Complex chronic comorbidities of COPD Fabbri, L. M; Luppi, F; Beghe, B ...
The European respiratory journal,
01/2008, Letnik:
31, Številka:
1
Journal Article
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Chronic obstructive pulmonary disease (COPD) is defined by fixed airflow limitation associated with an abnormal pulmonary and systemic inflammatory response of the lungs to cigarette smoke. The ...systemic inflammation induced by smoking may also cause chronic heart failure, metabolic syndrome and other chronic diseases, which may contribute to the clinical manifestations and natural history of COPD. Thus COPD can no longer be considered a disease only of the lungs, as it is often associated with a wide variety of systemic consequences. A better understanding of the origin and consequences of systemic inflammation, and of potential therapies, will most likely lead to better care of patients with COPD. Medical textbooks and clinical guidelines still largely ignore the fact that COPD seldom occurs in isolation. As the diagnosis and assessment of severity of COPD may be greatly affected by the presence of comorbid conditions, the current authors believe that lung function measurement, noninvasive assessment of cardiovascular and metabolic functions, and circulating inflammatory markers (e.g. C-reactive protein) might help to better characterise these patients. Similarly, preventive and therapeutic interventions should address the patient in their complexity.
To cite this article: Contoli M, Bousquet J, Fabbri LM, Magnussen H, Rabe KF, Siafakas NM, Hamid Q, Kraft M. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. ...Allergy 2010; 65: 141-151. The involvement of small airways in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) has been debated for a long time. However, a proper definition of small airway disease is still lacking, and neither a widely accepted biomarker nor a functional parameter to assess small airway abnormalities and to explore the effect of tested compounds on small airways is available. Aiming towards increased knowledge and consensus on this topic, this perspective paper intends to (i) strengthen awareness among the scientific community on the role of small airways in asthma and COPD; (ii) examine the pros and cons of some biological, functional and imaging parameters in the assessment of small airway abnormalities; and (iii) discuss the evidence for distal airway pharmacological targeting in asthma and COPD.
In 1995, the Global Initiative for Asthma (GINA) guidelines recommended goals for the management of asthma, which were updated in 2002. However, there are no recent international surveys on the real ...management of asthma.
The Asthma Insights and Reality surveys are the first large-scale surveys aimed at determining international variations in the severity, control, and management of asthma in children and adults.
A cross-section of households in 29 countries in North America, Europe, and Asia were surveyed to identify from the general population asthmatic patients with symptoms within the last year or who were taking current asthma medication. A standard questionnaire was administered to 7786 adults, and, through a proxy, to 3153 children with asthma. Objective and subjective patient perception of asthma control and severity were assessed, including access to medical care, health care use, missed work-school, and medication use.
Despite variations at a country level, a substantial effect of asthma on patients' lives was observed, with considerable loss of schooldays and workdays. The current level of asthma control worldwide falls far short of the goals for long-term management in international guidelines. A significant proportion of patients continue to have symptoms and lifestyle restrictions and to require emergency care. The proportion of adult asthmatic patients who were current smokers was also high. However, the use of anti-inflammatory preventative medication, even in patients with severe persistent asthma, was low, ranging from 26% in Western Europe to 9% in Japan, as was the use of objective lung function testing. The correlation between self-perceived severity of asthma and objective assessment of severity on the basis of GINA criteria was consistently poor in all areas.
We conclude that there is direct evidence for suboptimal asthma control in many patients worldwide, despite the availability of effective therapies, with long-term management falling far short of the goals set in the GINA guidelines.
To cite this article: Bousquet J, Siergiejko Z, Świebocka E, Humbert M, Rabe KF, Smith N, Leo J, Peckitt C, Maykut R, Peachey G. Persistency of response to omalizumab therapy in severe allergic ...(IgE‐mediated) asthma. Allergy 2011; 66: 671–678.
Background: The physician’s global evaluation of treatment effectiveness (GETE) at 16 weeks has been shown to be the most effective assessment of response to omalizumab (XOLAIR®). This randomized, open‐label, parallel‐group study evaluated the persistency of treatment responder classification in patients receiving omalizumab added to optimized asthma therapy (OAT).
Methods: Patients (12–75 years, n = 400) with severe allergic asthma, uncontrolled despite Global Initiative for Asthma 2004 Step 4 therapy, received OAT and omalizumab (n = 272) or OAT (n = 128) for 32 weeks. Response or nonresponse was evaluated at Weeks 16 and 32. Response was defined as an investigator’s (physician’s) GETE rating of excellent or good; nonresponse was defined as a rating of moderate, poor or worsening.
Results: Three hundred and forty‐nine patients had GETE ratings available at Weeks 16 and 32 (omalizumab n = 258, OAT n = 91). Omalizumab responders of about 171/187 (91.4%)and 44/71 (62.0%) omalizumab nonresponders at Week 16 persisted as responders or nonresponders at Week 32. The investigator’s GETE at Week 16 predicted persistency of response or nonresponse to omalizumab at Week 32 for 83.3% (215/258) of patients. OAT patients showed a lower persistency of response (18/28 64.3%) and a higher persistency of nonresponse (57/63 90.5%) than omalizumab patients. Excellent and good GETE ratings in omalizumab‐treated patients were reflected by improvements in exacerbation rates (P < 0.001), severe exacerbation rates (P = 0.023), hospitalizations (P = 0.003), total emergency visits (P = 0.026) and Asthma Control Questionnaire overall score (P < 0.001).
Conclusion: Response to omalizumab, as assessed by a physician’s GETE at 16 weeks, is an effective predictor of continuing persistent response to omalizumab for the majority of patients.
