2014;69(11):1053-1055.
Patients with COPD experience respiratory symptoms, impairments of daily living and recurrent exacerbations. The aim of integrated disease management (IDM) is to establish a programme of different components of care (ie, self-management, exercise, nutrition) in which several healthcare providers (ie, nurses, general practitioners, physiotherapists, pulmonologists) collaborate to provide efficient and good quality of care. The aim of this Cochrane systematic review was to evaluate the effectiveness of IDM on quality of life, exercise tolerance and exacerbation related outcomes. Searches for all available evidence were carried out in various databases. Included randomised controlled trials (RCTs) consisted of interventions with multidisciplinary (≥2 healthcare providers) and multitreatment (≥2 components) IDM interventions with duration of at least 3 months. Two reviewers independently searched, assessed and extracted data of all RCTs. A total of 26 RCTs were included, involving 2997 patients from 11 different countries with a follow-up varying from 3 to 24 months. In all 68% of the patients were men, with a mean age of 68 years and a mean forced expiratory volume in 1 s (FEV1) predicted value of 44.3%. Patients treated with an IDM programme improved significantly on quality of life scores and reported a clinically relevant improvement of 44 m on 6 min walking distance, compared to controls. Furthermore, the number of patients with ≥1 respiratory related hospital admission reduced from 27 to 20 per 100 patients. Duration of hospitalisation decreased significantly by nearly 4 days.
PMCID: PMC4215268  PMID: 24415716
COPD epidemiology
7.  Heterogeneity's ruses: the neglected role of between-individual variability in longitudinal studies of COPD exacerbations 
Thorax  2014;69(11):1043-1044.
Studying the causal and temporal association between past and future exacerbations in COPD is an active area of research. Standard survival analysis techniques often used in such studies typically produce results that pertain to the overall population, whereas the greatest interest is in the study of associations within individuals. A factor that can lead to profound discrepancies between population-level and individual-level survival patterns is the between-individual heterogeneity in the rate of exacerbations. We briefly review two studies that, while reporting valid results for the overall population, drew conclusions at the individual level that could not be supported by the observations. We caution on the distinction between population and individual-level associations in survival analysis, and recommend accounting for heterogeneity in future studies.
PMCID: PMC4215271  PMID: 24550058
COPD Exacerbations
8.  Emphysema: time to say farewell to therapeutic nihilism 
Thorax  2014;69(11):973-975.
PMCID: PMC4215288  PMID: 24985493
Emphysema; Lung Volume Reduction Surgery; Bronchoscopy
9.  Lung volume reduction coil treatment for patients with severe emphysema: a European multicentre trial 
Thorax  2014;69(11):980-986.
The lung volume reduction (LVR) coil is a minimally invasive bronchoscopic nitinol device designed to reduce hyperinflation and improve elastic recoil in severe emphysema. We investigated the feasibility, safety and efficacy of LVR coil treatment in a prospective multicentre cohort trial in patients with severe emphysema.
Patients were treated in 11 centres. Safety was evaluated by recording all adverse events, efficacy by the St George's Respiratory Questionnaire (SGRQ) as primary endpoint, and pulmonary function testing, modified Medical Research Council dyspnoea score (mMRC) and 6-min walk distance (6MWD) up to 12 months after the final treatment.
Sixty patients (60.9 ± 7.5 years, forced expiratory volume in 1 s (FEV1) 30.2 ± 6.3% pred) were bronchoscopically treated with coils (55 bilateral, 5 unilateral), with a median of 10 (range 5–15) coils per lobe. Within 30 days post-treatment, seven chronic obstructive pulmonary disease exacerbations (6.1%), six pneumonias (5.2%), four pneumothoraces (3.5%) and one haemoptysis (0.9%) occurred as serious adverse events. At 6 and 12 months, respectively, ΔSGRQ was −12.1±12.9 and −11.1±13.3 points, Δ6MWD was +29.7±74.1 m and +51.4±76 m, ΔFEV1 was +0.11±0.20 L and +0.11±0.30 L, and ΔRV (residual volume) was −0.65±0.90 L and −0.71±0.81 L (all p<0.01). Post hoc analyses showed significant responses for SGRQ, 6MWD and RV in patients with both heterogeneous and homogeneous emphysema.
