Prepandemic viral community-acquired pneumonia: Diagnostic sensitivity and specificity of nasopharyngeal swabs and performance of clinical severity scores.

The objectives of this work were to assess the diagnostic sensitivity and specificity of nasopharyngeal (NP) swabs for viral community-acquired pneumonia (CAP) and the performance of pneumonia severity index (PSI) and CURB-65 severity scores in the viral CAP in adults. A prospective observational cohort study of consecutive 341 hospitalized adults with CAP was performed between January 2018 and March 2020. Demographics, comorbidities, symptoms/signs, analytical data, severity scores, antimicrobials, and outcomes were recorded. Blood, NP swabs, sputum, and urine samples were collected at admission and assayed by multiplex real time-PCR, bacterial cultures, and Streptococcus pneumoniae and Legionella pneumophila antigens detection, to determine the etiologies and quantify the viral load. The etiology was identified in 174 (51.0%) patients, and in 85 (24.9%) it was viral, the most frequent rhinovirus and influenza virus. The sensitivity of viral detection in sputum (50.7%) was higher than in NP swabs (20.9%). Compared with sputum, the positive predictive value and specificity of NP swabs for viral diagnosis were 95.8% and 96.9%, respectively. Performance of PSI and CURB-65 scores in all CAP with etiologic diagnosis were as expected, with mortality associated with higher values, but they were not associated with mortality in patients with viral pneumonia. NP swabs have lower sensitivity but high specificity for the diagnosis of viral CAP in adults compared with sputum, reinforcing the use NP swabs for the diagnostic etiology work-up. The PSI and CURB-65 scores did not predict mortality in the viral CAP, suggesting that they need to be updated scores based on the identification of the etiological agent.

Inflammatory response in human lung cells stimulated with plasma from COPD patients.

Background: Chronic obstructive pulmonary disease (COPD) is a condition resulting from a persistent inflammatory state in the airways even after smoking cessation. Intriguingly, the reasons behind this persistence of the inflammatory influx without smoking exposure have not been fully unraveled. We aimed to explore the hypothesis that systemic inflammation in COPD patients influences lung cell inflammatory response. Methods: We cultured human lung fibroblast and human airway epithelial cell lines with plasma from COPD patients (four emphysematous-COPD, four asthma-COPD overlap, four chronic bronchitis-COPD, and four bronchiectasis- COPD), and four smokers or ex-smokers without COPD as controls. Non-stimulated cells were used as controls. We measured Interleukine-8 (IL-8), C-reactive protein (CRP) and matrix metalloproteinase-9 (MMP-9) in plasma and culture supernatants by ELISA. Results: Cells stimulated with plasma from COPD patients and non-COPD smoker subjects produced higher CRP, IL- 8 and MMP-9 levels, an increase for COPD in CRP (p=0.029) in epithelial cells and IL-8 (p=0.039) in fibroblasts and decrease for MMP-9 (p=0.039) in fibroblasts, compared with non-stimulated cells. The response was higher in epithelial cells for IL-8 (p=0.003) and in fibroblasts for MMP-9 (p=0.063). The plasma from chronic bronchitis and bronchiectasis phenotypes induced higher IL-8 in fibroblasts. Conclusions: Plasma from COPD patients increases the inflammatory response in lung epithelial cells and lung fibroblasts, with a different response depending on the cell type and clinical phenotype.

Effectiveness and Safety of Inhaled Antibiotics in Patients With Chronic Obstructive Pulmonary Disease. A Multicentre Observational Study.

