Recovery from chronic obstructive pulmonary disease (COPD) exacerbations is heterogeneous and has a profound impact on disease trajectories. Resolution of airway inflammation is an active process which may be driven by Specialized Pro-resolving Mediators (SPMs).

To characterize the temporal change in SPMs in the sputum of COPD patients during COPD exacerbations, their association with exacerbation triggers and exacerbation recovery.

Participants were recruited from the London COPD Exacerbation Cohort between 01/11/2016 and 01/04/2018. Participants were reviewed at baseline, exacerbation onset, 1 week, 2 weeks and 6 weeks during their exacerbation recovery. Sputum, nasopharyngeal swabs, phlebotomy, quality of life questionnaires and spirometry were performed at each visit. SPMs were measured in sputum by liquid chromatography tandem mass spectrometry. Respiratory viruses were measured by quantitative PCR and bacteria by microbiological culture.

There were 68 exacerbations during the study period. Median time to symptomatic recovery was 21 days for viral exacerbations compared to 13 days in non-viral exacerbations (P<0.001). There was a significant increase in Resolvin D1 (RvD1) at exacerbation onset in bacterial exacerbations but not viral exacerbations. Lower levels of RvD1 were associated with prolonged respiratory symptoms during the 1-week and 2-week recovery time points. Exogenous RvD1 significantly reduced IL-6 and CXCL8 response to rhinovirus infection in COPD bronchial epithelial cells.

There is a dynamic temporal change in airway SPMs during COPD exacerbations. Reduced levels of RvD1 were associated with prolonged respiratory symptoms. SPMs may be a potential therapeutic approach to promote exacerbation recovery.

In people living with chronic obstructive pulmonary disease (COPD), we aimed to estimate: (1) the prevalence of glucocorticoid-induced hyperglycaemia (GIH); (2) whether the prevalence of GIH varies by age, baseline diabetes status, treatment duration, ascertainment of glycaemia, definition of hyperglycaemia, study design and year of publication; and (3) the relative risk (RR) of new-onset hyperglycaemia in exposed vs non-exposed to systemic glucocorticoids.

We searched electronic databases until 9 November 2023 for randomised controlled trials and observational studies including adults diagnosed with COPD, with or without diabetes at baseline, using systemic glucocorticoids equivalent to prednisolone ≥5 mg/day for ≥3 days if exposed. Hyperglycaemia was defined as a blood glucose above a study-specific cut-off. We extracted data on study and participant characteristics, exposure and outcome. We performed random-effects meta-analysis to calculate pooled prevalence estimate of GIH. Prevalence was expressed as the proportion of people who developed hyperglycaemia among all exposed to systemic glucocorticoids during follow-up. We calculated RR of new-onset hyperglycaemia in exposed vs non-exposed to systemic glucocorticoids from eight studies.

Of 25,806 citations, we included 18 studies comprising 3642 people of whom 3125 received systemic glucocorticoids and 1189 developed hyperglycaemia. Pooled prevalence of GIH was 38.6% (95%CI 29.9%-47.9%) with significant heterogeneity, I2 = 96% (p < 0.010), which was partially explained by differences in study design. Pooled RR = 2.39 (95%CI 1.51-3.78). Publication bias was present.

The prevalence of GIH was 38.6%. Being treated with systemic glucocorticoids for COPD was associated with 2.4 times higher risk of new-onset hyperglycaemia versus no glucocorticoid treatment.

The latest advances in asthma treatment have highlighted the significance of eosinophilia and the possible role of some pro-eosinophilic mediators, like interleukins (IL) IL-5, IL-4/IL-13, and IL-33 in the disease's pathogenesis. Considering that a subgroup of patients with chronic obstructive pulmonary disease (COPD) may have blood eosinophilia akin to that seen in asthma, numerous studies in the last decade have suggested that eosinophilic COPD is a separate entity. While the exact role of blood eosinophils in the pathophysiology of COPD remains unclear, eosinophilia seems to increase the effectiveness of corticosteroid therapy. Currently, monoclonal antibodies targeting the interleukins (IL-5, IL-4, IL-13, and IL-33) or their receptors are being investigated in patients with COPD belonging in T2-high endotype. This review focuses on the mechanisms of eosinophilia in COPD, the effects of eosinophilia on disease outcome, and examines the most recent data on the use of peripheral blood eosinophilia in treating patients with COPD. Finally, we emphasize the current implication of monoclonal antibodies in COPD in the context of eosinophilic airway inflammation.

Severe, life-threatening asthma and COPD exacerbations are managed commonly in the ICU and are associated with significant morbidity and mortality. It is important to understand the commonalities and differences in the diagnosis and management of these obstructive lung diseases to improve patient outcomes via evidence-based care. In this review, we first outline triggers of acute asthma and COPD exacerbations and an initial diagnostic evaluation and severity assessment. We then review the pathophysiologic features of asthma and COPD exacerbations and create a framework for the management of exacerbations in critically ill adult patients aimed at reducing airway inflammation, reversing bronchospasm, and, in severe cases, supporting patients with mechanical ventilation or advanced therapies until clinical improvement is achieved.

Mucus plugs identified through chest computed tomography (CT) scans have emerged as potential prognostic factors in chronic obstructive pulmonary disease (COPD). This 5-year longitudinal study investigated their impact on exacerbations and FEV1 decline.

COPD patients with baseline chest CT and spirometric assessments were categorized based on mucus plug presence. Propensity-score matching yielded balanced groups. Exacerbation rates, time to exacerbation events, hazard ratio (HR) for exacerbations, and annual rates of FEV1 decline were evaluated. Sensitivity analysis was performed with stratification according to mucus plug scores of 0, 1-2, and ≥3.

