Frequent Exacerbator Phenotype Research Articles

Blood eosinophils levels in a Colombian cohort of biomass-and tobacco-related COPD patients.

Chronic obstructive pulmonary disease (COPD) is a major cause of illness and death among adults. In 2019, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy incorporated blood eosinophils as a biomarker to identify patients at increased risk of exacerbations which, with the history of exacerbations during the previous year, allows identification of patients who would benefit from anti-inflammatory treatment to reduce the risk of future exacerbations. The aim of this study was to describe demographic and clinical characteristics, eosinophil counts, and exacerbations in a cohort of COPD patients stratified by clinical phenotypes (non-exacerbator, frequent exacerbator, asthma-COPD overlap) in a Colombian cohort at 2600 meters above sea level. A descriptive analysis of a historical cohort of patients with a confirmed diagnosis of moderate to severe COPD (FEV1/FVC < 0.7 and at least one risk factor for COPD) from two specialized centers with comprehensive disease management programs was performed from January 2015 to March 2019. Data were extracted from medical records 1 year before and after the index date. 200 patients were included (GOLD B: 156, GOLD E: 44; 2023 GOLD classification); mean age was 77.9 (SD 7.9) years; 48% were women, and 52% had biomass exposure as a COPD risk factor. The mean FEV1/FVC was 53.4% (SD 9.8), with an FEV1 of 52.7% (20.7). No differences were observed between clinical phenotypes in terms of airflow limitation. The geometric mean of absolute blood eosinophils was 197.58 (SD 2.09) cells/μL (range 0 to 3,020). Mean blood eosinophil count was higher in patients with smoking history and frequent exacerbators. At least one moderate and one severe exacerbation occurred in the previous year in 44 and 8% of patients, respectively; during the follow-up year 152 exacerbations were registered, 122 (80%) moderate and 30 (20%) severe. The highest rate of exacerbations in the follow-up year occurred in the subgroup of patients with the frequent exacerbator phenotype and eosinophils ≥300 cells/μL. In this cohort, the frequency of biomass exposure as a risk factor is considerable. High blood eosinophil count was related to smoking, and to the frequent exacerbator phenotype.

Prevalence of Cardiovascular Disease and Rate of Major Adverse Cardiovascular Events in Severe Alpha-1 Antitrypsin Deficiency COPD.

Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD. Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE. Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001). In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.

A predictive model for frequent exacerbator phenotype of acute exacerbations of chronic obstructive pulmonary disease.

The frequent exacerbator phenotype of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is characterized by experiencing at least two exacerbations per year, leading to a significant economic burden on healthcare systems worldwide. Although several biomarkers have been shown to be effective in assessing AECOPD severity in recent years, there is a lack of studies on markers to predict the frequent exacerbator phenotype of AECOPD. The current study aimed to develop a new predictive model for the frequent exacerbator phenotype of AECOPD based on rapid, inexpensive, and easily obtained routine markers. This was a single-center, retrospective study that enrolled a total of 2,236 AECOPD patients. The participants were divided into two groups based on the frequency of exacerbations: infrequent group (n=1,827) and frequent group (n=409). They underwent a complete blood count, as well as blood biochemistry, blood lipid and coagulation testing, and general characteristics were also recorded. Univariate analysis and binary multivariate logistic regression analyses were used to explore independent risk factors for the frequent exacerbator phenotype of AECOPD, which could be used as components of a new predictive model. The receiver operator characteristic (ROC) curve was used to assess the predictive value of the new model, which consisted of all significant risk factors predicting the primary outcome. The nomogram risk prediction model was established using R software. Age, gender, length of stay (LOS), neutrophils, monocytes, eosinophils, direct bilirubin (DBil), gamma-glutamyl transferase (GGT), and the glucose-to-lymphocyte ratio (GLR) were independent risk factors for the frequent exacerbator phenotype of AECOPD. The area under the curve (AUC) of the new predictive model was 0.681 [95% confidence interval (CI): 0.653-0.708], and the sensitivity was 63.6% (95% CI: 58.9-68.2%) and the specificity was 65.0% (95% CI: 60.3-69.6%). A new predictive model based on demographic characteristics and blood parameters can be used to predict the frequency of acute exacerbations in the management of chronic obstructive pulmonary disease (COPD).

