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1.  THE EMERGENCE OF PARAPNEUMONIC EMPYEMA IN THE UNITED STATES 
Thorax  2011;66(8):663-668.
BACKGROUND
Although recent reports suggest the incidence of parapneumonic empyema increased in several regions of the United States, national trends in disease burden are unknown. We examined national trends in the incidence of parapneumonic empyema hospitalizations and changes in empyema by associated pathogens.
METHODS
National hospitalization data(1996–2008) were analyzed and rates estimated using Census estimates as denominators. Incidence rate ratios (IRR) compared 2008 with 1996 rates. Discharge diagnosis codes were used to characterize pathogens associated with empyema hospitalizations.
RESULTS
Overall, national parapneumonic empyema-related hospitalization rates increased from 3.04 per 100,000 in 1996 to 5.98 per 100,000 in 2008, a 2.0-fold increase (95% CI: 1.8–2.1). The increases were observed among children (IRR: 1.9 [95% CI: 1.4–2.7]) and adults aged 18–39, 40–64 and ≥65 years (IRRs: 1.8 [95% CI: 1.5–2.1], 2.0 [95% CI: 1.6–3.1] and 1.7 [95% CI: 1.5–2.0], respectively). Overall pneumococcal empyema rates remained relatively stable in all age groups, whereas streptococcal (non-pneumococcal) and staphylococcal-related empyema rates increased 1.9 and 3.3-fold, respectively, with consistent increases across age groups. The overall in-hospital case fatality ratio for parapneumonic empyema-related hospitalizations was 8.0% (95% CI: 6.4–9.5) in 1996 and 7.2% (95% CI: 6.3–8.1) in 2008 (p=0.395). Of the empyemas where study pathogens were listed (37.6%), Staphylococcal-related empyema had the largest absolute increases across age groups and was associated with longer hospital stay and higher in-hospital mortality than other empyemas.
CONCLUSIONS
Although parapneumonic empyema-related hospitalizations remained relatively rare, they increased substantially during the study period. A number of pathogens, especially staphylococcus, contributed to this increase.
doi:10.1136/thx.2010.156406
PMCID: PMC4820002  PMID: 21617169
2.  Respiratory health and disease in a UK population-based cohort of 85 year olds: The Newcastle 85+ Study 
Thorax  2016;71(3):255-266.
Background
People aged 85 years and older are the fastest growing age group worldwide. This study assessed respiratory health, prevalence of respiratory disease and use of spirometry in respiratory diagnosis in a population-based cohort of 85 year olds to better understand respiratory health and disease in this sector of society.
Methods
A single year birth-cohort of 85 year olds participated in a respiratory assessment at their home or residential institution including self-reporting of symptoms and measurement of spirometry. General practice medical records were reviewed for respiratory diagnoses and treatments.
Findings
In the 845 participants, a substantial burden of respiratory disease was seen with a prevalence of COPD in medical records of 16.6% (n=140). A large proportion of the cohort had environmental exposures through past or current smoking (64.2%, n=539) and occupational risk factors (33.6%, n=269). Spirometry meeting reliability criteria was performed in 87% (n=737) of participants. In the subgroup with a diagnosis of COPD (n=123), only 75.6% (n=93) satisfied Global Initiative in Obstructive Lung Disease (GOLD) criteria for airflow obstruction, and in a healthy subgroup without respiratory symptoms or diagnoses (n=151), 44.4% (n=67) reached GOLD criteria for airflow obstruction and 43.3% (n=29) National Institute of Health and Care Excellence criteria for at least moderate COPD.
Interpretation
Spirometry can be successfully performed in the very old, aged 85 years, and may help identify respiratory diseases such as COPD. However interpretation in this age group using current definitions of COPD based on spirometry indices may be difficult and lead to overdiagnosis in a healthy group with transient symptoms.
doi:10.1136/thoraxjnl-2015-207249
PMCID: PMC4789822  PMID: 26732736
Lung Physiology; COPD epidemiology; Respiratory Measurement
3.  Using venous blood gas analysis in the assessment of COPD exacerbations: a prospective cohort study 
Thorax  2015;71(3):210-215.