BACKGROUND: We aimed to describe the effectiveness and safety of inhaled antibiotics in chronic obstructive pulmonary disease (COPD) patients, as well as the patient profile in which they are usually prescribed and the patient groups that can most benefit from this treatment. METHODS: Multicentre retrospective observational cohort study in COPD patients who had received ≥1 dose of inhaled antibiotics in the last 5 years. Clinical data from the two years prior to and subsequent to the start of the treatment were compared. PRIMARY OUTCOME: COPD exacerbations. SECONDARY OUTCOMES: side effects, symptomatology (sputum purulence, dyspnoea), microbiological profile and pathogen eradication. RESULTS: Of 693 COPD patients analyzed (aged 74.1; 86.3% men; mean FEV1=43.7%), 71.7% had bronchiectasis and 46.6% presented chronic bronchial infection (CBI) by Pseudomonas aeruginosa (PA). After 1 year of treatment with inhaled antibiotics, there was a significant decrease in the number of exacerbations (-33.3%; P<.001), hospital admissions (-33.3%; P<.001) and hospitalization days (-26.2%; P=.003). We found no difference in effectiveness between patients with or without associated bronchiectasis. Positive patient outcomes were more pronounced in PA-eradicated patients. We found a significant reduction in daily expectoration (-33.1%; P=.024), mucopurulent/purulent sputum (-53.9%; P<.001), isolation of any potentially pathogenic microorganisms (PPM) (-16.7%; P<.001), CBI by any PPM (-37.4%; P<.001) and CBI by PA (-49.8%; P<.001). CBI by any PPM and ≥three previous exacerbations were associated with a better treatment response. 25.4% of patients presented non-severe side-effects, the most frequent of these being bronchospasm (10.5%), dyspnoea (8.8%) and cough (1.7%). CONCLUSIONS: In COPD patients with multiple exacerbations and/or CBI by any PPM (especially PA), inhaled antibiotics appear to be an effective and safe treatment, regardless of the presence of bronchiectasis.

Deconstructing Phenotypes in COPD: an Analysis of the TRACE Cohort. / Deconstruyendo los fenotipos en la EPOC: un análisis de la cohorte TRACE.

OBJECTIVES: In a clinical phenotype-based management strategy for COPD, it would be preferable to at least assign all patients to a phenotype, but to a single phenotype only. The aim of this study was to evaluate whether all patients are assigned to one and only one phenotype using the Spanish COPD guidelines (GesEPOC) and to evaluate the criteria that define these categories. METHOD: The Time-based Register and Analysis of COPD Endpoints study (TRACE; clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients attending annual visits since 2012, which collects GesEPOC phenotypes. Although the GesEPOC recommends that patients considered to be at low risk are not phenotyped, an analysis of the criteria for identifying high- and low-risk phenotypes was performed, comparing the distribution of phenotypes and the criteria applied between these 2 groups. RESULTS: The cohort included 970 patients with a confirmed diagnosis of COPD, divided into 427 (44.02%) low-risk and 543 (55.9%) high-risk patients. The most frequent phenotype was the non-exacerbator (44.9% of high-risk patients). Overall, 20.6% of low-risk patients met criteria for asthma-COPD overlap syndrome, while 9.2% of the cohort did not meet the diagnostic criteria for any phenotype, and 19.1% met the criteria for 2 phenotypes, with no differences between risk groups. CONCLUSIONS: Our data highlight some of the weaknesses of the current clinical phenotype strategy, revealing overlapping categories in some cases, and patients to whom no phenotype was assigned.

Predictors of Single Bronchodilation Treatment Response for COPD: An Observational Study with the Trace Database Cohort.

Chronic obstructive pulmonary disease (COPD) patients constitute a heterogeneous population in terms of treatment response. Our objective was to identify possible predictive factors of response to treatment with single bronchodilation monotherapy in patients diagnosed with COPD. The Time-based Register and Analysis of COPD Endpoints (TRACE; clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients who have been attending annual visits since 2012. Patients who were kept on a single bronchodilator during the first year of follow-up were selected. The responders were defined according to all of the following variables: any improvement in morning post-dose forced expiratory volume in 1 s or deterioration <100 mL, no change or improvement in dyspnea score, and no occurrence of exacerbations. Significant and plausible variables were analyzed using a proportional hazard Cox regression for single bronchodilator responders. We analyzed 764 cases, of whom 128 (16.8%) were receiving monotherapy with one bronchodilator. Of these, 85 patients (66.4%) were responders. Factors affecting responder status were: female gender (hazard ratio (HR) 0.276; 95% confidence interval (CI) 0.089-0.858), dyslipidemia (HR 0.436; 95%CI 0.202-0.939), not performing regular exercise (HR 0.523; 95%CI 0.254-1.076), active smoking (HR 0.413; 95%CI 0.186-0.920), and treatment adherence (HR 2.527; 95%CI 1.271-5.027). The factors associated with a single bronchodilation response are mainly non-pharmacological interventions and comorbidities.