LVR coil treatment results in significant clinical improvements in patients with severe emphysema, with a good safety profile and sustained results for up to 1 year.
Trial registration number:
PMCID: PMC4215297  PMID: 24891327
Emphysema; Bronchoscopy
10.  Serum uric acid and the risk of respiratory disease: a population-based cohort study 
Thorax  2014;69(11):1021-1026.
Uric acid is the most abundant molecule with antioxidant properties found in human blood serum. We examined the relationship between serum uric acid and the incidence of respiratory disease including any effect modification by smoking status.
A cohort with serum uric acid measured between 1 January 2000 and 31 December 2012 was extracted from The Health Improvement Network primary care research database. New diagnoses of COPD and lung cancer were ascertained based on diagnostic codes entered into the medical records.
During 1 002 496 person years (PYs) of follow-up, there were 3901 COPD diagnoses and 1015 cases of lung cancer. After multivariable adjustment, strong interactions with smoking status were detected (p<0.001) for both outcomes with significant negative relationships between serum uric acid and respiratory disease for current smokers but no strong relationships for never-smokers or ex-smokers. The relationships were strongest for lung cancer in heavy smokers (≥20 cigarettes per day) with predicted incidence rates 97 per 10 000 PYs (95% CI 68 to 126) in the lowest serum uric acid quintile (100–250 µmol/L) compared with a predicted 28 per 10 000 PYs (95% CI 14 to 41) in the highest quintile (438–700 µmol/L).
Low levels of serum uric acid are associated with higher rates of COPD and lung cancer in current smokers after accounting for conventional risk factors.
PMCID: PMC4215274  PMID: 24904021
COPD epidemiology; Lung Cancer; Oxidative Stress; Tobacco and the lung
11.  Effect of Mindfulness Training on Asthma Quality of Life and Lung Function: A Randomized Controlled Trial 
Thorax  2012;67(9):769-776.
Improving asthma patients’ quality of life is an important clinical outcome. This study evaluated the efficacy of mindfulness-based stress reduction (MBSR) in improving quality of life and lung function in patients with asthma.
A randomized controlled trial compared an 8 week MBSR group-based program (n = 42) to an educational control program (n = 41) in adults with mild, moderate or severe persistent asthma recruited at a university hospital outpatient primary care and pulmonary care clinic. Primary outcomes were quality of life assessed by the Asthma Quality of Life Questionnaire (AQOL), and lung function assessed by change from baseline in two-week average morning peak expiratory flow (PEF). Secondary outcomes were asthma control assessed by 2007 NIH/NHLBI guidelines, and stress assessed by Perceived Stress Scale. Follow-up assessments were conducted at 10 weeks, 6 and 12 months.
At 12 months MBSR resulted in clinically significant improvements in quality of life (intervention effect 0.55 (95% CI 0.21, 0.89, p=0.001)) and perceived stress (intervention effect −4.5 (95% CI −7.1, −1.9; p= 0.001)). No significant effect was found on lung function (morning PEF, PEF variability, and FEV1). At 12 months the percentage of patients in MBSR with well-controlled asthma showed a non-statistically significant increase (7.3% at baseline to 19.4%) compared to the control condition (7.5% and 7.9%, respectively) (p=0.30).
MBSR produced lasting clinically significant improvements in asthma-related quality of life and stress in patients with persistent asthma, even in the absence of improvements in lung function.
PMCID: PMC4181405  PMID: 22544892
Asthma; Complementary Medicine; Perception of Asthma/Breathlessness
12.  Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma 
Thorax  2014;69(10):895-902.
Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble mesothelin is the most studied and an FDA-approved biomarker for MM. A recent report showed promising results using fibulin-3 as a new diagnostic marker. The aim of this study was to compare the utility of fibulin-3 versus mesothelin, singly or in combination.
