To compare strategies for COPD case-finding using data from the Burden of Obstructive Lung Disease (BOLD) study.
Population-based samples of adults aged ≥40 years (n= 9390) from 14 countries completed a questionnaire and spirometry. We compared the screening efficiency of different staged algorithms that used questionnaire data and/or PEF to identify persons at risk for COPD and hence needing confirmatory spirometry. Separate algorithms were fitted for moderate/severe COPD and for severe COPD. We estimated the cost of each algorithm in 1000 people.
For moderate/severe COPD, use of questionnaire data alone permitted high sensitivity (97%), but required confirmatory spirometry on 80% of participants. Use of PEF only required confirmatory spirometry in only 19-22% of subjects with 83-84% sensitivity. For severe COPD, use of PEF achieved 91-93% sensitivity, requiring confirmatory spirometry in <9% of participants. Cost analysis suggested that a staged screening algorithm using only PEF initially, followed by confirmatory spirometry as needed, was the most cost-effective case finding strategy.
Our results support the use of PEF as a simple, cost-effective initial screening tool for conducting COPD case-finding in adults ≥40 years. These findings should be validated in real-world settings such as the primary care environment.
Adult; Chronic Obstructive Pulmonary Disease; Peak Expiratory Flow; questionnaire; screening; epidemiology
Clinical algorithms for evaluating HIV-infected individuals for tuberculosis (TB) prior to isoniazid preventive therapy (IPT) perform poorly, and interferon-γ release assays (IGRAs) have moderate accuracy for active TB. It is unclear whether, when used as adjunct tests, IGRAs add any clinical discriminatory value for active TB diagnosis in the pre-IPT assessment.
779 sputum smear-negative HIV-infected persons, established on or about to commence combined antiretroviral therapy (ART), were screened for TB prior to IPT. Stepwise multivariable logistic regression was used to develop clinical prediction models. The discriminatory ability was assessed by receiver operator characteristic area under the curve (AUC). QuantiFERON®-TB Gold in-tube (QFT-GIT) was evaluated.
The prevalence of smear-negative TB by culture was 6.4% (95% CI 4.9–8.4%). Used alone, QFT-GIT and the tuberculin skin test (TST) had comparable performance; the post-test probability of disease based on single negative tests was 3–4%. In a multivariable model, the QFT-GIT test did not improve the ability of a clinical algorithm, which included not taking ART, weight <60 kg, no prior history of TB, any one positive TB symptom/sign (cough ≥2 weeks) and CD4+ count <250 cells per mm3, to discriminate smear-negative culture-positive and -negative TB (72% to 74%; AUC comparison p=0.33). The TST marginally improved the discriminatory ability of the clinical model (to 77%, AUC comparison p=0.04).
QFT-GIT does not improve the discriminatory ability of current TB screening clinical algorithms used to evaluate HIV-infected individuals for TB ahead of preventive therapy. Evaluation of new TB diagnostics for clinical relevance should follow a multivariable process that goes beyond test accuracy.
Diagnostic research; HIV; incremental value; interferon-γ release assay; Mycobacterium tuberculosis; QuantiFERON®-TB Gold in-tube
Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not only reflects the major clinical and pathological features but also enables investigation into ALI resolution.
Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time points, lung injury was assessed by blood gases, respiratory mechanics, analysis of bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology.
Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance, and pulmonary inflammation (intra-alveolar leucocyte influx/ cytokine levels and histological injury scores). Moreover, mice displayed alveolar-capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble Receptor for Advanced Glycation End-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1-3, followed by almost complete recovery over days 5-10. Histology showed evidence of fibrosis at day 10.
The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.
Acid aspiration; Acute respiratory distress syndrome; Alveolar epithelium; Alveolar fluid clearance; Inflammation; Pulmonary oedema
The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement predicted mortality in idiopathic pulmonary fibrosis.
We examined 104 adults with idiopathic pulmonary fibrosis enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases. The titrated oxygen requirement was defined as the lowest oxygen flow rate required to maintain an oxyhemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time.
A higher titrated oxygen requirement was associated with a greater mortality rate independent of forced vital capacity and six-minute walk test results in idiopathic pulmonary fibrosis (adjusted hazard ratio per 1 L/min = 1.10, 95% confidence interval 1.01 to 1.20). The titrated oxygen requirement was at least as accurate as pulmonary function and six-minute walk testing at predicting 1-year mortality. Findings were similar in other interstitial lung diseases.