Among 623 eligible patients, the mucus plug group was 44.3%. Through 1:1 propensity-score matching, each group was comprised of 187 individuals with balanced covariates. The mucus plug group showed higher rates of moderate-to-severe (0.51/year vs. 0.58/year, P=0.035), severe exacerbations (0.21/year vs. 0.24/year, P=0.032), and non-eosinophilic exacerbations (0.45/year vs. 0.52/year, P=0.008). Mucus plugs were associated with increased hazard of moderate-to-severe (adjusted HR=1.502 [95% CI 1.116-2.020]), severe (adjusted HR=2.106 [95% CI, 1.429-3.103]), and non-eosinophilic exacerbations (adjusted HR=1.551 [95% CI, 1.132-2.125]). Annual FEV1 decline was accelerated in the mucus plug group (β-coefficient=-62 [95% CI, -120 to -5], P=0.035). Sensitivity analysis showed higher risk of exacerbations and accelerated FEV1 decline in mucus plug score ≥3 compared to score 0.

Mucus plugs are associated with increased risks of exacerbations, particularly non-eosinophilic, and accelerated FEV1 declines over 5 years. Our study identified the potential prognostic value of mucus plugs on future exacerbation risks and lung function decline trajectories.

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition characterised by chronic respiratory symptoms, fixed airway obstruction and persistent inflammation that leads to a progressive airflow limitation. Although COPD has traditionally been linked to neutrophilic inflammation, recent studies have identified a subset of patients - approximately 20%-40% - with elevated eosinophil levels in blood and sputum. Emerging evidence suggests that eosinophilic inflammation has a pivotal role in a subset of COPD patients and may influence disease progression, exacerbation frequency and therapeutic responses. This narrative review provides a comprehensive analysis of the role of eosinophils in COPD with particular attention to their role as biomarkers in blood and sputum. We evaluate the prevalence of eosinophilic inflammation in COPD exanimating different thresholds used in blood and in sputum to define it. In addition, we focus on eosinophilic COPD phenotype as a treatable trait, emphasising recent evidence that supports the effectiveness of biological target therapy.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause for emergency department (ED) visits. Still, large scale studies that assess the management of AECOPD in the ED are limited. Our aim was to evaluate treatment characteristics of AE-COPD in the ED on a national scale. A prospective study as part of the COPD Israeli survey, conducted between 2017 and 2019, in 13 medical centers. Patients hospitalized with AECOPD were included and interviewed. Clinical data related to their ED and hospital stay were collected. 344 patients were included, 38% females, mean age of 70 ± 11 years. Median (IQR) time to first ED treatment was 59 (23-125) minutes and to admission 293 (173-490) minutes. Delayed ED treatment (> 1 h) was associated with older age (p = 0.01) and lack of a coded diagnosis of COPD in hospital records (p = 0.01). Long ED length-of-stay (> 5 h) was linked with longer hospitalizations (p = 0.01). Routine ED care included inhalations of short-acting bronchodilators (246 patients, 72%) and systemic steroids (188 patients, 55%). Receiving routine ED care was associated with its continuation during hospitalization (p < 0.001). In multivariate analysis, predictors for patients not receiving routine care were obesity (adjusted odds ratio 0.5, 95% CI 0.3-0.8, p = 0.01) and fever (AOR 0.3, 95% CI 0.1-0.6, p < 0.01), while oxygen saturation < 91% was an independent predictor for ED routine treatment (AOR 3.6, 95% CI 2.1-6.3, p < 0.01). Our findings highlight gaps in the treatment of AECOPD in the ED on a national scale, with specific predictors for their occurrence.

The varied treatment response to inhaled corticosteroids (ICS) in patients with COPD and the associated increased risk of pneumonia necessitate a personalized ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment.

Does (1) BEC measured on ICS treatment (2) BEC measured off ICS treatment, or (3) the change in BEC during ICS treatment best predict treatment response to ICS in COPD?

The Fluticasone Salmeterol on COPD Exacerbations Trial (FLAME), a 52-week, double-blind randomized controlled trial compared long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs) with LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing BEC before and after the run-in period to represent BEC on and off ICS, respectively. In this post hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS-containing regimen.

Our study showed that LABA/LAMA combination was superior, or at least noninferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off ICS, higher BEC on ICS, and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of exacerbation rate, time to first exacerbation, and time to first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment (≥ 200 cells/μL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC was not predictive of treatment effects on lung function and health status.

This exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response.

ClinicalTrials.gov; No.: NCT01782326; URL: www.

gov.

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation. While corticosteroids (CS) are frequently prescribed during exacerbations of these conditions, their repeated use is associated with numerous side effects. The aim of this review is to synthesize the recent literature on the indications, benefits, and risks of short-term CS therapy for these two diseases. French guidelines recommend short-term CS as a first-line treatment during asthma exacerbation (0,5 to 1mg/kg/day, not exceeding 60mg/day, for at least 5 to 7 days) or as a second-line treatment for COPD exacerbation (5 days, 30 to 40mg/day). However, these recommendations are not without limitations; they are primarily based on studies conducted in hospital settings, raising questions about the generalizability of their results to primary care, and as they employ a "one size fits all" strategy, they do not take into account the phenotypic heterogeneity of different patients. Moreover, repeated short-term CS courses generate side effects that even at low doses can appear early in young asthma patients, and they can exacerbate pre-existing comorbidities in COPD patients. The concept of a threshold dose should be employed in routine practice in view of accurately assessing the risk of side effects. In the near future, it will be important to consider recently published data supporting the use of predictive biomarkers for responses to CS, particularly in COPD cases.

Most physicians in general, and family physicians in particular, are familiar with certain parameters when ordering a hematological study, such as hemoglobin (including hematocrit and its features), leukocytes (including lymphocytes) and platelets. Nevertheless, there are two values that we use to overlook which are eosinophils and basophils. Specifically, eosinophils have a tendency to increase with allergic pathology. This article focuses on this type of cells, helping to interpret the values obtained and highlighting their importance in two of the most frequent respiratory pathologies in primary care: asthma and COPD. In addition to observing how the increase or normality of these parameters condition the diagnosis, phenotype and even the treatment.

