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Contemporary perspectives in COPD: Patient burden, the role of gender and trajectories of multimorbidity.
Buttery, SC, Zysman, M, Vikjord, SAA, Hopkinson, NS, Jenkins, C, Vanfleteren, LEGW
Respirology (Carlton, Vic.). 2021;(5):419-441
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Abstract
An individual's experience of COPD is determined by many factors in addition to the pathological features of chronic bronchitis and emphysema and the symptoms that derive directly from them. Multimorbidity is the norm rather than the exception, so most people with COPD are living with a range of other medical problems which can decrease overall quality of life. COPD is caused by the inhalation of noxious particles or gases, in particular tobacco smoke, but also by early life disadvantage impairing lung development and by occupations where inhaled exposures are common (e.g. industrial, farming and cleaning work). Wealthy people are therefore relatively protected from developing COPD and people who do develop the condition may have reduced resources to cope. COPD is also no longer a condition that predominantly affects men. The prevalence of COPD among women has equalled that of men since 2008 in many high-income countries, due to increased exposure to tobacco, and in low-income countries due to biomass fuels. COPD is one of the leading causes of death in women in the USA, and death rates attributed to COPD in women in some countries are predicted to overtake those of men in the next decade. Many factors contribute to this phenomenon, but in addition to socioeconomic and occupational factors, there is increasing evidence of a higher susceptibility of females to smoking and pollutants. Quality of life is also more significantly impaired in women. Although most medications (bronchodilators and inhaled corticosteroids) used to treat COPD demonstrate similar trends for exacerbation prevention and lung function improvement in men and women, this is an understudied area and clinical trials frequently have a preponderance of males. A better understanding of gender-based predictors of efficacy of all therapeutic interventions is crucial for comprehensive patient care. There is an urgent need to recognize the increasing burden of COPD in women and to facilitate global improvements in disease prevention and management in this specific population. Many individuals with COPD follow a trajectory of both lung function decline and also multimorbidity. Unfavourable lung function trajectories throughout life have implications for later development of other chronic diseases. An enhanced understanding of the temporal associations underlying the development of coexisting diseases is a crucial first step in unravelling potential common disease pathways. Lessons can be learned from exploring disease trajectories of other NCD as well as multimorbidity development. Further research will be essential to explain how early life risk factors commonly influence trajectories of COPD and other diseases, how different diseases develop in relation to each other in a temporal way and how this ultimately leads to different multimorbidity patterns in COPD. This review integrates new knowledge and ideas pertaining to three broad themes (i) the overall burden of disease in COPD, (ii) an unappreciated high burden in women and (iii) the contrast of COPD trajectories and different multimorbidity patterns with trajectories of other NCD. The underlying pathology of COPD is largely irreversible, but many factors noted in the review are potentially amenable to intervention. Health and social care systems need to ensure that effective treatment is accessible to all people with the condition. Preventive strategies and treatments that alter the course of disease are crucial, particularly for patients with COPD as one of many problems.
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Withdrawal of inhaled corticosteroids versus continuation of triple therapy in patients with COPD in real life: observational comparative effectiveness study.
Magnussen, H, Lucas, S, Lapperre, T, Quint, JK, Dandurand, RJ, Roche, N, Papi, A, Price, D, Miravitlles, M, ,
Respiratory research. 2021;(1):25
Abstract
BACKGROUND Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. METHOD Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. RESULTS A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10-1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03-2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL. CONCLUSIONS In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).
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Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial.
Schuh, S, Sweeney, J, Rumantir, M, Coates, AL, Willan, AR, Stephens, D, Atenafu, EG, Finkelstein, Y, Thompson, G, Zemek, R, et al
JAMA. 2020;(20):2038-2047
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Abstract
IMPORTANCE While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown. OBJECTIVE To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy. DESIGN, SETTING, AND PARTICIPANTS A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed. INTERVENTIONS Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408). MAIN OUTCOMES AND MEASURES The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes. RESULTS Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, -4.2%; absolute risk difference 95% [exact] CI, -11% to 2.8%]; P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, -0.23 to 0.50]; P = .46); respiratory rate (0.17 breaths/min [95% CI, -1.32 to 1.67]; P = .82); oxygen saturation (-0.04% [95% CI, -0.53% to 0.46%]; P = .88); systolic blood pressure (0.78 mm Hg [95% CI, -1.48 to 3.03]; P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11]; P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%). CONCLUSIONS AND RELEVANCE Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01429415.
