Although chronic obstructive pulmonary disease (COPD) is a major global health burden there is a lack of patient awareness of disease severity, particularly in relation to exacerbations.
We conducted a global patient survey using an innovative, internet-based methodology to gain insight into patient perceptions of COPD and exacerbations in a real-world sample typical of today’s working-age COPD population.
Two thousand patients with COPD (53%), chronic bronchitis (52%) and/or emphysema (22%) from 14 countries completed an online questionnaire developed by the authors. The Medical Research Council (MRC) breathlessness scale was used to delineate symptom severity. Over three quarters of patients (77%) had experienced an exacerbation, with 27% of MRC 1 and 2 patients and 52% of MRC 3, 4 and 5 patients requiring hospitalization as a result of an exacerbation. While a majority of MRC 1 and 2 patients (51%) reported being back to normal within a few days of an exacerbation, 23% of MRC 3, 4 and 5 patients took several weeks to return to normal and 6% never fully recovered. A high proportion of patients (39%) took a ‘wait and see’ approach to exacerbations.
Despite the high prevalence of exacerbations and their negative impact on quality of life, 73% of MRC 1 and 2 patients and 64% of MRC 3, 4 and 5 patients felt that they had control of their COPD. However, 77% of all patients were worried about their long-term health, and 38% of MRC 1 and 2 patients and 59% of MRC 3, 4 and 5 patients feared premature death due to COPD.
To reduce the adverse effects of COPD on patients’ quality of life and address their fears for the future, we need better patient education and improved prevention and treatment of exacerbations.
COPD; Exacerbation; Patient-reported; Survey
Recent studies suggest that the incidence of idiopathic pulmonary fibrosis (IPF) is rising. Accurate epidemiological data on IPF, however, are sparse and the results of previous studies are contradictory. This study was undertaken to gain insight into the various methods used in the epidemiological research of IPF, and to get accurate and comparable data on these different methodologies.
A systematic database search was performed in order to identify all epidemiological studies on IPF after the previous guidelines for diagnosis and treatment were published in 2000. Medline (via Pubmed), Science Sitation Index (via Web of Science) and Embase databases were searched for original epidemiological articles published in English in international peer-reviewed journals starting from 2001. After pre-screening and a full-text review, 13 articles were accepted for data abstraction.
Three different methodologies of epidemiological studies were most commonly used, namely: 1) national registry databases, 2) questionnaire-based studies, and 3) analysis of the health care system’s own registry databases. The overall prevalence and incidence of IPF varied in these studies between 0.5–27.9/100,000 and 0.22–8.8/100,000, respectively. According to four studies the mortality and incidence of IPF are rising.
We conclude that there are numerous ways to execute epidemiological research in the field of IPF. This review offers the possibility to compare the different methodologies that have been used, and this information could form a basis for future studies investigating the prevalence and incidence of IPF.
Interstitial lung disease; Incidence; Prevalence; Mortality; Register
The importance of the lung parenchyma in the pathophysiology of asthma has previously been demonstrated. Considering that nitric oxide synthases (NOS) and arginases compete for the same substrate, it is worthwhile to elucidate the effects of complex NOS-arginase dysfunction in the pathophysiology of asthma, particularly, related to distal lung tissue. We evaluated the effects of arginase and iNOS inhibition on distal lung mechanics and oxidative stress pathway activation in a model of chronic pulmonary allergic inflammation in guinea pigs.
Guinea pigs were exposed to repeated ovalbumin inhalations (twice a week for 4 weeks). The animals received 1400 W (an iNOS-specific inhibitor) for 4 days beginning at the last inhalation. Afterwards, the animals were anesthetized and exsanguinated; then, a slice of the distal lung was evaluated by oscillatory mechanics, and an arginase inhibitor (nor-NOHA) or vehicle was infused in a Krebs solution bath. Tissue resistance (Rt) and elastance (Et) were assessed before and after ovalbumin challenge (0.1%), and lung strips were submitted to histopathological studies.
Ovalbumin-exposed animals presented an increase in the maximal Rt and Et responses after antigen challenge (p<0.001), in the number of iNOS positive cells (p<0.001) and in the expression of arginase 2, 8-isoprostane and NF-kB (p<0.001) in distal lung tissue. The 1400 W administration reduced all these responses (p<0.001) in alveolar septa. Ovalbumin-exposed animals that received nor-NOHA had a reduction of Rt, Et after antigen challenge, iNOS positive cells and 8-isoprostane and NF-kB (p<0.001) in lung tissue. The activity of arginase 2 was reduced only in the groups treated with nor-NOHA (p <0.05). There was a reduction of 8-isoprostane expression in OVA-NOR-W compared to OVA-NOR (p<0.001).
In this experimental model, increased arginase content and iNOS-positive cells were associated with the constriction of distal lung parenchyma. This functional alteration may be due to a high expression of 8-isoprostane, which had a procontractile effect. The mechanism involved in this response is likely related to the modulation of NF-kB expression, which contributed to the activation of the arginase and iNOS pathways. The association of both inhibitors potentiated the reduction of 8-isoprostane expression in this animal model.
