LABA/LAMA as First-Line Therapy for COPD: A Summary of the Evidence and Guideline Recommendations

COPD; Bronchodilator; Inhaled corticosteroidEPOC; Broncodilatador; Corticosteroides inhaladosMPOC; Broncodilatador; Corticosteroides inhalatsInhaled bronchodilators (alone or in combination) are the cornerstone of treatment for symptomatic patients with COPD, either as initial/first-line treatment or for second-line/treatment escalation in patients who experience persistent symptoms or exacerbations on monotherapy. The Global Initiative for Chronic Obstructive Lung Disease 2022 report recommends initial pharmacological treatment with a long-acting muscarinic antagonist (LAMA) or a long-acting β2-agonist (LABA) as monotherapy for most patients, or dual bronchodilator therapy (LABA/LAMA) in patients with more severe symptoms, regardless of exacerbation history. The recommendations for LABA/LAMA are broader in the American Thoracic Society treatment guidelines, which strongly recommend LABA/LAMA combination therapy over LAMA or LABA monotherapy in patients with COPD and dyspnea or exercise intolerance. However, despite consistent guideline recommendations, real-world prescribing data indicate that LAMA and/or LABA without an inhaled corticosteroid are not the most widely prescribed therapies in COPD. This article reviews global and regional/national guideline recommendations for the use of LABA/LAMA in COPD, examines the evidence for the effectiveness and safety of LABA/LAMA versus other therapies and offers a practical guide for clinicians to help ensure appropriate use of LABA/LAMA therapy.This research and the APC were funded by Boehringer Ingelheim

Overexpression of Chitinase 3-Like 1/YKL-40 in Lung-Specific IL-18-Transgenic Mice, Smokers and COPD

We analyzed the lung mRNA expression profiles of a murine model of COPD developed using a lung-specific IL-18-transgenic mouse. In this transgenic mouse, the expression of 608 genes was found to vary more than 2-fold in comparison with control WT mice, and was clustered into 4 groups. The expression of 140 genes was constitutively increased at all ages, 215 genes increased gradually with aging, 171 genes decreased gradually with aging, and 82 genes decreased temporarily at 9 weeks of age. Interestingly, the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. However, IL-13 gene deletion did not reduce the level of Chi3l1 protein in the lungs of IL-18 transgenic mice. Based on our murine model gene expression data, we analyzed the protein level of YKL-40, the human homolog of Chi3l1, in sera of smokers and COPD patients. Sixteen COPD patients had undergone high resolution computed tomography (HRCT) examination. Emphysema was assessed by using a density mask with a cutoff of −950 Hounsfield units to calculate the low-attenuation area percentage (LAA%). We observed significantly higher serum levels in samples from 28 smokers and 45 COPD patients compared to 30 non-smokers. In COPD patients, there was a significant negative correlation between serum level of YKL-40 and %FEV1. Moreover, there was a significant positive correlation between the serum levels of YKL-40 and LAA% in COPD patients. Thus our results suggest that chitinase-related genes may play an important role in establishing pulmonary inflammation and emphysematous changes in smokers and COPD patients

Decreased CTLA4(+) and Foxp3(+) CD25(high)CD4(+) cells in induced sputum from patients with mild atopic asthma.

ABSTRACTBackgroundDetails of the comparisons between airway and peripheral blood regulatory T cells (Tregs) in patients with atopic asthma are still unclear. The objective of this study is to investigate the profiles of both airway and circulating Tregs in atopic asthma.MethodsWe measured the numbers of Tregs and eosinophils in induced sputum and peripheral blood in 28 patients with mild atopic asthma and compared these with numbers in 18 healthy controls. The frequency (%) of Tregs (surface CTLA4+, intracellular Foxp3+, and CTLA4+Foxp3+ on CD25highCD4+ T cells) in sputum and blood was determined by intracellular 5-color flow cytometry. We also correlated the numbers with the level of airway hyperresponsiveness (AHR) in asthmatics.ResultsThe mean frequencies of cells expressing CTLA4+ (19.4 ± 2.1%, p = 0.075), Foxp3+ (16.4 ± 3.3%, p = 0.001), and CTLA4+Foxp3+ (7.0 ± 1.1%, p = 0.008) in induced sputum from asthmatics were significantly lower than controls (27.2 ± 3.7%, 37.4 ± 4.7%, and 18.2 ± 3.6%, respectively), whereas in peripheral blood, there was no inter-group difference in the frequencies of cells expressing CTLA4+ (7.1 ±1.5% vs 5.7 ± 1.7%, p > 0.05), Foxp3+ (35.7 ± 3.2% vs 21.1 ± 3.9%, p > 0.05), and CTLA4+Foxp3+ (6.6 ± 1.5% vs 4.2 ± 1.0%, p > 0.05). Moreover, the frequency of CD25highCD4+ cells expressing CTLA4+, but not Foxp3+, in induced sputum was associated with AHR (r = 0.60, p = 0.009) and airway eosinophilic inflammation (r = −0.60, p = 0.008) in asthmatics.ConclusionsAirway, but not circulating, Tregs are decreased in mild atopic asthmatics, and are negatively correlated to an increase of airway eosinophilic inflammation and AHR

