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1.
Diagnosis and Outpatient Management of Chronic Obstructive Pulmonary Disease: A Review.
Riley, CM, Sciurba, FC
JAMA. 2019;(8):786-797
Abstract
IMPORTANCE There are 30 million adults (12%) in the United States who have chronic obstructive pulmonary disease (COPD). Chronic obstructive pulmonary disease accounts for 3.2% of all physician office visits annually and is the fourth leading cause of death (126 000 deaths per year). Most patients are diagnosed by their primary care clinicians who must address the highly variable clinical features and responses to therapy. The diagnosis and treatment of COPD is rapidly changing, so understanding recent advances is important for the delivery of optimal patient care. OBSERVATIONS Chronic obstructive pulmonary disease is characterized by incompletely reversible expiratory airflow limitation. Spirometry is the reference standard for diagnosing and assessing the severity of COPD. All patients should be counseled about and receive preventive measures such as smoking cessation and vaccination. Treatment should be guided by the severity of lung impairment, symptoms such as dyspnea, the amount of cough and sputum production, and how often a patient experiences an exacerbation. When dyspnea limits activity or quality of life, COPD should be treated with once- or twice-daily maintenance long-acting anticholinergic and β-agonist bronchodilators. Patients with acute exacerbations may benefit from the addition of inhaled corticosteroids, particularly those with elevated peripheral eosinophil levels. Pulmonary rehabilitation, which includes strength and endurance training and educational, nutritional, and psychosocial support, improves symptoms and exercise tolerance but is underutilized. Supplemental oxygen for patients with resting hypoxemia (defined as Spo2 <89%) improves survival. CONCLUSIONS AND RELEVANCE Chronic obstructive pulmonary disease is a complicated disease requiring intensive treatment. Appropriate use of long-acting maintenance bronchodilators, inhaled corticosteroids, and pulmonary rehabilitation decreases symptoms, optimizes functional performance, and reduces exacerbation frequency. Supplemental oxygen in patients with resting hypoxemia prolongs life, and other advanced treatments are available based on specific patient characteristics.
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2.
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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3.
Inhalable co-amorphous budesonide-arginine dry powders prepared by spray drying.
Lu, W, Rades, T, Rantanen, J, Yang, M
International journal of pharmaceutics. 2019;:1-8
Abstract
Spray drying is a well-established technology to produce inhalable dry powders. However, the amorphous nature of the particles typically obtained from the process can lead to physically and chemically unstable products. The purpose of this study was to investigate whether spray-drying could be used as a manufacturing method to produce co-amorphous drug amino acid powders with high physical stability and inhalable particulate properties. Budesonide (BUD), a compound for the treatment of lung inflammation, was co-spray-dried at a 1:1 M ratio with arginine (ARG) to produce co-amorphous powders. Two experimental factors, the solid concentration (0.85, 1.00 and 1.13%, w/v) and the ethanol concentration (55 and 75%, v/v) of the feed solution were varied to investigate the formation of co-amorphous BUD-ARG. X-ray powder diffraction (XRPD), modulated temperature differential scanning calorimetry (mDSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used for solid state characterization. The particle morphology, the median mass aerodynamic diameter and the aerodynamic properties of the resulting co-amorphous powders were investigated using scanning electron microscopy (SEM), an aerodynamic particle sizer (APS), and a next generation impactor (NGI), respectively. Furthermore, the physical stability of the obtained dry powder was examined. The co-spray-dried BUD-ARG samples prepared within the experimental range were predominantly amorphous. However, it was observed that while using the feed solution with both high solid and ethanol concentrations, some residual crystallinity related to budesonide was observed. The formation of co-amorphous BUD-ARG, rather than two separate amorphous phases, was confirmed by mDSC analyses. In addition, FTIR analyses indicated that hydrogen bonding occurs between the carbonyl groups of BUD and the amide groups of ARG in the co-amorphous BUD-ARG mixtures. The NGI results indicated that the particulate properties of the co-spray-dried co-amorphous BUD-ARG were at an inhalable range, with emitted doses >80%, and fine particle fractions >50%. In addition, the co-amorphous BUD-ARG was more physically stable than spray-dried BUD when stored at room temperature under dry conditions. This study demonstrated that spray drying is a useful manufacturing approach to produce physically stable co-amorphous dry powders for inhalation purposes.