Lung parenchyma; Arginase; iNOS; Nitric oxide; Guinea-pig; nor-NOHA; Oxidative stress
Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough and a potential risk factor for exacerbation of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the prevalence and risk factors of GERD in patients with COPD and association between GERD and COPD exacerbation.
Data were collected from the National Health Insurance Database of Korea. The subjects were 40 years old and older, who had COPD as primary or secondary diagnosis codes and utilized health care resource to receive prescriptions of COPD medication at least twice in 2009. Univariate logistic regression was performed to understand the relationship between COPD and GERD, and multiple logistic regression analysis was performed with adjustment for several confounding factors.
The prevalence of GERD in COPD patients was 28% (39,987/141,057). Old age, female gender, medical aid insurance type, hospitalization, and emergency room (ER) visit were associated with GERD. Most of COPD medications except inhaled muscarinic antagonists were associated with GERD. The logistic regression analysis showed that the presence of GERD was associated with increased risk of hospitalization (OR 1.54, CI 1.50 to 1.58, p<0.001) and frequent ER visits (OR 1.55, CI 1.48 to 1.62, p<0.001).
The prevalence of GERD in patients with COPD was high. Old age, female gender, medical aid insurance type, and many COPD medications except inhaled muscarinic antagonists were associated with GERD. The presence of GERD was associated with COPD exacerbation.
Gastroesophageal reflux; Obstructive lung disease; Prevalence; Exacerbation; Anticholinergic
The six-minute walk test (6MWT) is a simple, low tech, safe and well established, self-paced assessment tool to quantify functional exercise capacity in adults. The definition of normal 6MWT in children is especially demanding since not only parameters like height, weight and ethnical background influence the measurement, but may be as crucial as age and the developmental stage. The aim of this study is establishing reference values for the 6MWT in healthy children and adolescents in Switzerland and to investigate the influence of age, anthropometrics, heart rate, blood pressure and physical activity on the distance walked.
Children and adolescents between 5–17 years performed a 6MWT. Short questionnaire assessments about their health state and physical activities. anthropometrics and vitals were measured before and after a 6-minute walk test and were previously defined as secondary outcomes.
Age, height, weight and the heart rate after the 6MWT all predicted the distance walked according to different regression models: age was the best single predictor and mostly influenced walk distance in younger age, anthropometrics were more important in adolescents and females. Heart rate after the 6MWT was an important distance predictor in addition to age and outreached anthropometrics in the majority of subgroups assessed.
The 6MWT in children and adolescents is feasible and practical. The 6MWT distance depends mainly on age; however, heart rate after the 6MWT, height and weight significantly add information and should be taken into account mainly in adolescents. Reference equations allow predicting 6-minute walk test distance and may help to better assess and compare outcomes in young patients with cardiovascular and respiratory diseases and are highly warranted for different populations.
6-minute walk test; Healthy children; Exercise physiology; Exercise testing; Predicted equation; Reference value
Standardised evidenced-based materials and mechanisms to facilitate the delivery of the education component of pulmonary rehabilitation are not widely available. The aims of this study were: 1) to adapt the self-management programme Living Well with COPD (LWWCOPD) programme, for embedding in pulmonary rehabilitation; and, 2) to conduct a process evaluation of the adapted programme.
The adaptations to the LWWCOPD programme were informed by focus groups, current practice, relevant research and guideline documents. Pulmonary rehabilitation sites used the adapted programme, the LWWCOPD programme for pulmonary rehabilitation, to deliver the education component of pulmonary rehabilitation. A process evaluation was conducted: elements included reach (patients’ attendance rates), dose delivered (amount of programme delivered), dose received (health professional and patient satisfaction) and fidelity (impact on patients’ knowledge, understanding and self-efficacy on the Understanding COPD questionnaire). Descriptive statistics (mean, SD) were used to summarise demographics and key data from the feedback questionnaires. Qualitative feedback on the programme was collated and categorised. Changes in the Understanding COPD questionnaire were examined using paired t-tests.
The LWWCOPD programme for pulmonary rehabilitation was delivered in eleven hospital- and community-based programmes (n=25 health professionals, n=57 patients with COPD). It consisted of six weekly 30–45 minute sessions. The process evaluation showed positive results: 62.3% of patients attended ≥ 4 education sessions (reach); mean (SD) 90 (10)% of the session content were delivered (dose delivered); the majority of sessions were rated as excellent or good by health professionals and patients. Patients’ satisfaction was high: mean (SD) Section B of the Understanding COPD questionnaire: 91.67 (9.55)% (dose received). Knowledge, understanding and self-efficacy improved significantly: mean change (95% CI): Section A of the Understanding COPD questionnaire: 26.75 (21.74 to 31.76)%, BCKQ 10.64 (6.92 to 14.37)% (fidelity).
