Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

Zataria multiflora affects pulmonary function tests, respiratory symptoms, bronchodilator drugs use and hematological parameters in chronic obstructive pulmonary disease patients: A randomized doubled-blind clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora is employed as an antitussive, anti-spasmodic, analgesic and etc. Agent in traditional medicine. The modern medical studies are also confirmed effects of this plant for treatment of respiratory problems via anti-inflammatory, anti-oxidant and immunomodulatory properties. AIM OF STUDY: We evaluated efficacy of Z. multiflora on tests of pulmonary function, respiratory symptoms, inhaled bronchodilator drugs use, and hematological factors in COPD patients. METHODS: Patients (n = 45) were randomly grouped in the following three groups: placebo group (P), groups received Z. multiflora extract 3 and 6 mg/kg/day (Z3 and Z6). FEV1 and MEF25-75, respiratory symptoms, inhaled bronchodilator drugs use and hematological factors were evaluated before and 1-2 months after treatment. RESULTS: Z. multiflora led to significant enhancement of FEV1 (p < 0.05 to p < 0.01). Respiratory symptoms were also considerably ameliorated following treatment with extracts for 1 and 2 months compared to baseline values (p < 0.05 to p < 0.001). In groups received extract, inhaled bronchodilator drugs use was remarkably declined at the end of study (both, p < 0.05). Reduction of total WBC was observed 1-2 months after treatment in treated groups with extract compared to baseline values (p < 0.05 to p < 0.001). Neutrophils were remarkably declined in Z3 and Z6 groups after 2-monthes compared to 1-month treatment (p < 0.05 to p < 0.01). CONCLUSION: The evidence show therapeutic effect of this herb on COPD patients which could be result from properties that help to decrease inflammation.

Clinical standards for the diagnosis and management of asthma in low- and middle-income countries.

BACKGROUND: The aim of these clinical standards is to aid the diagnosis and management of asthma in low-resource settings in low- and middle-income countries (LMICs).METHODS: A panel of 52 experts in the field of asthma in LMICs participated in a two-stage Delphi process to establish and reach a consensus on the clinical standards.RESULTS: Eighteen clinical standards were defined: Standard 1, Every individual with symptoms and signs compatible with asthma should undergo a clinical assessment; Standard 2, In individuals (>6 years) with a clinical assessment supportive of a diagnosis of asthma, a hand-held spirometry measurement should be used to confirm variable expiratory airflow limitation by demonstrating an acute response to a bronchodilator; Standard 3, Pre- and post-bronchodilator spirometry should be performed in individuals (>6 years) to support diagnosis before treatment is commenced if there is diagnostic uncertainty; Standard 4, Individuals with an acute exacerbation of asthma and clinical signs of hypoxaemia or increased work of breathing should be given supplementary oxygen to maintain saturation at 94-98%; Standard 5, Inhaled short-acting beta-2 agonists (SABAs) should be used as an emergency reliever in individuals with asthma via an appropriate spacer device for metered-dose inhalers; Standard 6, Short-course oral corticosteroids should be administered in appropriate doses to individuals having moderate to severe acute asthma exacerbations (minimum 3-5 days); Standard 7, Individuals having a severe asthma exacerbation should receive emergency care, including oxygen therapy, systemic corticosteroids, inhaled bronchodilators (e.g., salbutamol with or without ipratropium bromide) and a single dose of intravenous magnesium sulphate should be considered; Standard 8, All individuals with asthma should receive education about asthma and a personalised action plan; Standard 9, Inhaled medications (excluding dry-powder devices) should be administered via an appropriate spacer device in both adults and children. Children aged 0-3 years will require the spacer to be coupled to a face mask; Standard 10, Children aged <5 years with asthma should receive a SABA as-needed at step 1 and an inhaled corticosteroid (ICS) to cover periods of wheezing due to respiratory viral infections, and SABA as-needed and daily ICS from step 2 upwards; Standard 11, Children aged 6-11 years with asthma should receive an ICS taken whenever an inhaled SABA is used; Standard 12, All adolescents aged 12-18 years and adults with asthma should receive a combination inhaler (ICS and rapid onset of action long-acting beta-agonist [LABA] such as budesonide-formoterol), where available, to be used either as-needed (for mild asthma) or as both maintenance and reliever therapy, for moderate to severe asthma; Standard 13, Inhaled SABA alone for the management of patients aged >12 years is not recommended as it is associated with increased risk of morbidity and mortality. It should only be used where there is no access to ICS.The following standards (14-18) are for settings where there is no access to inhaled medicines. Standard 14, Patients without access to corticosteroids should be provided with a single short course of emergency oral prednisolone; Standard 15, Oral SABA for symptomatic relief should be used only if no inhaled SABA is available. Adjust to the individual's lowest beneficial dose to minimise adverse effects; Standard 16, Oral leukotriene receptor antagonists (LTRA) can be used as a preventive medication and is preferable to the use of long-term oral systemic corticosteroids; Standard 17, In exceptional circumstances, when there is a high risk of mortality from exacerbations, low-dose oral prednisolone daily or on alternate days may be considered on a case-by-case basis; Standard 18. Oral theophylline should be restricted for use in situations where it is the only bronchodilator treatment option available.CONCLUSION: These first consensus-based clinical standards for asthma management in LMICs are intended to help clinicians provide the most effective care for people in resource-limited settings.

