Multicomponent Disease Research Articles

A basic overview of multiple sclerosis immunopathology.

Multiple sclerosis (MS) is a multi-component disease characterized by inflammation, neurodegeneration and failure of central nervous system (CNS) repair mechanisms. Immune dysregulation appears to originate with dendritic cells (antigen-presenting cells) which have an activated phenotype in individuals with MS. Dendritic cells migrate across the blood-brain barrier and induce differentiation of memory T cells into pro-inflammatory T helper 1 (Th1) and Th17 lymphocytes. In turn, induction of macrophage and microglial activation produces other pro-inflammatory cytokines and oxygen and nitric oxide radicals responsible for the demyelination and axonal loss. Other known mediators of MS pathology include CD8+ T cells and memory B cells within the CNS. Some pathological hallmarks of MS are early axonal degeneration and progressive decline of brain volume in patients with clinically isolated syndromes who progress to clinically definite MS. Many new options to interfere with the course of MS have become available in recent years. To limit inflammatory demyelinating processes and delay disease progression, intervention to control inflammation must begin as early as possible. Each distinct type of immunotherapy (immunomodulation, immunosuppression and immune-selective intervention - blockade type, sequestering type or depleting type) corresponds to a specific underlying immunopathology of MS.

Is tryptophan metabolism involved in sleep apnea-related cardiovascular co-morbidities and cancer progression?

Obstructive sleep apnea (OSA) is a multi-component chronic disease affecting 6–17% of adults in the general population. The main hallmark of OSA, intermittent hypoxia (IH), is reported as the main trigger for cardiometabolic co-morbidities. Recent studies, both in rodent models exposed to IH and in humans, have suggested an enhanced incidence and accelerated progression of cancer. However, mechanisms underlying the relationships between OSA and cardiovascular disease on one hand, and cancer on the other hand, have not been entirely deciphered yet. Tryptophan (TRP) metabolism results in nicotinamid and serotonin production, but also in the production of numerous intermediates such as kynurenine, anthranilic and kynurenic acids, 3-hydroxykynurenine, 3-hydroxyanthranilic and quinolinic acids. Each of these metabolites has been linked to cardiovascular disease and cancer mainly in epidemiologic studies. We hypothesize that an alteration of TRP metabolism may play a role in OSA-related cardiovascular co-morbidities and might be one of the players in the relationship between cancer and intermittent hypoxia/OSA. If this is true, interventions aiming to modify TRP metabolism, may constitute a new therapeutic strategy against cardiovascular disease progression and cancer occurrence in OSA populations.

Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls.

PurposeTo assess the importance of inflammation in chronic obstructive pulmonary disease (COPD) by measuring airway and systemic inflammatory biomarkers in Japanese patients with the disease and relevant control groups.Patients and methodsThis was the first study of its type in Japanese COPD patients. It was a non-treatment study in which 100 participants were enrolled into one of three groups: nonsmoking controls, current or ex-smoking controls, and COPD patients. All participants underwent standard lung function assessments and provided sputum and blood samples from which the numbers of inflammatory cells and concentrations of biomarkers were measured, using standard procedures.ResultsThe overall trends observed in levels of inflammatory cells and biomarkers in sputum and blood in COPD were consistent with previous reports in Western studies. Increasing levels of neutrophils, interleukin 8 (IL-8), surfactant protein D (SP-D), and Krebs von den Lungen 6 (KL-6) in sputum and clara cell 16 (CC-16), high-sensitivity C-reactive protein (hs-CRP), and KL-6 in serum and plasma fibrinogen were seen in the Japanese COPD patients compared with the non-COPD control participants. In sputum, significant correlations were seen between total cell count and matrix metalloproteinase 9 (MMP-9; P<0.001), neutrophils and MMP-9 (P<0.001), macrophages and KL-6 (P<0.01), total cell count and IL-8 (P<0.05), neutrophils and IL-8 (P<0.05), and macrophages and MMP-9 (P<0.05). Significant correlations were also observed between some inflammatory cells in sputum and biomarkers in serum, with the most significant between serum CC-16 and both total cell count (P<0.005) and neutrophils (P<0.005) in sputum.ConclusionThese results provide evidence for the first time that COPD in Japanese patients is a multicomponent disease, involving both airway and systemic inflammation, in addition to airway obstruction. Therefore, intervention with anti-inflammatory therapy may provide additional benefit in disease management of COPD in Japan.