This rigorous process evaluation has demonstrated that the LWWCOPD programme for pulmonary rehabilitation can be used to deliver high quality, consistent and equitable education sessions during hospital and community-based pulmonary rehabilitation. This programme is now available worldwide (http://www.livingwellwithcopd.com/living-well-and-pulmonary-rehabilitation.html).
This study was registered with clinicaltrials.gov (reference number: NCT01226836)
Pulmonary rehabilitation; COPD; Education; Self-management
Chronic lung diseases are marked by progressive inflammation, tissue damage and remodelling. Bone marrow-derived progenitor cells may contribute to these processes. The objectives of this study were to (1) to quantify CD45+Collagen-1+ fibrocytes and a novel epithelial-like population of bone marrow-derived cells, which express Clara Cell Secretory Protein, in patients at the time of lung transplant and (2) to evaluate mediators that may act to recruit these cells during injury.
Using an observational design, progenitor cells were quantified by flow cytometry from both bone marrow (BM) and peripheral blood (PB). Migration was tested using in vitro transwell assays. Multiplex bead-based assays were used to quantify plasma cytokines.
An increase in CD45+Collagen-1+ fibrocytes was found in pulmonary fibrosis and bronchiolitis obliterans patients. Cystic fibrosis patients had an increase in CCSP+ cells in both the BM and PB. The proportion of CCSP+ cells in the BM and PB was correlated. CCSP+ cells express the chemokine receptors CCR2, CCR4, CXCR3, and CXCR4, and significantly migrated in vitro toward Stromal Derived Factor-1 (SDF-1) and Stem Cell Growth Factor-β (SCGF-β). Plasma cytokine levels differed between disease groups, with a significant correlation between SCGF-β and CCSP+ cells and between Monocyte Chemotactic Protein-1 and fibrocytes.
Different bone marrow-derived cells are found in various lung diseases. Increased fibrocytes were associated with fibrotic lung diseases. An increase in the novel CCSP+ epithelial-like progenitors in cystic fibrosis patients was found. These differences may be mediated by alterations in plasma cytokines responsible for cell recruitment.
Fibrocytes; Clara cell; Lung progenitor; Migration
Heparin-binding protein is released by neutrophils during inflammation and disrupts the integrity of the alveolar and capillary endothelial barrier implicated in the development of acute lung injury and systemic organ failure. We sought to investigate whether oral administration of simvastatin to patients with acute lung injury reduces plasma heparin-binding protein levels and improves intensive care unit outcome.
Blood samples were collected from patients with acute lung injury with 48 h of onset of acute lung injury (day 0), day 3, and day 7. Patients were given placebo or 80 mg simvastatin for up to 14 days. Plasma heparin-binding protein levels from patients with acute lung injury and healthy volunteers were measured by ELISA.
Levels of plasma heparin-binding protein were significantly higher in patients with acute lung injury than healthy volunteers on day 0 (p = 0.011). Simvastatin 80 mg administered enterally for 14 days reduced plasma level of heparin-binding protein in patients. Reduced heparin-binding protein was associated with improved intensive care unit survival.
A reduction in heparin-binding protein with simvastatin is a potential mechanism by which the statin may modify outcome from acute lung injury.
Current controlled trials: ISRCTN70127774
Acute lung injury; Simvastatin; Heparin-binding protein; Inflammation; Neutrophils
It remains unclear to what extent asthma in adults is linked to allergic rhinitis (AR), gastroesophageal reflux disease (GERD), and acetylsalicylic acid exacerbated respiratory disease (AERD), and how these comorbidities may affect asthma outcomes in the general population. We therefore aimed to assess the prevalence of these major comorbidities among adults with asthma and examine their impact on asthma exacerbations requiring hospital care.
A total of 22,050 adults 18 years and older were surveyed in the German National Health Telephone Interview Survey (GEDA) 2010 using a highly standardized computer-assisted interview technique. The study population comprised participants with self-reported physician-diagnosed asthma, among which the current (last 12 months) prevalence of AR and GERD-like symptoms (GERS), and life-time prevalence of AERD was estimated. Weighted bivariate analyses and logistic regression models were applied to assess the association of each comorbid condition with the asthma outcome (any self-reported asthma-related hospitalization and/or emergency department (ED) admission in the past year).
Out of 1,136 adults with asthma, 49.6% had GERS and 42.3% had AR within the past 12 months; 14.0% met the criteria of AERD, and 75.7% had at least one out of the three conditions. Overall, the prevalence of at least one exacerbation requiring emergency room or hospital admission within the past year was 9.0%. Exacerbation prevalence was higher among participants with comorbidities than among those without (9.8% vs. 8.2% for GERS; 11.2% vs. 7.6% for AR, and 22.2% vs. 7.0% for AERD), but only differences in association with AERD were statistically significant. A strong association between asthma exacerbation and AERD persisted in multivariable logistic regression analyses adjusting for sex, age group, level of body mass index, smoking status, educational attainment, and duration of asthma: odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.5–8.2.