Triple therapy for COPD: a crude analysis from a systematic review of the evidence.

We systematically reviewed the current knowledge on fixed-dose triple therapies for the treatment of chronic obstructive pulmonary disease (COPD), with a specific focus on its efficacy versus single bronchodilation, double fixed dose combinations, and open triple therapies. Articles were retrieved from PubMed, Embase, and Scopus up to 3 August 2018. We selected articles with randomized controlled or crossover design conducted in patients with COPD and published as full-length articles or scientific letters, evaluating triple therapy combinations in a single or different inhaler, and with efficacy data versus monocomponents, double combinations, or open triple therapies. Our systematic search reported 108 articles, of which 24 trials were finally selected for the analysis. A total of 7 studies with fixed dose triple therapy combinations, and 17 studies with open triple therapies combinations. Triple therapy showed improvements in lung function [trough forced expiratory volume (FEV1) ranging from not significant (NS) to 147 ml], health status using the St. George's Respiratory Questionnaire [(SGRQ) from NS to 8.8 points], and exacerbations [risk ratio (RR) from NS to 0.59 for all exacerbations] versus single or double therapies with a variability in the response, depending the specific combination, and the comparison group. The proportion of adverse effects was similar between study groups, the exception being the increase in pneumonia for some inhaled corticosteroid (ICS) containing groups. The reviews of this paper are available via the supplementary material section.

Understanding of COPD among final-year medical students.

Objective: Several previous studies have shown a suboptimal level of understanding of COPD among different population groups. Students in their final year of Medicine constitute a population that has yet to be explored. The evaluation of their understanding provides an opportunity to establish strategies to improve teaching processes. The objective of the present study is to determine the current level of understanding of COPD among said population. Methods: A cross-sectional observational study was done using digital surveys given to medical students in their final year at the Universidad de Sevilla. Those surveyed were asked about demographic data, smoking habits as well as the clinical manifestation, diagnosis and treatment of COPD. Results: Of the 338 students contacted, responses were collected from 211 of them (62.4%). Only 25.2% had an accurate idea about the concept of the disease. The study found that 24.0% of students were familiar with the three main symptoms of COPD. Tobacco use was not considered a main risk factor for COPD by 1.5% of students. Of those surveyed, 22.8% did not know how to spirometrically diagnose COPD. Inhaled corticosteroids were believed to be part of the main treatment for this disease among 51.0% of the students. Results show that 36.4% of respondents believed that home oxygen therapy does not help COPD patients live longer. Only 15.0% considered the Body-mass index, airflow Obstruction, Dyspnea, and Exercise (BODE) index to be an important parameter for measuring the severity of COPD. Giving up smoking was not believed to prevent worsening COPD among 3.4% of students surveyed. Almost half of students (47.1%) did not recommend that those suffering from COPD undertake exercise. Conclusion: The moderate level of understanding among the population of medical students in their final year shows some strengths and some shortcomings. Teaching intervention is required to reinforce solid knowledge among this population.

Double bronchodilation in chronic obstructive pulmonary disease: a crude analysis from a systematic review.

OBJECTIVE: The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting ß2-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation. METHODS: A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations. RESULTS: We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies. CONCLUSION: Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes.

Seasonal variability in clinical care of COPD outpatients: results from the Andalusian COPD audit.