The titrated oxygen requirement is a simple, inexpensive bedside measurement that aids prognostication in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis; Interstitial lung diseases; Outcome prediction; Pulmonary fibrosis; Pulmonary gas exchange
Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.
We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB.
After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies.
Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.
Contact tracing; early diagnosis; human; Mycobacterium tuberculosis; systematic review; tuberculosis
Pre-eclamptic toxaemia (PET) may be associated with both endothelial dysfunction (ED) and sleep-disordered breathing (SDB). It was hypothesised that females with PET would demonstrate both SDB and ED, and that a correlation between these two would suggest a potential causative association.
A total of 17 females with PET and 25 matched females with uncomplicated pregnancy were studied. They underwent a nocturnal ambulatory sleep study (using Watch_PAT100) and noninvasive evaluation of endothelial function utilising the reactive hyperaemia test (using Endo_PAT 2000). A higher ratio of post- to pre-occlusion pulse-wave amplitude (endothelial function index (EFI)) indicated better endothelial function.
Females with PET had a significantly higher respiratory disturbance index (RDI) and lower EFI than controls (18.4±8.4 versus 8.3±1.3·h−1, and 1.5±0.1 versus 1.8±0.1, respectively). Blood pressure significantly correlated with RDI and with EFI. EFI tended to correlate with RDI.
In conclusion, these results suggest that both sleep-disordered breathing and endothelial dysfunction are more likely to occur in females with pre-eclamptic toxaemia than in females with uncomplicated pregnancies. The current authors speculate that respiratory disturbances contribute to the functional abnormality of the blood vessels seen in females with pre-eclamptic toxaemia, although causality cannot be determined based on this study.
Endothelial dysfunction; hypertension; pre-eclampsia; sleep-disordered breathing
We hypothesised that pentobarbital would improve upper airway mechanics based on an increase in latency to arousal and amplitude of the phasic genioglossus electromyogram (EMG), and a decrease in the active upper airway critical closing pressure (Pcrit).
12 healthy subjects received pentobarbital (100 mg) or placebo in a double-blind, crossover protocol. During wakefulness, we measured the genioglossus reflex response to negative pressure pulses. During sleep, carbon dioxide was insufflated into the inspired air. Airway pressure was then decreased in a stepwise fashion until arousal from sleep.
With basal breathing during sleep: flow rate was lower in volunteers given pentobarbital; end-tidal CO2 concentration and upper airway resistance were greater; and Pcrit was unaffected (pentobarbital mean±sd -11.7±4.5 versus placebo -10.25±3.6 cmH2O; p=0.11). Pentobarbital increased the time to arousal (297±63s versus 232±67 s; p<0.05), at which time phasic genioglossus EMG was higher (6.2±4.8% maximal versus 3.1±3%; p<0.05) as were CO2 levels. The increase in genioglossus EMG after CO2 administration was greater after pentobarbital versus placebo. Pentobarbital did not affect the genioglossus negative-pressure reflex.
Pentobarbital increases the time to arousal and stimulates genioglossus muscle activity, but it also increases upper airway resistance during sleep.
Airway; arousal threshold; lung; obstructive sleep apnoea/hypopnoea syndrome; sleep-disordered breathing
This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction (FeNO) and no bronchodilator responsiveness (BDR <12%)) is uncommon in paediatric DA.
We report on 102 children, mean±SD age 11.6±2.8 yrs, with DA in a cross-sectional study. 89 children underwent spirometry, BDR and FeNO before and after 2 weeks of systemic corticosteroids (corticosteroid response study). Bronchoscopy was performed after the corticosteroid trial.