Chronic obstructive pulmonary disease (COPD), a global healthcare and socioeconomic burden, is a multifaceted respiratory disorder that results in substantial decline in health status and life quality. Acute exacerbations of the disease contribute significantly to increased morbidity and mortality. Consequently, the identification of reliable and effective biomarkers for rapid diagnosis, prediction, and prognosis of exacerbations is imperative. In addition, biomarkers play a crucial role in monitoring responses to therapeutic interventions and exploring innovative treatment strategies. Although established markers such as CRP, fibrinogen and neutrophil count are routinely used, a universal marker is lacking. Fortunately, an increasing number of studies based on next generation analytics have explored potential biomarkers in COPD. Here we review those advances and the need for standardized validation studies in the appropriate clinical setting.

Bronchiectasis presents a significant challenge due to its rising prevalence, associated economic burden and clinical heterogeneity. This review synthesises contemporary understanding and literature of bronchiectasis exacerbations, addressing the transition from stable state to exacerbations, underlining the importance of early and precise recognition, rigorous severity assessment, prompt treatment, and prevention measures, as well as emphasising the need for strategies to assess and improve early and long-term patient outcomes. The review highlights the interplay between stable state phases and exacerbations in bronchiectasis, introducing the concept of "exogenous and endogenous changes in airways homeostasis" and the "adapted island model" with a particular focus on "frequent exacerbators", a group of patients associated with specific clinical characteristics and worse outcomes. The pathophysiology of exacerbations is explored through the lens of microbial and nonmicrobial triggers and the presence and the activity of comorbidities, elaborating on the impact of both exogenous insults, such as infections and pollution, and endogenous factors such as inflammatory endotypes. Finally, the review proposes a multidisciplinary approach to care, integrating advancements in precision medicine and biomarker research, paving the way for tailored treatments that challenge the traditional antibiotic paradigm.

Corticosteroids have been utilized in modern medicine for decades. Many indications have been investigated across various treatment settings with both benefit and harm observed. Given the instability of critically ill patients, the increased risk of corticosteroid-related complications, and the pervasive comorbidities, patients who receive corticosteroids must be carefully managed. Common critical care disease states in which corticosteroids have been studied and are routinely utilized include acute respiratory distress syndrome, adrenal insufficiency, angioedema, asthma, chronic obstructive pulmonary disease, community-acquired pneumonia, coronavirus disease 2019, septic shock, and spinal cord injury. Benefits of corticosteroids include an improvement in disease state-specific outcomes, decreased hospital length of stay, decreased mechanical ventilatory support, and decreased mortality. The harm of corticosteroids is well documented through adverse effects that include, but are not limited to, hyperglycemia, tachycardia, hypertension, agitation, delirium, anxiety, immunosuppression, gastrointestinal bleeding, fluid retention, and muscle weakness. Furthermore, corticosteroids are associated with increased health care costs through adverse effects as well as drug acquisition and administration costs. Given the assortment of agents, dosing, benefits, risks, and utilization in the critical care setting, there may be difficulty with identifying the appropriate places for use of corticosteroids in therapy. There currently exists no comprehensive report detailing the use of corticosteroids in the aforementioned disease states within the critical care setting. This narrative review sets out to describe these in detail.

The phenotyping of chronic obstructive pulmonary disease (COPD) has increasingly gained attention in recent years, as it leads to new and individualized therapeutic concepts.

The aim is to provide an overview of the heterogeneity of COPD and to summarize current drug therapy concepts, particularly in the context of eosinophilic airway inflammation.

Several prospective, randomized, placebo-controlled studies have shown a reduction in exacerbations and overall mortality with inhaled triple therapy using an inhaled corticosteroid and dual bronchodilation. The higher the eosinophils in the blood, the greater the expected effect. In addition, a reduction in exacerbations with biologics in COPD with eosinophilia has been demonstrated for dupilumab. Eosinophil-guided therapy for acute exacerbations is the subject of current research.

For COPD without exacerbations, dual bronchodilation forms the basis of inhaled therapy. With exacerbations, inhaled triple therapy is indicated for patients with a blood eosinophil count of ≥ 300/µl. This type of treatment may also be useful when eosinophils are between 100 and 300/µl. Therapy with dupilumab is a possible option for the eosinophilic phenotype in the near future.

For the treatment of COPD exacerbations, systemic corticosteroids are recommended in addition to short-acting bronchodilators. Although there have been several systemic reviews, many of the included studies were conducted before 2007 and a re-evaluation has not been performed since 2014. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety profile of systemic corticosteroids in patients with COPD during exacerbations.

We searched relevant randomized control trials (RCTs) and analyzed the treatment failure, relapse, lung function, improvement in PaO2 and PaCO2, dyspnea, quality of life (QOL), length of stay in hospital and adverse events including hyperglycemia and mortality as the outcomes of interest.

We identified a total of 12 RCTs (N = 1336). Systemic corticosteroids significantly reduced the treatment failure (odds ratios; OR 0.41, 95% confidence intervals; CI 0.25 to 0.67) and hospital length of stay (mean difference; MD -1.57 days, 95% CI -2.36 to -0.78) and improved FEV1 (MD 0.18 L, 95% CI 0.08 to 0.28) and dyspnea (transitional dyspnea index; MD 1.90, 95% CI 0.26 to 3.54) in COPD exacerbations compared to placebo. However, systemic corticosteroids were associated with a significantly higher incidence of adverse events (OR 1.83, 95% CI 1.25 to 2.69) and hyperglycemia (OR 2.94, 95% CI 1.68 to 5.14).