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4.
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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5.
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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6.
Effects of fluticasone propionate and budesonide on the expression of immune defense genes in bronchial epithelial cells.
van den Berge, M, Jonker, MR, Miller-Larsson, A, Postma, DS, Heijink, IH
Pulmonary pharmacology & therapeutics. 2018;:47-56
Abstract
BACKGROUND COPD patients have increased risk of pneumonia when treated with fluticasone propionate (FP), whereas this is generally not the case with budesonide (BUD) treatment. We hypothesized that BUD and FP differentially affect the expression of immune defense genes. METHODS Human bronchial epithelial 16HBE cells and air-liquid interface (ALI)-cultured primary bronchial epithelial cells (PBECs) were pre-treated with clinically equipotent concentrations of BUD or FP (0.16-16 nM BUD and 0.1-10 nM FP), and the expression of immune defense genes was studied at baseline and after exposure to rhinovirus (RV16). RESULTS Using microfluidic cards, we observed that both BUD and FP significantly suppressed CXCL8, IFNB1 and S100A8 mRNA expression in unstimulated 16HBE cells. Interestingly, BUD, but not FP, significantly increased lactotransferrin (LTF) expression. The difference between the effect of BUD and FP on LTF expression was statistically significant and confirmed by qPCR and at the protein level by western blotting. RV16 infection of ALI-cultured PBECs significantly increased the expression of CCL20, IFNB1 and S100A8, but not of LTF or CAMP/LL-37. In these RV16-exposed cells, LTF expression was again significantly higher upon pre-treatment with BUD than with FP. The same was observed for S100A8, but not for CCL20, IFNB1 or CAMP/LL-37 expression. CONCLUSIONS Treatment of human bronchial epithelial cells with BUD results in significantly higher expression of specific immune defense genes than treatment with FP. The differential regulation of these immune defense genes may help to explain the clinical observation that BUD and FP treatment differ with respect to the risk of developing pneumonia in COPD.
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7.
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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8.
Inhaled magnesium sulfate in the treatment of acute asthma in children.
Normansell, R, Knightly, R, Milan, SJ, Knopp-Sihota, JA, Rowe, BH, Powell, C
Paediatric respiratory reviews. 2018;:31-33
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9.
Asthma, urticaria and less rare than expected FPIES.
Roberts, G
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2017;(12):1510-1511
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10.
Inhaled short-acting bronchodilators for managing emergency childhood asthma: an overview of reviews.
Pollock, M, Sinha, IP, Hartling, L, Rowe, BH, Schreiber, S, Fernandes, RM
Allergy. 2017;(2):183-200
Abstract
International guidelines provide conflicting recommendations on how to use bronchodilators to manage childhood acute wheezing conditions in the emergency department (ED), and there is variation within and among countries in how these conditions are managed. This may be reflective of uncertainty about the evidence. This overview of systematic reviews (SRs) aimed to synthesize, appraise, and present all SR evidence on the efficacy and safety of inhaled short-acting bronchodilators to treat asthma and wheeze exacerbations in children 0-18 years presenting to the ED. Searching, review selection, data extraction and analysis, and quality assessments were conducted using methods recommended by The Cochrane Collaboration. Thirteen SRs containing 56 relevant trials and 5526 patients were included. Results demonstrate the efficacy of short-acting beta-agonist (SABA) delivered by metered-dose inhaler as first-line therapy for younger and older children (hospital admission decreased by 44% in younger children, and ED length of stay decreased by 33 min in older children). Short-acting anticholinergic (SAAC) should be added to SABA for older children in severe cases (hospital admission decreased by 27% and 74% when compared to SABA and SAAC alone, respectively). Continuous nebulization, addition of magnesium sulfate to SABA, and levosalbutamol compared to salbutamol cannot be recommended in routine practice.