Introduction
Identifying acute hypercapnic respiratory failure is crucial in the initial management of acute exacerbations of COPD. Guidelines recommend obtaining arterial blood samples but these are more difficult to obtain than venous. We assessed whether blood gas values derived from venous blood could replace arterial at initial assessment.
Methods
Patients requiring hospital treatment for an exacerbation of COPD had paired arterial and venous samples taken. Bland–Altman analyses were performed to assess agreement between arterial and venous pH, CO2 and . The relationship between SpO2 and SaO2 was assessed. The number of attempts and pain scores for each sample were measured.
Results
234 patients were studied. There was good agreement between arterial and venous measures of pH and (mean difference 0.03 and −0.04, limits of agreement −0.05 to 0.11 and −2.90 to 2.82, respectively), and between SaO2 and SpO2 (in patients with an SpO2 of >80%). Arterial sampling required more attempts and was more painful than venous (mean pain score 4 (IQR 2–5) and 1 (IQR 0–2), respectively, p<0.001).
Conclusions
Arterial sampling is more difficult and more painful than venous sampling. There is good agreement between pH and values derived from venous and arterial blood, and between pulse oximetry and arterial blood gas oxygen saturations. These agreements could allow the initial assessment of COPD exacerbations to be based on venous blood gas analysis and pulse oximetry, simplifying the care pathway and improving the patient experience.
doi:10.1136/thoraxjnl-2015-207573
PMCID: PMC4789825  PMID: 26628461
COPD Exacerbations
4.  Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial 
Thorax  2013;68(9):812-817.
Background
The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery.
Methods
Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation—after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study.
Results
DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs −0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events.
Conclusions
Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.
doi:10.1136/thoraxjnl-2013-203207
PMCID: PMC4770250  PMID: 23681906
Bronchiectasis; Respiratory Infection
5.  Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD 
Thorax  2015;71(2):118-125.
Objective
We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy.
Methods
Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57–75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level.
Results
For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ.
Discussion
Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations.
doi:10.1136/thoraxjnl-2015-207021
PMCID: PMC4752631  PMID: 26585525
COPD Exacerbations
6.  Occam's razor or Hickam's dictum? Allergic bronchopulmonary aspergillosis and eosinophilic granulomatosis with polyangiitis* 
Thorax  2015;71(2):193-195.
doi:10.1136/thoraxjnl-2015-207280
PMCID: PMC4752619  PMID: 26699763
ANCA Related Vasculitides; Aspergillus Lung Disease; Systemic disease and lungs
7.  Validation of the DECAF score to predict hospital mortality in acute exacerbations of COPD 
Thorax  2016;71(2):133-140.
Background
Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high. The DECAF score was derived for accurate prediction of mortality and risk stratification to inform patient care. We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools.
Methods
The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014. Consecutive admissions were identified by screening admissions and searching coding records. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve.
Results
In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV1 45.5 (18.3) per cent predicted. Overall mortality was 7.7%. The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality.
Conclusions
DECAF is a robust predictor of mortality, using indices routinely available on admission. Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0–1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3–6) for escalation planning or appropriate early palliation.
Trial registration number
UKCRN ID 14214.
doi:10.1136/thoraxjnl-2015-207775
PMCID: PMC4752621  PMID: 26769015
COPD Exacerbations
8.  Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK) 
Thorax  2015;71(2):187-189.
The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.
doi:10.1136/thoraxjnl-2015-207326
PMCID: PMC4752622  PMID: 26205878
Asthma Mechanisms
9.  Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group 
Thorax  2015;71(2):177-184.
Background
There is currently no Europe-wide consensus on the appropriate preanalytical measures and workflow to optimise procedures for tissue-based molecular testing of non-small-cell lung cancer (NSCLC). To address this, a group of lung cancer experts (see list of authors) convened to discuss and propose standard operating procedures (SOPs) for NSCLC.