Inflammatory biomarkers in chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a multicomponent disease. There is a need for biological markers for better evaluation of patients with COPD. ObjectiveTo test the hypothesis that elevated levels of inflammatory biomarkers fibrinogen, C-reactive protein (CRP) and leukocyte count (WBC) in individuals with stable COPD are associated with an increased risk of exacerbation. Patients and methodsNinety-eight COPD patients diagnosed and classified as COPD and 30 age and gender matched healthy subjects with normal pulmonary function were observed. Patient follow-up was performed to evaluate the strength of the associations between inflammatory biomarker levels and future outcome. ResultsInflammatory biomarkers increase with exacerbation compared to the remission state, mean WBC, CRP and fibrinogen at 12.212×109/L, 39.462mg/L and 5.09g/L in exacerbation respectively compared to 7.877×109/L, 4.142mg/L and 2.299g/L in remission with P values <0.001, <0.001 and <0.004, respectively.Statistically significant correlation was noticed between the levels of fibrinogen and the % predicted FEV1 (r=0.209, P=0.038) however CRP and WBC did not correlate with % predicted FEV1 (r=−0.031, P=0.765) for CRP, and that for WBC (r=0.125, P=0.221). ConclusionElevated levels of CRP, fibrinogen and leukocyte count in individuals with COPD were associated with increased exacerbation risk. Fibrinogen in particular has emerged as a potentially useful biomarker and requires further investigation.

Disturbed Intestinal Integrity in Patients With COPD: Effects of Activities of Daily Living

COPD is accepted to be a multicomponent disease with various comorbidities. To our knowledge, the contribution of the GI tract to the systemic manifestation of COPD has never been investigated. This metabolically active organ may experience recurring local oxygen deficits during daily life, leading to disturbed intestinal integrity in patients with COPD.Eighteen patients with moderate COPD (mean FEV₁, 55 ± 3% predicted) and 14 matched healthy control subjects were tested on two occasions: a baseline measurement at rest and, on another day, during the performance of activities of daily living (ADLs). To assess enterocyte damage, plasma intestinal fatty acid binding protein (IFABP) levels were determined, whereas urinary excretion of orally ingested sugar probes was measured using liquid chromatography and mass spectrometry to assess GI permeability.Plasma IFABP concentrations were not different between patients with COPD and healthy control subjects at rest. In contrast, 0- to 3-h urinary lactulose to rhamnose and sucralose to erythritol ratios and 5- to 24-h urinary sucralose to erythritol ratios were significantly higher in patients with COPD compared with control subjects, indicating increased permeability of the small intestine and colon. Furthermore, the performance of ADLs led to significantly increased plasma IFABP concentrations in patients with COPD but not in control subjects. Similarly, the intestinal permeability difference between patients and control subjects was intensified.Besides an altered intestinal permeability in patients with COPD when at rest, performing ADLs led to enterocyte damage in addition to intestinal hyperpermeability in patients with COPD but not in control subjects, indicating functional alteration in the GI tract. Hence, intestinal compromise should be considered as a new component of the multisystem disorder COPD.ISRCTN Register; No.: ISRCTN33686980; URL: www.controlled-trials.com.

Prevalence and correlates of osteoporosis in chronic obstructive pulmonary disease patients in India.