In patients with moderate and severe COPD and severe obstructive impairment during exacerbations, systemic corticosteroids cause more adverse events, including hyperglycemia, than placebo but significantly reduce the treatment failure and hospital length of stay and improve FEV1 and dyspnea.

Chronic obstructive pulmonary disease (COPD) is a common condition with an estimated prevalence of 12% in adults over the age of 30 years worldwide. COPD is a leading cause of morbidity and mortality globally, with a substantial economic and social burden. There are an estimated 3 million deaths annually due to COPD. However, most of the patients with COPD respond to routine interventions like bronchodilator therapy, assessing supplemental oxygen needs, smoking cessation, vaccinations, and pulmonary rehabilitation. There is a significant number of patients who unfortunately progress to have persistent symptoms despite these interventions. Refractory COPD is not yet formally defined. Patients with severe persistent symptoms or exacerbations despite appropriate care can be considered to have refractory COPD. Managing refractory COPD needs a multidimensional approach. In this review article, we will discuss essential interventions like ensuring adequate inhaler techniques, exploring the need for non-invasive ventilatory support, use of chronic antibiotics and phosphodiesterase inhibitors to advanced therapies like bronchoscopic lung volume reduction surgery, and the upcoming role of anti-IL5 agents in managing patients with refractory COPD. We will also discuss non-pharmacologic interventions like psycho-social support and nutritional support. We will conclude by discussing the palliative care aspect of managing patients with refractory COPD. Through this review article, we aim to better the approach to managing patients with refractory COPD and discuss new upcoming therapies.

Recent studies have suggested elevated blood eosinophils are independent predictors of response to corticosteroid therapy in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Smoking status has been shown to affect corticosteroid response. Whether the association between high blood eosinophils and corticosteroid treatment failure is modified by smoking has not been fully investigated so far.

This study aimed to assess whether the association between high blood eosinophils and corticosteroid treatment failure is modified by smoking.

We included 3402 inpatients with AECOPD treated with corticosteroids at Beijing Chao-Yang Hospital from July 2013 to June 2021. Blood eosinophil counts were measured within 24 hours of admission. An eosinophil percentage ≥2% was considered as high eosinophilic. Smokers in this study were defined as current or former smokers. Treatment failure was defined as a worsening of AECOPD that led to adverse clinical outcomes or required further treatment or an extended hospital stay or hospitalisation following the exacerbation. Multivariate-adjusted logistic models were used to estimate the OR and 95% CI associated with treatment failure.

There were 958 (28.2%) treatment failure events occurring. Patients with high eosinophils had a lower risk of treatment failure (OR 0.74, 95% CI 0.63 to 0.87) than patients with low eosinophils. Compared with never smoking and low eosinophilic group, the ORs for treatment failure were 0.70 (95% CI 0.52 to 0.96) for never smoking and high eosinophilic group, 0.82 (95% CI 0.64 to 1.05) for smoking and low eosinophilic group and 0.62 (95% CI 0.47 to 0.81) for smoking and high eosinophilic group. Furthermore, there was no significant interaction between eosinophils and smoking status in relation to treatment failure (p for interaction=0.73). Similar results were obtained from multiple secondary outcomes and subgroup analyses.

Elevated blood eosinophils are associated with a lower rate of corticosteroid treatment failure, regardless of smoking status. Smoking does not modify the association between blood eosinophil level and corticosteroid treatment failure among inpatients with AECOPD.

This review highlights key aspects of treating chronic obstructive pulmonary disease (COPD) exacerbation, focusing on the optimisation of systemic corticosteroid and antibiotic use through personalised treatment using biomarkers. Eosinophil-guided therapy reduces corticosteroid usage which might reduce side effects, while procalcitonin-guided therapy contributes to reduced antibiotic consumption. These approaches, documented through well-conducted randomized controlled trials, suggest the possibility of enhancing COPD exacerbation management, reducing potential side effects, and addressing concerns related to antibiotic resistance.

Patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) exhibit heterogeneous responses to corticosteroid treatment. We aimed to determine whether combining eosinophil levels with other routine clinical indicators can enhance the predictability of corticosteroid treatment outcomes and to come up with a scoring system.

Consecutive patients admitted with AECOPD receiving corticosteroid treatment between July 2013 and March 2022 at Beijing Chao-Yang Hospital were retrospectively analyzed. Data on patients' demographics, smoking status, hospitalization for AECOPD in the previous year, comorbidities, blood laboratory tests, in-hospital treatment and clinical outcomes were collected. Least absolute shrinkage and selection operator (LASSO) regression and backward logistic regression were used for predictor selection, and predictive nomograms were developed. The discrimination and calibration of the nomograms were assessed using the area under the receiver operating curve (AUC) and calibration plots. Internal validation was performed using the 500-bootstrap method, and clinical utility was evaluated using decision curve analysis (DCA).

Among the 3254 patients included, 804 (24.7%) had treatment failure. A nomogram of eosinophils, platelets, C-reactive protein (CRP), low density lipoprotein cholesterol, prognostic nutritional index (PNI), hospitalization for AECOPD in the previous year, ischemic heart diseases and chronic hepatic disease was developed to predict treatment failure for patients with a smoking history. For patients without a smoking history, a nomogram of CRP, PNI, ischemic heart diseases and chronic hepatic disease was developed. Although the AUCs of these two nomograms were only 0.644 and 0.647 respectively, they were significantly superior to predictions based solely on blood eosinophil levels.

We developed easy-to-use comprehensive nomograms utilizing readily available clinical biomarkers related to inflammation, nutrition and immunity, offering modestly enhanced predictive value for treatment outcomes in corticosteroid-treated patients with AECOPD. Further investigations into novel biomarkers and additional patient data are imperative to optimize the predictive performance.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, characterized by intense lung infiltrations of immune cells (macrophages and monocytes). While existing studies have highlighted the crucial role of the competitive endogenous RNA (ceRNA) regulatory network in COPD development, the complexity and characteristics of the ceRNA network in monocytes remain unexplored.