Data from this large nation-wide study provide evidence that GERS, AR and AERD are all common comorbidities among adults with asthma. Our data underline the public health and clinical impact of asthma with complicating AERD, contributing considerably to disease-specific hospitalization and/or ED admission in a defined asthma population, and emphasize the importance of its recognition in asthma care.
Acetylsalicylic acid exacerbated respiratory disease; Adult; Allergic rhinitis; Aspirin-induced asthma; Asthma; Gastroesophageal reflux disease; Gastroesophageal reflux; Hospitalization; National health survey
The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and the Medical Outcomes Study Short Form 36 (SF-36) are widely used to assess patient-reported outcome in individuals with pulmonary hypertension (PH). The aim of the study was to compare the psychometric properties of the two measures.
Participants were recruited from specialist PH centres in Australia and New Zealand. Participants completed the CAMPHOR and SF-36 at two time points two weeks apart. The SF-36 is a generic health status questionnaire consisting of 36 items split into 8 sections. The CAMPHOR is a PH-specific measure consisting of 3 scales; symptoms, activity limitations and needs-based QoL. The questionnaires were assessed for distributional properties (floor and ceiling effects), internal consistency (Cronbach's alpha), test-retest reliability and construct validity (scores by World Health Organisation functional classification).
The sample comprised 65 participants (mean (SD) age = 57.2 (14.5) years; n(%) male = 14 (21.5%)). Most of the patients were in WHO class 2 (27.7%) and 3 (61.5%). High ceiling effects were observed for the SF-36 bodily pain, social functioning and role emotional domains. Test-retest reliability was poor for six of the eight SF-36 domains, indicating high levels of random measurement error. Three of the SF-36 domains did not distinguish between WHO classes. In contrast, all CAMPHOR scales exhibited good distributional properties, test retest reliability and distinguished between WHO functional classes.
The CAMPHOR exhibited superior psychometric properties, compared with the SF-36, in the assessment of PH patient-reported outcome.
Tumors with a massive inflammatory infiltration are described in several organs. There is agreement about considering the inflammatory infiltration as the host’s immune response to neoplastic cells; such neoplasms indeed have a better prognostic outcome than non-inflammatory counterparts. Only seventeen cases of pulmonary adenocarcinoma with massive lymphocytic infiltration (AMLI) have been reported in literature so far.
We present a case of pulmonary adenocarcinoma with massive lymphocytic infiltration occurring in a 71 years old male smoker. He came under our attention because of dyspnea, and underwent a left lower lobectomy. Histological examination showed a moderately differentiated (G2) acinar adenocarcinoma associated with a stromal desmoplastic reaction and a massive inflammatory infiltration, made up mostly of CD3+ lymphocytes. pTNM stage was pT2a, N0 (clinical stage: Ib).
Molecular testing of EGFR gene showed no mutations and immunohistochemistry for ALK resulted negative.
EBV infection was ruled out by EBV in situ hybridization.
Literature review showed seventeen similar cases, with a 16/1 male/female ratio and a mean age of 70,2 years. In eight out of seventeen cases EBV-infection was demonstrated with immunohistochemical or molecular biology techniques.
Similarly to the cases previously reported in literature our patient is a male smoker, without lymph node metastasis and he is still alive after a follow-up period of six months without recurrent or residual disease.
Because of histological, biological and clinical peculiarity, we propose to take into account pulmonary adenocarcinomas with massive inflammatory infiltration for a separate pathological classification.
Pulmonary adenocarcinoma; Tumoral host response; Lymphocytic infiltration
Exhaled breath volatile organic compound (VOC) analysis for airway disease monitoring is promising. However, contrary to nitric oxide the method for exhaled breath collection has not yet been standardized and the effects of expiratory flow and breath-hold have not been sufficiently studied. These manoeuvres may also reveal the origin of exhaled compounds.
15 healthy volunteers (34 ± 7 years) participated in the study. Subjects inhaled through their nose and exhaled immediately at two different flows (5 L/min and 10 L/min) into methylated polyethylene bags. In addition, the effect of a 20 s breath-hold following inhalation to total lung capacity was studied. The samples were analyzed for ethanol and acetone levels immediately using proton-transfer-reaction mass-spectrometer (PTR-MS, Logan Research, UK).
Ethanol levels were negatively affected by expiratory flow rate (232.70 ± 33.50 ppb vs. 202.30 ± 27.28 ppb at 5 L/min and 10 L/min, respectively, p < 0.05), but remained unchanged following the breath hold (242.50 ± 34.53 vs. 237.90 ± 35.86 ppb, without and with breath hold, respectively, p = 0.11). On the contrary, acetone levels were increased following breath hold (1.50 ± 0.18 ppm) compared to the baseline levels (1.38 ± 0.15 ppm), but were not affected by expiratory flow (1.40 ± 0.14 ppm vs. 1.49 ± 0.14 ppm, 5 L/min vs. 10 L/min, respectively, p = 0.14). The diet had no significant effects on the gasses levels which showed good inter and intra session reproducibility.