Theophylline for the management of respiratory disorders in adults in the 21st century: A scoping review from the American College of Clinical Pharmacy Pulmonary Practice and Research Network.

Theophylline is an oral methylxanthine bronchodilator recommended as alternate therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD). However, it is not generally recommended for the treatment of other respiratory disorders such as obstructive sleep apnea (OSA) or hypoxia. Most clinical practice guidelines rely on evidence published prior to the year 2000 to make these recommendations. This scoping review aimed to gather and characterize evidence describing theophylline for the management of respiratory disorders in adults between January 1, 2000 and December 31, 2020. Databases searched included Ovid MEDLINE, Embase, CINAHL Complete, Scopus, and International Pharmaceutical Abstracts. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Studies were included if they were published in English, theophylline was used for any respiratory disorder, and the study outcomes were disease- or patient-oriented. After removal of duplicates, 841 studies were screened and 55 studies were included. Results aligned with current clinical guideline recommendations relegating theophylline as an alternative therapy for the treatment of respiratory disorders, in favor of inhaled corticosteroids and inhaled bronchodilators. This scoping review identified the need for future research including: theophylline versus other medications deemed alternative therapies for asthma and COPD, meta-analyses of low-dose theophylline, and studies evaluating evidence-based patient-oriented outcomes for OSA, hypoxia, ventilator-induced diaphragmatic dysfunction, and spinal cord injury-related pulmonary function.

The Role of Long-Acting Antimuscarinic Agents in the Treatment of Asthma.

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Investigating the rationale for COPD maintenance therapy prescription across Europe, findings from a multi-country study.

This study aims to understand healthcare professionals' thoughts and motivations about optimal management and treatment of patients with chronic obstructive pulmonary disease (COPD). We conducted a DELPHI survey through an online questionnaire distributed to 220 panellists from six European countries and a discrete choice experiment to describe the relationship between selected clinical criteria and the initial COPD treatment of choice. One hundred twenty-seven panellists (general practitioners [GPs] and pulmonologists) completed the survey. Despite the familiarity and use (89.8%) of the GOLD classification for initial treatment selection, a frequent use of LAMA/LABA/ICS was noted. In fact, panellists agreed that inhaled corticosteroids (ICS) are over-prescribed in the primary care setting. Our study showed that GPs felt less confident than pulmonologists with ICS withdrawal. This mismatch observed between best practice and behaviour indicates the need to increase awareness and efforts to improve the adherence to guidelines in clinical practice.

[Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)].