Fibulin-3 and soluble mesothelin were determined by ELISA in the plasma and pleural fluid of 153 patients presenting with a pleural effusion including 82 with MM, 36 with non-MM malignant effusions and 35 with benign effusions. Biomarker concentrations were determined in the plasma of an additional 49 cases with benign asbestos-related disease.
Mesothelin provides better diagnostic accuracy than fibulin-3 for MM whether measured in plasma or pleural effusion: area under the curve (AUC) for plasma was 0.822 (95% CI 0.76 to 0.87) compared with 0.671 (0.61 to 0.73), respectively, and for pleural fluid AUC was 0.815 (0.74 to 0.87) compared with 0.588 (0.51 to 0.67), respectively. Effusion fibulin-3 was an independent significant prognostic factor for survival in MM patients; HR 2.08 (1.14 to 3.82), p=0.017. MM patients with effusion fibulin-3 levels below the median survived significantly longer than those with levels above the median (14.1 vs 7.9 months, p=0.012). Mesothelin and neutrophil to lymphocyte ratio were not significant prognostic markers.
Soluble mesothelin is a superior diagnostic biomarker for MM compared with fibulin-3, whereas fibulin-3 provides superior prognostic information compared with mesothelin.
PMCID: PMC4174124  PMID: 25037982
13.  Epithelial-mesenchymal transition: potential role in obliterative bronchiolitis? 
Thorax  2009;64(9):742-743.
PMCID: PMC4172368  PMID: 19717708
14.  Correction 
Thorax  2014;69(9):810.
PMCID: PMC4145462
15.  Association between obstructive lung disease and markers of HIV infection in a high-risk cohort 
Thorax  2011;67(4):309-314.
Evidence suggests an association between HIV infection and the presence of obstructive lung disease (OLD). However, the associations between specific markers of HIV infection and OLD remain unclear. A study was undertaken to determine the independent associations of HIV infection, CD4 cell count and plasma HIV viral load with the presence of OLD in an urban cohort.
Clinical, laboratory and spirometric data from the AIDS Linked to the Intravenous Experience (ALIVE) study, an observational study of current and former injection drug users in Baltimore, Maryland, were analysed. Multivariable logistic regression models were generated to identify HIV infection indices independently associated with OLD.
Of 1077 participants (mean±SD age 48±8 years), 89% were African-American, 65% were men and 86% were current smokers. A total of 303 (28%) were HIV infected and 176 (16%) had spirometry-defined OLD. Higher viral load was independently associated with OLD. HIV-infected individuals with viral load >200 000 copies/ml had a 3.4-fold increase in the odds of OLD compared with HIV-negative participants (95% CI 1.24 to 9.39; p=0.02). The association between higher HIV viral load and OLD persisted after accounting for antiretroviral therapy use (OR 4.06, 95% CI 1.41 to 11.7; p=0.01). No association was observed between HIV serostatus or CD4 cell count and the presence of OLD.
In a cohort at risk for OLD and HIV infection, high viral load but not CD4 cell count was associated with an increased prevalence of spirometry-defined OLD. These findings suggest that higher viral load may contribute mechanistically to the increased risk of OLD in patients with HIV infection.
PMCID: PMC4135473  PMID: 22090038
16.  IL-17A inhibits airway reactivity induced by RSV infection during allergic airway inflammation 
Thorax  2013;68(8):717-723.
Viral infections are the most frequent cause of asthma exacerbations and are linked to increased airway reactivity (AR) and inflammation. Mice infected with respiratory syncytial virus (RSV) during ovalbumin (OVA)-induced allergic airway inflammation (OVA/RSV) had increased AR compared to OVA or RSV mice alone. Further, IL-17A was only increased in OVA/RSV mice.
To determine if IL-17A increases AR and inflammation in the OVA/RSV model.