OBJECTIVES: Clinical practice in chronic obstructive pulmonary disease (COPD) can be influenced by weather variability throughout the year. To explore the hypothesis of seasonal variability in clinical practice, the present study analyzes the results of the 2013-2014 Andalusian COPD audit with regard to changes in clinical practice according to the different seasons. METHODS: The Andalusian COPD audit was a pilot clinical project conducted from October 2013 to September 2014 in outpatient respiratory clinics of hospitals in Andalusia, Spain (8 provinces with more than 8 million inhabitants) with retrospective data gathering. For the present analysis, astronomical seasons in the Northern Hemisphere were used as reference. Bivariate associations between the different COPD guidelines and the clinical practice changes over the seasons were explored by using binomial multivariate logistic regression analysis with age, sex, Charlson comorbidity index, type of hospital, and COPD severity by forced expiratory volume in 1 second as covariates, and were expressed as odds ratio (OR) with 95% confidence intervals (CIs). RESULTS: The Andalusian COPD audit included 621 clinical records from 9 hospitals. After adjusting for covariates, only inhaler device satisfaction evaluation was found to significantly differ according to the seasons with an increase in winter (OR, 3.460; 95% CI, 1.469-8.151), spring (OR, 4.215; 95% CI, 1.814-9.793), and summer (OR, 3.371; 95% CI, 1.391-8.169) compared to that in autumn. The rest of the observed differences were not significant after adjusting for covariates. However, compliance with evaluating inhaler satisfaction was low. CONCLUSION: The various aspects of clinical practice for COPD care were found to be quite homogeneous throughout the year for the variables evaluated. Inhaler satisfaction evaluation, however, presented some significant variation during the year. Inhaler device satisfaction should be evaluated during all clinical visits throughout the year for improved COPD management.

Specific networks of plasma acute phase reactants are associated with the severity of chronic obstructive pulmonary disease: a case-control study.

Objectives. A detailed understanding of the intricate relationships between different acute phase reactants (APRs) in chronic obstructive pulmonary disease (COPD) can shed new light on its clinical course. In this case-control study, we sought to identify the interaction networks of a number of plasma APRs in COPD, with a special focus on their association with disease severity. Methods. COPD cases and healthy smoking controls (3:1 ratio) were recruited in our outpatient pulmonary clinic. Cardiopulmonary exercise testing was used to rule out the presence of ischemic heart disease. All subjects were males as per protocol. Multiple plasma APRs - including α-2-macroglobulin, C-reactive protein (CRP), ferritin, fibrinogen, haptoglobin, procalcitonin (PCT), serum amyloid A (SAA), serum amyloid P, and tissue plasminogen activator (tPA) - were measured using commercial Acute Phase Bio-Plex Pro Assays and analyzed on the Bio-Plex manager software. Correlations between different APRs were investigated using a heat map. Network visualization and analyses were performed with the Cytoscape software platform. Results. A total of 96 COPD cases and 33 controls were included in the study. Plasma A2M, CRP, and SAP levels were higher in COPD patients than in controls. Circulating concentrations of haptoglobin and tPA were found to increase in parallel with the severity of the disease. Increasing disease severity was associated with distinct intricate networks of APRs, which were especially evident in advanced stages. Conclusions. We identified different networks of APRs in COPD, which were significantly associated with disease severity.

Occupational and Biomass Exposure in Chronic Obstructive Pulmonary Disease: Results of a Cross-Sectional Analysis of the On-Sint Study. / Exposición laboral y a biomasa en la enfermedad pulmonar obstructiva crónica: resultados de un análisis transversal del estudio On-Sint.

BACKGROUND: Although tobacco smoke is the main risk factor for chronic obstructive pulmonary disease (COPD), other inhaled toxics have also been associated with the disease. The present study analyzes data from exposure to these substances in a cohort of patients with COPD and assesses their impact on the clinical presentation of the disease. METHODS: This is a cross-sectional analysis of the Clinical presentation, diagnosis and course of chronic obstructive pulmonary disease (On-Sint) study. All patients were smokers or ex-smokers as per protocol. In addition, during the inclusion visit patients were enquired about their occupational and biomass exposure history. The clinical features of patients with and without an added risk factor to tobacco were compared and those significant were entered in a multivariate logistic regression analysis, expressed as odds ratio (OR). RESULTS: The sample size was 1214 patients with COPD, of which 1012 (83.4%) had tobacco as the only risk factor and 202 (16.6%) had additional ones, mainly 174 (14.3%) with occupational gases and 32 (2.6%) with biomass exposure. The geographical distribution of this exposure showed a preference for the northern parts of the country and the East coast. The biomass exposure was rather low. Male gender (OR: 2.180), CAT score (OR: 1.036) and the use of long-term oxygen therapy (OR: 1.642) were associated with having an additional risk factor in the multivariate analysis. CONCLUSIONS: Occupational exposures are more common than biomass in Spain. COPD caused by tobacco plus other inhalants has some differential features and a more impaired quality of life.