We downloaded messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) microarray data from GSE146560, GSE102915, and GSE71220 in the Gene Expression Omnibus (GEO) database. This data was used to identify differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs). Predicted miRNAs that bind to DElncRNAs were intersected with DEmiRNAs, forming a set of intersecting miRNAs. This set was then used to predict potential binding mRNAs, intersected with DEmRNAs, and underwent functional enrichment analysis using R software and the STRING database. The resulting triple regulatory network and hub genes were constructed using Cytoscape. Comparative Toxicomics Database (CTD) was utilized for disease correlation predictions, and ROC curve analysis assessed diagnostic accuracy.

Our study identified 5 lncRNAs, 4 miRNAs, and 149 mRNAs as differentially expressed. A lncRNA-miRNA-mRNA regulatory network was constructed, and hub genes were selected through hub analysis. Enrichment analysis highlighted terms related to cell movement and gene expression regulation. We established a LINC00482-has-miR-6088-PRRC2B ceRNA network with diagnostic relevance for COPD. ROC analysis demonstrated the diagnostic value of these genes. Moreover, a positive correlation between LINC00482 and PRRC2B expression was observed in COPD PBMCs. The CTD database indicated their involvement in inflammatory responses.

In summary, our study not only identified pivotal hub genes in peripheral blood mononuclear cells (PBMCs) of COPD but also constructed a ceRNA regulatory network. This contributes to understanding the pathophysiological processes of COPD through bioinformatics analysis, expanding our knowledge of COPD, and providing a foundation for potential diagnostic and therapeutic targets for COPD.

This meta-analysis compares the efficacy and safety of inhaled versus systemic corticosteroids for COPD exacerbations.Following a pre-registered protocol, we appraised eligible randomised controlled trials (RCTs) according to Cochrane methodology, performed random-effects meta-analyses for all outcomes prioritised in the European Respiratory Society COPD core outcome set and rated the certainty of evidence as per Grading of Recommendations Assessment, Development and Evaluation methodology.We included 20 RCTs totalling 2140 participants with moderate or severe exacerbations. All trials were at high risk of methodological bias. Low-certainty evidence did not reveal significant differences between inhaled and systemic corticosteroids for treatment failure rate (relative risk 1.75, 95% CI 0.76-4.02, n=569 participants); breathlessness (mean change: standardised mean difference (SMD) -0.11, 95% CI -0.36-0.15, n=239; post-treatment scores: SMD -0.18, 95% CI -0.41-0.05, n=293); serious adverse events (relative risk 1.47, 95% CI 0.56-3.88, n=246); or any other efficacy outcomes. Moderate-certainty evidence implied a tendency for fewer adverse events with inhaled compared to systemic corticosteroids (relative risk 0.80, 95% CI 0.64-1.0, n=480). Hyperglycaemia and oral fungal infections were observed more frequently with systemic and inhaled corticosteroids, respectively.Limited available evidence suggests potential noninferiority of inhaled to systemic corticosteroids in COPD exacerbations. Appropriately designed and powered RCTs are warranted to confirm these findings.

Systemic glucocorticoids are recommended for use in chronic obstructive pulmonary disease (COPD) exacerbations; however, there is increased harm associated with their use. We hypothesised that the use of eosinophil biomarker-directed oral prednisolone therapy at the time of an exacerbation of COPD was effective at reducing prednisolone use without affecting adverse outcomes.

The studying acute exacerbations and response (STARR2) study was a multicentre, randomised, double-blind, placebo-controlled trial conducted in 14 primary care practices in the UK. We included adults (aged ≥40 years), who were current or former smokers (with at least a 10 pack year smoking history) with a diagnosis of COPD, defined as a post-bronchodilator FEV1/forced vital capacity ratio of less than 0·7 previously recorded by the primary care physician, and a history of at least one exacerbation in the previous 12 months requiring systemic corticosteroids with or without antibiotics. All study staff and participants were masked to study group allocation and to treatment allocation. Participants were randomly assigned (1:1) to blood eosinophil-directed treatment (BET; to receive oral prednisolone 30 mg once daily if eosinophil count was high [≥2%] or placebo if eosinophil count was low [<2%]) or to standard care treatment (ST; to receive prednisolone 30 mg once daily irrespective of the point-of-care eosinophil result). Treatment was prescribed for 14 days and all patients also received antibiotics. The primary outcome was the rate of treatment failure, defined as any need for re-treatment with antibiotics or steroids, hospitalisation for any cause, or death, assessed at 30 days after exacerbation in the modified intention-to-treat population. Participants were eligible for re-randomisation at further exacerbations (with a maximum of four exacerbations per participant). A safety analysis was conducted on all randomly assigned participants. Although designed as a superiority trial, after identification of an error in the randomisation code before data lock the study converted to show non-inferiority. An upper margin of 1·105 for the 95% CI was defined as the non-inferiority margin. This study was registered with EudraCT, 2017-001586-24, and is complete.

Between Nov 6, 2017, and April 30, 2020, 308 participants were recruited from 14 general practices. 144 exacerbations (73 in the BET group and 71 in the ST group) from 93 participants (mean age 70 years [range 46-84] and mean percent predicted FEV1 60·9% [SD 19·4]; 52 [56%] male and 41 [44%] female; ethnicity data was not collected]) were included in the modified intention-to-treat analysis. There were 14 (19%) treatment failures at 30 days post-exacerbation in the BET group and 23 (32%) in the ST group; we found a large non-significant estimated effect between BET and ST (RR 0·60 [95% CI 0·33-1·04]; p=0·070) in reducing treatment failures after a COPD exacerbation. The non-inferiority analysis supported that BET was non-inferior to ST. Frequency of adverse events were similar between the study groups; glycosuria (2/102 [2%] in BET group and 1/101 [1%] in the ST group) and hospital admission for COPD exacerbation (2/102 [2%] in BET group and 1/101 [1%] in the ST group) were the two most common adverse events in both groups. No deaths occurred in the study.