Sputum microbiome α-diversity is a key feature of the COPD frequent exacerbator phenotype

BackgroundThe lung microbiome is an inflammatory stimulus whose role in COPD pathogenesis is incompletely understood. We hypothesised that the frequent exacerbator phenotype is associated with decreased α-diversity and increased lung inflammation. Our objective was to assess correlations between the frequent exacerbator phenotype, the microbiome and inflammation longitudinally during exacerbation-free periods.MethodsWe conducted a case–control longitudinal observational study of the frequent exacerbator phenotype and characteristics of the airway microbiome. 81 subjects (41 frequent and 40 infrequent exacerbators) provided nasal, oral and sputum microbiome samples at two visits over 2–4 months. Exacerbation phenotype, relevant clinical factors and sputum cytokine values were associated with microbiome findings.ResultsThe frequent exacerbator phenotype was associated with lower sputum microbiome α-diversity (p=0.0031). This decrease in α-diversity among frequent exacerbators was enhanced when the sputum bacterial culture was positive (p&lt;0.001). Older age was associated with decreased sputum microbiome α-diversity (p=0.0030). Between-visit β-diversity was increased among frequent exacerbators and those who experienced a COPD exacerbation between visits (p=0.025 and p=0.014, respectively). Sputum cytokine values did not differ based on exacerbation phenotype or other clinical characteristics. Interleukin (IL)-17A was negatively associated with α-diversity, while IL-6 and IL-8 were positively associated with α-diversity (p=0.012, p=0.012 and p=0.0496, respectively). IL-22, IL-17A and IL-5 levels were positively associated withMoraxellaabundance (p=0.027, p=0.0014 and p=0.0020, respectively).ConclusionsEven during exacerbation-free intervals, the COPD frequent exacerbator phenotype is associated with decreased sputum microbiome α-diversity and increased β-diversity. Decreased sputum microbiome α-diversity andMoraxellaabundance are associated with lung inflammation.

Analysis of Influence of Cigarette Smoke on Signaling Pathways of Innate Immune System in Monocytes of Peripheral Blood

INTRODUCTION: Tobacco smoking is an important medical problem since it has a significant impact on the development and progression of chronic obstructive pulmonary disease (COPD). The components of tobacco smoke can initiate and support local and systemic inflammation with participation of monocytes and macrophages.&#x0D; AIM: To study molecular mechanisms associated with the impact of cigarette smoke on signaling pathways of the innate immune system in monocytes of peripheral blood.&#x0D; MATERIALS AND METHODS: The methods of in silico analysis was used to identify genes associated with the impact of tobacco smoke. On the basis of the data obtained, a cellular model of inflammation was created in vitro using tobacco smoke extract and monocytes of peripheral blood isolated by immunomagnetic separation. An enzyme-linked immunoassay (ELISA) kit was used to measure the concentration of tumor necrosis factor- (TNF-), interleukin-1 (IL-1) in cell supernatants, and of Toll-like receptor 4 (TLR4), ATP-binding cassette A1 (ABCA1) in homogenates of cell membranes of native monocytes and monocytes exposed to 4% tobacco smoke extract. These data were compared with the levels of TNF-, IL-1, TLR4 and ABCA1 in monocytes of peripheral blood of patients with COPD with frequent exacerbation phenotype and with obliterating atherosclerosis of lower limb arteries (OALLA). For statistical processing and visualization of the data, MedCalc 20.1.4 and R (version 4.2.2) software was used.&#x0D; RESULTS: Tobacco smoke influences TLR4, TNF- signaling pathways and lipid metabolism. Cigarette smoke extract enhanced the expression of proinflammatory cytokines TNF- and IL-1 in cell supernatants, increased the level of TLR4 and decreased that of ABCA1 in plasmolemma of monocytes of peripheral blood. In patients with COPD with frequent exacerbation phenotype and with OALLA, there were shown increase in the levels of proinflammatory TNF- and IL-1 cytokines in cell supernatants, increase in the level of TLR4 and reduction of the level of ABCA1 in plasmolemma of monocytes of peripheral blood compared to native monocytes of healthy individuals.&#x0D; CONCLUSION: Cigarette smoke enhances the production of proinflammatory TNF- and IL-1 cytokines, increases the levels of TLR4 protein and reduces the amount of ABCA1 transporter in membranes of monocytes of peripheral blood. This may partially explain the cause of the influence of cigarette smoke on development of the pulmonary and cardiovascular diseases. COPD with frequent exacerbation phenotype and OALLA are characterized by enhancement of inflammation with participation of monocytes.

