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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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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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Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma.
Bjermer, L, Abbott-Banner, K, Newman, K
Pulmonary pharmacology & therapeutics. 2019;:101814
Abstract
INTRODUCTION This study aimed to investigate the dose-response and pharmacology of a range of single doses of nebulised ensifentrine (RPL554), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor in patients with asthma. METHODS In this randomised, placebo-controlled, double-blind crossover study, patients received single nebulised doses of ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo. Eligible patients were adults with asthma, pre-bronchodilator forced expiratory volume in 1 s (FEV1) 60-90% predicted and ≥1.5 L, with post-salbutamol FEV1 increase ≥15%. The co-primary objectives were peak and average FEV1 over 12 h for ensifentrine vs placebo and salbutamol. Secondary endpoints included: peak and average systolic and diastolic blood pressure, pulse rate and ECG heart rate; and safety and tolerability (adverse events [AEs], and serum potassium). ClinicalTrials.gov: NCT02427165. RESULTS A total of 29 patients were randomised, with 25 (89%) completing the study. For the two co-primary endpoints there was a clear ensifentrine dose-response relationship, with all treatments superior to placebo (p < 0.001). There was no relationship between the ensifentrine dose and AE incidence or blood pressure. Ensifentrine 0.4, 1.5 and 6 mg had significantly lower effects than both salbutamol doses on pulse and heart rates. Ensifentrine did not impact potassium, whereas there was a was a dose-related reduction for salbutamol. Inhalation of ensifentrine resulted in a dose-related increase in plasma exposure. CONCLUSIONS Single-dose ensifentrine demonstrated dose-dependent bronchodilation, and was as effective as a therapeutic dose of nebulised salbutamol. All ensifentrine doses were similarly well tolerated, and did not show the characteristic β2-agonist systemic adverse effects.
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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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Fluctuation Analysis of Peak Expiratory Flow and Its Association with Treatment Failure in Asthma.
Kaminsky, DA, Wang, LL, Bates, JH, Thamrin, C, Shade, DM, Dixon, AE, Wise, RA, Peters, S, Irvin, CG
American journal of respiratory and critical care medicine. 2017;(8):993-999
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Abstract
RATIONALE Temporal fluctuations have been demonstrated in lung function and asthma control, but the effect of controller therapy on these fluctuations is unknown. OBJECTIVES To determine if fluctuations in peak expiratory flow (PEF) are predictive of subsequent treatment failure and may be modified by controller therapy. METHODS We applied detrended fluctuation analysis to once-daily PEF data from 493 participants in the LOCCS (Leukotriene Modifier Corticosteroid or Corticosteroid-Salmeterol) trial of the American Lung Association Airways Clinical Research Centers. We evaluated the coefficient of variation of PEF (CVpef) and the scaling exponent α, reflecting self-similarity of PEF, in relation to treatment failure from the run-in period of open-label inhaled fluticasone, and the treatment periods for subjects randomized to (1) continued twice daily fluticasone (F), (2) once daily fluticasone plus salmeterol (F + S), or (3) once daily oral montelukast (M). MEASUREMENTS AND MAIN RESULTS The CVpef was higher in those with treatment failure in the F and F + S groups in the run-in phase, and all three groups in the treatment phase. α was similar between those with and without treatment failure in all three groups during the run-in phase but was higher among those with treatment failure in the F and F + S groups during the treatment phase. Participants in all three groups showed variable patterns of change in α leading up to treatment failure. CONCLUSIONS We conclude that increased temporal self-similarity (α) of more variable lung function (CVpef) is associated with treatment failure, but the pattern of change in self-similarity leading up to treatment failure is variable across individuals.
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Zinc sulphate for acute bronchiolitis: A double-blind placebo-controlled trial.