Of the 102 patients in the cross-sectional study, 88 (86%) were atopic, 60 (59%) were male and 52 (51%) had additional or alternative diagnoses. Out of the 81 patients in the corticosteroid response study, nine (11%) were complete responders. Of the 75 patients with symptom data available, 37 (49%) responded symptomatically, which was less likely if there were smokers in the home (OR 0.31, 95% CI 0.02–0.82). Of the 75 patients with available spirometry data, 35 (46%) had normal spirometry, with associations being BAL eosinophilia (OR 5.43, 95% CI 1.13–26.07) and high baseline forced expiratory volume in 1 s (FEV1) (OR 1.08, 95% CI 1.02–1.12). Of these 75 patients, BDR data were available in 64, of whom 36 (56%) had <12% BDR. FeNO data was available in 70 patients, of whom 53 (75%) had normal FeNO. Airflow limitation data was available in 75 patients, of whom 17 (26%) had persistent airflow limitation, which was associated with low baseline FEV1 (OR 0.93, 95% CI 0.90–0.97).
Only 11% of DA children exhibited complete corticosteroid responsiveness. The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with DA.
Corticosteroid responsiveness; difficult asthma; eosinophil; nitric oxide; paediatric asthma
Pseudomonas aeruginosa chronically infects patients with cystic fibrosis and is associated with greater morbidity. There has been limited progress on the clinical development of new antibiotics with novel modes of action. This review addresses some of the latest research developments on the exploitation of candidate adjuvant therapeutic agents that may act alongside conventional antibiotics as an alternative therapeutic strategy. After considering key mechanisms this opportunistic pathogen employs to control virulence, the progress of various strategies including the inhibition of quorum sensing, efflux pumps and lectins, as well as the use of iron chelators, bacteriophages, immunisation and immunotherapy is reviewed. Both, therapeutic approaches in early development and clinical phase are discussed.
Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses.
Wildtype mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1+/− and ROCK2+/− respectively) were sensitized and challenged with ovalbumin. ROCK expression and activation were assessed by Western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment.
Compared to wildtype mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1+/− and ROCK2+/− mice, respectively, without changes in the other isoform. In wildtype lungs, ROCK activation increased after ovalbumin challenge, was sustained for several hours, and was reduced in ROCK1+/− and ROCK2+/− lungs. Airway responsiveness was comparable in wildtype, ROCK1+/−, and ROCK2+/− mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in wildtype, but not ROCK1+/− or ROCK2+/− mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1+/− and ROCK2+/− versus wildtype mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5, and lymphocytes were also reduced in ROCK1+/− mice.
Both ROCK1 and ROCK2 are important in regulating allergic airway responses.
airway hyperresponsiveness; eosinophils; goblet cell hyperplasia; interleukin-13; interleukin-5
Studies systematically comparing the performance of health-related quality-of-life (HRQL) instruments in pulmonary arterial hypertension (PAH) are lacking. We sought to address this gap by comparing cardiac and respiratory-specific measures of HRQL in PAH.
We prospectively assessed HRQL in 128 patients with catheterization-confirmed PAH at baseline and at 6, 12, and 24+ months. Cardiac-specific HRQL was assessed using the Minnesota Living with Heart Failure Questionnaire (LHFQ); respiratory-specific HRQL using the Airways Questionnaire 20 (AQ20); and general health status using the 36-item Short Form physical component summary (SF-36 PCS).
The LHFQ and AQ20 were highly intercorrelated. Both demonstrated strong internal consistency and converged with the SF-36 PCS. Both discriminated among patients based on World Health Organization functional class (FC), 6-minute walk distance (6MWD), and Borg Dyspnea Index (BDI), except for a potential floor effect associated with low 6MWD. The LHFQ was more responsive than the AQ20 to changes over time in FC, 6MWD, and BDI. In multivariate analyses, the LHFQ and AQ20 were each longitudinal predictors of general health status, independent of FC, 6MWD and BDI.
In conclusion, both cardiac-specific and respiratory-specific measures appropriately assess HRQL in most patients with PAH. Overall, the LHFQ demonstrates stronger performance characteristics than the AQ20.
pulmonary hypertension; quality of life
Selective leukocyte trafficking and recruitment is primarily regulated by a specific family of small proteins called “chemokines”. This extended family shepherds and guides leukocytes through their lives, facilitating their development, regulating their interactions with other leukocyte types, and guiding their recruitment to sites of inflammation.
Through the actions of chemokines, allergen sensitization is regulated in atopic asthma, through the controlled migration of dendritic cells, T- and B-lymphocytes, mast cells and basophils. Subsequently, atopic inflammation is driven by chemokine-directed recruitment of eosinophils, basophils and lymphocytes. Diseases from cancer to chronic obstructive pulmonary disease to interstitial fibrosis are all potential targets for chemokine receptor antagonism.
