EPOC: Enfoque personalizado para el tratamiento según la guía GOLD 2021

<b>Background:</b> In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. <b>Methods:</b> KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 μg, GFF 14.4/10 μg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 μg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12–24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. <b>Results:</b> Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS &#x3c;300 cells/mm³. In this group, BGF significantly improved morning pre-dose trough FEV₁ versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted <i>p</i> &#x3c; 0.0001 and 51 mL [20, 81], unadjusted <i>p</i> = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted <i>p</i> = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS &#x3c;300 cells/mm³ and the overall population. <b>Conclusions:</b> In patients with moderate-to-very-severe COPD without airway reversibility and EOS &#x3c;300 cells/mm³, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. <b>Trial registration:</b> ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001

Efficacy of budesonide/glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts

Background In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. Methods KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 μg, GFF 14.4/10 μg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 μg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12–24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. Results Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population. Conclusions In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001

Impact of baseline clinical asthma characteristics on the response to mepolizumab: a post hoc meta-analysis of two Phase III trials

Background Severe asthma is associated with a broad range of phenotypes and clinical characteristics. This analysis assessed whether select baseline patient characteristics could prognosticate mepolizumab efficacy in severe eosinophilic asthma. Methods This was a post hoc meta-analysis of data from the Phase III MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862) studies. Patients aged ≥ 12 years with severe eosinophilic asthma and a history of exacerbations were randomised to receive placebo (MENSA/MUSCA), mepolizumab 75 mg intravenously (MENSA) or 100 mg subcutaneously (SC) (MENSA/MUSCA) every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations and changes from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) total score and Asthma Control Questionnaire (ACQ)-5 score. Analyses were performed by baseline age of asthma onset (< 18 years; 18–40 years; ≥ 40 years); lung function (% predicted FEV1 ≤ 60; 60–80; > 80); airway reversibility (reversible [≥ 12% change in FEV1]; non-reversible [< 12% change in FEV1]); perennial and/or seasonal allergen sensitivity (yes/no); asthma control (uncontrolled [ACQ-5 score ≥ 1.5]; partial/complete control [ACQ-5 score < 1.5]). Results Overall, 936 patients received mepolizumab 100 mg SC or placebo. Across age at asthma onset, lung function and airway reversibility subgroups, mepolizumab reduced the rate of clinically significant exacerbations by 49–63% versus placebo. Improvements in lung function, SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across most age and lung function subgroups. Clinically significant exacerbations were reduced with mepolizumab versus placebo irrespective of season or allergen sensitivity; SGRQ total and ACQ-5 scores were generally improved across seasons. Conclusions Mepolizumab efficacy was consistent for patients with varying age at asthma onset, lung function, airway reversibility and allergen sensitivities at baseline. Our results indicate that mepolizumab is likely to be beneficial for patients with severe eosinophilic asthma with a broad range of baseline clinical characteristics; large-scale real-world studies are needed to confirm the external validity of these findings. Trial registration Post hoc meta-analysis of data from MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862)

Impulse Oscillometry May Be Useful in Evaluation of Bronchiectasis Severity and Prediction of Airway Reversibility.