Background:Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by the abnormal inflammatory reaction of the airway and lung parenchyma. Osteoporosis is one of the major extrapulmonary manifestations of COPD. The, prevalence of osteoporosis in COPD patients in Indian population is unknown.Objectives:To study the prevalence of osteoporosis in COPD and to define various risk factors associated with reduced bone mineral density (BMD) in COPD.Materials and Methods:The study was done in the department of Pulmonary Medicine of a tertiary care hospital. All the diagnosed cases of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines were included in this study. The present study was a prospective study in for a period of 1 year. A brief history of the patients was taken, especially regarding duration of illness, number of exacerbations in the past 3 years, smoking in pack years, and history of steroid use (both systemic and inhaled steroids) after which cumulative dose of steroids was calculated. Spirometry was done in all these patients to stage the severity of COPD according to GOLD criteria. DEXA scan of the lumbar spine was done using bone densitometer to determine osteoporosis. A world Health Organization (WHO) criterion for definition of osteoporosis was applied and patients with T-score of > –2.5 standard deviation (SD) were diagnosed to have osteoporosis, –1 SD to –2.5 SD were diagnosed to have osteopenia and < –1 SD as normal. Statistical analysis for association of COPD with osteoporosis was done using chi-square test. Risk factors for osteoporosis were identified by univariate and multivariate logistic regression analysis.Results:A total of 102 COPD patients were included in the study. Among these, 68 patients (66.6%) had osteoporosis and 20 patients (19.6%) had osteopenia. Majority (64.7%) of the patients who had osteoporosis had stage III and stage IV COPD disease. It was observed that as the severity grade of COPD increased, the risk of osteoporosis also increased. The bone mineral density (BMD) showed a significant difference among different stages of COPD. As the severity of the stage of COPD increased, BMD decreased. It was also observed that patients with lower body mass index (BMI) had higher prevalence of osteoporosis (37.3%) as compared to overweight patients. On univariate analysis, it was observed that risk factors for osteoporosis were female sex, higher number of exacerbations, BMI, and severity of COPD. After using multivariate logistic regression analysis, stage IV COPD (odds ratio (OR): 34.48, 95% confidence interval (CI): 1.59–1,000, P < 0.02), number of acute exacerbations >3 (OR: 30.3, 95% CI: 4.74–200, P < 0.01), and steroid cumulative dose >1,000 mg (OR: 7.35, 95% CI: 0.92–58.5, P < 0.04) were observed to be significant risk factors for osteoporosis in COPD patients.Conclusions:In the present study, the prevalence of osteoporosis was 66.6% and another 19.6% had osteopenia. As the severity of COPD increased, the risk of osteoporosis increased. GOLD stage III and stage IV patient had significantly lower BMD as compared to stage I and stage II of COPD disease. Stage IV COPD disease, use of oral or parenteral glucocorticoids, and repeated number of exacerbations were found to be independent risk factors for osteoporosis in COPD patients. Thus, high clinical suspicion and early diagnosis and treatment is required in the evaluation of osteoporosis in COPD patients so that the quality of life can be improved in these patients.

Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

Metabolic syndrome (MetS) is a chronic, multi-component disease characterised by central obesity, hyperglycaemia, dyslipidaemia, and hypertension. Since MetS leads to type 2 diabetes, cardiovascular disease, development of certain cancers, and eventually to premature death, it is not surprising that it draws the attention of scientists around the world. The aetiopathology of MetS is complex and still not fully understood. This review focuses on the role of endocrine factors such as cortisol and insulin in the development of MetS. It also takes a look at some of the contributing lifestyle and genetic factors as well as at the current knowledge about its treatment.

Co-morbidities and Hyperinflation Are Independent Risk Factors of All-cause Mortality in Very Severe COPD

Background: COPD is a multi-component disease that is not sufficiently reflected by FEV1 alone. We studied in patients with very severe COPD, which dimensions of the disease, including co-morbidities, dominate prognosis. Methods: In patients with FEV1 < 30% predicted, anthropometric, laboratory, spirometric and body plethysmographic data, smoking status, alcohol consumption, the level of dyspnoea and exercise performance were assessed. Co-morbidities were categorized by the Charlson-index and the COPD-specific co-morbidity test (COTE). The prognostic value of multiple dimensions was explored using uni- and multivariate survival analyses regarding death from any or respiratory cause. Results: Among 209 patients included (58/151 female/male; FEV1 25.0 (22.0–26.9)%predicted), arterial hypertension (54.1%), hyperlipidemia (38.3%) and diabetes (19.6%) were most common, 57.9% showing a COTE-index of ≥1 point. During follow-up (28 (14–45) months), 121 patients had died, mostly (56.2%) due to respiratory causes. Age, BMI, the ratio of residual volume to total lung capacity (RV/TLC), co-morbidities in terms of the COTE- and Charlson-index, but not FEV1, were significantly associated with all-cause and respiratory mortality. The association of the median values of the Charlson- (HR 1.911 [95%-CI 1.338–2.730]) and COTE-index (HR 1.852 [95%-CI 1.297–2.644], p < 0.001 each) with mortality was similar and stronger when combined with age. In multivariate analyses, only RV/TLC and co-morbidities were independent risk factors of all-cause mortality (p < 0.05 each). Conclusion: In very severe COPD, resting hyperinflation and co-morbidities provide the major prognostic information, whereas the association of the recently introduced COTE-index with mortality was similar to that of the established Charlson-index and even stronger when including age.