Wild-type BALB/c and IL-17A KO mice underwent mock, RSV, OVA, or OVA/RSV protocols. Lungs, bronchoalveolar lavage (BAL) fluid, and/or mediastinal lymph nodes (MLNs) were harvested post infection. Cytokine expression was determined by flow cytometry and ELISA in the lungs or BAL fluid. MLNs were restimulated with either OVA (323–229) peptide or RSV M2 (127–135) peptide and IL-17A protein expression was analyzed. AR was determined by methacholine challenge.
RSV increased IL-17A protein expression by OVA-specific T cells 6 days post infection. OVA/RSV mice had decreased IFN-α and IFN-β protein expression compared to RSV mice. OVA/RSV mice had increased IL-23 mRNA expression in lung homogenates compared to mock, OVA, or RSV mice. Unexpectedly, IL-17A KO OVA/RSV mice had increased AR compared to WT OVA/RSV mice. Further, IL-17A KO OVA/RSV mice had increased eosinophils, lymphocytes, and IL-13 protein expression in BAL fluid compared to WT OVA/RSV mice.
IL-17A negatively regulated AR and airway inflammation in OVA/RSV mice. This finding is important because IL-17A has been identified as a potential therapeutic target in asthma, and inhibiting IL-17A in the setting of virally induced asthma exacerbations may have adverse consequences.
PMCID: PMC3916091  PMID: 23422214
IL-17A; airway reactivity; CD4+ T cells; allergic inflammation; RSV
17.  Determinants and outcomes of physical activity in patients with COPD: a systematic review 
Thorax  2014;69(8):731-739.
The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed. Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD.
We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012. Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence.
86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both. Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence. Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low. As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence. Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV1 but based on cross-sectional studies and low to very low quality evidence.
Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment.
PMCID: PMC4112490  PMID: 24558112
COPD epidemiology; Exercise; COPD Exacerbations
18.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Cross-sectional population-based study of adults age 45-84 years in the United States
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
19.  Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome 
Thorax  2014;69(7):623-629.
Acute respiratory distress syndrome (ARDS) affects over 200,000 people annually in the US. Despite causing severe, and often refractory, hypoxemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined.
Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls.
Main results
Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex-vivo with GM-CSF were retained on first-pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to PAF were initially retained, but subsequently released such that only 14% remained in the lungs at 40 minutes. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS, compared to both perioperative control and septic patients.
We have demonstrated minimal delay or retention of un-primed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then ‘de-prime’ and are re-released into the systemic circulation. Further, we show that this physiological de-priming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.
PMCID: PMC4055272  PMID: 24706039
Acute respiratory distress syndrome (ARDS); multi-organ dysfunction; neutrophils
20.  The relation between dietary intake of individual fatty acids, FEV1 and respiratory disease in Dutch adults 
Thorax  2007;63(3):208-214.
A reduced dietary intake of n-3 fatty acids, in association with increased n-6 fatty acid intake, has been proposed as a potential aetiological factor for chronic obstructive pulmonary disease (COPD) and asthma. However, the relative importance of individual fatty acids within the n-3 and n-6 categories on this effect has not been widely investigated. We have studied the relation between individual fatty acid intakes, lung function and self-reported respiratory symptoms and diagnoses in a representative sample of more than 13 000 Dutch adults.
Intake of individual fatty acids was estimated by a food frequency questionnaire and analysed in relation to measures of forced expiratory volume in 1 s (FEV1) and to questionnaire reported wheeze, asthma and COPD symptoms.
After adjusting for confounding, we found no protective association between individual n-3 fatty acid intakes and FEV1. Higher intakes of some n-6 fatty acids were associated with lower FEV1, this effect being most marked for c22:4 n-6 docosatetraenoic acid (reduction in FEV1 between the highest and lowest quintile of intake 54.5 ml (95% CI –81.6 to –27.4)). Most of the n-6 fatty acid effects interacted significantly with smoking, their effects being strongest in current smokers. Individual n-3 fatty acid intakes were generally associated with a higher risk of wheeze in the past year, but otherwise there was little or no association between fatty acid intake and wheeze, doctor diagnosed asthma or other respiratory symptoms.