Reference Ranges for Exhaled Nitric Oxide Fraction in Healthy Japanese Adult Population

Background: The measurement of the exhaled nitric oxide fraction (FEno) is proposed as a useful marker of airway inflammation. In healthy adults, there have been a few studies of the reference ranges for FEno in Caucasians. A community study in other regions may reveal any possible ethnic differences in the FEno levels. Methods: A total of 240 healthy adults aged between 18 to 74 years were recruited from four medical centers in Japan. Current smokers and subjects having a history of atopic disease were not included. FEno was measured using an online electrochemical nitric oxide analyzer according to the current guidelines. The reference ranges for FEno were estimated using two different statistical methods recommended by International Federation of Clinical Chemistry and Laboratory Medicine. Results: The mean FEno was 16.9 ppb (parts per billion) with a 95% prediction interval (2.5 to 97.5 percentiles) of 6.5 to 35.0 ppb in healthy Japanese adults. Normality assumptions were met for the logarithm- transformed FEno. The geometric mean FEno was 15.4 ppb with a mean ± two standard deviations of 6.5 to 36.8 ppb. Age, gender, height, and past smoking history were not associated with the FEno levels. Conclusions: The reference ranges for FEno in healthy Japanese adults were similar to those of Caucasians. It seems reasonable that the upper limit of FEno for healthy adults should be set at approximately 36.0 ppb irrespective of ethnic differences

Endobronchial cryptococcosis with bronchial stenosis in a patient with severe asthma treated with inhaled corticosteroids: A case report

Abstract Cryptococcosis typically manifests as pulmonary lesions, with endobronchial lesions occurring rarely. Inhaled corticosteroids (ICS) may be a risk factor for cryptococcosis of the larynx but not of the bronchi. Here, we report a case involving a 73‐year‐old Japanese man who developed endobronchial cryptococcosis during ICS treatment for asthma. Chest computed tomography showed right mainstem bronchial stenosis and asthma control worsening when he received adequate asthma treatments. Bronchoscopy revealed multiple elevated lesions with white slough from the trachea to the right mainstem bronchus and the right mainstem bronchus lumen entrance narrowing. Bronchial lavage culture revealed Cryptococcus neoformans. Combination treatment with the antifungal agent, mepolizumab, and bronchodilation surgery successfully controlled cryptococcosis and asthma. Attention should be paid to central airway lesions during ICS treatment for uncontrolled asthma

Endogenous and Exogenous Thioredoxin 1 Prevents Goblet Cell Hyperplasia in a Chronic Antigen Exposure Asthma Model

Background: Goblet cell hyperplasia with mucus hypersecretion contribute to increased morbidity and mortality in bronchial asthma. We have reported that thioredoxin 1 (TRX1), a redox (reduction/oxidation)-active protein acting as a strong antioxidant, inhibits pulmonary eosinophilic inflammation and production of chemoki- nes and Th2 cytokines in the lungs, thus decreasing airway hyperresponsiveness (AHR) and airway remodeling in mouse asthma models. In the present study, we investigated whether endogenous or exogenous TRX1 inhibits goblet cell hyperplasia in a mouse asthma model involving chronic exposure to antigen. Methods: We used wild-type Balb/c mice and Balb/c background human TRX1-transgenic mice constitutively overproducing human TRX1 protein in the lungs. Mice were sensitized 7 times (days 0 to 12) and then challenged 9 times with ovalbumin (OVA) (days 19 to 45). Every second day from days 18 to 44 (14 times) or days 35 to 45 (6 times), Balb/c mice were treated with 40 μg recombinant human TRX1 (rhTRX1) protein. Goblet cells in the lungs were examined quantitatively on day 34 or 45. Results: Goblet cell hyperplasia was significantly prevented in TRX1-transgenic mice in comparison with TRX1 transgene-negative mice. rhTRX1 administration during OVA challenge (days 18 to 44) significantly inhibited goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice. Moreover, rhTRX1 administration after the establishment of goblet cell hyperplasia (days 35 to 45) also significantly ameliorated goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice. Conclusions: Our results suggest that TRX1 prevents the development of goblet cell hyperplasia, and also ameliorates established goblet cell hyperplasia