Level of primary DNA damage in the early stage of metabolic syndrome

Metabolic syndrome (MetS) is a multi-component disease, characterised by abdominal obesity, hypertension, hyperglycaemia and dyslipidaemia. Since the number of MetS patients has significantly increased over the past two decades and because MetS may lead to development of cardiovascular diseases, diabetes type-2, and cancer, it has become important to extend the knowledge on the pathogenesis of MetS and to establish its possible early biomarkers. Studies on MetS and DNA damage are few and are inconclusive. The aim of this study was to elucidate the involvement of DNA damage in the development of MetS and to establish if DNA damage can serve as early biomarker of MetS. A total of 121 subjects participated in the study: 56 healthy controls and 65 MetS patients who were diagnosed with MetS for the first time. The amount of primary DNA damage in peripheral leukocytes of the subjects was assessed with three types of comet assay: the alkaline, the hOGG1-modified, and the neutral comet assay. In addition, the extent of oxidative DNA damage was monitored in urine by assessing 8-oxo-dG. The parameters of the three types of comet assay did not differ between the control and the MetS group. Interestingly, urinary 8-oxo-dG level in the control group was higher than in the MetS group. Our results imply that DNA damage is not involved in the early stage of MetS and, therefore, DNA damage cannot serve as an early marker of MetS.

Systemic Biomarkers in the Evaluation and Management of COPD Patients: Are We Getting Closer to Clinical Application?

Chronic obstructive pulmonary disease (COPD) is a complex, multicomponent disease at the clinical, cellular, and molecular levels. Over the past few years there has been a growing interest in the field of biomarkers in COPD and a large number of studies have evaluated potential candidate molecules in different patient settings. Data on systemic biomarkers from large cohorts, including the well-characterized population of the ECLIPSE study, are now available and provide exciting information on the association of biomarkers with clinically important outcomes, including exacerbations, hospitalizations and mortality. Moreover, recent research has provided proof for the existence of distinct "systemic inflammatory" phenotypes. This review summarizes the currently available evidence on systemic biomarkers in COPD, providing clinically relevant information on the possible role of systemic biomarkers in the evaluation of disease activity and severity, phenotypes, outcomes, COPD exacerbations and treatment response and guidance. Despite the fact that no single biomarker is currently ready to characterize sufficiently the status of COPD patients, guide treatment options, and predict future events, recent studies have rendered our current knowledge definitely more advanced than a few years ago and the possible use of biomarkers in the diagnosis and management of COPD patients looks even more promising.

Relationship between age, sex and body mass index with fundamental motor skills among 3 to 6 years-old children

The prevalence of childhood obesity is a serious public health problem. This problem is a multi-component disease and several factors are involved in its development. The childhood obesity led to poor mastery of fundamental motor skills (FMS) and failure to develop in specialized skills that required in organized sports and activities. Thus, the purpose of this study was to examine the relationship between age, sex and body mass index (BMI) with FMS in 3 to 6 years-old children. A total of 600 preschool children (300 boys and 300 girls) between the ages of 3 to 6 years old participated in this research. Subjects were selected through multi-stage cluster random sampling in five regions in Tehran. Using the Ohio State University Scale of Intra Gross Motor Assessment (OSU-SIGMA) FMS were assess. Body mass index (BMI) was directly measured from height (m)2/weight (kg) for each child. The results showed that the negative correlations between jumping, skipping, hopping and throwing skills and BMI in any 3 groups children were significant (P 0.05). The boys were performed better than girls in all FMS except hopping and skipping skills. In these skills the girls were better performed in all ages. These results highlight the need to provide organized opportunities which facilitate FMS and decreased high BMI levels in preschool children.

Cigarette Smoke Suppresses the Surface Expression ofc-kitand FcεRI on Mast Cells

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. COPD is mostly associated with cigarette smoking. Cigarette smoke contains over 4,700 chemical compounds, including free radicals and LPS (a Toll-Like Receptor 4 agonist) at concentrations which may contribute to the pathogenesis of diseases like COPD. We have previously shown that short-term exposure to cigarette smoke medium (CSM) can stimulate several inflammatory cells via TLR4 and that CSM reduces the degranulation of bone-marrow-derived mast cells (BMMCs). In the current study, the effect of CSM on mast cells maturation and function was investigated. Coculturing of BMMC with CSM during the development of bone marrow progenitor cells suppressed the granularity and the surface expression of c-kit and FcεRI receptors. Stimulation with IgE/antigen resulted in decreased degranulation and release of Th1 and Th2 cytokines. The effects of CSM exposure could not be mimicked by the addition of LPS to the culture medium. In conclusion, this study shows that CSM may affect mast cell development and subsequent response to allergic activation in a TLR4-independent manner.