Cystic fibrosis (CF) is one of the most common autosomal recessive genetic diseases in Caucasians, but CF patients in China are rare, and it was listed as the first batch of rare diseases in China in 2018. In recent years, CF has been gradually recognized in China, and the number of CF patients reported in China in the past 10 years is more than 2.5 times the total number in the previous 30 years, and the total number of CF patients is estimated to be more than 20 000. The research progress of CF gene modification has led to the innovation of CF treatment. However, the sweat test as an important test for the diagnosis of CF has not been widely implemented in China. At present, the diagnosis and treatment of CF in China still lacks standardized recommendations. In view of these updates, the Chinese Experts Cystic Fibrosis Consensus Committee has formed "the Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis" based on extensive opinion gathering, literatures review, multiple meetings and discussions. This consensus collects 38 core issues related to CF, including pathogenesis, epidemiology, clinical characteristics, diagnosis, treatment, rehabilitation, and patient management. Finally, 32 recommendations were formulated. The consensus used the modified GRADE methodology to grade the evidence evaluation and recommendations. This is the current state of CF consensus in China, and we hope to improve the diagnosis and treatment of CF in China in the future.Summary of recommendationsQuestion 1: How can CF be identified?CF should be suspected if there is: (1) a family history of CF; (2) delayed meconium expulsion or meconium ileus; (3) pancreatic exocrine insufficiency, mainly characterized by long-standing steatorrhea and malnutrition; (4) recurrent lower respiratory tract infections of infantile onset, especially Pseudomonas aeruginosa (PA), Staphylococcus aureus infections of respiratory aetiology; (5) chronic sinusitis, especially when combined with juvenile presentation of nasal polyps; (6) chest CT abnormalities such as the presence of air trapping, bronchiectasis (upper lobe predominant); (7) pseudo-Bartter syndrome; (8) absence of vas deferens in males; (9) clubbing in young bronchiectasis patients(1C).Question 2: What are the diagnostic criteria for CF?1.1 Presence of one or more of the characteristic clinical manifestations or family history consistent with CF, and meeting at least one of the following definite diagnostic criteria in 1.2 or 1.3.1.2 Sweat chloride testing:(1) Concentrations of more than 60 mmol/L are diagnostic; (2) concentrations between 30-59 mmol/L are intermediate, and genetic variation must be considered to confirm the diagnosis; (3) concentrations less than 30 mmol/L are considered normal.1.3 Genetic testing:(1) Detection of two disease-causing CFTR(cystic fibrosis transmembrane conductance regulator) mutations on biallelic alleles; (2) The CFTR variants are of undetermined significance, but tests such as sweat chloride concentration, intestinal current measurement, or nasal mucosal potential difference suggest abnormal CFTR function, then CF is diagnostic(1C).Question 3: What is the diagnostic process for CF arranged?Sweat chloride testing and CFTR gene analysis are recommended in all patients suspected of CF(1D).Question 4: What is the value of sweat chloride testing in the diagnosis of CF?Sweat chloride testing is the gold standard for the clinical diagnosis of CF(1C).Question 5: What is the value of CFTR genetic testing in Chinese CF diagnosis?Biallelic pathogenic variants of CFTR are a definitive diagnosis of CF(1D).Question 6: What is the diagnostic value of imaging for CF?Chest CT is a sensitive test for early stages of lung disease in patients with CF and is appropriate in younger patients and to assess disease progression. The imaging findings of abdominal visceral involvement in CF lack specificity(2C).Question 7: How to evaluate the pancreatic function of CF patients?Fecal elastase may be used as the first indicator to assess pancreatic exocrine function in patients with CF (2C).Question 8: How to diagnose hepatic abnormality of CF?CF related liver disease was diagnosed when CF was confirmed and 2 of the following 4 criteria were met: (1) hepatomegaly and/or splenomegaly confirmed by ultrasound; (2) ALT, AST, and GGT on three consecutive occasions above the upper limit of normal on three consecutive occasions for more than 12 months and excluding other causes; (3) had evidence of liver involvement, portal hypertension, or bile duct dilatation by ultrasound; (4) liver biopsy confirmation (focal biliary cirrhosis or multilobular cirrhosis) may be indicated if the diagnosis is suspected(2D).Question 9: How to identify pulmonary exacerbations in patients with CF?Pulmonary exacerbations are indicated when any 4 of the following 12 signs or symptoms are met: increased sputum; new onset haemoptysis or increased haemoptysis; exacerbation of cough; increased dyspnea; malaise, fatigue, or somnolence; body temperature above 38 ℃; anorexia or weight loss; sinus pain or tenderness; increased sinus secretions; new chest signs; FEV1≥10% decline from previous; imaging changes suggestive of pulmonary infection(2D).Question 10: How to diagnose CF related diabetes?Diagnostic criteria for CF related diabetes are the same as those for diabetes in the population(1D).Question 11: How to evaluate the nutritional status of CF patients?Anthropometric parameters reflecting nutritional status should be assessed regularly. And the goal of nutritional assessment is to evaluate and monitor whether pediatric patients are achieving normal standards of growth and development or whether adult patients are maintaining adequate nutritional status(1C).Question 12: Does CF require pathological examination as a diagnostic basis?Pathohistological biopsy is not recommended as a first-line diagnostic method in patients with a suspected diagnosis of CF(1D).Question 13: Do CF patients need long-term macrolides?At least 6 months of azithromycin treatment is recommended for CF patients with chronic PA infection(2A).Question 14: Do CF patients need long-term inhalation of hypertonic saline?Long term treatment with hypertonic saline is recommended for patients with CF(1A).Question 15: Do CF patients need long-term inhalation of Dornase alfa(DNase)?Long term use of DNase is recommended in patients with CF aged 6 years and older(1A).Question 16: Do CF patients need inhalation of mannitol?Inhaled mannitol therapy is recommended for more than 6 months in patients with CF aged 18 years and older when other inhaled treatments are unavailable or intolerable(2A).Question 17: How to deal with PA found in the sputum culture of CF patients?When sputum cultures from patients with CF are positive for PA, it needs to determine the characteristics of the infection first. The purpose for acute infection is to eradicate PA. Chronic colonization does not need to be eradicated, and the main purpose is to reduce the bacterial load and improve symptoms(1A).Question 18: Do CF patients need inhalation of antibiotics?Inhaled antibiotic therapy is recommended for CF patients with PA infection(1A).Question 19: Do CF patients need inhaled or systemic corticosteroids?In patients with CF without asthma or ABPA, routine inhaled or systemic glucocorticoids are not recommended (2A).Question 20: Do CF patients need to inhale bronchodilators?Bronchodilators can be used in the short term to improve symptoms in patients with CF in the presence of airway obstruction, but the long-term benefit is insufficient (2B).Question 21: Do CF patients need expectorant medicine?Patients with CF can take acetylcysteine orally or aerosolized(2A).Question 22: How to deal with acute pulmonary exacerbation in CF patients?Intensive implementation of non-antimicrobial therapy is recommended during pulmonary exacerbations in patients with CF. Antimicrobials with activity against PA were selected for empirical treatment, and the treatment was adjusted according to the results of bacterial culture and drug susceptibility testing. A 21-day long course of anti-infective therapy is not recommended(1B).Question 23: How to treat CF patients with ABPA?Medical therapy is recommended for CF patients with ABPA who meet any of the following criteria: patients with elevated immunoglobulin E levels and concomitant worsening of pulmonary function and/or pulmonary symptoms, or imaging suggesting new infiltrative foci in the chest(1D).Glucocorticoids are recommended for ABPA exacerbations in CF patients without contraindications(2D).Itraconazole should be added if the patient presents with poor response to corticosteroids, recurrence of ABPA, corticosteroid dependence, or corticosteroid toxicity(2D).Question 24: Is lung transplantation recommended for patients with CF? When is it recommended?Patients with CF may be evaluated for lung transplantation when they meet the following criteria after optimal medical therapy: (1) FEV1<30% predicted; (2) FEV1<40% predicted (<50% predicted in children) with the following: 6-minute walk distance<400 meters; PaCO2>50 mmHg(1 mmHg=0.133 kPa); hypoxia at rest or after activity; pulmonary artery pressure measured by cardiotocography>50 mmHg or right heart dysfunction; continued deterioration despite aggressive supplementation of nutritional support; two exacerbations requiring intravenous antibiotic therapy per year; massive hemoptysis (>240 ml) requiring pulmonary artery embolization; presented with pneumothorax; (3) FEV1<50% predicted and rapid decline in lung function or rapid worsening of symptoms; (4) Presented with an acute exacerbation requiring positive pressure mechanical ventilation(2C).Question 25: How to deal with pancreatic disease in CF patients?Pancreatic enzyme replacement therapy is recommended in patients with CF pancreatic disease(1A).Question 26:How to deal with hepatobiliary disease in CF patients?Ursodeoxycholic acid is not recommended in asymptomatic patients with CF hepatobiliary disease(2B).Question 27: How to deal with gastrointestinal problems such as acid regurgitation in CF patients?Acid suppression is recommended for CF patients with gastrointestinal symptoms such as acid regurgitation (2B).Question 28: How to deal with CF related diabetes?Insulin therapy is recommended in CF related diabetes(1B).Question 29: How should nutritional support be given to patients with CF?Energy intake in patients with CF is recommended to be 110%-200% of the energy requirement of a healthy person under equivalent physiological conditions. And maintaining adequate protein, appropriate intake of fats, electrolytes, and fat-soluble vitamins are recommanded(1A).Question 30: How should respiratory rehabilitation be performed in patients with CF?Airway clearance therapy and appropriate exercise are recommended for patients with CF(1A).Question 31: What is included in the follow-up of CF patient?Patients with CF should have regular follow-up. Adult patients are recommended to be followed every 3-6 months, and children should be followed more frequently(2A).Question 32: How should CF patients avoid infections?Inpatients and outpatients are recommended to be separated according to microbiota carriage status(1D).Good hand hygiene is recommended for the patients with CF and their contacts(1D).It is recommended that CF patients wear masks in healthcare settings. This may reduce the release of potentially infectious aerosols during coughing (1D).Annual influenza vaccination is recommended for patients with CF>6 months of age and for all family members of patients with CF and all healthcare workers caring for these patients(2D).Palivizumab may be considered for the prevention of respiratory syncytial virus infection in patients with CF under two years of age(2A).

