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      Clinical utility of fractional exhaled nitric oxide and blood eosinophils counts in the diagnosis of asthma–COPD overlap

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          Asthma–COPD overlap (ACO) is difficult to diagnose because it is characterized by persistent airflow limitation, and patients present with several manifestations that are usually associated with both asthma and COPD. In this retrospective study, we aimed to evaluate the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) and blood eosinophil counts for the clinical diagnosis of ACO.

          Patients and methods

          A total of 121 patients were divided into two study groups, COPD alone or ACO, which was based on criteria from the joint document by the Global Initiative for Asthma and the Global initiative for chronic Obstructive Lung Disease. From July 2014 to April 2017, FeNO levels and blood eosinophil counts were measured in specimens from patients naïve to inhaled corticosteroids (ICS) and those using ICS. Receiver operating characteristic curve analysis was used to determine the cutoff values of FeNO and blood eosinophil levels that provided the best differential diagnosis between ACO and COPD.


          Among a total of 121 patients, 65 patients were diagnosed with COPD and 56 patients with ACO. The FeNO level was higher in patients with ACO than in patients with COPD (median 24.5 vs 16.0 ppb, respectively; P<0.01). Among patients naïve to ICS, the area under the receiver operating characteristic curve of FeNO values was 0.726, and the optimal diagnostic cutoff level of FeNO was 25.0 ppb, with 60.6% sensitivity and 87.7% specificity for differentiating ACO from COPD. FeNO (≥25.0 ppb) combined with blood eosinophil counts (≥250/μL) showed 96.1% specificity.


          These results demonstrate that the FeNO level combined with blood eosinophil count is useful for the differential diagnosis between ACO and COPD.

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          Most cited references 17

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          The clinical features of the overlap between COPD and asthma

          Background The coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma. Methods We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study. Results 119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p = 0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p = 0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p < 0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p < 0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness. Conclusion Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history. Trial registration NCT00608764
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            Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis.

            Recent studies have suggested a possible association between pneumonia and the use of inhaled corticosteroids. We aimed to ascertain the risk of pneumonia with long-term inhaled corticosteroid use among patients with chronic obstructive pulmonary disease (COPD). We performed systematic searches with no date restrictions through June 30, 2008, of MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, regulatory documents, and trial registries. We included randomized controlled trials of any inhaled corticosteroid vs a control treatment for COPD, with at least 24 weeks of follow-up and reporting of pneumonia as an adverse event. Outcomes evaluated included any pneumonia, serious pneumonia, pneumonia-related mortality, and overall mortality. Eighteen randomized controlled trials (n = 16 996) with 24 to 156 weeks of follow-up were included after a detailed screening of 97 articles. Inhaled corticosteroids were associated with a significantly increased risk of any pneumonia (relative risk [RR], 1.60; 95% confidence interval [CI], 1.33-1.92 [P < .001]; I(2) = 16%) and serious pneumonia (1.71; 1.46-1.99 [P < .001]; I(2) = 0%) but without a significantly increased risk of pneumonia-related mortality (1.27; 0.80-2.03 [P = .31]; I(2) = 0%) or overall mortality (0.96; 0.86-1.08 [P = .51]; I(2) = 0%). Inhaled corticosteroids were associated with a significantly increased risk of serious pneumonia when compared with placebo (RR, 1.81; 95% CI, 1.44-2.29 [P < .001]) or when the combination of inhaled corticosteroids and long-acting beta-agonists was compared with long-acting beta-agonists (1.68; 1.20-2.34 [P = .002]). Among patients with COPD, inhaled corticosteroid use for at least 24 weeks is associated with a significantly increased risk of serious pneumonia, without a significantly increased risk of death.
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              Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis.

              Recent studies of inhaled corticosteroid (ICS) therapy for managing stable chronic obstructive pulmonary disease (COPD) have yielded conflicting results regarding survival and risk of adverse events. To systematically review and quantitatively synthesize the effects of ICS therapy on mortality and adverse events in patients with stable COPD. Search of MEDLINE, CENTRAL, EMBASE, CINAHL, Web of Science, and PsychInfo through February 9, 2008. Eligible studies were double-blind, randomized controlled trials comparing ICS therapy for 6 or more months with nonsteroid inhaled therapy in patients with COPD. Two authors independently abstracted data including study characteristics, all-cause mortality, pneumonia, and bone fractures. The I(2) statistic was used to assess heterogeneity. Study-level data were pooled using a random-effects model (when I(2) > or = 50%) or a fixed-effects model (when I(2) < 50%). For the primary outcome of all-cause mortality at 1 year, our meta-analysis was powered to detect a 1.0% absolute difference in mortality, assuming a 2-sided alpha of .05 and power of 0.80. Eleven eligible randomized controlled trials (14,426 participants) were included. In trials with mortality data, no difference was observed in 1-year all-cause mortality (128 deaths among 4636 patients in the treatment group and 148 deaths among 4597 patients in the control group; relative risk [RR], 0.86; 95% confidence interval [CI], 0.68-1.09; P = .20; I(2) = 0%). In the trials with data on pneumonia, ICS therapy was associated with a significantly higher incidence of pneumonia (777 cases among 5405 patients in the treatment group and 561 cases among 5371 patients in the control group; RR, 1.34; 95% CI, 1.03-1.75; P = .03; I(2) = 72%). Subgroup analyses indicated an increased risk of pneumonia in the following subgroups: highest ICS dose (RR, 1.46; 95% CI, 1.10-1.92; P = .008; I(2) = 78%), shorter duration of ICS use (RR, 2.12; 95% CI, 1.47-3.05; P < .001; I(2) = 0%), lowest baseline forced expiratory volume in the first second of expiration (RR, 1.90; 95% CI, 1.26-2.85; P = .002; I(2) = 0%), and combined ICS and bronchodilator therapy (RR, 1.57; 95% CI, 1.35-1.82; P < .001; I(2) = 24%). Among patients with COPD, ICS therapy does not affect 1-year all-cause mortality. ICS therapy is associated with a higher risk of pneumonia. Future studies should determine whether specific subsets of patients with COPD benefit from ICS therapy.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                21 August 2018
                : 13
                : 2525-2532
                Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku City, Kochi, Japan, honi@
                Author notes
                Correspondence: Hiroshi Ohnishi, Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan, Tel +81 88 880 2345, Fax +81 88 880 2348, Email honi@
                © 2018 Takayama et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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