Improving diabetes care: Multi-component cardiovascular disease risk reduction strategies for people with diabetes in South Asia—The CARRS Multi-center Translation Trial

AimsCardiovascular disease (CVD) is the leading cause of morbidity and mortality in people with diabetes in South Asia. The CARRS Translation Trial tests the effectiveness, cost-effectiveness, and sustainability of a clinic-based multi-component CVD risk reduction intervention among people with diabetes in India and Pakistan. MethodsWe randomly assigned 1146 adults with diabetes recruited from 10 urban clinic sites, to receive usual care by physicians or to receive an integrated multi-component CVD risk reduction intervention. The intervention involves electronic health record management, decision-support prompts to the healthcare team, and the support of a care coordinator to actively facilitate patient and provider adherence to evidence-based guidelines. The primary outcome is a composite of multiple CVD risk factor control (blood glucose and either blood pressure or cholesterol, or all three). Other outcomes include control of the individual CVD risk factors, process and patient-centered measures, cost-effectiveness, and acceptability/feasibility. ConclusionThe CARRS Translation Trial tests a low-cost diabetes care delivery model in urban South Asia to achieve comprehensive cardio-metabolic disease case-management of high-risk patients (clinicaltrials.gov number: NCT01212328).

A relation between TGF-β and mast cell tryptase in experimental emphysema models

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. The aim of this study was to investigate the effect of cigarette smoke exposure on mast cells and mast cell function in vitro and in vivo in order to get further insight in the role of mast cells in the pathogenesis of emphysema. Cigarette smoke conditioned medium (CSM) induced the expression of mast cell tryptase (MMCP-6) in primary cultured mast cells. This tryptase expression was caused by the CSM-stimulated production of TGF-β in culture and neutralization of TGF-β suppressed the CSM-induced expression of tryptase in mast cells. An increase in mast cell tryptase expression was also found in an experimental model for emphysema. Exposure of mice to cigarette smoke increased the number of mast cells in the airways and the expression of mast cell tryptase. In accordance with the in vitro findings, TGF-β in bronchoalveolar lavage fluid of smoke-exposed animals was significantly increased. Our study indicates that mast cells may be a source of TGF-β production after cigarette smoke exposure and that in turn TGF-β may change the tryptase expression in mast cells.

Associations between BODE Index and Systemic Inflammatory Biomarkers in COPD

Background: COPD is a multicomponent disease and systemic inflammation represents one of the possible mechanisms responsible for its systemic manifestations, including skeletal muscle weakness and cachexia. Fat-free mass index (FFMI) that reflects the skeletal muscle mass, has been shown to be associated with both dyspnoea and exercise capacity. We hypothesized that the multidimensional BODE index, that reflects the multicomponent nature of COPD, might be related to biomarkers of systemic inflammation. We further evaluated associations between FFMI and systemic inflammation. Methods: BODE index and FFMI were calculated in 222 stable COPD patients and 132 smokers or ex-smokers with normal lung function. Systemic inflammation was evaluated with the measurement of leptin, adiponectin, CRP, IL-6, and TNF-α in serum samples of COPD patients. Results: In patients with COPD, both BODE index and FFMI presented significant positive and negative associations respectively with leptin levels (R2 0.61 and 0.65, respectively), whereas FFMI presented an additional negative association with the levels of TNF-α (R2 0.38). No significant associations were observed in smokers or ex-smokers with normal lung function. Conclusions: Both BODE index and FFMI, are related to the circulating levels of leptin in patients with COPD, suggesting a possible role for leptin in the systemic component of COPD. The additional association of FFMI with TNF-α may further support a role of systemic inflammation in muscle wasting in COPD.

Nurse‐led health promotion interventions improve quality of life in frail older home care clients: lessons learned from three randomized trials in Ontario, Canada

This paper explores the lessons learned from a series of three randomized controlled trials that included 498 community-living frail older adults (≥65 years) using home care services in Southern Ontario, Canada. Each study was designed to evaluate the effectiveness of different multi-component nurse-led health promotion and disease prevention (HPDP) interventions. The nurse-led HPDP interventions were 6- or 12-month multi-component and evidence-based strategies targeting known risk factors for functional decline and frailty. Across the three studies, a common approach was used to measure the change in health-related quality of life (HRQOL) (SF-36) and the costs of use of health services (Health and Social Services Utilization Inventory) from baseline to the end of the intervention. The main lesson learned from the three studies is that nurse-led HPDP interventions for frail older home care clients provide greater improvements in HRQOL compared with usual home care. Such approaches are highly acceptable to this population and can be implemented using existing home care resources. Nurse-led HPDP interventions should include multiple home visits, multidimensional screening and assessment, multi-component evidence-based HPDP strategies, intensive case management, inter-professional collaboration, providers with geriatric training and experience, referral to and coordination of community services, and theory use. The results of the three trials underscore the need to reinvest in nurse-led HPDP interventions in home care to optimize HRQOL and promote ageing in place in the target population of frail older adults. More studies are needed to evaluate the effectiveness of additional nurse-led HPDP interventions in other contexts and settings.