The effects of different inhalation therapies on less symptomatic chronic obstructive pulmonary disease patients in a Chinese population: a real-world study.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document suggests that patients with chronic obstructive pulmonary disease (COPD) should be divided into a less symptomatic group. Moreover, single-inhaled drugs are recommended as initial inhalation therapy for them. However, many less symptomatic patients are provided double or triple-inhaled drugs as initial therapy in the real world. This study aimed to describe the inhalation prescriptions and compare the effects of different inhalation therapies on less symptomatic COPD patients. PATIENTS AND METHODS: This was an observational study. Stable COPD patients were recruited and divided into a less symptomatic group including Groups A and C based on the GOLD 2019 document. We collected the data of inhalation therapies prescriptions. Then, the patients were classified into long-acting muscarinic antagonist (LAMA), long-acting ß2-agonist (LABA) + inhaled corticosteroid (ICS), LABA + LAMA, and LABA + LAMA + ICS groups. All the patients were followed up for 1 year to collect exacerbation and mortality data. RESULTS: We found that only 45.4% of patients in Group A and 43.6% of patients in Group C received reasonable inhalation therapy in reference to the GOLD document. In addition, the LAMA group had a higher forced expiratory volume in one second (FEV1), FEV1%pred, FEV1/forced vital capacity and peak expiratory flow compared with LABA + ICS, LABA + LAMA and LABA + LAMA + ICS groups. However, we did not find any significant differences of exacerbation, hospitalization and mortality during the follow-up among different inhalation therapies groups on less symptomatic COPD patients. CONCLUSION: Over half of the less symptomatic patients received inhalation therapy that were inconsistent with the GOLD document recommendations in a Chinese population in the real world. In fact, the single inhaled drug of LAMA should be recommended and pulmonary function is not a good indicator for the choice of initial inhalation therapy in less symptomatic COPD patients.KEY MESSAGESOver half of the less symptomatic COPD patients received inhalation therapy that were inconsistent with the GOLD document recommendations in a Chinese population in the real world.The clinicians should offer a single inhaled drug of LAMA to less symptomatic COPD patients and pulmonary function is not a good indicator for the choice of initial inhalation therapy.