Innate immunity (the early pattern-recognition responses to stimuli such as lipopolysaccharide, viral proteins and bacterial DNA) needs to bridge the gap to specific immunity and antibody production and immunological memory. Again, chemokines are likely to be fundamental mediators of these responses.
Chemokines are fundamental regulators of leukocyte homeostasis and inflammation, and their antagonism by small molecule chemokine receptor antagonists may be of enormous importance in the future treatment of human respiratory disease.
Allergy; asthma; chemokines; immunoresponse; inflammation
The glutathione S-transferase (GST) enzymes catalyze the conjugation of xenobiotics to glutathione. Based on reports that inherited copy number variations (CNV) modulate some GST gene expression levels, and that the small airway epithelium (SAE) and alveolar macrophages (AM) are involved early in the pathogenesis of smoking-induced lung disease, we asked: do germline CNVs modulate GST expression levels in SAE and AM?
Microarrays were used to survey GST gene expression in SAE and AM obtained by bronchoscopy from current smokers and nonsmokers, and to determine CNV genotypes.
Twenty six % of subjects were null for both GSTM1 alleles, with reduced GSTM1 mRNA levels seen in both SAE and AM. Thirty % of subjects had homozygous deletions of GSTT1 with reduced mRNA levels in both tissues. Interestingly, GSTT2B, exhibited homozygous deletion in blood in 27% of subjects and was not expressed in SAE in the remainder of subjects but was expressed in AM of heterozygotes and wild type subjects, proportionate to genotype.
These data show a germline CNV-mediated linear relationship of genotype to expression level suggesting minimal compensation of gene expression levels in heterozygotes consistent with GST polymorphisms playing a role in the risk of smoking-associated xenobiotic-induced lung disease.
The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB).
The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting.
A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed.
These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.
European Respiratory Society; European Union Standards; guidelines; MDR-TB; TB
Airway remodelling is associated with chronic asthma but it remains unclear whether it results from airway inflammation in response to allergens or immune-mediated events such as viral infections. Although the acute inflammation associated with asthma has been modelled extensively both in vitro and in vivo, the structural changes occurring in the lung have only recently been investigated. These in vitro, in vivo and in silico systems have been designed to examine the pathways leading to allergen-induced airway remodelling and have enabled investigators to draw conclusions about the participation of key cells and molecules in the development of allergen-induced airway remodelling. However, fundamental questions remain regarding the genesis of remodelling as well as the relationship between functional symptoms and pathological changes that occur. In this review the key questions relating allergen exposure to development of remodelling are discussed, as well as the steps that are being undertaken to investigate them.
Airway function; airway remodelling; asthma; eosinophils; inflammation
Chronic obstructive pulmonary disease (COPD) is predicted to become the third commonest cause of death and disability worldwide by 2020.
The prevalence of COPD defined by the lower limit of normal was estimated using high quality spirometry in surveys of 14 populations aged 40 years and over. The strength and consistency of associations were assessed using random effects meta-analysis.
Pack-years of smoking were associated with risk of COPD at each site. After adjusting for this effect, we still observed significant associations of COPD risk with age (Odds Ratio (OR): 1.52/10 years (95%CI: 1.35,1.71), body mass index (OR: 0.50 in obese compared with normal weight (95%CI: 0.37, 0.67)), level of education (OR: 0.76/stage of education completed (95%CI: 0.67, 0.87)), hospitalisation with a respiratory problem before age 10 years (OR: 2.35 (95%CI: 1.42, 3.91)), passive cigarette smoke exposure (OR: 1.24 (95%CI: 1.05, 1.47)), tuberculosis (OR: 1.78 (95%CI: 1.17, 2.72)), and a family history of COPD (OR: 1.50 (95%CI: 1.159, 1.90)).
Although smoking is the most important risk factor for COPD, other risk factors are also important. More research is required to elucidate relevant risk factors in low and middle-income countries where the greatest impact of COPD will occur.
The status of stressful life events as a risk factor for asthma is unclear and may be dependent on pre-existing allergic rhinitis. This study examined whether exposure to stressful life events predicted the onset of asthma in adults.