Methods
Based on earlier meetings and scientific expertise on lung cancer, a multidisciplinary group meeting was aligned. The aim was to include all relevant aspects concerning NSCLC diagnosis. After careful consideration, the following topics were selected and each was reviewed by the experts: surgical resection and sampling; biopsy procedures for analysis; preanalytical and other variables affecting quality of tissue; tissue conservation; testing procedures for epidermal growth factor receptor, anaplastic lymphoma kinase and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) in lung tissue and cytological specimens; as well as standardised reporting and quality control (QC). Finally, an optimal workflow was described.
Results
Suggested optimal procedures and workflows are discussed in detail. The broad consensus was that the complex workflow presented can only be executed effectively by an interdisciplinary approach using a well-trained team.
Conclusions
To optimise diagnosis and treatment of patients with NSCLC, it is essential to establish SOPs that are adaptable to the local situation. In addition, a continuous QC system and a local multidisciplinary tumour-type-oriented board are essential.
doi:10.1136/thoraxjnl-2014-206677
PMCID: PMC4752623  PMID: 26530085
Non-Small Cell Lung Cancer; Histology/Cytology
10.  UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening 
Thorax  2015;71(2):161-170.
Background
Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial.
Methods
The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction.
Results
247 354 individuals aged 50–75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm3 or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm3 at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569).
Conclusions
The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective—this needs to be confirmed using data on observed lung cancer mortality reduction.
Trial registration
ISRCTN 78513845.
doi:10.1136/thoraxjnl-2015-207140
PMCID: PMC4752629  PMID: 26645413
Lung Cancer; Imaging/CT MRI etc
11.  Patient adherence in COPD 
Thorax  2008;63(9):831-838.
Patient adherence to treatment in chronic obstructive pulmonary disease (COPD) is essential to optimise disease management. As with other chronic diseases, poor adherence is common and results in increased rates of morbidity, healthcare expenditures, hospitalisations and possibly mortality, as well as unnecessary escalation of therapy and reduced quality of life. Examples include overuse, underuse, and alteration of schedule and doses of medication, continued smoking and lack of exercise. Adherence is affected by patients’ perception of their disease, type of treatment or medication, the quality of patient provider communication and the social environment. Patients are more likely to adhere to treatment when they believe it will improve disease management or control, or anticipate serious consequences related to non-adherence. Providers play a critical role in helping patients understand the nature of the disease, potential benefits of treatment, addressing concerns regarding potential adverse effects and events, and encouraging patients to develop self-management skills. For clinicians, it is important to explore patients’ beliefs and concerns about the safety and benefits of the treatment, as many patients harbour unspoken fears. Complex regimens and polytherapy also contribute to suboptimal adherence. This review addresses adherence related issues in COPD, assesses current efforts to improve adherence and highlights opportunities to improve adherence for both providers and patients.
doi:10.1136/thx.2007.086041
PMCID: PMC4747423  PMID: 18728206
12.  US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis 
Thorax  2015;71(Suppl 1):i1-i22.
Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition.
doi:10.1136/thoraxjnl-2015-207360
PMCID: PMC4717371  PMID: 26666259
Cystic Fibrosis; Bacterial Infection
13.  The molecular targets of approved treatments for pulmonary arterial hypertension 
Thorax  2015;71(1):73-83.
Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)—prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy.
doi:10.1136/thoraxjnl-2015-207170
PMCID: PMC4717417  PMID: 26219978
Primary Pulmonary Hypertension
14.  Research in progress—LungSEARCH: a randomised controlled trial of surveillance for the early detection of lung cancer in a high-risk group 
Thorax  2015;71(1):91-93.
Low-dose CT screening for lung cancer is effective but expensive. Therefore, cheaper or more focused screening strategies may be required. LungSEARCH is a randomised prospective trial of 1568 high-risk individuals (ie, current or former moderate to heavy smokers with mild/moderate COPD) who undergo either annual sputum cytology/cytometry testing or no screening. Those with abnormal sputum then receive annual CT and fluorescent bronchoscopy for the remainder of 5 years, to identify early stage lung cancer. It is hoped that these simple initial tests could identify those requiring expensive CT scans, and the aim is to demonstrate a stage shift towards early stage cancers.