The prevention and management strategies for neonatal chronic lung disease.

INTRODUCTION: Survival from even very premature birth is improving, but long-term respiratory morbidity following neonatal chronic lung disease (bronchopulmonary dysplasia (BPD)) has not reduced. Affected infants may require supplementary oxygen at home, because they have more hospital admissions particularly due to viral infections and frequent, troublesome respiratory symptoms requiring treatment. Furthermore, adolescents and adults who had BPD have poorer lung function and exercise capacity. AREAS COVERED: Antenatal and postnatal preventative strategies and management of infants with BPD. A literature review was undertaken using PubMed and Web of Science. EXPERT OPINION: There are effective preventative strategies which include caffeine, postnatal corticosteroids, vitamin A, and volume guarantee ventilation. Side-effects, however, have appropriately caused clinicians to reduce use of systemically administered corticosteroids to infants only at risk of severe BPD. Promising preventative strategies which need further research are surfactant with budesonide, less invasive surfactant administration (LISA), neurally adjusted ventilatory assist (NAVA) and stem cells. The management of infants with established BPD is under-researched and should include identifying the optimum form of respiratory support on the neonatal unit and at home and which infants will most benefit in the long term from pulmonary vasodilators, diuretics, and bronchodilators.

[Where we stand with asthma: optimized medical care and biologic therapy for children]. / Le point sur l'asthme en pédiatrie : optimisation de la prise en charge et thérapies biologiques.

Asthma recommendations are in constant evolution. Salbutamol exclusivity as the historical reference treatment for asthma exacerbations is now questioned. In case of light to moderate crisis, budesonide/formoterol, combining an inhaled corticosteroid and a fast acting long lasting beta2 agonist, can now be proposed as first line as needed treatment, for adolescents older than 12 years old. In addition, progress in fundamental research revealed the heterogeneous nature of asthma and allowed for the emergence of new-targeted therapies.

La prise en charge de l'asthme est en constante évolution. L'exclusivité du salbutamol, traitement historique de référence des exacerbations aiguës, même légères, est remise en question depuis plusieurs années. En cas de symptômes ou crise légère à modérée, le budésonide/formotérol, combiné de corticostéroïde inhalé et bronchodilatateur (ß2-agoniste) d'action rapide et prolongée, peut dorénavant être proposé en première intention, à la demande, y compris en pédiatrie, notamment à partir de 12 ans. De plus, les progrès en recherche fondamentale ont permis de révéler la nature hétérogène de l'asthme et de faire émerger de nouvelles cibles thérapeutiques. En particulier, les patients asthmatiques peuvent bénéficier de l'entrée des biologiques dans l'arsenal thérapeutique.

Effects of a QI intervention on pediatric asthma treatment using patient outcomes and workflow in an emergency department.

OBJECTIVE: Evaluate a nurse-initiated quality improvement (QI) intervention aimed at enhancing asthma treatment in a pediatric emergency department (ED), utilizing outcomes and workflow. METHODS: We evaluated the impact of QI interventions for pediatric patients presenting to the ED with asthma with pre-post analysis. A pediatric asthma score (PAS) of >8 indicated moderate to severe asthma. This secondary analysis of the electronic health record (EHR), evaluated on 1) patient outcomes (time to clinical treatment, ED length of stay [EDLOS], admissions and discharges home), 2) clinical workflow. RESULTS: We compared 886 visits occurring between 01/01/2015 and 09/27/2015 (pre-implementation period) with 752 visits between 01/01/2016 and 09/27/2016 (post-implementation). Time to first documentation of PAS was decreased post-intervention (p<.001) by >30 min (75 ± 57 to 39 ± 54 min). There were significant decreases in time to treatment with both steroid and bronchodilator administration (both p<.001). EDLOS did not significantly change. Based on acuity level, those discharged home from the ED with high acuity (PAS score ≥8), had a significant decrease in time to initial PAS, steroid and bronchodilator use and EDLOS. Of those with high acuity who were admitted to the hospital, there was a difference pre- to post-implementation, in time to first PAS (p<.05), but not to treatment. Workflow visualization provided additional insights and detailed (task level) comparisons of the timing of ED activities. CONCLUSIONS: Nurse-initiated ED interventions, can significantly improve the timeliness of pediatric asthma evaluation and treatment. Examining workflow along with the outcomes, can better inform QI evaluations and clinical management.