Blood eosinophil-directed prednisolone therapy at the time of an acute exacerbation of COPD is non-inferior to standard care and can be used to safely reduce systemic glucocorticoid use in clinical practice.

National Institute for Health and Care Research.

Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is punctuated by acute episodes of increased respiratory symptoms, termed exacerbations of chronic obstructive pulmonary disease (ECOPD). ECOPD are important events in the natural history of the disease, as they are associated with lung function decline and prolonged negative effects on quality of life. The present-day therapy for ECOPD with short courses of antibiotics and steroids and escalation of bronchodilators has resulted in only modest improvements in outcomes. Recent data indicate that ECOPD are heterogeneous, raising the need to identify distinct etioendophenotypes, incorporating traits of the acute event and of patients who experience recurrent events, to develop novel and targeted therapies. These characterizations can provide a complete clinical picture, the severity of which will dictate acute pharmacological treatment, and may also indicate whether a change in maintenance therapy is needed to reduce the risk of future exacerbations. In this review we discuss the latest knowledge of ECOPD types on the basis of clinical presentation, etiology, natural history, frequency, severity, and biomarkers in an attempt to characterize these events.

Blood eosinophil counts have been studied in patients with stable chronic obstructive pulmonary disease (COPD) and are a useful biomarker to guide inhaled corticosteroid use. Less is known about eosinophil counts during severe exacerbation.

In this retrospective study, 2645 patients admitted consecutively with COPD exacerbation across six UK hospitals were included in the study, and the clinical diagnosis was confirmed by a respiratory specialist. The relationship between admission eosinophil count, inpatient death and 1-year death was assessed. In a backward elimination, Poisson regression analysis using the log-link function with robust estimates, patients' markers of acute illness and stable-state characteristics were assessed in terms of their association with eosinopenia.

1369 of 2645 (52%) patients had eosinopenia at admission. Those with eosinopenia had a 2.5-fold increased risk of inpatient death compared with those without eosinopenia (12.1% vs 4.9%, RR=2.50, 95% CI 1.88 to 3.31, p<0.001). The same mortality risk with eosinopenia was seen among the subgroup with pneumonic exacerbation (n=788, 21.3% vs 8.5%, RR=2.5, 95% CI 1.67 to 2.24, p<0.001). In a regression analysis, eosinopenia was significantly associated with: older age and male sex; a higher pulse rate, temperature, neutrophil count, urea and C reactive protein level; a higher proportion of patients with chest X-ray consolidation and a reduced Glasgow Coma Score; and lower systolic and diastolic blood pressure measurements and lower oxygen saturation, albumin, platelet and previous admission counts.

During severe COPD exacerbation, eosinopenia is common and associated with inpatient death and several markers of acute illness. Clinicians should be cautious about using eosinophil results obtained during severe exacerbation to guide treatment decisions regarding inhaled corticosteroid use.

Over the past decades, chronic obstructive pulmonary disease (COPD) has become a major public health problem due to increasing morbidity and mortality. COPD is characterized by airflow limitation due to inflammation of the bronchial tree and remodeling of the small airways. In 20-40% of patients with COPD, eosinophilic inflammation of the airways is observed, as in bronchial asthma. Eosinophilic COPD has recently been shown to be a distinct disease and is associated with more pronounced airway remodeling. Although the role of eosinophils in the pathogenesis of COPD is not fully understood, the level of eosinophils can be used in the prognosis and administration of corticosteroids, and their effectiveness is higher in eosinophilia. Currently, monoclonal antibodies directed against interleukins (IL-5, IL-4 and IL-13) or their receptors are being tested in the T2 endotype of COPD. This review focuses on the mechanisms of eosinophilia in COPD, the use of blood and sputum eosinophils as a biomarker, and the advisability of using monoclonal antibodies in the treatment of eosinophilic COPD.

Prednisolone given universally for COPD exacerbations causes harm without any benefit. Patients deserve blood eosinophil-guided prednisolone treatment for COPD exacerbations. https://bit.ly/3pR2BSY.

Systemic corticosteroids (CSs), a keystone in pulmonology, are drugs with strong antiinflammatory activity. They are cheap, easily available, and accessible, but with common and serious side effects. Moreover, the use of exogenous CSs may suppress the hypothalamic-pituitary-adrenal (HPA) axis, predisposing to adrenal insufficiency. Safe CS treatment is a challenge of pharmacological research. This narrative review examined the indications of CSs in some respiratory diseases, analyzing what types, dosages, and length of treatment are required as the dosage and duration of CS treatments need to be minimized. Chronic maintenance treatments with CSs are associated with poor prognosis, but they are still prescribed in patients with severe asthma, Chronic obstructive pulmonary disease (COPD), and interstitial lung diseases. When CS discontinuation is not possible, all efforts should be made to achieve clinically meaningful reductions. Guidelines suggest the use of methylprednisolone at a dose of 20-40 mg/day or equivalent for up to 10 days in subjects with COVID-19 pneumonia (but not other respiratory viral diseases) and respiratory failure, exacerbations of asthma, and COPD. Some guidelines suggest that CS treatment shorter than 10-14 days can be abruptly stopped, strictly monitoring subjects with unexplained symptoms after CS withdrawal, who should promptly be tested for adrenal insufficiency (AI) and eventually treated. CSs are often used in severe community-acquired pneumonia associated with markedly increased serum inflammation markers, in acute respiratory distress syndrome (ARDS), in septic shock unresponsive to hydro-saline replenishment and vasopressors, and acute exacerbations of interstitial lung diseases. As these cases often require higher doses and longer duration of CS treatment, CS tapering should be gradual and, when useful, supported by an evaluation of HPA axis function.