A high intake of n-3 fatty acids does not appear to protect against COPD or asthma, but a high intake of several n-6 fatty acids is associated with a significant reduction in FEV1, particularly in smokers. These findings indicate that high dietary intake of n-6 fatty acids, rather than reduced n-3 intake, may have an adverse effect on lung health.
PMCID: PMC3979330  PMID: 17901161
21.  Hygiene, atopy and wheeze–eczema–rhinitis symptoms in schoolchildren from urban and rural Ecuador 
Thorax  2013;69(3):232-239.
Rural residence is protective against atopy and wheeze–rhinitis–eczema symptoms in developed countries, an effect attributed to farming and poor hygiene exposures. There are few data from developing countries addressing this question. We compared atopy and wheeze–rhinitis–eczema symptoms between urban and rural Ecuador, and explored the effects of farming and poor hygiene exposures.
We performed cross sectional studies of schoolchildren living in rural and urban Ecuador. Data on symptoms and farming/hygiene exposures were collected by parental questionnaire, atopy by allergen skin prick test reactivity and geohelminth infections by stool examinations.
Among 2526 urban and 4295 rural schoolchildren, prevalence was: atopy (10.0% vs 12.5%, p=0.06), wheeze (9.4% vs 10.1%, p=0.05), rhinitis (8.1% vs 6.4%, p=0.02) and eczema (5.9% vs 4.7%, p=0.06). A small proportion of symptoms were attributable to atopy (range 3.9–10.7%) with greater attributable fractions for respiratory symptoms observed in urban schoolchildren. Respiratory symptoms were associated with poor hygiene/farming exposures: wheeze with lack of access to potable water; and rhinitis with household pets, no bathroom facilities and contact with large farm animals. Birth order was inversely associated with respiratory symptoms. Area of residence and atopy had few effects on these associations.
Urban schoolchildren living in Ecuador have a similar prevalence of atopy, eczema and wheeze but a higher prevalence of rhinitis compared with rural children. Some farming and poor hygiene exposures were associated with an increase in the prevalence of wheeze or rhinitis while birth order was inversely associated with these symptoms.
PMCID: PMC3932750  PMID: 24105783
Wheeze-Rhinitis-Eczema; Atopy; Hygiene; Farming; Urban-Rural
22.  Survival of patients with small cell lung cancer undergoing lung resection in England, 1998–2009 
Thorax  2013;69(3):269-273.
Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC), except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected SCLC is limited but this is widely offered.
Data on 359 873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC or non-SCLC (NSCLC)) and whether they underwent a surgical resection. We explored their survival using Kaplan–Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socioeconomic status.
The survival of 465 patients with resected SCLC was lower than patients with resected NSCLC (5-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 ‘elective’ SCLC cases where the diagnosis was most likely known before resection than for the subgroup of 267 ‘incidental’ cases where the SCLC diagnosis was likely to have been made after resection.
These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. Patients with SCLC treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected patients with SCLC.
PMCID: PMC3932952  PMID: 24172710
Lung Cancer; Small Cell Lung Cancer
23.  Increased ectodomain shedding of lung epithelial cell adhesion molecule 1 as a cause of increased alveolar cell apoptosis in emphysema 
Thorax  2013;69(3):223-231.
Alveolar epithelial cell apoptosis and protease/antiprotease imbalance based proteolysis play central roles in the pathogenesis of pulmonary emphysema but molecular mechanisms underlying these two events are not yet clearly understood. Cell adhesion molecule 1 (CADM1) is a lung epithelial cell adhesion molecule in the immunoglobulin superfamily. It generates two membrane associated C terminal fragments (CTFs), αCTF and βCTF, through protease mediated ectodomain shedding.
To explore the hypothesis that more CADM1-CTFs are generated in emphysematous lungs through enhanced ectodomain shedding, and cause increased apoptosis of alveolar epithelial cells.