Exhalation parameters such as expiratory flow and breath-hold may affect VOC levels significantly; therefore standardisation of exhaled VOC measurements is mandatory. Our preliminary results suggest a different origin in the respiratory tract for these two gasses.
Serum levels of N–terminal proB–type natriuretic peptide (NT–proBNP) are elevated in patients acute respiratory distress syndrome (ARDS). Recent studies showed a lower incidence of acute cor pulmonale in ARDS patients ventilated with lower tidal volumes. Consequently, serum levels of NT–proBNP may be lower in these patients.
We investigated the relation between serum levels of NT–proBNP and tidal volumes in critically ill patients without ARDS at the onset of mechanical ventilation.
Secondary analysis of a randomized controlled trial of lower versus conventional tidal volumes in patients without ARDS. NT–pro BNP were measured in stored serum samples. Serial serum levels of NT–pro BNP were analyzed controlling for acute kidney injury, cumulative fluid balance and presence of brain injury. The primary outcome was the effect of tidal volume size on serum levels of NT–proBNP. Secondary outcome was the association with development of ARDS.
Samples from 150 patients were analyzed. No relation was found between serum levels of NT–pro BNP and tidal volume size. However, NT-proBNP levels were increasing in patients who developed ARDS. In addition, higher levels were observed in patients with acute kidney injury, and in patients with a more positive cumulative fluid balance.
Serum levels of NT–proBNP are independent of tidal volume size, but are increasing in patients who develop ARDS.
Mechanical ventilation; Acute lung injury; Tidal volume; Ventilator–associated lung injury; NT–proBNP
Chronic Obstructive Pulmonary Disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible and usually progressive. Current guidelines, among which the Dutch, have so far based their management strategy mainly on lung function impairment as measured by FEV1, while it is well known that FEV1 has a poor correlation with almost all features of COPD that matter to patients. Based on this discrepancy the GOLD 2011 update included symptoms and impact in their treatment algorithm proposal. Health status measures capture both symptoms and impact and could therefore be used as a standardized way to capture the information a doctor could otherwise only collect by careful history taking and recording. We hypothesize that a treatment algorithm that is based on a simple validated 10 item health status questionnaire, the Clinical COPD Questionnaire (CCQ), improves health status (as measured by SGRQ) and classical COPD outcomes like exacerbation frequency, patient satisfaction and health care utilization compared to usual care based on guidelines.
This hypothesis will be tested in a randomized controlled trial (RCT) following 330 patients for two years. During this period general practitioners will receive treatment advices every four months that are based on the patient’s health status (in half of the patients, intervention group) or on lung function (the remaining half of the patients, usual care group).
During the design process, the selection of outcomes and the development of the treatment algorithm were challenging. This is discussed in detail in the manuscript to facilitate researchers in designing future studies in this changing field of implementation research.
Netherlands Trial Register, NTR2643
There is insufficient evidence of the cost-effectiveness of Chronic Obstructive Pulmonary Disease (COPD) Disease Management (COPD-DM) programs. The aim of this review is to evaluate the economic impact of COPD-DM programs and investigate the relation between the impact on healthcare costs and health outcomes. We also investigated the impact of patient-, intervention, and study-characteristics.
We conducted a systematic literature review to identify cost-effectiveness studies of COPD-DM. Where feasible, results were pooled using random-effects meta-analysis and explorative subgroup analyses were performed.
Sixteen papers describing 11 studies were included (7 randomized control trials (RCT), 2 pre-post, 2 case–control). Meta-analysis showed that COPD-DM led to hospitalization savings of €1060 (95% CI: €2040 to €80) per patient per year and savings in total healthcare utilization of €898 (95% CI: €1566 to €231) (excl. operating costs). In these health economic studies small but positive results on health outcomes were found, such as the St Georges Respiratory Questionnaire (SGRQ) score, which decreased with 1.7 points (95% CI: 0.5-2.9). There was great variability in DM interventions-, study- and patient-characteristics. There were indications that DM showed greater savings in studies with: severe COPD patients, patients with a history of exacerbations, RCT study design, high methodological quality, few different professions involved in the program, and study setting outside Europe.
COPD-DM programs were found to have favourable effects on both health outcomes and costs, but there is considerable heterogeneity depending on patient-, intervention-, and study-characteristics.
Chronic obstructive pulmonary disease; Efficiency; Cost-effectiveness; Costs; Meta-analysis; Review; Integrated care; Disease management; COPD; Economic evaluation
A clear relationship between asthma and obesity has been reported, but the mechanisms remain unclear. The aim of this study was to evaluate the influence of obesity on eosinophil activity (chemotaxis and adhesion) in asthmatic children and adolescents compared with cells from healthy volunteers.