Asthma management guidelines provide recommendations for the optimum control of asthma. This survey assessed the current levels of asthma control as reported by patients, which partly reflect the ...extent to which guideline recommendations are implemented. Current asthma patients were identified by telephone by screening 73,880 households in seven European countries. Designated respondents were interviewed on healthcare utilization, symptom severity, activity limitations and asthma control. Current asthma patients were identified in 3,488 households, and 2,803 patients (80.4%) completed the survey. Forty-six per cent of patients reported daytime symptoms and 30% reported asthma-related sleep disturbances, at least once a week. In the past 12 months, 25% of patients reported an unscheduled urgent care visit, 10% reported one or more emergency room visits and 7% reported overnight hospitalization due to asthma. In the past 4 weeks, more patients had used prescription quick-relief medication (63%) than inhaled corticosteroids (23%). Patient perception of asthma control did not match their symptom severity; approximately 50% of patients reporting severe persistent symptoms also considered their asthma to be completely or well controlled. The current level of asthma control in Europe falls far short of the goals for long-term asthma management. Patients' perception of asthma control is different from their actual asthma control.
The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown.
To assess the safety and efficacy of golimumab in a ...large population of patients with uncontrolled, severe persistent asthma.
From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting beta(2) agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1) and the number of severe asthma exacerbations through Week 24.
No significant differences were observed for the change in percent-predicted FEV1 (least squares mean: placebo, 2.44 95% confidence interval (CI) -0.574 to 5.461; combined 100-mg and 200-mg, 2.91 0.696-5.116) or severe exacerbations (mean +/- SD: placebo, 0.5 +/- 1.07 vs. combined 100-mg and 200-mg 0.5 +/- 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk-benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups.
Overall, treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00207740).
Summary Interleukin-8 (IL-8; CXCL8) is a cytokine of the CXC chemokine family that is involved in neutrophil recruitment and activation. In addition, IL-8 has been implicated in a wide variety of ...other processes, including angiogenesis and metastasis in lung cancer. Lung adenocarcinoma and muco-epidermoid carcinoma cells produce substantial amounts of IL-8, and express both CXCR1 and CXCR2 IL-8 receptors. We hypothesized that IL-8 stimulates proliferation of non-small cell lung cancer cells, involving transactivation of the epidermal growth factor receptor (EGFR). The EGFR plays a central role in regulating cell proliferation and it has been therefore implicated in lung cancer. Both EGFR ligands and transactivation of the receptor may lead to downstream signalling events, including mitogen-activated protein kinase (MAPK) activation. Transactivation of the EGFR has been shown to occur in response to ligands of various G-protein coupled receptors (GPCRs) and involves metalloproteinase-mediated release of membrane bound EGFR ligands. The aim of the present study was to investigate the effect of IL-8 on proliferation of lung adenocarcinoma and muco-epidermoid carcinoma cells, and to explore the mechanisms leading to this proliferation in two different non-small cell lung cancer cell lines (A549 and NCI-H292). In both NSCLC cell lines, we observed that IL-8 stimulates epithelial cell proliferation in a dose-dependent manner. The ability of IL-8 to increase cell proliferation was blocked both by an inhibitor of EGFR tyrosine kinase, by a specific anti-EGFR blocking antibody and by a panmetalloproteinase inhibitor. Similar results were obtained using the GPCR inhibitor pertussis toxin. Inhibition of the MAPK p42/44 (ERK1/2) also blocked the mitogenic effect of IL-8, while a p38 MAPK inhibitor did not affect IL-8-induced cell proliferation. These results suggest that IL-8 increases cell proliferation in NSCLC cell lines via transactivation of the EGFR and that this mechanism involves metalloproteinase activity.
A tissue diagnosis of mediastinal nodes is frequently needed for accurate lung cancer staging as well as the assessment of mediastinal masses. Transbronchial needle aspiration (TBNA) is a safe ...procedure that is performed during routine bronchoscopy. Provided mediastinal metastases are confirmed, TBNA has a high impact on patient management. Unfortunately, TBNA remains underused in current daily practice, mainly due to the lack of real-time needle visualisation. The introduction of echo-endoscopes has overcome this problem. Endobronchial ultrasound-guided TBNA (EBUS-TBNA) allows real-time controlled tissue sampling of paratracheal, subcarinal and hilar lymph nodes. Mediastinal lymph nodes located adjacent to the oesophagus can be assessed by transoesophageal ultrasound-guided fine needle aspiration (EUS-FNA). Owing to the complementary reach of EBUS-TBNA and EUS-FNA in assessing different regions of the mediastinum, recent studies suggest that complete and accurate mediastinal staging can be achieved by the combination of both procedures. It is expected that implementation of minimally invasive endoscopic methods of endobronchial ultrasound-guided transbronchial needle aspiration and transoesophageal ultrasound-guided fine needle aspiration will reduce the need for surgical staging of lung cancer significantly.
Context:
The phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a ...history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism.
Objective:
Our objective was to investigate the effects of roflumilast on glucose homeostasis and body weight.
Design and Setting:
We conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients.
Patients:
Patients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study.
Interventions:
Roflumilast 500 μg or placebo was administered once daily.
Primary Outcome:
We evaluated mean change in blood glycated hemoglobin levels.
Secondary Outcomes:
We also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters.
Results:
Roflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = −0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit −0.7 (0.4) kg was not statistically significant (P = 0.0584).
Conclusion:
Roflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis.
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