BackgroundImpulse oscillometry (IOS) can be used to evaluateairway impedance in patients with obstructive airway diseases. Previous studies have demonstrated that IOS parameters differ betweenbronchiectasis patients and healthy controls. This study aims to explore the usefulness of IOS in assessing disease severity and airway reversibility in bronchiectasis.MethodSeventy-four patients with non-cystic fibrosis bronchiectasis who visited our Respiratory Medicine outpatient clinic were consecutively recruited. Spirometry, plethysmography and IOS tests were performed. Patients were stratified into mild, moderate and severe disease according to Reiff, Bhalla, BSI, FACED, and BRICS scores. Airway reversibility was measured by bronchodilation test (BDT) and the result was classified as positive or negative.. ROC curves of IOS parameters was used to assess the usefulness of IOS parameters in predicting airway reversibility. Correlations between the IOS, spirometric lung function and bronchiectasis severity parameters were analysed.ResultsMany IOS parameters, such as airway resistance at 5Hz (R5), small airways resistance (R5–R20), total airway reactance (X5), resonance frequency (Fres), total airway impedance at 5Hz (Z5), and peripheral resistance (Rp) increased with increased bronchiectasis severity according to the FACED, BSI and Reiff scores. Large airway resistance (R20) and central resistance (Rc) were not significantly different among groups with differentbronchiectasis severity. The difference between R5 and R20 (R5-R20) showed 81.0% sensitivity, and 69.8%specificity in predicting the airway reversibility in bronchiectasis with AUC of 0.794 (95%CI, 0.672-0.915).ConclusionIOS measurements are useful indicators of bronchiectasis severity and may be useful for predicting the airway reversibility.

EVALUATION OF SMALL AIRWAY REVERSIBILITY AMONG ASTHMATIC PATIENTS WITH NON-OBSTRUCTIVE PATTERNS OF SPIROMETRY

Background: Although the forced expiratory flow parameters are increasingly used in the diagnosis of small airway disease (SAD), the reversibility of these indicators is rarely described. The aim of this study is to evaluate the association of small airways reversibility with the presence of SAD and bronchodilator reversibility (BDR) of the proximal airways. Methods: The forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and the indicators of SAD (FEF25%, FEF50%, FEF75%, FEF25-75%, and FEF75-85%) were measured before and 20 minutes after salbutamol administration (200 mcg by using inhaler/Spacer). Positive BDR was accepted when FEV1 or FVC was increased ? 12% and > 200 ml, indicating responsive proximal airways. Positive small airway reversibility was diagnosed when any of the small airway indicators is increased ? 30% above the baseline results. All measurements were performed with the All-flow spirometer (Clement Clarke International, Harlow, UK). Results: Evidence of SAD was found in 62.1% of all participants and in 75.2% of those who showed responsive proximal airways. The positive predictive value of the SAD in diagnosing responsive proximal airways was 67.8%. The reversibility of the small airway indicators showed insignificant association with the FEV1 or FVC BDR. The reversibility of FEF50%, FEF75% and FEF25-75% showed significant association with the diagnosis of SAD, with specificities ranging from 75.5%-81.1%. Conclusion: SAD has a significant association with positive reversibility of both the proximal and the peripheral airways. Further studies are needed to evaluate the clinical significance of positive small airway reversibility in the diagnosis and management of obstructive lung diseases. Keywords: Asthma; Small airway disease; Bronchodilator Reversibility, FEV1, FVC; FEF25-75%

Dietary Acid Load: A Novel Nutritional Target in Overweight/Obese Children with Asthma?

Obesity has been repeatedly linked to asthma, and several potential mechanisms have been proposed in the etiologies of the obese-asthma phenotype. Considering that lungs play an important role in systemic pH and acid–base regulation, are a key organ in asthma development, and that nutritional inadequacy of several nutrients and high dietary acid load can affect airway inflammation and reactivity, we aimed to test the hypothesis that dietary acid load may be associated with asthma in children. Data on 699 children (52% females), aged 7–12 years, were analyzed. Anthropometric measurements were performed to assess body mass index. Dietary acid load was calculated using potential renal acid load (PRAL) equations from a 24 h dietary recall administrated to children. Adjusted PRAL for total energy intake was applied with the use of the residual method. Lung function and airway reversibility were assessed with spirometry. Asthma was defined by a positive bronchodilation or self-reported medical diagnosis with reported symptoms (wheezing, dyspnea, or dry cough) in the past 12 months. After adjustment for energy intake, sex, age, parent’s education level, and physical activity, positive and significant associations were found between asthma and PRAL [odds ratio (OR) = 1.953, 95% CI = 1.024, 3.730) in overweight/obese children. Our findings suggest that dietary acid load might be a possible mechanism in overweight/obese-asthma phenotype development.