Asthmatic obese (AO), asthmatic non-obese (ANO), non-asthmatic obese (NAO) and non-asthmatic non-obese (NANO) individuals were included in the present study. The chemotaxis of eosinophils after stimulation with eotaxin (300 ng/ml), platelet-activating factor (10 μM; PAF) and RANTES (100 ng/ml) was performed using a microchemotaxis chamber. The eosinophil peroxidase activity was measured to determine the adhesion activity of eosinophils cultivated on fibronectin-coated plates. The serum leptin, adiponectin, TNF-α and IgE levels were quantified using ELISA assays.
The serum IgE levels and eosinophil counts were significantly higher in asthmatic (obese and non-obese) individuals compared with non-asthmatic individuals (obese and non-obese). Spontaneous eosinophil chemotaxis was greater in the AO group compared with either the ANO or NANO groups. The activation of eosinophils using eotaxin and PAF increased eosinophil chemotaxis in the AO group. RANTES treatment increased eosinophil chemotaxis in the NAO group compared with the NANO or ANO groups. The activation of eosinophils using eotaxin significantly increased eosinophil adhesion in the AO group compared with other groups. The serum leptin and TNF-α levels were higher in obese subjects (asthmatic and non-asthmatic), whereas the levels of adiponectin did not significantly differ among these groups.
This study is the first to show increased eosinophilic activity (chemotaxis and adhesion) associated with high serum leptin and TNF-α levels in atopic asthmatic obese children and adolescents compared with non-obese healthy volunteers.
The majority of the global population cannot afford existing asthma pharmacotherapy. Physical training as an airway anti-inflammatory therapy for asthma could potentially be a non-invasive, easily available, affordable, and healthy treatment modality. However, effects of physical training on airway inflammation in asthma are currently inconclusive. The main objective of this review is to summarize the effects of physical training on airway inflammation in asthmatics.
A peer reviewed search was applied to Medline, Embase, Web of Science, Cochrane, and DARE databases. We included all observational epidemiological research studies and RCTs. Studies evaluating at least one marker of airway inflammation in asthmatics after a period of physical training were selected. Data extraction was performed in a blinded fashion. We decided a priori to avoid pooling of the data in anticipation of heterogeneity of the studies, specifically heterogeneity of airway inflammatory markers studied as outcome measures.
From the initial 2635 studies; 23 studies (16 RCTs and 7 prospective cohort studies) were included. Study sizes were generally small (median sample size = 30). There was a reduction in C-reactive protein, malondialdehyde, nitric oxide, sputum cell counts and IgE in asthmatics with physical training. Mixed results were observed after training for fractional excretion of nitric oxide and bronchial hyperresponsiveness. The data was not pooled owing to significant heterogeneity between studies, and a funnel plot tests for publication bias were not performed because there were less than 10 studies for almost all outcome measures. Physical training intervention type, duration, intensity, frequency, primary outcome measures, methods of assessing outcome measures, and study designs were heterogeneous.
Due to reporting issues, lack of information and heterogeneity there was no definite conclusion; however, some findings suggest physical training may reduce airway inflammation in asthmatics.
Chronic airway inflammation; Physical exercise; Asthma therapy; Adherence; Meta-analysis
The aim of this substudy of the ghrelin treatment, multicenter, randomized, double-blind, placebo-controlled trial was to investigate the effects of ghrelin administration on exercise capacity and the underlying mechanisms in underweight patients with chronic obstructive pulmonary disease (COPD) using cardiopulmonary exercise testing.
Twenty underweight COPD patients were randomized to pulmonary rehabilitation with intravenous ghrelin (2 μg/kg, n = 10) or placebo (n = 10) twice daily for 3 weeks in a double-blind fashion. The primary outcome was changes in peak oxygen uptake V•o2. Secondary outcomes included changes in exertional cardio-respiratory functions: O2-pulse, physiologic dead space/tidal volume-ratio (VD/VT), ventilatory equivalent for oxygen V•E/V•o2, and ventilatory equivalent for carbon dioxide V•E/V•co2.
With incremental exercise, at peak exercise, there was a significant difference in the mean difference (ghrelin minus placebo), i.e., treatment effect in: i) peak V•o2 (1.2 mL/kg/min, 95% CI: 0.2-2.3 mL/kg/min, between-group p = 0.025); ii) V•E/V•o2 (-4.2, 95% CI: -7.9 to -0.5, between-group p = 0.030); iii) V•E/V•co2 (-4.1, 95% CI: -8.2 to -0.1, between-group p = 0.045); iv) VD/VT (-0.04, 95% CI: -0.08 to -0.00, between-group p = 0.041); and v) O2-pulse (0.7 mL/beat, 95% CI: 0.3 to 1.2 mL/beat, between-group p = 0.003). Additionally, repeated-measures analysis of variance (ANOVA) indicated a significant time-course effect of ghrelin versus placebo in the peak V•o2 (p = 0.025).
Ghrelin administration was associated with improved exertional capacity and improvements in ventilatory-cardiac parameters.