An in silico and in vitro integrated analysis method to reveal the curative mechanisms and pharmacodynamic substances of Bufei granule on chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high disability and mortality. Clinical studies have shown that the Traditional Chinese Medicine Bufei Granule (BFG) has conspicuous effects on relieving cough and improving lung function in patients with COPD and has a reliable effect on the treatment of COPD, whereas the therapeutic mechanism is vague. In the present study, the latent bronchodilators and mechanism of BFG in the treatment of COPD were discussed through the method of network pharmacology. Then, the molecular docking and molecular dynamics simulation were performed to calculate the binding efficacy of corresponding compounds in BFG to muscarinic receptor. Finally, the effects of BFG on bronchial smooth muscle were validated by in vitro experiments. The network pharmacology results manifested the anti-COPD effect of BFG was mainly realized via restraining airway smooth muscle contraction, activating cAMP pathways and relieving oxidative stress. The results of molecular docking and molecular dynamics simulation showed alpinetin could bind to cholinergic receptor muscarinic 3. The in vitro experiment verified both BFG and alpinetin could inhibit the levels of CHRM3 and acetylcholine and could be potential bronchodilators for treating COPD. This study provides an integrating network pharmacology method for understanding the therapeutic mechanisms of traditional Chinese medicine, as well as a new strategy for developing natural medicines for treating COPD.

Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with COPD: a systematic review and meta-analysis.

INTRODUCTION: Accumulated high-quality data from randomised controlled trials (RCTs) indicate that long-acting muscarinic antagonist (LAMA)/long-acting ß2 agonist (LABA) combination therapy significantly improves clinical symptoms and health status in patients with chronic obstructive pulmonary disease (COPD) and reduces exacerbation risk. However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD. METHODS: Two reviewers independently searched Embase, PubMed and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular end-points. The primary outcome was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, myocardial infarction or stroke. RESULTS: A total of 51 RCTs enrolling 91 021 subjects were analysed. Both dual LAMA/LABA (1.6% versus 1.3%; relative risk 1.42, 95% CI 1.11-1.81) and triple therapy (1.6% versus 1.4%; relative risk 1.29, 95% CI 1.03-1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1% per year. Compared with LAMA only, LABA only or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power. CONCLUSION: Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies for symptoms and exacerbation rates in patients with COPD, especially in those with a MACE risk of >1% per year.

The clinical characteristics and outcomes of different inhaled therapies in chronic obstructive pulmonary disease patients with frequent cough.

BACKGROUND: Cough is a common symptom in patients with chronic obstructive pulmonary disease (COPD). Patients with cough may exhibit various clinical characteristics and experience varying outcomes based on inhaled therapies they receive. OBJECTIVES: This study aimed to explore the clinical characteristics and outcomes of various inhaled therapies in COPD patients with frequent cough. METHODS: This was a multicenter, prospective cohort study. Of these patients, the median cough score in COPD assessment test (CAT) was two. Patients were classified into frequent cough group if they scored two or over in the first item of CAT and infrequent cough group otherwise. Patients with frequent cough were then divided into long-acting antimuscarinic (LAMA), long-acting beta2-agonist (LABA)/LAMA, inhaled corticosteroids (ICS)/LABA and ICS/LABA/LAMA groups. Minimum clinically important difference (MCID) (CAT scores decreased ≥2 from baseline) and the improvement of cough (cough score decreased ≥1 from baseline) were collected in the six-month follow-up. Frequent exacerbations (experiencing at least two exacerbations) were collected in the one-year follow-up. RESULTS: Of 906 patients, 581 (64.1%) patients reported frequent cough at the initial visit. Frequent cough was associated with the current smokers and CAT scores (p < 0.05). The MCID showed no significant difference between frequent cough and infrequent cough groups in the follow-up. More patients with frequent cough experienced future frequent exacerbations compared to those with infrequent cough. After receiving inhaled therapies, 62% of patients with frequent cough got the cough improved. More patients with frequent cough treated with LABA/LAMA or ICS/LABA/LAMA attained MCID and fewer experienced exacerbations than those treated with LAMA or ICS/LABA (p < 0.05). The change in cough score showed no difference among various inhaled therapies in patients with frequent cough. CONCLUSION: COPD patients with frequent cough were related to current smokers and higher CAT scores. These patients had a higher incidence of frequent exacerbations than those with infrequent cough. Patients with frequent cough who were treated with LABA/LAMA or ICS/LABA/LAMA were more likely to attain MCID and at a lower risk of exacerbation than those treated with LAMA or ICS/LABA.

Cost-Effectiveness Analysis of Triple Therapy with Budesonide/ Glycopyrronium/ Formoterol Fumarate versus Dual Therapy in Patients with Chronic Obstructive Pulmonary Disease in Spain.