This is a prospective, population-based cohort study of 16,881 men and women, aged 20–54 and free of diagnosed asthma at the beginning of the follow-up (January 1, 2004). Data about stressful life events were gathered with a postal survey. The onset of asthma was ascertained through national registers until December 31, 2005.
During the follow-up period, 192 incident cases of asthma were identified. High total exposure to stressful life events, as indicated by a cumulative severity score, predicted the onset of asthma (HR 1.96; 95% CI 1.22–3.13). This association was robust to adjustment for demographics, smoking, and having a cat/dog at home, and it was observed both among those with and without allergic rhinitis at the baseline. Of the 10 most stressful life events, the illness of a family member, marital problems, divorce or separation, and conflicts with a supervisor were associated with the onset of asthma.
Our study suggests that stressful life events may increase the onset of asthma.
asthma; asthma epidemiology; asthma onset; stressful life events
Although radon gas is a known cause of lung cancer, the association between residential radon and mortality from non-malignant respiratory disease has not been well characterised.
The Cancer Prevention Study-II is a large prospective cohort study of nearly 1.2 million Americans recruited in 1982. Mean county-level residential radon concentrations were linked to study participants' residential address based on their ZIP code at enrolment (mean±sd 53.5±38.0 Bq·m−3). Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for non-malignant respiratory disease mortality associated with radon concentrations. After necessary exclusions, a total of 811,961 participants in 2,754 counties were included in the analysis.
Throughout 2006, there were a total of 28,300 non-malignant respiratory disease deaths. Radon was significantly associated with chronic obstructive pulmonary disease (COPD) mortality (HR per 100 Bq·m−3 1.13, 95% CI 1.05–1.21). There was a significant positive linear trend in COPD mortality with increasing categories of radon concentrations (p<0.05).
Findings suggest residential radon may increase COPD mortality. Further research is needed to confirm this finding and to better understand possible complex inter-relationships between radon, COPD and lung cancer.
Chronic obstructive pulmonary disease; cohort study; radon; USA
A new and potentially more pathogenic group of human rhinoviruses (HRV), group C (HRVC) has recently been discovered. We hypothesised that HRVC would be present in children with acute asthma and cause more severe attacks than other viruses or HRV groups.
Children with acute asthma (n=128, 2–16 years) were recruited on presentation to an emergency department. Asthma exacerbation severity was assessed and respiratory viruses and HRV strains were identified in a nasal aspirate.
The majority of the children studied had moderate to severe asthma (85.2%) and 98.9% were admitted to hospital. HRV was detected in 87.5% and other respiratory viruses in 14.8% of children, most of whom also had HRV. HRVC were present in the majority of children with acute asthma (59.4%) and associated with more severe asthma. Children with HRVC (n=76) had higher asthma severity scores than children whose HRV infection was HRVA or HRVB only (n=34, p=0.018), and all other children (n=50, p=0.016). Of 19 children with a non-HRV virus, 13 had HRV co-infections, seven of these being HRVC.
HRVC accounts for the majority of asthma attacks in children presenting to hospital and causes more severe attacks than previously-known HRV groups and other viruses.
Acute asthma; Children; Exacerbation severity; Human rhinovirus C; Rhinovirus
The Burden of Obstructive Lung Disease (BOLD) initiative provides standardised estimates of the burden of chronic obstructive pulmonary disease (COPD) worldwide. We estimate the current and future economic burden of COPD in Reykjavik, Iceland and Bergen, Norway using data from the BOLD initiative.
Data on utilisation of healthcare resources were gathered from the BOLD survey, existing literature and unit costs from national sources. Economic data were applied to a Markov model using transition probabilities derived from Framingham data. Sensitivity analyses were conducted varying unit costs, utilisation and prevalence of disease.
The cost of COPD was €478 per patient per yr in Iceland and €284 per patient per yr in Norway. The estimated cumulative costs of COPD for the population aged ≥40 yrs, were €130 million and €1,539 million for the following 10 yrs in Iceland and Norway, respectively. Costs of COPD accounted for 1.2 and 0.7% of healthcare budgets in Iceland and Norway, respectively. Sensitivity analyses showed estimates were most sensitive to changes in exacerbation frequency.
COPD has a significant economic burden in both Iceland and Norway and will grow in the future. Interventions aimed at avoiding exacerbations will have the most impact on costs of COPD over the next 20 yrs.