Trial registration numbers ISRCTN: ISRCTN80745975, clinicaltrials.gov: NCT00512746.
doi:10.1136/thoraxjnl-2015-207433
PMCID: PMC4717418  PMID: 26138736
Lung Cancer
15.  Underweight as a risk factor for respiratory death in the Whitehall cohort study: exploring reverse causality using a 45-year follow-up 
Thorax  2015;71(1):84-85.
Underweight adults have higher rates of respiratory death than the normal weight but it is unclear whether this association is causal or reflects illness-induced weight loss (reverse causality). Evidence from a 45-year follow-up of underweight participants for respiratory mortality in the Whitehall study (N=18 823; 2139 respiratory deaths) suggests that excess risk among the underweight is attributable to reverse causality. The age-adjusted and smoking-adjusted risk was 1.55-fold (95% CI 1.32 to 1.83) higher among underweight compared with normal weight participants, but attenuated in a stepwise manner to 1.14 (95% CI 0.76 to 1.71) after serial exclusions of deaths during the first 5–35 years of follow-up (Ptrend<0.001).
doi:10.1136/thoraxjnl-2015-207449
PMCID: PMC4717419  PMID: 26253581
COPD epidemiology
16.  US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary 
Thorax  2016;71(1):88-90.
Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease, such as cystic fibrosis (CF). Pulmonary disease (PD) caused by NTM has emerged as a major threat to the health of individuals with CF, but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened a panel of 19 experts to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF. PICO (population, intervention, comparison, outcome) methodology and systematic literature reviews were employed to inform draft recommendations, which were then modified to achieve consensus and subsequently circulated for public consultation within the USA and European CF communities. We have thus generated a series of pragmatic, evidence-based recommendations as an initial step in optimising management for this challenging condition.
doi:10.1136/thoraxjnl-2015-207983
PMCID: PMC4717423  PMID: 26678435
Atypical Mycobacterial Infection; Cystic Fibrosis; Respiratory Infection
17.  Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress 
Thorax  2015;71(1):52-63.
Background
Sensitisation with Aspergillus fumigatus (Af) is known to be associated with severe allergic lung inflammation, but the mechanism remains to be clarified. Phosphoinositide 3-kinase (PI3K)-δ and endoplasmic reticulum (ER) stress are suggested to be involved in steroid-resistant lung inflammation. We aimed to elucidate the role of PI3K-δ and its relationship with ER stress in fungus-induced allergic lung inflammation.
Methods
Using Af-exposed in vivo and in vitro experimental systems, we examined whether PI3K-δ regulates ER stress, thereby contributing to steroid resistance in fungus-induced allergic lung inflammation. Moreover, we checked expression of an ER stress marker in lung tissues isolated from patients with allergic bronchopulmonary aspergillosis.
Results
Af-exposed mice showed that ER stress markers, unfolded protein response (UPR)-related proteins, phosphorylated Akt, generation of mitochondrial reactive oxygen species (mtROS), eosinophilic allergic inflammation, and airway hyperresponsiveness (AHR) were increased in the lung. Similarly, glucose-regulated protein 78 was increased in lung tissues of patients with ABPA. A PI3K-δ inhibitor reduced Af-induced increases in ER stress markers, UPR-related proteins, allergic inflammation and AHR in mice. However, dexamethasone failed to reduce Af-induced allergic inflammation, AHR and elevation of ER stress. Administration of an ER stress inhibitor or a mtROS scavenger improved Af-induced allergic inflammation. The PI3K-δ inhibitor reduced Af-induced mtROS generation and the mtROS scavenger ameliorated ER stress. In primary cultured tracheal epithelial cells, Af-induced ER stress was inhibited by blockade of PI3K-δ.
Conclusions
These findings suggest that PI3K-δ regulates Af-induced steroid-resistant eosinophilic allergic lung inflammation through ER stress.
doi:10.1136/thoraxjnl-2015-207096
PMCID: PMC4717427  PMID: 26543090
Allergic lung disease; Asthma Mechanisms; Aspergillus Lung Disease
18.  International Committee on Mental Health in Cystic Fibrosis: Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus statements for screening and treating depression and anxiety 
Thorax  2015;71(1):26-34.