UMIN (University Hospital Medical Information Network in Japan) C000000061
Dyspnea; Exercise; Pulmonary rehabilitation; Sympathetic nerve activity; Underweight
The imbalance between proteases and antiproteases has been proposed to participate to the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. Gene level variation in different metalloproteinases, metalloproteinase inhibitors, and cytokines affecting them may contribute to this imbalance and destruction of the lung parenchyma. We investigated whether polymorphisms in selected protease-antiprotease balance pathway genes predispose to different emphysema subtypes (centrilobular, paraseptal, panlobular, and bullae) and airflow limitation among Finnish construction workers.
Eleven single nucleotide polymorphisms (SNPs) from seven genes (GC: rs7041 and rs4588; MMP1: rs1799750; MMP9: rs3918242; MMP12: rs652438; TIMP2: rs2277698; TNF: rs1799724 and rs1800629; TGFB1: rs1800469, rs1800470, and rs2241718) were analyzed from 951 clinically and radiologically characterized construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and maximal expiratory flow at 50% of FVC (MEF50) by using linear and logistic regression analyses, adjusted for potential confounders.
The TIMP2 rs2277698 SNP was associated with overall (p = 0.022) and paraseptal (p = 0.010) emphysema, as well as with FEV1/FVC ratio (p = 0.035) and MEF50 (p = 0.008). The TGFB1 rs2241718 and MMP9 rs3918242 SNPs were associated with centrilobular emphysema (p = 0.022 and p = 0.008), and the TNF rs1800629 SNP with paraseptal emphysema (p = 0.017). In stratified analysis, individuals with at least one TIMP2 rs2277698 or TNF rs1800629 variant allele were found to be at around two-fold risk for pathological paraseptal changes (OR 1.94, 95% CI 1.14-3.30; OR 2.10, 95% CI 1.24-3.56). On the contrary, the risk for pathological centrilobular changes was halved for individuals with at least one MMP9 rs3918242 (OR 0.51, 95% CI 0.30-0.86) or TGFB1 rs2241718 (OR 0.53, 95% CI 0.30-0.90) variant allele, or TGFB1 rs1800469-rs1800470 AT-haplotype (OR 0.55, 95% CI 0.33-0.93). MEF50, in turn, was significantly reduced among individuals with at least one TIMP2 rs2277698 variant allele (p = 0.011).
Our findings strengthen the hypothesis of the importance of protease-antiprotease balance in pathogenesis of emphysema and shed light on the aetiology of different emphysema subtypes by associating MMP9 and TGFB1 to centrilobular emphysema, and TIMP2 and TNF to paraseptal emphysema and/or airflow obstruction.
Emphysema; Lung function; Genetics; Protease-antiprotease balance
The GOLD 2011 document proposed a new classification system for COPD combining symptom assessment by COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores, and exacerbation risk. We postulated that classification of COPD would be different by the symptom scale; CAT vs mMRC.
Outpatients with COPD were enrolled from January to June in 2012. The patients were categorized into A, B, C, and D according to the GOLD 2011; patients were categorized twice with mMRC and CAT score for symptom assessment, respectively. Additionally, correlations between mMRC scores and each item of CAT scores were analyzed.
Classification of 257 patients using the CAT score vs mMRC scale was as follows. By using CAT score, 60 (23.3%) patients were assigned to group A, 55 (21.4%) to group B, 21 (8.2%) to group C, and 121 (47.1%) to group D. On the basis of the mMRC scale, 97 (37.7%) patients were assigned to group A, 18 (7.0%) to group B, 62 (24.1%) to group C, and 80 (31.1%) to group D. The kappa of agreement for the GOLD groups classified by CAT and mMRC was 0.510. The mMRC score displayed a wide range of correlation with each CAT item (r = 0.290 for sputum item to r = 0.731 for dyspnea item, p < 0.001).
The classification of COPD produced by the mMRC or CAT score was not identical. Care should be taken when stratifying COPD patients with one symptom scale versus another according to the GOLD 2011 document.
COPD; CAT; mMRC scores
Bronchiectasis is a progressive and fatal disease despite the available treatment regimens. Gastroesophageal reflux (GER) may play an important role in the progression of bronchiectasis. However, active anti-reflux intervention such as Stretta radiofrequency (SRF) and/or laparoscopic fundoplication (LF) have rarely been used to treat Bronchiectasis.
Seven patients’ clinical outcomes for treating GER-related deteriorated bronchiectasis were retrospective reviewed. All patients were treated by SRF and/or LF, and had follow-up periods ranging from one to five years. Typical GER symptoms, respiratory symptoms, medication consumption and general health status were assessed during the follow-ups. At the latest follow-up all patients were alive. The typical GER symptoms disappeared in five people and were significantly improved in the other two. Two had complete remissions of both respiratory symptoms and bronchiectasis exacerbations; four had significantly improved respiratory symptoms to mild/moderate degrees as well as reduced or zero bronchiectasis exacerbations, which allowed them to resume the physical and social functions; one’s respiratory symptoms and bronchiectasis exacerbations were not much improved, yet she was in stable condition and satisfied with the results.