Evaluation of the visit frequency and the use of questionnaires and indices for COPD: a national survey from the On-Sint study.

INTRODUCTION: Despite widespread recommendations to use standardized questionnaires and multidimensional indices for the assessment of patients with chronic obstructive pulmonary disease (COPD), few data are available on the application of these tools in clinical practice. This study evaluates the attitude of physicians participating in the On-Sint cohort toward the use of health status questionnaires and multidimensional indices, as well as toward the frequency of visits and spirometry in primary care and specialized care. METHODS: During the constitution of the On-Sint cohort, the participating physicians were surveyed about their clinical practice. They were questioned on the frequency of spirometry and visits and on the use of various questionnaires and indices. The health status questionnaires assessed were St. George's respiratory questionnaire, chronic respiratory questionnaire, airways questionnaire 20 and COPD assessment test (CAT). Physicians were also asked about the use of the medical research council (MRC) dyspnea scale and multidimensional indices such as body mass index, airflow obstruction, dyspnea, exercise capacity (BODE). RESULTS: Of the 356 physicians who participated in the study, 258 (72.5 %) completed the investigator's questionnaire (185 primary care, 73 specialized care). Nonscheduled visits were inversely proportional to the severity of COPD. Overall, 34.1% reported using health status questionnaires, mainly CAT (20.9%). We found differences between primary and specialized care in the use of multidimensional indices (84.9% vs 47.6%; P < 0.001). Of all the participants, 33.3% reported using the MRC scale and 28.7% the BODE index. CONCLUSIONS: Multidimensional indices and questionnaires are not commonly used with some differences between primary care and specialized care physicians. There is a considerable variability in the frequency of follow-up visits and spirometry.

Determinants for changing the treatment of COPD: a regression analysis from a clinical audit.

INTRODUCTION: This study is an analysis of a pilot COPD clinical audit that evaluated adherence to guidelines for patients with COPD in a stable disease phase during a routine visit in specialized secondary care outpatient clinics in order to identify the variables associated with the decision to step-up or step-down pharmacological treatment. METHODS: This study was a pilot clinical audit performed at hospital outpatient respiratory clinics in the region of Andalusia, Spain (eight provinces with over eight million inhabitants), in which 20% of centers in the area (catchment population 3,143,086 inhabitants) were invited to participate. Treatment changes were evaluated in terms of the number of prescribed medications and were classified as step-up, step-down, or no change. Three backward stepwise binominal multivariate logistic regression analyses were conducted to evaluate variables associated with stepping up, stepping down, and inhaled corticosteroids discontinuation. RESULTS: The present analysis evaluated 565 clinical records (91%) of the complete audit. Of those records, 366 (64.8%) cases saw no change in pharmacological treatment, while 99 patients (17.5%) had an increase in the number of drugs, 55 (9.7%) had a decrease in the number of drugs, and 45 (8.0%) noted a change to other medication for a similar therapeutic scheme. Exacerbations were the main factor in stepping up treatment, as were the symptoms themselves. In contrast, rather than symptoms, doctors used forced expiratory volume in 1 second and previous treatment with long-term antibiotics or inhaled corticosteroids as the key determinants to stepping down treatment. CONCLUSION: The majority of doctors did not change the prescription. When changes were made, a number of related factors were noted. Future trials must evaluate whether these therapeutic changes impact clinically relevant outcomes at follow-up.