Studies measuring psychological distress in individuals with cystic fibrosis (CF) have found high rates of both depression and anxiety. Psychological symptoms in both individuals with CF and parent caregivers have been associated with decreased lung function, lower body mass index, worse adherence, worse health-related quality of life, more frequent hospitalisations and increased healthcare costs. To identify and treat depression and anxiety in CF, the CF Foundation and the European CF Society invited a panel of experts, including physicians, psychologists, psychiatrists, nurses, social workers, a pharmacist, parents and an individual with CF, to develop consensus recommendations for clinical care. Over 18 months, this 22-member committee was divided into four workgroups: Screening; Psychological Interventions; Pharmacological Treatments and Implementation and Future Research, and used the Population, Intervention, Comparison, Outcome methodology to develop questions for literature search and review. Searches were conducted in PubMed, PsychINFO, ScienceDirect, Google Scholar, Psychiatry online and ABDATA by a methodologist at Dartmouth. The committee reviewed 344 articles, drafted statements and set an 80% acceptance for each recommendation statement as a consensus threshold prior to an anonymous voting process. Fifteen guideline recommendation statements for screening and treatment of depression and anxiety in individuals with CF and parent caregivers were finalised by vote. As these recommendations are implemented in CF centres internationally, the process of dissemination, implementation and resource provision should be closely monitored to assess barriers and concerns, validity and use.
doi:10.1136/thoraxjnl-2015-207488
PMCID: PMC4717439  PMID: 26452630
Cystic Fibrosis; Psychology
19.  Chronic Bronchitis Before Age 50 Years Predicts Incident Airflow Limitation and Mortality Risk 
Thorax  2009;64(10):894-900.
Background
Previous studies on the relation of chronic bronchitis to incident airflow limitation and all-cause mortality have provided conflicting results, with positive findings reported mainly by studies that included populations of young adults. We sought to determine whether having chronic cough and sputum production in the absence of airflow limitation is associated with onset of airflow limitation, all-cause mortality, and serum levels of CRP and IL-8, and whether subjects’ age influences these relations.
Methods
We identified 1412 participants in the long-term Tucson Epidemiological Study of Airway Obstructive Disease who at enrollment (1972–73) were 21–80 years old and had FEV1/FVC≥70% and no asthma. Chronic bronchitis was defined as cough and phlegm production on most days for ≥three months in ≥two consecutive years. Incidence of airflow limitation was defined as the first follow-up survey with FEV1/FVC<70%. Serum IL-8 and CRP levels were measured in cryopreserved samples from the enrollment survey.
Results
After adjusting for covariates, chronic bronchitis at enrollment increased significantly the risk for incident airflow limitation and all-cause mortality among subjects <50 years old (Hazard Ratios, 95% CI: 2.2, 1.3–3.8; and 2.2, 1.3–3.8; respectively), but not among subjects ≥50 years old (0.9, 0.6–1.4; and 1.0, 0.7–1.3). Chronic bronchitis was associated with increased IL-8 and CRP serum levels only among subjects <50 years old.
Conclusions
Among adults <50 years old, chronic bronchitis unaccompanied by airflow limitation may represent an early marker of susceptibility to the effects of cigarette smoking on systemic inflammation and long-term risk for chronic obstructive pulmonary disease and all-cause mortality.
doi:10.1136/thx.2008.110619
PMCID: PMC4706745  PMID: 19581277
All-cause mortality; chronic bronchitis; chronic obstructive pulmonary disease; CRP
20.  Combined effects of parental and active smoking on early lung function deficits: a prospective study from birth to age 26 years 
Thorax  2013;68(11):1021-1028.
Background
Cross-sectional reports have suggested that, among active smokers, previous exposure to parental smoking may increase susceptibility to development of chronic obstructive pulmonary disease. We assessed prospectively whether parental smoking enhances the effects of active smoking on early deficits of lung function in young adults.
Methods
We used data from the prospective birth cohort, the Tucson Children’s Respiratory Study. Maternal and paternal smoking was assessed via questionnaires completed by the parents at the time of the participant’s birth. Active smoking by participants was assessed via personal questionnaires completed at ages 16 (YR16), 22, and 26 years. Four groups were generated based on the combination of parental smoking at the time of child’s birth and active smoking reported at YR16, YR22, or YR26. Lung function parameters, including FEV1/FVC ratio, were assessed by spirometry before and after inhalation of 180 µg of albuterol at YR11, YR16, YR22, and YR26.