Chronic obstructive pulmonary disease; computer simulation; cost of illness; disease progression; Iceland; Markov chains; Norway
Published guidelines recommend spirometry to accurately diagnose chronic obstructive pulmonary disease (COPD). However, even spirometry-based COPD prevalence estimates can vary widely. We compared properties of several spirometry-based COPD definitions using data from the international Burden of Obstructive Lung Disease (BOLD)study.
14 sites recruited population-based samples of adults aged ≥40 yrs. Procedures included standardised questionnaires and post-bronchodilator spirometry. 10,001 individuals provided usable data.
Use of the lower limit of normal (LLN) forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio reduced the age-related increases in COPD prevalence that are seen among healthy never-smokers when using the fixed ratio criterion (FEV1/FVC <0.7) recommended by the Global Initiative for Chronic Obstructive Lung Disease. The added requirement of an FEV1 either <80% predicted or below the LLN further reduced age-related increases and also led to the least site-to-site variability in prevalence estimates after adjusting for potential confounders. Use of the FEV1/FEV6 ratio in place of the FEV1/FVC yielded similar prevalence estimates.
Use of the FEV1/FVC
Adult; chronic obstructive pulmonary disease; epidemiology
We determined the role of p38 mitogen-activated protein kinase (MAPK) in the increased airway smooth muscle (ASM) contractile responses following ozone and modulation by corticosteroids.
Mice were exposed to air or ozone (3 ppm for 3 h) and isometric contractile responses of bronchial rings to acetylcholine (ACh) were measured using a myograph in the presence of p38 MAPK inhibitor, SB239063 (10−6 M) or dexamethasone (10−6 M). Because MAPK phosphatase (MKP)-1 is a negative regulator of p38 MAPK, we also studied these effects in MKP-1-/- mice.
Bronchial rings from ozone-exposed wild-type and MKP-1-/- mice showed increased contractile responses, with a leftward shift of the dose–response curve in MKP-1-/- mice. SB239063 inhibited bronchial contraction equally in air- and ozone-exposed C57/BL6 and MKP-1-/- mice. Dexamethasone inhibited ACh-induced bronchial contraction in both air- and ozone-exposed C57/BL6 mice, but not in air- or ozone-exposed MKP-1-/- mice. ACh-stimulated p38 MAPK and heat shock protein (HSP)27 phosphorylation, as measured by Western blotting, and this effect was suppressed by SB239063 in C57/BL6 and MKP-1-/- mice, but not by dexamethasone in either air- or ozone-exposed MKP-1-/- mice.
p38 MAPK plays a role in maximal ACh-induced isometric contractile responses and increased contractility induced by ozone. Dexamethasone inhibits ACh-induced ASM contraction through phosphorylation of p38 MAPK and HSP27.
Acetylcholine; airway smooth muscle; dexamethasone; heat shock protein 27; p38 mitogen-activated protein kinase; mitogen-activated protein kinase phosphatase-1
Chronic inflammation is an important component of the fibroproliferative changes that characterise pulmonary hypertensive vasculopathy. Fibrocytes contribute to tissue remodelling in settings of chronic inflammation, including animal models of pulmonary hypertension (PH). We sought to determine whether circulating fibrocytes were increased in children and young adults with PH.
26 individuals with PH and 10 with normal cardiac anatomy were studied. Fresh blood was analysed by flow cytometry for fibrocytes expressing CD45 and procollagen. Fibrocyte numbers were correlated to clinical and haemodynamic parameters, and circulating CC chemokine ligand (CCL)2 and CXC chemokine ligand (CXCL)12 levels.
We found an enrichment of circulating fibrocytes among those with PH. No differences in fibrocytes were observed among those with idiopathic versus secondary PH. Higher fibrocytes correlated to increasing mean pulmonary artery pressure and age, but not to length or type of treatment. Immunofluorescence analysis confirmed flow sorting specificity. Differences in plasma levels of CCL2 or CXCL12, which could mobilise fibrocytes from the bone marrow, were not found.
We conclude that circulating fibrocytes are significantly increased in individuals with PH compared with controls. We speculate that these cells might play important roles in vascular remodelling in children and young adults with pulmonary hypertension.
Fluorescence-activated cell sorting; inflammation; mononuclear phagocyte; progenitor cells; vascular remodelling
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