Objective: To evaluate the cost-effectiveness of Budesonide/Glycopyrronium/Formoterol (BUD/GLY/FOR) versus LAMA/LABA and ICS/LABA, respectively, in patients with moderate to severe COPD, from the Spanish National Healthcare System (NHS) perspective. Methods: A lifetime Markov model with monthly cycle length was developed with baseline and treatment effect data from ETHOS clinical trial, together with utility values from literature and Spanish healthcare resource costs (€, 2021). A 3% annual discount rate was used for costs and benefits. The model comprised ten health states: nine forced expiratory volume in 1 second (FEV1)-related, which were divided by three levels of severity: moderate (FEV1 ≥50% and <80%); severe (FEV1 ≥30% and <50%) and very severe (FEV1 <30%) and a death state. Each FEV1-health state was divided into no exacerbation, moderate exacerbation, and severe exacerbations. An expert panel validated data and assumptions. Outcomes were measured as incremental cost per exacerbation avoided, per life year (LY) gained, and per quality-adjusted life-year (QALY) gained (ICUR). One-way (OWSA), scenario, and probabilistic sensitivity analyses (PSA) were performed. Results: According to this cost-effectiveness analysis based on a Markov model, BUD/GLY/FOR was associated with a lower totals exacerbation per patient (12.80) compared to LAMA/LABA (13.36) and ICS/LABA (13.23) and higher LYs (10.32 vs 10.14 and 10.06, respectively) and QALYs (7.55 vs 7.41 and 7.32, respectively). The incremental costs were €850.95, and €2422.26, respectively, per exacerbation avoided, €2733.38 and €4111.15, respectively, per LY gained and €3461.19 and €4545.24 per QALY gained. OWSA showed that the model was most sensitive to the costs of treatments following discontinuation, but the ICUR remained below the cost-effectiveness threshold of €25,000 per QALY gained. In the PSA, the probability of BUD/GLY/FOR being cost-effective was 91.32% vs LAMA/LABA and 99.29% vs ICS/LABA. Conclusion: BUD/GLY/FOR is a cost-effective treatment strategy for Spanish NHS patients with COPD compared to dual therapies.

Economic impact of implementing prescription of single-inhaler triple therapies versus current multiple-inhaler triple therapies for COPD in the Apulia Region.

BACKGROUND: The most impacting direct costs associated to COPD for the National Health Systems (NHS) are those related to accesses to the emergency room and hospital admissions, due to the onset of one or more COPD exacerbations. At the same time, severe COPD treatment, that often require a combination of medicaments, represents a substantial economic burden for the National Health Systems (NHS). This study aimed to evaluate the potential saving deriving from the implementation in the prescription of the two currently available single-inhaler triple therapies (SITTs) versus the currently used multiple-inhaler triple therapies (MITTs) in an eligible COPD population residing in the Apulia Region. METHODS: A budget impact model was developed hypothesizing the progressive replacement of the different MITTs on the reference market (Scenario A) with the pre-established SITTs, assuming a degree of penetration of 30%, 50% and 100% (Scenario B). Drug costs were based on prices published on the Official Gazette and therapy durations were based on prescribing information over the year 2019 (IQVIA™ prescription dataset). RESULTS: Our analysis showed that the extemporaneous MITT with the highest prevalence on the reference market was the inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA) combination plus a long-acting muscarinic antagonists (LAMA). This association of medicaments was paradoxically also the one associated to the highest expense value. The expanded use of a pre-established ICS/LAMA/LABA SITT was associated to a significant economic saving, ranging from a minimum of -€ 1,108,814 (SITT use: 30%) to a maximum of -€ 3,658,950 (SITT use: 100%). The cheapest pre-established SITT contained the fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) combination. CONCLUSION: A pre-fixed ICS/LAMA/LABA SITT is cost-saving, compared to the different currently used extemporaneous MITTs. Clinicians should consider the potential benefits of finding less expensive regimens while maintaining adequate efficacy in the prescriptive decision making process of COPD patients.

Prescription Pathways from Initial Medication Use to Triple Therapy in Older COPD Patients: A Real-World Population Study.

BACKGROUND AND OBJECTIVE: Triple therapy with an inhaled corticosteroid (ICS), a long-acting ß2-agonist bronchodilator (LABA) and a long-acting muscarinic antagonist (LAMA) is recommended as step-up therapy for chronic obstructive pulmonary disease (COPD) patients who continue to have persistent symptoms and increased risk of exacerbation despite treatment with dual therapy. We sought to evaluate different treatment pathways through which COPD patients were escalated to triple therapy. METHODS: We used population health databases from Ontario, Canada to identify individuals aged 66 or older with COPD who started triple therapy between 2014 and 2017. Median time from diagnosis to triple therapy was estimated using the Kaplan-Meier method. We classified treatment pathways based on treatments received prior to triple therapy and evaluated whether pathways differed by exacerbation history, blood eosinophil counts or time period. RESULTS: Among 4108 COPD patients initiating triple therapy, only 41.2% had a COPD exacerbation in the year prior. The three most common pathways were triple therapy as initial treatment (32.5%), LAMA to triple therapy (29.8%), and ICS + LABA to triple therapy (15.4%). Median time from diagnosis to triple therapy was 362 days (95% confidence interval:331-393 days) overall, but 14 days (95% CI 12-17 days) in the triple therapy as initial treatment pathway. This pathway was least likely to contain patients with frequent or severe exacerbations (22.0% vs. 31.5%, p < 0.001) or with blood eosinophil counts ≥300 cells/µL (18.9% vs. 22.0%, p < 0.001). CONCLUSION: Real-world prescription of triple therapy often does not follow COPD guidelines in terms of disease severity and prior treatments attempted.