Results
Complete data were available for 519 participants. Pre-bronchodilator FEV1/FVC values did not differ at YR11, YR16, or YR22 by parental or active smoking. However, at YR26 participants with exposure to both parental and active smoking had pre-bronchodilator FEV1/FVC levels that were, on average 2.8% (0.9%–4.8%; p=0.003) lower than participants who were not exposed to either. In contrast, subjects who were only exposed to active smoking or only exposed to parental smoking did not differ from those who were not exposed to either. Between YR11 and YR26, participants with exposure to both parental and active smoking had the steepest decline in sex-, age-, and height-adjusted residuals of FEV1/FVC, FEV1, FEF25–75, and FEF25–75/FVC (all p values between 0.03 and <0.001).
Conclusions
Parental and active smoking act synergistically to affect early lung function deficits in young adulthood.
doi:10.1136/thoraxjnl-2013-203538
PMCID: PMC4706750  PMID: 23847259
smoking; environmental tobacco smoke; lung function; airflow limitation
21.  Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis 
Thorax  2014;70(1):48-56.
Background
There is microscopic spatial and temporal heterogeneity of pathologic changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in IPF patients.
Methods
Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterization and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of IPF patients (N=80).
Results
2940 genes were significantly differentially expressed between IPF and control samples (|fold change| > 1.5, p < 0.05). Two clusters of co-regulated genes related to bronchiolar epithelium or lymphoid aggregates exhibited substantial heterogeneity within the IPF population. Gene expression in bronchiolar and lymphoid clusters corresponded to the extent of bronchiolization and lymphoid aggregates determined by immunohistochemistry in adjacent tissue sections. Elevated serum levels of MMP3, encoded in the bronchiolar cluster, and CXCL13, encoded in the lymphoid cluster, corresponded to disease severity and shortened survival time (p < 10−7 for MMP3 and p < 10−5 for CXCL13; Cox proportional hazards model).
Conclusions
Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolization and lymphoid aggregates. MMP3 and CXCL13 are systemic biomarkers that reflect the aggregate burden of these pathological features across total lung tissue. These biomarkers may have clinical utility as prognostic and/or surrogate biomarkers of disease activity in interventional studies in IPF.
doi:10.1136/thoraxjnl-2013-204596
PMCID: PMC4472447  PMID: 25217476
MMP3; CXCL13; bronchiolization; lymphoid aggregates
22.  Using absolute risks to assess the risks and benefits of treatment 
Thorax  2014;69(7):604-605.
doi:10.1136/thoraxjnl-2014-205175
PMCID: PMC4686127  PMID: 24550059
23.  Clinical application of autologous technetium-99m-labelled eosinophils to detect focal eosinophilic inflammation in the lung 
Thorax  2015;70(11):1085-1086.
The detection of focal eosinophilic inflammation by non-invasive means may aid the diagnosis and follow-up of a variety of pulmonary pathologies. All current methods of detection involve invasive sampling, which may be contraindicated or too high-risk to be performed safely. The use of injected autologous technetium-99m (Tc-99m)-labelled eosinophils coupled to single-photon emission computed tomography (SPECT) has been demonstrated to localise eosinophilic inflammation in the lungs of a patient with antineutrophil cytoplasmic antibody-positive vasculitis. Here, we report on the utility of this technique to detect active eosinophilic inflammation in a patient with focal lung inflammation where a biopsy was contraindicated.
doi:10.1136/thoraxjnl-2015-207156
PMCID: PMC4680123  PMID: 26108571
Eosinophil Biology; Imaging/CT MRI etc; Pulmonary eosinophilia
24.  Achieving high treatment success for multidrug-resistant TB in Africa: initiation and scale-up of MDR TB care in Ethiopia—an observational cohort study 
Thorax  2015;70(12):1181-1188.