Relationships Among Composite Severity Indices, Depressive and Anxious Symptoms, and Health-Related Quality of Life in Patients With COPD

PURPOSE: Chronic obstructive pulmonary disease (COPD) is recognized as a multi-component disease with impaired health status. Several composite severity indices have been developed and validated for predicting prognosis of patients with COPD. The aim of this study was to evaluate relationships among composite severity indices, depressive and anxious symptoms, and health-related quality of life in patients with COPD.

Anti-Tissue Antibodies Are Related to Lung Function in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease. Autoimmunity can contribute to the pathogenesis of COPD. This study investigates the prevalence of circulating antinuclear antibodies (ANA) and anti-tissue (AT) antibodies, two common markers of autoimmunity, in COPD and their relationship with several components of the disease. We determined lung function, the serum titers of ANA and AT by immunofluorescence, and the serum levels of C-reactive protein (CRP) by high sensitivity nephelometry in 328 patients with clinically stable COPD and in 67 healthy controls recruited in the PAC-COPD study. Multiple linear and logistic regression analysis was used to analyze results. The prevalence of abnormal ANA and AT titers was 34% and 26% in patients and 3% and 6% in controls, respectively. Levels of AT greater than or equal to 1:320 were seen in 21% of patients with COPD and were independently associated with the severity of airflow limitation and gas transfer impairment (P < 0.05). Neither ANA or AT titers was related to body mass index, current smoking status, use of inhaled steroids, the Charlson index, or serum C-reactive protein values. Between a quarter and a third of patients with clinically stable COPD present abnormal titers of circulating ANA and AT. The observed relationship between AT and lung function supports a role for autoimmunity in the pathogenesis of COPD.

Multicomponent staging indices for chronic obstructive pulmonary disease in daily patient care: what’s the yield?

Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation that is not fully reversible (1). For years, the focus of COPD disease management has been to delay the progression of airflow obstruction. However, this mission was rarely successful as the current pharmacotherapy (i.e., inhaled corticosteroids and bronchodilators) does not result in relevant protective effects in terms of lung function decline (2,3). The only way in which accelerated lung function decline can successfully be prevented is to persvade and support patients to quit smoking. Unfortunately, many patients with COPD are reluctant or unable to do so (4). Presently, COPD is no longer considered to be almost synonymous to chronic progressive airflow obstruction, but is considered to be a multicomponent disease that involves extrapulmonary effects such as decreased exercise capacity and peripheral muscle depletion. These extrapulmonary effects of COPD also contribute to the progressive nature of the disease (5,6). Moreover, the levels of functional impairment may differ substantially between patients with COPD who have the same level of airflow obstruction (7). To be able to translate this present-day understanding of the disease to daily practice requires a multicomponent staging index that produces a 'composite picture' of COPD disease severity (8). In this perspective study, we discuss the latest developments with regard to staging indexes for COPD and their value for primary care.

"Show me the money": a fair criticism of economic studies on inhaled bronchodilators for COPD

Chronic obstructive pulmonary disease (COPD) represents a significant burden for healthcare systems that is expected to grow further in the future. Inhaled long-acting bronchodilators, including tiotropium, represent the cornerstone of management of COPD patients. Economic studies evaluating the cost-effectiveness ratio of inhaled bronchodilators have to take into account several parameters, including the reduction of COPD exacerbations and related hospitalizations, as well as disease modification and improvement in quality of life and mortality. At an era when the healthcare resources are unlikely to grow as quickly as demand, economic analyses remain the cornerstone for the justification of the broad use of medication with an acceptable cost-effectiveness ratio. The greatest importance of such studies in COPD is the identification of subgroups of patients that will have the most benefit with an acceptable cost-effectiveness ratio for the healthcare providers. The development of models that will incorporate a global evaluation of the different aspects of this multi-component disease, in order to provide the best available care to each individual patient is urgently needed.