Effects of omega-3 supplementation on quality of life, nutritional status, inflammatory parameters, lipid profile, exercise tolerance and inhaled medications in chronic obstructive pulmonary disease.

BACKGROUND: The omega-3 polyunsaturated fatty acids (PUFAs) have an anti-inflammatory effect, beneficial for allergies, asthma, chronic obstructive pulmonary disease (COPD), reduce cholesterol and triglyceride levels and blood inflammatory parameters [C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α)]. The aim of our cross-sectional study was to monitor omega-3 supplementation in patients with severe COPD and assess its association with quality of life, nutritional status, inflammatory parameters, lipid profile, comorbidities, exercise tolerance and inhaled medications. METHODS: Our questionnaire on dietary supplement habits and our validated self-completion questionnaires were filled in by 400 patients with COPD at the National Koranyi Institute of Pulmonology, Hungary, mean age 67 [61-73] years; forced expiratory volume in one second (FEV1) (ref%): 46 [34-58]; 47.5% male, 52.5% female. We used the disease-specific COPD Assessment Test (CAT) questionnaire to measure quality of life. RESULTS: More than half of the study participants (61%) did not consume fish or oilseeds at all. Nineteen patients (4.75%) took omega-3 supplementation regularly, mainly on medical advice (0.5 g/day). We observed significantly lower serum CRP levels [6.0 (1-7.3) vs. 9.7 (7.4-14.4); P=0.044], more favourable lipid profile [triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol] with higher mean body mass index (BMI) [28.1 (22.0-35.3) vs. 24.7 (24.5-30.1); P=0.118], better quality of life {CAT: 25 [21-30.5] vs. 26 [20-31]; P=0.519}, lower inhaled short-acting bronchodilators use [short-acting beta-agonists (SABAs): 6 (31.58) vs. 209 (54.86); P=0.047], lower number of exacerbations in the previous half year [0 (0-1) vs. 1 (0-2); P=0.023], and higher 6-minute walking distance (6MWD) {300 [177-387] vs. 251 [150-345]; P=0.120} in the group with omega-3 supplementation. CONCLUSIONS: PUFAs are anti-inflammatory and affect the immune system. Our study shows that omega-3 intake of COPD patients is insufficient, and there is an urgent need to develop new anti-inflammatory strategies because only one drug (such as corticosteroids) cannot ease the chronically progressive inflammatory process of COPD.

Potential biomedical applications of Araucaria araucana as an antispasmodic, bronchodilator, vasodilator, and antiemetic: Involvement of calcium channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Since pre-Columbian era, the resin of Araucaria araucana tree has been used traditionally for the treatment of ulcers and wounds. Araucaria species have also been used to treat inflammation, respiratory problems, viral infections, ulcers, and rheumatoid, cardiovascular, and neurological disorders. AIMS AND OBJECTIVE: Due to its popular use, the authors aimed to scrutinize the potential of this plant as an antispasmodic and an antiemetic agent. Furthermore broncho- and vasodilatory effects of this plant was explored to rationalize its folkloric uses. MATERIALS AND METHODS: Araucaria araucana crude extract (Aa.Cr) was evaluated in isolated preparations of rabbit jejunum, trachea, aorta, and atria to investigate the antispasmodic, bronchodilator, and vasodilator effects. The potential mechanistic approaches were compared with the standard drug 'verapamil'. The antiemetic activity was determined and compared with the standard drug 'domperidone' via chick emesis model. RESULTS: Aa.Cr dose-dependently relaxed both spontaneous and K+-induced contractions in the isolated jejunum preparations of rabbits. In concentration-response curves of calcium (Ca++), Aa.Cr also triggered the rightward shift like verapamil. Applying carbachol and phenylephrine (1 µM) and K+ (80 mM) to the isolated tracheal and aortic tissue preparation, respectively, resulted in broncho- and vasodilatory activities, respectively which may be due to the inhibition of Ca++ channels. Aa.Cr inhibited atrial force and spontaneous contractions in the rabbit's right atria. Aa.Cr exhibited significant antiemetic activity (P < 0.001 vs. saline) in dose-dependent (50-150 mg/kg) manner like domperidone. In silico molecular docking was performed to investigate the biological targets of purified components of Aa.Cr which revealed that cadinol dominantly targets ß2 receptors to cause bronchodilation, however, eudesmin binds non-specifically to all the selected targets, while secoisolariciresinol mediated high hydrogen bonding with muscarinic receptors (M1 and M3) and Ca++ channels, thus shows the suggested mechanistic pathways of targeted activities. CONCLUSIONS: The results of this study indicates that Aa.Cr may exhibit antispasmodic activity, bronchodilation, and vasodilation by inhibiting voltage-dependent Ca++ channels and release of subcellular calcium. This explains its folkloric use in hypertension, bronchospasms, gastrointestinal spasms, and emesis.

Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-Analysis.

INTRODUCTION: Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting ß2-agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD. METHODS: This NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV1), annualized rate of combined moderate and severe exacerbations, St George's Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible). RESULTS: The NMA was informed by five trials reporting FEV1 at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV1 (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6). CONCLUSION: The findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.