Clinical application of a simple questionnaire for the differentiation of asthma and chronic obstructive pulmonary disease

AbstractBackground: Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic diseases characterized by airflow limitation. Both diseases have a distinct pathogenesis and require unique treatment approaches. Due to some common characteristic traits, asthma and COPD are often lumped together in clinical practice. We sought to develop a simple questionnaire for the distinction of asthma and COPD.Methods: Clinical discriminants of asthma and COPD were retrospectively identified by multiple logistic regression using files from 547 consecutive adult patients presenting to a pulmonary specialist practice with a diagnosis of asthma or COPD. With these features, we generated a simple quantitative questionnaire supporting a diagnosis of COPD with high scores and asthma with low scores (range 0–15 points). Questionnaire results were compared with physician's diagnosis based on GINA and GOLD guidelines including skin tests, spirometry and reversibility data.Results: 210 patients had COPD and 337 had asthma. Age of onset, smoking history, atopy status, and cough quality were significantly associated with a diagnosis of asthma or COPD. Questionnaire scores for COPD patients were higher than those for asthmatics (mean score 10.5±0.18 vs. 4±0.12, P<0.0001). Receiver operational characteristics (ROC) analysis revealed a cutoff score of 7 with the highest discriminant power (87.6% sensitivity, 87.2% specificity for COPD, 87.4% correctly classified, area under the ROC curve: 0.954). The overlap between asthma and COPD (score 6–8) comprised about 20% of the total population, these patients included a higher proportion of COPD patients with atopy, and smoking asthmatics.Conclusions: In patients with obstructive airway diseases, a simple questionnaire can support the differentiation of asthma and COPD in everyday clinical practice. Further prospective trials are necessary to confirm these initial observations

The impact of treatment with indacaterol in patients with COPD:A post-hoc analysis according to GOLD 2011 categories A to D

AbstractBackgroundIndacaterol is an inhaled, once-daily, ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). We report on the effectiveness of indacaterol and other bronchodilators compared with placebo in patients across the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 categories A to D.MethodsA post-hoc, subgroup pooled analysis of 6-month efficacy data from three randomized, placebo-controlled, parallel-group studies involving 3862 patients was performed across GOLD 2011 categories A to D, according to baseline forced expiratory volume in 1 s (FEV1) % predicted, modified Medical Research Council (mMRC) dyspnea scale, and exacerbation history in the 12 months prior to entry. Efficacy of once-daily indacaterol 150 and 300 μg, open-label tiotropium 18 μg, twice-daily salmeterol 50 μg, and formoterol 12 μg was compared with placebo. End points analysed were trough FEV1, transition dyspnea index (TDI), and St George's Respiratory Questionnaire (SGRQ) total score, all at Week 26, and mean rescue medication use over 26 weeks.ResultsIndacaterol 150 and 300 μg significantly improved FEV1, compared with placebo across all GOLD groups. Indacaterol 150 and 300 μg also significantly improved TDI, SGRQ total score, and mean rescue medication use compared with placebo across most GOLD subgroups.ConclusionsTreatment selection according to patient's symptoms as well as lung function is an important consideration in maintenance treatment of COPD. Indacaterol 150 and 300 μg effectively improved lung function and symptoms in patients across all GOLD 2011 categories

A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison

SummaryThis dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled β2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected.In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV1⩾40% of predicted and ⩾1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400μg or placebo via multi-dose dry powder inhaler, or indacaterol 400μg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18μg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC22–24h) on Day 1.Clinically relevant improvements versus placebo in FEV1 AUC22–24h were seen for 400 and 200μg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200μg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension.The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled β2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile

The impact of treatment with indacaterol in patients with COPD: A post-hoc analysis according to GOLD 2011 categories A to D

BACKGROUND: Indacaterol is an inhaled, once-daily, ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). We report on the effectiveness of indacaterol and other bronchodilators compared with placebo in patients across the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 categories A to D. METHODS: A post-hoc, subgroup pooled analysis of 6-month efficacy data from three randomized, placebo-controlled, parallel-group studies involving 3862 patients was performed across GOLD 2011 categories A to D, according to baseline forced expiratory volume in 1 s (FEV1) % predicted, modified Medical Research Council (mMRC) dyspnea scale, and exacerbation history in the 12 months prior to entry. Efficacy of once-daily indacaterol 150 and 300 μg, open-label tiotropium 18 μg, twice-daily salmeterol 50 μg, and formoterol 12 μg was compared with placebo. End points analysed were trough FEV1, transition dyspnea index (TDI), and St George's Respiratory Questionnaire (SGRQ) total score, all at Week 26, and mean rescue medication use over 26 weeks. RESULTS: Indacaterol 150 and 300 μg significantly improved FEV1, compared with placebo across all GOLD groups. Indacaterol 150 and 300 μg also significantly improved TDI, SGRQ total score, and mean rescue medication use compared with placebo across most GOLD subgroups. CONCLUSIONS: Treatment selection according to patient's symptoms as well as lung function is an important consideration in maintenance treatment of COPD. Indacaterol 150 and 300 μg effectively improved lung function and symptoms in patients across all GOLD 2011 categories