Mahyar, A, Ayazi, P, Ahmadi, NK, Pour Nikoo, ST, Hamzehloo, S, Taremiha, A, Yazdi, Z, Esmaeily, S
Le infezioni in medicina. 2016;(4):331-336
Abstract
The use of adjunctive therapies to achieve rapid recovery from clinical symptoms of acute bronchiolitis would appear necessary. This study was performed to determine the effect of zinc sulphate on treating acute bronchiolitis. In this study, 100 children affected with acute bronchiolitis were investigated. Fifty patients received oral zinc sulphate and 50 patients placebo. Signs and symptoms of the disease were compared between two groups at the time of admission and then 24, 48, 72, 96 and 120 hours after the beginning of treatment. The trend of recovery of clinical signs and symptoms was more favourable in the case group than in the control group in 24, 48, 72, 96 and 120 hours after beginning of the treatment. The significant differences were observed between the two groups in terms of improvements in coughing and wheezing 48 and 72 hours after the beginning of the treatment (P<0.05). Full recovery was observed in 49 (98%) patients receiving zinc sulphate within 72 hours of the beginning of treatment (P=0.0001). The present study showed that administration of zinc sulphate accelerates improvement from clinical signs and symptoms of acute bronchiolitis. Thus we recommend the use of zinc sulphate for the treatment of acute bronchiolitis.
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Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Albuterol (Salbuterol) Multi-dose Dry-Powder Inhaler and ProAir(®) Hydrofluoroalkane for the Treatment of Persistent Asthma: Results of Two Randomized Double-Blind Studies.
Kerwin, EM, Taveras, H, Iverson, H, Wayne, D, Shah, T, Lepore, MS, Miller, DS
Clinical drug investigation. 2016;(1):55-65
Abstract
BACKGROUND AND OBJECTIVE Metered-dose inhalers require patients to coordinate inhalation with actuation. The present albuterol multi-dose dry-powder inhaler (mDPI) does not require patients to coordinate inspiration with actuation, thereby simplifying delivery of albuterol to the lungs. The aim of the present study was to compare the efficacy, pharmacokinetics, pharmacodynamics, extrapulmonary pharmacodynamics, and safety of albuterol (salbuterol) delivered via a ProAir® hydrofluoroalkane (HFA) metered-dose inhaler and an mDPI. METHODS Two double-blind, randomized, double-dummy, crossover, multicenter, placebo-controlled studies in persistent asthma patients were conducted. Study 1: 47 adult patients were treated with cumulative doses of albuterol mDPI or ProAir HFA (90 µg/inhalation; 1 + 1 + 2 + 4 + 8 inhalations) or placebo. Study 2: 71 patients aged ≥12 years were randomly assigned to receive 90 or 180 μg of albuterol mDPI or ProAir HFA, or placebo. Primary efficacy endpoints were baseline-adjusted forced expiratory volume in 1 s (FEV1) at 30 min (30-min FEV1) after each cumulative dose (Study 1) and FEV1 area under the effect curve over 6 h (FEV1 AUEC0-6) after dosing (Study 2). RESULTS Study 1: differences, with corresponding 90% confidence intervals, between albuterol mDPI and ProAir HFA in FEV1 after each cumulative dose and in FEV1 AUEC0-6 after the final dose were within pre-established equivalence limits. The difference in FEV1 at high vs. low doses was significant for both active treatments (p < 0.0001). Active treatments were similar in systemic exposure, extrapulmonary pharmacodynamics, and safety. Study 2: mean FEV1 AUEC0-6 was significantly greater than for placebo for both doses of albuterol mDPI and ProAir HFA (p < 0.0001). Albuterol mDPI was comparable to ProAir HFA at 90 and 180 µg. Both study treatments were generally well tolerated. CONCLUSION The bronchodilatory efficacy and pharmacokinetic/pharmacodynamic profiles of albuterol mDPI and ProAir HFA are comparable, with a safety profile consistent with that of inhaled albuterol.
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3% Hypertonic Saline Versus Normal Saline in Inpatient Bronchiolitis: A Randomized Controlled Trial.
Silver, AH, Esteban-Cruciani, N, Azzarone, G, Douglas, LC, Lee, DS, Liewehr, S, Nazif, JM, Agalliu, I, Villegas, S, Rhim, HJ, et al
Pediatrics. 2015;(6):1036-43
Abstract
BACKGROUND AND OBJECTIVES Bronchiolitis, the most common reason for hospitalization in children younger than 1 year in the United States, has no proven therapies effective beyond supportive care. We aimed to investigate the effect of nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS) on length of stay (LOS) in infants hospitalized with bronchiolitis. METHODS We conducted a prospective, randomized, double-blind, controlled trial in an urban tertiary care children's hospital in 227 infants younger than 12 months old admitted with a diagnosis of bronchiolitis (190 completed the study); 113 infants were randomized to HS (93 completed the study), and 114 to NS (97 completed the study). Subjects received 4 mL nebulized 3% HS or 4 mL 0.9% NS every 4 hours from enrollment until hospital discharge. The primary outcome was median LOS. Secondary outcomes were total adverse events, subdivided as clinical worsening and readmissions. RESULTS Patient characteristics were similar in groups. In intention-to-treat analysis, median LOS (interquartile range) of HS and NS groups was 2.1 (1.2-4.6) vs 2.1 days (1.2-3.8), respectively, P = .73. We confirmed findings with per-protocol analysis, HS and NS groups with 2.0 (1.3-3.3) and 2.0 days (1.2-3.0), respectively, P = .96. Seven-day readmission rate for HS and NS groups were 4.3% and 3.1%, respectively, P = .77. Clinical worsening events were similar between groups (9% vs 8%, P = .97). CONCLUSIONS Among infants admitted to the hospital with bronchiolitis, treatment with nebulized 3% HS compared with NS had no difference in LOS or 7-day readmission rates.