Blood eosinophil is a promising biomarker for phenotyping patients with acute exacerbation of COPD (AECOPD). We aimed to evaluate the prognostic value of eosinophil on short- and long-term outcomes stratified by corticosteroid treatment among AECOPD inpatients.

In this retrospective cohort study, we included patients hospitalized for AECOPD from July 2013 to June 2021 in Beijing, China. Clinical data were collected from electronic medical records. The blood eosinophil count was measured within 24h after admission. Eosinophilic AECOPD was defined as having an eosinophil percentage ≥ 2%. The study outcomes were length of stay (LOS), treatment failure, and AECOPD readmission risk within 3 years of discharge. Multivariable models were used to analyze the associations between blood eosinophil count and outcomes stratified by corticosteroid treatment during hospitalization.

A total of 2406 AECOPD patients were included. The median LOS of AECOPD patients was 10 (interquartile range: 8-14) days. The eosinophil percentage was negatively associated with LOS (P-trend=0.014). Compared with the non-eosinophilic AECOPD group, the eosinophilic group had a 58% lower risk of treatment failure (OR=0.42, 95% CI: 0.20-0.89) in patients treated with systemic corticosteroids, but no association was observed in those treated with inhaled corticosteroids (ICS) only (OR=0.95, 95% CI: 0.60-1.52). The eosinophilic group had an increased risk of 90-day re-admission in patients treated with ICS only (HR=1.51, 95% CI: 1.00-2.29), but not in patients treated with systemic corticosteroids during hospitalization (HR=0.67, 95% CI: 0.39-1.15). No statistically significant results were found for 180-day, 1-year, or 3-year readmission risk.

Elevated blood eosinophils in AECOPD were associated with shorter length of stay and improved response to treatment with systemic corticosteroids, but not inhaled corticosteroids. Our study suggested that a therapeutic approach of using systemic corticosteroid may benefit patients present with eosinophilic AECOPD.

Exacerbation of chronic obstructive pulmonary disease (ECOPD) is a complex phenomenon, with marked heterogeneity in the aetiology, pathophysiology and clinical manifestations. This study aimed to evaluate the clinical characteristics and long-term outcomes of patients with 30-day exacerbation among those hospitalised with ECOPD in China.

Data from the Acute Exacerbations of Chronic Obstructive Pulmonary Disease Inpatient Registry were used in this study. The patients were divided into re-event and non-event groups based on the incidence of re-exacerbation within 30 days of discharge. Exacerbation, severe exacerbation and all-cause readmissions in the following 12 months were the outcomes of interest. The cumulative incidence rates and incidence densities were calculated. Multivariate hazard function models were used to determine the association between 30-day re-exacerbation and the long-term outcomes after accounting for the competing risk of death.

Re-exacerbation within 30 days of discharge was observed in 4.9% (n=242) of the patients (n=4963). The cumulative incidence rates and incidence densities of exacerbation, severe exacerbation and all-cause readmissions in the event group were significantly higher than those in the non-event group. After adjustment, re-exacerbation within 30 days of discharge was associated with increased risks of exacerbation, severe exacerbation and all-cause readmissions in the following 12 months (adjusted HR: 3.85 (95% CI: 3.09 to 4.80), 3.46 (2.66 to 4.50) and 3.28 (2.52 to 4.25) accordingly).

Re-exacerbation of COPD within 30 days of discharge is a significant predictor of long-term prognosis. In clinical practice, short-term re-exacerbation is a significant clinical phenotype of ECOPD that requires careful management at the earliest.

Pharmacological management of airway obstructive diseases is a fast-evolving field. Several advances in unravelling disease mechanisms as well as intracellular and molecular pathways of drug action have been accomplished. While the clinical translation and implementation of in vitro results to the bedside remains challenging, advances in comprehending the mechanisms of respiratory medication are expected to assist clinicians and scientists in identifying meaningful read-outs and designing clinical studies. This European Respiratory Society Research Seminar, held in Naples, Italy, 5-6 May 2022, focused on current and future developments of the drugs used to treat asthma and COPD; on mechanisms of drug action, steroid resistance, comorbidities and drug interactions; on prognostic and therapeutic biomarkers; on developing novel drug targets based on tissue remodelling and regeneration; and on pharmacogenomics and emerging biosimilars. Related European Medicines Agency regulations are also discussed, as well as the seminar's position on the above aspects.

Acute lung injury (ALI) has the attribution of excessive inflammation of the lung. Jinzhen oral liquid (JO), a famous Chinese recipe used to treat ALI, has a favorable therapeutic effect on ALI. However, its anti-inflammatory mechanism has not been extensively studied.

This study was to elucidate the effects of JO on lipopolysaccharide (LPS)-induced ALI and its molecular mechanism.

An ALI model was established by intratracheal instillation of LPS (2 mg/50 μl). The open field experiment was carried out to explore the spontaneous movement and exploratory behavior of ALI mice. Cytokines levels concentrations (IL-6, IL-10 and TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Network pharmacology was used to predict the mechanism of JO against ALI. Immunofluorescence, co-immunoprecipitation, fluorescence resonance energy transfer (FRET), Western blot and RT-PCR were used to verify the molecular mechanisms of JO.