Cigarette Smoke Decreases the Maturation of Lung Myeloid Dendritic Cells.

BACKGROUND: Conflicting data exist on the role of pulmonary dendritic cells (DCs) and their maturation in patients with chronic obstructive pulmonary disease (COPD). Herein, we investigated whether disease severity and smoking status could affect the distribution and maturation of DCs in lung tissues of patients undergoing elective pneumectomy or lobectomy for suspected primary lung cancer. MATERIALS AND METHODS: A total of 75 consecutive patients were included. Spirometry testing was used to identify COPD. Lung parenchyma sections anatomically distant from the primary lesion were examined. We used flow cytometry to identify different DCs subtypes-including BDCA1-positive myeloid DCs (mDCs), BDCA3-positive mDCs, and plasmacytoid DCs (pDCs)-and determine their maturation markers (CD40, CD80, CD83, and CD86) in all participants. We also identified follicular DCs (fDCs), Langerhans DCs (LDCs), and pDCs in 42 patients by immunohistochemistry. RESULTS: COPD was diagnosed in 43 patients (16 current smokers and 27 former smokers), whereas the remaining 32 subjects were classified as non-COPD (11 current smokers, 13 former smokers, and 8 never smokers). The number and maturation of DCs did not differ significantly between COPD and non-COPD patients. However, the results of flow cytometry indicated that maturation markers CD40 and CD83 of BDCA1-positive mDCs were significantly decreased in smokers than in non-smokers (P = 0.023 and 0.013, respectively). Immunohistochemistry also revealed a lower number of LDCs in COPD patients than in non-COPD subjects. CONCLUSIONS: Cigarette smoke, rather than airflow limitation, is the main determinant of impaired DCs maturation in the lung.

Guideline Adherence in Outpatient Clinics for Chronic Obstructive Pulmonary Disease: Results from a Clinical Audit.

OBJECTIVES: Previous clinical audits of COPD have provided relevant information about medical intervention in exacerbation admissions. The present study aims to evaluate adherence to current guidelines in COPD through a clinical audit. METHODS: This is a pilot clinical audit performed in hospital outpatient respiratory clinics in Andalusia, Spain (eight provinces with more than 8 million inhabitants), including 9 centers (20% of the public centers in the area) between 2013 and 2014. Cases with an established diagnosis of COPD based on risk factors, clinical symptoms, and a post-bronchodilator FEV1/FVC ratio of less than 0.70 were deemed eligible. The performance of the outpatient clinics was benchmarked against three guidance documents available at the time of the audit. The appropriateness of the performance was categorized as excellent (>80%), good (60-80%), adequate (40-59%), inadequate (20-39%), and highly inadequate (<20%). RESULTS: During the audit, 621 clinical records were audited. Adherence to the different guidelines presented a considerable variability among the different participating hospitals, with an excellent or good adherence for symptom recording, MRC or CAT use, smoking status evaluation, spirometry, or bronchodilation therapy. The most outstanding areas for improvement were the use of the BODE index, the monitoring of treatments, the determination of alpha1-antitrypsin, the performance of exercise testing, and vaccination recommendations. CONCLUSIONS: The present study reflects the situation of clinical care for COPD patients in specialized secondary care outpatient clinics. Adherence to clinical guidelines shows considerable variability in outpatient clinics managing COPD patients, and some aspects of the clinical care can clearly be improved.

Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by both local and systemic inflammation. Because inflammation plays a critical role in the development, course and severity of COPD, inflammatory markers have the potential to improve the current diagnostic and prognostic approaches. Local inflammation in COPD is characterized by an infiltration of inflammatory cells, with an increased expression of cytokines, chemokines, enzymes, growth factors and adhesion molecules. Systemic low-grade inflammation is another common but nonspecific finding in COPD. Exacerbations of COPD are acute clinical events accompanied by an exaggerated inflammatory response. Future investigations in the field of COPD biomarkers should take into account different study designs and biochemical assays, disease course and duration, variations in symptom severity and timing of measurement.