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma:pooled analysis of phase 3 trials

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO

Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme

BACKGROUND : The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA). METHODS : We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1). RESULTS : After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P = 0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P = 0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo. CONCLUSIONS : Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses

The Colorectal cancer disease-specific transcriptome may facilitate the discovery of more biologically and clinically relevant information

<p>Abstract</p> <p>Background</p> <p>To date, there are no clinically reliable predictive markers of response to the current treatment regimens for advanced colorectal cancer. The aim of the current study was to compare and assess the power of transcriptional profiling using a generic microarray and a disease-specific transcriptome-based microarray. We also examined the biological and clinical relevance of the disease-specific transcriptome.</p> <p>Methods</p> <p>DNA microarray profiling was carried out on isogenic sensitive and 5-FU-resistant HCT116 colorectal cancer cell lines using the Affymetrix HG-U133 Plus2.0 array and the Almac Diagnostics Colorectal cancer disease specific Research tool. In addition, DNA microarray profiling was also carried out on pre-treatment metastatic colorectal cancer biopsies using the colorectal cancer disease specific Research tool. The two microarray platforms were compared based on detection of probesets and biological information.</p> <p>Results</p> <p>The results demonstrated that the disease-specific transcriptome-based microarray was able to out-perform the generic genomic-based microarray on a number of levels including detection of transcripts and pathway analysis. In addition, the disease-specific microarray contains a high percentage of antisense transcripts and further analysis demonstrated that a number of these exist in sense:antisense pairs. Comparison between cell line models and metastatic CRC patient biopsies further demonstrated that a number of the identified sense:antisense pairs were also detected in CRC patient biopsies, suggesting potential clinical relevance.</p> <p>Conclusions</p> <p>Analysis from our <it>in vitro </it>and clinical experiments has demonstrated that many transcripts exist in sense:antisense pairs including <it>IGF2BP2</it>, which may have a direct regulatory function in the context of colorectal cancer. While the functional relevance of the antisense transcripts has been established by many studies, their functional role is currently unclear; however, the numbers that have been detected by the disease-specific microarray would suggest that they may be important regulatory transcripts. This study has demonstrated the power of a disease-specific transcriptome-based approach and highlighted the potential novel biologically and clinically relevant information that is gained when using such a methodology.</p

Comparative Lipidomics in Clinical Isolates of Candida albicans Reveal Crosstalk between Mitochondria, Cell Wall Integrity and Azole Resistance

Prolonged usage of antifungal azoles which target enzymes involved in lipid biosynthesis invariably leads to the development of multi-drug resistance (MDR) in Candida albicans. We had earlier shown that membrane lipids and their fluidity are closely linked to the MDR phenomenon. In one of our recent studies involving comparative lipidomics between azole susceptible (AS) and azole resistant (AR) matched pair clinical isolates of C. albicans, we could not see consistent differences in the lipid profiles of AS and AR strains because they came from different patients and so in this study, we have used genetically related variant recovered from the same patient collected over a period of 2-years. During this time, the levels of fluconazole (FLC) resistance of the strain increased by over 200-fold. By comparing the lipid profiles of select isolates, we were able to observe gradual and statistically significant changes in several lipid classes, particularly in plasma membrane microdomain specific lipids such as mannosylinositolphosphorylceramides and ergosterol, and in a mitochondrial specific phosphoglyceride, phosphatidyl glycerol. Superimposed with these quantitative and qualitative changes in the lipid profiles, were simultaneous changes at the molecular lipid species levels which again coincided with the development of resistance to FLC. Reverse transcriptase-PCR of the key genes of the lipid metabolism validated lipidomic picture. Taken together, this study illustrates how the gradual corrective changes in Candida lipidome correspond to the development of FLC tolerance. Our study also shows a first instance of the mitochondrial membrane dysfunction and defective cell wall (CW) in clinical AR isolates of C. albicans, and provides evidence of a cross-talk between mitochondrial lipid homeostasis, CW integrity and azole tolerance