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24-Hour Serial Spirometric Assessment of Once-Daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-Daily Budesonide/Formoterol in Patients with COPD: Analysis of the FULFIL Study.
Lipson, DA, Birk, R, Brealey, N, Zhu, CQ
Advances in therapy. 2020;(12):4894-4909
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Abstract
INTRODUCTION Few studies have utilized 24-h serial spirometry to compare the effects of inhaled chronic obstructive pulmonary disease (COPD) therapies on lung function. The FULFIL study previously reported significant lung function improvements with once-daily single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus twice-daily single-inhaler budesonide/formoterol (BUD/FOR) in patients with symptomatic COPD at risk of exacerbations. METHODS This prespecified analysis evaluated 24-h serial spirometry data from a subgroup of 406 patients in FULFIL. BUD/FOR twice-daily dosing was maintained during 24-h spirometry. A post hoc analysis evaluated serial forced expiratory volume in 1 s (FEV1) at day 1 and week 24 by disease severity at screening (FEV1 < 50% predicted and no moderate or severe exacerbation in prior year, FEV1 < 50% predicted and ≥ 1 moderate or severe exacerbation in prior year, and FEV1 ≥ 50% and < 80% predicted and ≥ 2 moderate or ≥ 1 severe exacerbations in prior year). RESULTS Odds of achieving a ≥ 100-mL increase from baseline in FEV1 within the first 6 h post dose on day 1 were significantly greater with FF/UMEC/VI than BUD/FOR [odds ratio 2.79 (95% confidence interval 1.56-4.98); p < 0.001]. FF/UMEC/VI led to greater improvements in weighted mean FEV1 over 0-6, 0-12, 0-24, and 12-24 h on day 1 and at week 24, with the greatest between-group differences at week 24 (range 196-210 mL; all p < 0.001). Significant between-treatment differences in FEV1 and forced vital capacity (FVC) in favor of FF/UMEC/VI versus BUD/FOR were seen at all time points at week 24 (FEV1 range 156-231 mL, all p < 0.001; FVC range 139-309 mL, all p ≤ 0.002). Serial FEV1 results were consistent irrespective of disease severity at screening. CONCLUSION These findings further demonstrate sustained lung function benefits with once-daily FF/UMEC/VI single-inhaler triple therapy in patients with symptomatic COPD at risk of exacerbations across a range of disease severities.
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A multinational observational study identifying primary care patients at risk of overestimation of asthma control.
Kritikos, V, Price, D, Papi, A, Infantino, A, Ställberg, B, Ryan, D, Lavorini, F, Chrystyn, H, Haughney, J, Lisspers, K, et al
NPJ primary care respiratory medicine. 2019;(1):43
Abstract
Factors related to the discrepancy between patient-perceived and actual disease control remain unclear. Identifying patients at risk of overestimation of asthma control remains elusive. This study aimed to (i) investigate the relationship between patient-reported and actual level of asthma control (ii), compare the characteristics between patients who believe their asthma is well controlled that accurately report 'well-controlled' asthma with those that do not, and (iii) identify factors associated with inaccurately reported 'well-controlled' asthma. A historical, multinational, cross-sectional study using data from the iHARP (initiative Helping Asthma in Real-life Patients) review service for adults with asthma prescribed fixed-dose combination therapy. Data from 4274 patients were analysed. A major discrepancy between patient-reported and Global Initiative for Asthma defined asthma control was detected; 71.1% of patients who reported 'well-controlled' asthma were inaccurate in their perception despite receiving regular maintenance therapy. Significant differences were noted in age, gender, body mass index, education level, medication use, side effects, attitudes to preventer inhaler use, inhaler technique review and respiratory specialist review between patients who accurately reported 'well-controlled' asthma and those who did not. Independent risk factors associated with inaccurately reported 'well-controlled' asthma were: having taken a maximum of 5-12 puffs or more of reliever inhaler on at least one day within the previous 4 weeks; being female; having seen a respiratory specialist more than a year ago (rather than in the previous year); and having required oral corticosteroids for worsening asthma in the previous year. The study highlighted the significant hidden burden associated with under-recognition of poor asthma control, on the part of the patient and the need for targeted interventions designed to address the continuing discrepancy between perceived and actual disease control.