The in vivo results suggested that JO (1, 2, 4 g/kg) dose-dependently improved the exercise performance of mice and reduced the lung W/D weight ratio as well as the production of IL-6 and TNF-α, but increased the release of IL-10 in the ALI group. The network pharmacological analysis demonstrated that the Toll-like receptor (TLR) pathway might be the fundamental action mechanisms of JO against ALI. Immunofluorescence staining and co-immunoprecipitation analysis showed that JO decreased the expression levels of TLR4 and MyD88 and reduced their interaction in the lung tissue of ALI mice. Meanwhile, JO decreased nuclear translocation and phosphorylation of NF-κB P65. The results from cellular experiments were in line with those in vivo. The FRET experiment also confirmed that JO disturbed the interaction of TLR4 and MyD88. Subsequently, we also found that the six indicative components of JO have the similar therapeutic effect as JO.

In summary, we suggested that JO suppressed the TLR4/MyD88/NF-κB signaling pathway, thus inhibiting LPS-induced ALI in vitro and in vivo. The clarified mechanism provided an important theoretical basis and a novel treatment strategy for the ALI treatment of JO.

Corticosteroid is one of the most commonly used medications in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The increasing understanding of these side-effects of systematic corticosteroids and their better response to treatment among patients with COPD with higher blood eosinophil counts has led to an interest in a more targeted approach to systematic corticosteroid treatment. However, there is a lack of evidence from high-quality randomised controlled trial (RCT) studies about whether initial systematic corticosteroids should be given to patients with AECOPD with elevated eosinophilia. The aim of the present research was to test this hypothesis.

This is a multicentre, double-blind, superiority RCT in the respiratory departments of 12 general hospitals in China. It is anticipated that 456 patients with AECOPD with a blood eosinophil count >2% or >300 cells/µL at admission will be recruited. Eligible patients will be randomised (1:1) to the intervention group receiving 40 mg oral prednisone daily or identical-appearing placebo (control group) for five consecutive days. Follow-up visits are performed during hospitalisation, followed by clinic interviews on days 30, 60 and 90 after discharge. The primary outcome is treatment failure rates comprising requiring or receiving invasive or non-invasive mechanical ventilation, requiring or transferring to intensive care unit during the index hospitalisation, length of index hospitalisation longer than 14 days, death during the index hospitalisation or within 30 days after discharge and readmission with acute exacerbations of COPD within 30 days after discharge. The results of this trial will provide insight into the value of using blood eosinophil counts as a biomarker of eosinophilic exacerbation and initiating systematic corticosteroid treatment for patients with AECOPD with higher eosinophil levels.

This study was approved by Beijing Chaoyang Hospital Institutional Review Board (approval number: 2020-KE-544) and the main results and secondary results will be published in peer-reviewed journals.

NCT05059873.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with distinct phenotypes, each having distinct treatment needs. Eosinophilic airway inflammation is present in a subset of COPD patients in whom it can act as a driver of exacerbations. Blood eosinophil counts are a reliable way to identify patients with an eosinophilic phenotype, and these measurements have proven to be successful in guiding the use of corticosteroids in moderate and severe COPD exacerbations. Antibiotic use in COPD patients induces a risk of Clostridium difficile infection, diarrhea, and antibiotic resistance. Procalcitonin could possibly guide antibiotic treatment in patients admitted with AECOPD. Current studies in COPD patients were successful in reducing exposure to antibiotics with no changes in mortality or length of stay. Daily monitoring of blood eosinophils is a safe and effective way to reduce oral corticosteroid exposure and side effects for acute exacerbations. No evidence on time-updated treatment guidance for stable COPD exists yet, but a current trial is testing an eosinophil-guided approach on inhaled corticosteroid use. Procalcitonin-guided antibiotic treatment in AECOPD shows promising results in safely and substantially reducing antibiotic exposure both in time-independent and time-updated algorithms.

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.

This meta-analysis explored the safety and effectiveness of mucolytics as an add-on treatment for chronic obstructive pulmonary disease (COPD) exacerbations. Based on a pre-registered protocol and following Cochrane methods, we systematically searched for relevant randomised or quasi-randomised controlled trials (RCTs). We used the Risk of Bias v2 tool for appraising the studies and performed random-effect meta-analyses when appropriate. We assessed certainty of evidence using GRADE. This meta-analysis included 24 RCTs involving 2192 patients with COPD exacerbations, entailing at least some concerns of methodological bias. We demonstrated with moderate certainty that mucolytics increase the rate of treatment success (relative risk 1.37, 95% CI 1.08-1.73, n=383), while they also exert benefits on overall symptom scores (standardised mean difference 0.86, 95% CI 0.63-1.09, n=316), presence of cough at follow-up (relative risk 1.93, 95% CI 1.15-3.23) and ease of expectoration (relative risk 2.94, 95% CI 1.68-5.12). Furthermore, low or very low certainty evidence suggests mucolytics may also reduce future risk of exacerbations and improve health-related quality of life, but do not impact on breathlessness, length of hospital stay, indication for higher level of care or serious adverse events. Overall, mucolytics could be considered for COPD exacerbation management. These findings should be validated in further, rigorous RCTs.

Inhaled bronchodilator therapy with long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) in combination is currently the mainstay of treatment for chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend the addition of inhaled corticosteroids (ICS) to LABA/LAMA only in patients with a history of frequent/severe exacerbations and high blood eosinophil counts, or in those with concomitant asthma. Despite this, real-world data suggest that clinicians are not adhering to this guidance and that ICS are frequently overused. This is possibly due to the incorrect assumption that when LABA/LAMA therapy is not sufficient, adding an ICS to the treatment regimen is the logical next step. In this narrative review, we describe global and country-specific guideline recommendations from Germany, Spain, and Japan and compare these with real-world data on LABA/LAMA and ICS use in clinical practice. We also provide a clinical guide to the use of add-on therapies with LABA/LAMA for different patient phenotypes, including (1) patients still symptomatic (but not exacerbating) despite LABA/LAMA treatment; (2) patients still exacerbating despite LABA/LAMA treatment who have high blood eosinophil counts; and (3) patients still exacerbating despite LABA/LAMA treatment who do not have high blood eosinophils or concomitant asthma.