Background
In Africa, fewer than half of patients receiving therapy for multidrug-resistant TB (MDR TB) are successfully treated, with poor outcomes reported for HIV-coinfected patients.
Methods
A standardised second-line drug (SLD) regimen was used in a non-governmental organisation–Ministry of Health (NGO-MOH) collaborative community and hospital-based programme in Ethiopia that included intensive side effect monitoring, adherence strategies and nutritional supplementation. Clinical outcomes for patients with at least 24 months of follow-up were reviewed and predictors of treatment failure or death were evaluated by Cox proportional hazards models.
Results
From February 2009 to December 2014, 1044 patients were initiated on SLD. 612 patients with confirmed or presumed MDR TB had ≥24 months of follow-up, 551 (90.0%) were confirmed and 61 (10.0%) were suspected MDR TB cases. 603 (98.5%) had prior TB treatment, 133 (21.7%) were HIV coinfected and median body mass index (BMI) was 16.6. Composite treatment success was 78.6% with 396 (64.7%) cured, 85 (13.9%) who completed treatment, 10 (1.6%) who failed, 85 (13.9%) who died and 36 (5.9%) who were lost to follow-up. HIV coinfection (adjusted HR (AHR): 2.60, p<0.001), BMI (AHR 0.88/kg/m2, p=0.006) and cor pulmonale (AHR 3.61, p=0.003) and confirmed MDR TB (AHR 0.50, p=0.026) were predictive of treatment failure or death.
Conclusions
We report from Ethiopia the highest MDR TB treatment success outcomes so far achieved in Africa, in a setting with severe resource constraints and patients with advanced disease. Intensive treatment of adverse effects, nutritional supplementation, adherence interventions and NGO-MOH collaboration were key strategies contributing to success. We argue these approaches should be routinely incorporated into programmes.
doi:10.1136/thoraxjnl-2015-207374
PMCID: PMC4680185  PMID: 26506854
Tuberculosis
25.  Neural respiratory drive predicts clinical deterioration and safe discharge in exacerbations of COPD 
Thorax  2015;70(12):1123-1130.
Rationale
Hospitalised patients with acute exacerbation of COPD may deteriorate despite treatment, with early readmission being common.
Objectives
To investigate whether neural respiratory drive, measured using second intercostal space parasternal muscle electromyography (EMGpara), would identify worsening dyspnoea and physician-defined inpatient clinical deterioration, and predict early readmission.
Methods
Patients admitted to a single-site university hospital with exacerbation of COPD were enrolled. Spirometry, inspiratory capacity (IC), EMGpara, routine physiological parameters, modified early warning score (MEWS), modified Borg scale for dyspnoea and physician-defined episodes of deterioration were recorded daily until discharge. Readmissions at 14 and 28 days post discharge were recorded.
Measurements and main results
120 patients were recruited (age 70±9 years, forced expiratory volume in 1 s (FEV1) of 30.5±11.2%). Worsening dyspnoea, defined as at least one-point increase in Borg scale, was associated with increases in EMGpara%max and MEWS, whereas an increase in EMGpara%max alone was associated with physician-defined inpatient clinical deterioration. Admission-to-discharge change (Δ) in the normalised value of EMGpara (ΔEMGpara%max) was inversely correlated with ΔFEV1 (r=−0.38, p<0.001) and ΔIC (r=−0.44, p<0.001). ΔEMGpara%max predicted 14-day readmission (OR 1.13, 95% 1.03 to 1.23) in the whole cohort and 28-day readmission in patients under 85 years (OR 1.09, 95% CI 1.01 to 1.18). Age (OR 1.08, 95% CI 1.03 to 1.14) and 12-month admission frequency (OR 1.29, 1.01 to 1.66), also predicted 28-day readmission in the whole cohort.
Conclusions
Measurement of neural respiratory drive by EMGpara represents a novel physiological biomarker that may be helpful in detecting inpatient clinical deterioration and identifying the risk of early readmission among patients with exacerbations of COPD.
Trial registration
NCT01361451.
doi:10.1136/thoraxjnl-2015-207188
PMCID: PMC4680187  PMID: 26194996
COPD Exacerbations; Respiratory Muscles; Lung Physiology

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