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Intravenous magnesium sulfate for acute wheezing in young children: a randomised double-blind trial.
Pruikkonen, H, Tapiainen, T, Kallio, M, Dunder, T, Pokka, T, Uhari, M, Renko, M
The European respiratory journal. 2018;(2)
Abstract
Magnesium sulfate has been shown to be an effective treatment in older children with asthma exacerbations, but it has not been investigated in acute severe virus-induced wheezing in young children.The study enrolled 61 children aged 6 months to 4 years. Inclusion criteria were severe wheezing, classified as a score of ≥6 points as assessed by the Respiratory Distress Assessment Instrument (RDAI) after initial treatment with salbutamol, and the symptoms of acute viral infection. The children were randomly allocated to receive either an infusion of magnesium sulfate (40 mg·kg-1) or 0.9% sodium chloride as a placebo infusion for 20 min. Primary outcome measure was mean change in RDAI scores from baseline to 6 h after the treatment.Change in the severity of wheezing from baseline to 6 h after the treatment, as measured by mean±sd RDAI scores, was 4.7±2.6 in the magnesium sulfate group and 4.2±4.2 in the placebo group (difference 0.5, 95% CI -1.3 to 2.3, p=0.594).Intravenous magnesium sulfate was ineffective in treating acute severe virus-induced wheezing in young children, in contrast to the previous efficacy demonstrated in older children.
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Guideline on management of the acute asthma attack in children by Italian Society of Pediatrics.
Indinnimeo, L, Chiappini, E, Miraglia Del Giudice, M, ,
Italian journal of pediatrics. 2018;(1):46
Abstract
BACKGROUND Acute asthma attack is a frequent condition in children. It is one of the most common reasons for emergency department (ED) visit and hospitalization. Appropriate care is fundamental, considering both the high prevalence of asthma in children, and its life-threatening risks. Italian Society of Pediatrics recently issued a guideline on the management of acute asthma attack in children over age 2, in ambulatory and emergency department settings. METHODS The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was adopted. A literature search was performed using the Cochrane Library and Medline/PubMed databases, retrieving studies in English or Italian and including children over age 2 year. RESULTS Inhaled ß2 agonists are the first line drugs for acute asthma attack in children. Ipratropium bromide should be added in moderate/severe attacks. Early use of systemic steroids is associated with reduced risk of ED visits and hospitalization. High doses of inhaled steroids should not replace systemic steroids. Aminophylline use should be avoided in mild/moderate attacks. Weak evidence supports its use in life-threatening attacks. Epinephrine should not be used in the treatment of acute asthma for its lower cost / benefit ratio, compared to β2 agonists. Intravenous magnesium solphate could be used in children with severe attacks and/or forced expiratory volume1 (FEV1) lower than 60% predicted, unresponsive to initial inhaled therapy. Heliox could be administered in life-threatening attacks. Leukotriene receptor antagonists are not recommended. CONCLUSIONS This Guideline is expected to be a useful resource in managing acute asthma attacks in children over age 2.
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COPD patients' self-reported adherence, psychosocial factors and mild cognitive impairment in pulmonary rehabilitation.
Pierobon, A, Sini Bottelli, E, Ranzini, L, Bruschi, C, Maestri, R, Bertolotti, G, Sommaruga, M, Torlaschi, V, Callegari, S, Giardini, A
International journal of chronic obstructive pulmonary disease. 2017;:2059-2067
Abstract
In addition to clinical comorbidities, psychological and neuropsychological problems are frequent in COPD and may affect pulmonary rehabilitation delivery and outcome. The aims of the study were to describe a COPD population in a rehabilitative setting as regards the patients depressive symptoms, anxiety, mild cognitive impairment (MCI) and self-reported adherence and to analyze their relationships; to compare the COPD sample MCI scores with normative data; and to investigate which factors might predict adherence to prescribed physical exercise. This was a multicenter observational cross-sectional study. Of the 117 eligible stable COPD inpatients, 84 were enrolled according to Global initiative for chronic Obstructive Lung Disease (GOLD) criteria (mainly in Stage III-IV). The assessment included Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), anxiety, depression and self-reported pharmacological and nonpharmacological adherence. From the MMSE, 3.6% of patients were found to be impaired, whereas from the MoCA 9.5% had a likely MCI. Patients referred had mild-severe depression (46.7%), anxiety (40.5%), good pharmacological adherence (80.3%) and difficulties in following prescribed diet (24.1%) and exercise (51.8%); they struggled with disease acceptance (30.9%) and disease limitations acceptance (28.6%). Most of them received good family (89%) or social (53%) support. Nonpharmacological adherence, depression, anxiety and MCI showed significant relations with 6-minute walking test, body mass index (BMI) and GOLD. Depression was related to autonomous long-term oxygen therapy modifications, disease perception, family support and MCI. In the multivariate logistic regression analysis, higher BMI, higher depression and lower anxiety predicted lower adherence to exercise prescriptions (P=0.0004, odds ratio =0.796, 95% CI =0.701, 0.903; P=0.009, odds ratio =0.356, 95% CI =0.165, 0.770; and P=0.05, odds ratio =2.361, 95% CI =0.995, 5.627 respectively). In COPD patients, focusing on pharmacological and nonpharmacological adherence enhance the possibility of tailored pulmonary rehabilitation programs.