Methods and results
Western blot analyses revealed that CADM1-CTFs increased in human emphysematous lungs in association with increased ectodomain shedding. Increased apoptosis of alveolar epithelial cells in emphysematous lungs was confirmed by terminal nucleotide nick end labelling (TUNEL) assays. NCI-H441 lung epithelial cells expressing mature CADM1 but not CTFs were induced to express αCTF both endogenously (by shedding inducers phorbol ester and trypsin) and exogenously (by transfection). Cell fractionation, immunofluorescence, mitochondrial membrane potentiometric JC-1 dye labelling and TUNEL assays revealed that CADM1-αCTF was localised to mitochondria where it decreased mitochondrial membrane potential and increased cell apoptosis. A mutation in the intracytoplasmic domain abrogated all three abilities of αCTF.
CADM1 ectodomain shedding appeared to cause alveolar cell apoptosis in emphysematous lungs by producing αCTF that accumulated in mitochondria. These data link proteolysis to apoptosis, which are two landmark events in emphysema.
PMCID: PMC3933066  PMID: 24092566
Airway Epithelium; Emphysema
24.  Fungi and pollen exposure in the first months of life and risk of early childhood wheezing 
Thorax  2009;64(4):10.1136/thx.2007.090241.
Many studies have found that risk of childhood asthma varies by month of birth, but few have examined ambient aeroallergens as an explanatory factor.
To examine whether birth during seasons of elevated ambient fungal spore or pollen concentrations is associated with risk of early wheezing or blood levels of Th1- and Th2-type cells at 24 months of age.
514 children were enrolled before birth and followed to 24 months of age. Early wheezing was determined from medical records and Th1 and Th2-type cells were measured in peripheral blood using flow cytometry. Ambient aeroallergen concentrations were measured throughout the study period and discrete seasons of high spore and pollen concentrations were defined.
A seasonal pattern was observed, with birth in the fall-winter (the fungal spore season) associated with increased odds of early wheezing (adjusted odds ratio = 3.1; 95% confidence interval: 1.3, 7.4). Increasing mean daily concentrations of basidiospores and ascospores in the first three months of life were associated with increased odds of wheeze, as were increasing mean daily concentrations of total and specific pollen types. Levels of Th1 cells at age 24 months were positively associated with mean fungal spore concentrations and negatively associated with mean pollen concentrations in the first three months of life.
Children with higher exposure to fungal spores and pollen in the first three months of life were at increased risk of early wheezing. This association was independent of other seasonal factors, including ambient PM2.5 levels and lower respiratory infections.
PMCID: PMC3882001  PMID: 19240083
asthma; wheeze; birth season; mold; pollen; epidemiology
25.  Incremental value of T-SPOT.TB for diagnosis of active pulmonary tuberculosis in children in a high-burden setting: a multivariable analysis 
Thorax  2013;68(9):860-866.
Interferon γ release assays (IGRAs) are increasingly used for tuberculosis (TB) infection, but their incremental value beyond patient demographics, clinical signs and conventional tests for active disease has not been evaluated in children.
The incremental value of T-SPOT.TB was assessed in 491 smear-negative children from two hospitals in Cape Town, South Africa. Bayesian model averaging was used to select the optimal set of patient demographics and clinical signs for predicting culture-confirmed TB. The added value of T-SPOT.TB over and above patient characteristics and conventional tests was measured using statistics such as the difference in the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI).
Cough longer than 2 weeks, fever longer than 2 weeks, night sweats, malaise, history of household contact and HIV status were the most important predictors of culture-confirmed TB. Binary T-SPOT.TB results did not have incremental value when added to the baseline model with clinical predictors, chest radiography and the tuberculin skin test. The AUC difference was 3% (95% CI 0% to 7%). Using risk cut-offs of <10%, 10–30% and >30%, the NRI was 7% (95% CI −8% to 31%) but the CI included the null value. The IDI was 3% (95% CI 0% to 11%), meaning that the average predicted probability across all possible cut-offs improved marginally by 3%.
In a high-burden setting, the T-SPOT.TB did not have added value beyond clinical data and conventional tests for diagnosis of TB disease in smear-negative children.
PMCID: PMC3862980  PMID: 23674550
Clinical Epidemiology; Tuberculosis

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