Potentially, GER plays an important role in some patients with bronchiectasis, and active anti-reflux treatments can be beneficial. Future clinical studies are suggested to clarify GER’s role in bronchiectasis and to further determine whether anti-reflux interventions for GER can improve the outcomes of patients with bronchiectasis.
Gastroesophageal reflux; Bronchiectasis; Asthma; Stretta radiofrequency; Laparoscopic fundoplication
Gastro-esophageal reflux disease (GERD) predisposes to airway disease through a vagally-mediated esophago-bronchial reflex. This study investigates this vagal response to esophageal acid perfusion.
40 asthmatics with mild stable asthma participated. Each subject underwent spirometry and autonomic function testing (valsalva maneuver, heart rate response to deep breathing and to standing from supine position) four times: a) before intubation, b) after intubation, and then immediately after perfusion with, in random order, c) concentrated lime juice solution (pH 2–3) and d) 0.9% saline. Subjects were blinded to the solution perfused.
Asthmatics were of mean (SD) age 34.3 years (1.3), and 67.5% of them were females. pH monitoring demonstrated that 20 subjects had abnormal reflux and 20 did not. In each group 10 subjects had a positive GERD symptom score. Following perfusion with acid compared to saline, all subjects showed significant decreases in FEV1 and PEFR and significant increases in the mean valsalva ratio and heart rate difference on deep breathing from baseline values, but no changes in FVC or heart rate ratio on standing. There were no significant differences in any of the parameters between subjects with and without reflux.
Acid stimulation of the distal esophagus results in increased parasympathetic activity and concomitant broncho-constriction in asthmatics irrespective of their reflux state. This strengthens the hypothesis that GER triggers asthma-like symptoms through a vagally mediated esophago-bronchial reflex and encourages a possible role for anti-cholinergic drugs in the treatment of reflux-associated asthma.
Asthma; Gastro-esophageal reflux disease; Vagal activity; Spirometry; Autonomic function testing
The role of antibiotics in treating mild or moderate exacerbations in patients with acute chronic obstructive pulmonary disease (COPD) is unclear. The aims were to: (i) describe patient characteristics associated with acute exacerbations amongst a representative COPD population, (ii) explore the relationship between COPD severity and outcomes amongst patients with exacerbations, and (iii) quantify variability by general practice in prescribing of antibiotics for COPD exacerbations.
A cohort of 62,747 patients with COPD was identified from primary care general practices (GP) in England, and linked to hospital admission and death certificate data. Exacerbation cases were matched to three controls and characteristics compared using conditional logistic regression. Outcomes were compared using incidence rates and Cox regression, stratified by disease severity. Variability of prescribing at the GP level was evaluated graphically and by using multilevel models.
COPD severity was found to be associated with exacerbation and subsequent mortality (very severe vs. mild, odds ratio for exacerbation 2.12 [95%CI 19.5–2.32]), hazard ratio for mortality 2.14 [95%CI 1.59–2.88]). Whilst 61% of exacerbation cases were prescribed antibiotics, this proportion varied considerably between GP practices (interquartile range, 48–73%). This variation is greater than can be explained by patient characteristics alone.
There is significant variability between GP practices in the prescribing of antibiotics to COPD patients experiencing exacerbations. Combined with a lack of evidence on the effects of treatment, this supports the need and opportunity for a large scale pragmatic randomised trial of the prescribing of antibiotics for COPD patients with exacerbations, in order to clarify their effectiveness and long term outcomes whilst ensuring the representativeness of subjects.
Chronic obstructive pulmonary disease; Disease exacerbation; Clinical practice variation; Anti-bacterial agents; Primary health care; General practice
Combined pulmonary fibrosis and emphysema (CPFE) is an umbrella term encompassing upper lobe emphysema and lower lobe pulmonary fibrosis with pathogenesis elusive. The aim of our study was to investigate the incidence of autoimmune markers in patients with CPFE.
In this multicenter study we retrospectively evaluated records from patients with CPFE (n=40) and IPF (n=60) without emphysema. Baseline demographic characteristics, high-resolution computed tomography (HRCT), spirometry, histopathological, treatment, serum immunologic and survival data were investigated. B cell presence was estimated with CD20 immunostaining in representative lung biopsy samples from CPFE patients and control subjects.
A statistically significant increased number of CPFE patients with elevated serum ANA with or without positive p-ANCA titers compared to patients with IPF without emphysema was observed. Patients with CPFE and positive autoimmune markers exhibited improved survival compared to patients with a negative autoimmune profile. A massive infiltration of clusters of CD20+ B cells forming lymphoid follicles within the fibrotic lung in CPFE patients with positive serum immunologic profile compared to patients with negative profile, was noted and positively correlated with improved survival.
A significant proportion of patients with CPFE may present with underlying auto-immune disorders that may reside insidiously and be associated with favorable prognosis. Early identification of these patients using a panel of auto-antibodies may lead to more targeted and effective therapeutic applications.
Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality.
We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1.
To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered.
AFOP; Influenza A/H1N1; Acute lung failure; Lung transplantation; Viral infection