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Intracellular interactions of umeclidinium and vilanterol in human airway smooth muscle.
Shaikh, N, Johnson, M, Hall, DA, Chung, KF, Riley, JH, Worsley, S, Bhavsar, PK
International journal of chronic obstructive pulmonary disease. 2017;:1903-1913
Abstract
BACKGROUND Intracellular mechanisms of action of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a long-acting β2-adrenoceptor (β2R) agonist, were investigated in target cells: human airway smooth-muscle cells (ASMCs). MATERIALS AND METHODS ASMCs from tracheas of healthy lung-transplant donors were treated with VI, UMEC, UMEC and VI combined, or control compounds (salmeterol, propranolol, ICI 118.551, or methacholine [MCh]). Cyclic adenosine monophosphate (cAMP) was measured using an enzyme-linked immunosorbent assay, intracellular free calcium ([Ca2+]i) using a fluorescence assay, and regulator of G-protein signaling 2 (RGS2) messenger RNA using real-time quantitative polymerase chain reaction. RESULTS VI and salmeterol (10-12-10-6 M) induced cAMP production from ASMCs in a concentration-dependent manner, which was greater for VI at all concentrations. β2R antagonism by propranolol or ICI 118.551 (10-12-10-4 M) resulted in concentration-dependent inhibition of VI-induced cAMP production, and ICI 118.551 was more potent. MCh (5×10-6 M, 30 minutes) attenuated VI-induced cAMP production (P<0.05), whereas pretreatment with UMEC (10-8 M, 1 hour) restored the magnitude of VI-induced cAMP production. ASMC stimulation with MCh (10-11-5×10-6 M) resulted in a concentration-dependent increase in [Ca2+]i, which was attenuated with UMEC pretreatment. Reduction of MCh-induced [Ca2+]i release was greater with UMEC + VI versus UMEC. UMEC enhanced VI-induced RGS2 messenger RNA expression. CONCLUSION These data indicate that UMEC reverses cholinergic inhibition of VI-induced cAMP production, and is a more potent muscarinic receptor antagonist when in combination with VI versus either alone.
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Comparative Meta-Analysis of the Efficacy of Once-Daily Fluticasone Furoate 100 µG Versus Twice-Daily Fluticasone Propionate 250 µG in Adolescents and Adults with Persistent Asthma.
Tomlinson, R, Parks, D, Martin, A
Lung. 2017;(5):571-574
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Fluticasone furoate and fluticasone propionate are recommended options for prophylactic maintenance treatment of persistent asthma. Using data from two previous clinical studies (GSK studies: FFA109685/NCT00603278, FFA112059/NCT01159912), this meta-analysis compared change from baseline in clinic visit mean trough forced expiratory volume in 1 s (FEV1) with fluticasone furoate 100 µg once-daily (FF100) versus fluticasone propionate 250 µg twice-daily (FP250) in adolescents and adults with persistent asthma. Using a DerSimonian-Laird random-effects model (primary meta-analysis), there was no statistically significant difference between FF100 and FP250 in change from baseline in trough FEV1 (-1.7 mL [95% CI -80.4, +77.0], p = 0.9664) and FF100 was non-inferior to FP250. Supporting analyses using least squares mean and fixed-effects model approaches produced similar findings. In this analysis, FF100 and FP250 demonstrated a comparable treatment effect on trough FEV1 in patients aged ≥12 years with persistent asthma; however, results interpretation should consider study design and methodological limitations.