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Nebulized Magnesium Sulfate in Acute Bronchiolitis: A Randomized Controlled Trial.
Modaresi, MR, Faghihinia, J, Kelishadi, R, Reisi, M, Mirlohi, S, Pajhang, F, Sadeghian, M
Indian journal of pediatrics. 2015;(9):794-8
Abstract
OBJECTIVE To assess the efficacy of nebulized magnesium sulfate as a bronchodilator in infants hospitalized with acute bronchiolitis. METHODS This three-center double masked randomized clinical trial comprised 120 children with moderate to severe bronchiolitis. They were randomly assigned into two groups: the first group was treated with nebulized magnesium sulfate (40 mg/kg) and nebulized epinephrine (0.1 ml/kg) and the second group (control) was treated with nebulized epinephrine (0.1 ml/kg). The primary outcome was the length of hospital stay. The use of oxygen, temperature, oxygen saturation (SPO2), pulse rate (PR), respiratory rate (RR) and respiratory distress assessment instrument (RDAI) score were measured in the beginning of the study and during hospitalization. RESULTS The mean (SD) age of 120 infants was 5.1(± 2.6) mo and 60% were boys. The length of hospital stay was not different between the two groups (P > 0.01). Use of oxygen supplementation, SPO2 and vital signs were similar in the two groups. Improvement in RDAI score was significantly better in infants treated with nebulized magnesium sulfate than in the other group (P 0.01). CONCLUSIONS Thus, in infants with acute bronchiolitis, the effect of nebulized magnesium sulfate is comparable to nebulized epinephrine. However nebulized magnesium sulfate can improve the clinical score so it may have additive effect to reduce symptoms during hospitalization.
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Assessment of montelukast, doxofylline, and tiotropium with budesonide for the treatment of asthma: which is the best among the second-line treatment? A randomized trial.
Rajanandh, MG, Nageswari, AD, Ilango, K
Clinical therapeutics. 2015;(2):418-26
Abstract
PURPOSE Data comparing various second-line treatments for asthma with subjective and objective assessment are lacking. This study aimed to compare the efficacy and safety of montelukast, doxofylline, and tiotropium with a low-dose budesonide in patients with mild to moderate persistent asthma. METHODS Patients, all of whom were concurrently using inhaled budesonide (400 µg), were treated for 6 months with formoterol (12 µg), montelukast (10 mg), doxofylline (400 mg), or tiotropium (18 µg). Outcomes included forced expiratory volume in 1 second (FEV1), Saint George Respiratory Questionnaire (SGRQ) scores, asthma symptom scores (daytime and nighttime), and assessment of tolerability and rescue medication use. FINDINGS A total of 297 patients completed the study. In all 4 groups, significant improvements were observed in all the outcome measures, with formoterol treatment having greater and earlier improvements than the other 3 second-line controller medications with budesonide. Among the second-line treatments, monteradlukast improved the FEV1 from day 45 (P < 0.01), SGRQ scores from day 30 (P < 0.0001), daytime scores from day 30 (P < 0.05), nighttime scores from day 30 (P < 0.0001), and rescue medication use from day 15 (P < .0001) at a faster rate than doxofylline or tiotropium with budesonide. No patients discontinued the treatment because of adverse reactions. IMPLICATIONS Among the tested second-line treatment regimens, the budesonide/montelukast combination was found to be superior to either the budesonide/doxofylline or budesonide/tiotropium combination in all the outcome measures without adversely affecting the tolerability of the patients. Further clinical studies with blinding techniques are likely to be useful.