EFFICACY AND SAFETY OF DIPEPTIDYL PEPTIDASE-1 INHIBITION WITH BRENSOCATIB IN THE FREQUENT EXACERBATOR PHENOTYPE: A SUBGROUP ANALYSIS FROM THE WILLOW TRIAL

EFFICACY AND SAFETY OF DIPEPTIDYL PEPTIDASE-1 INHIBITION WITH BRENSOCATIB IN THE FREQUENT EXACERBATOR PHENOTYPE: A SUBGROUP ANALYSIS FROM THE WILLOW TRIAL

Are We Missing the Opportunity to Disseminate GOLD Recommendations Through AECOPD Discharge Letters?

Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) lead to poor outcomes and increased burden for patients and healthcare systems. The Global Initiative for COPD (GOLD) includes specific recommendations for AECOPD interventions, discharge criteria, and follow-up. Aligning the AECOPD discharge letters (DL) with GOLD guidelines could facilitate dissemination of recommendations among general practitioners (GPs). This study was conducted to assess the compliance of DL with the GOLD recommendations in Croatia. Pre-pandemic DL of patients presenting for AECOPD to emergency room (ER) were analyzed and stratified by clinical decision to hospitalize (HDL) or discharge patients for outpatient treatment (ERDL). Experienced pulmonologists checked the information from DL against guidelines by using online study-specific questionnaires. In total, 225 HDL and 368 ERDL were analyzed. In most cases, the GOLD ABCD categories (85% HDL, 92% ERDL) or the spirometry-based degree of severity (90% HDL, 91% ERDL) were not included. The number of AEs in the previous year was recorded, but the specific frequent exacerbator phenotype not explicitly stated. The AE phenotype was included in two thirds of HDL and one third of ERDL. The blood eosinophil count was frequently available, but not considered decision-relevant information. Adjustments of previous maintenance therapy, mostly escalation, were recommended in 58.4% HDL and 27.9% ERDL, respectively. Education on proper use of inhalers was recommended only in 15.6% of HDL. Smoking cessation measures were advised in 23.1% HDL and 7.9% ERDL; pulmonary rehabilitation in 35.6% HDL and 0.8% ERDL. Early follow-up was frequently advised (>50%), but rarely appointed. Significant deficiencies in compliance with the GOLD guidelines were identified, translating into a missed opportunity for GPs to become acquainted with GOLD recommendations. These findings emphasize the necessity to increase compliance with guidelines first at specialist level and consequent standardization of DL.

Identification of frequent acute exacerbations phenotype in COPD patients based on imaging and clinical characteristics

BackgroundChronic obstructive pulmonary disease (COPD) is a common disease with high morbidity, with acute exacerbations manifesting as a worsening of respiratory symptoms. This study aimed to identify the frequent acute exacerbation phenotype in patients with COPD based on imaging and clinical characteristics. MethodsPatients with COPD (n = 201) were monitored for acute exacerbations one year after their initial hospital admission and further divided into frequent and non-frequent exacerbation groups according to the frequency and severity of acute exacerbations. All patients underwent high resolution CT scans and low attenuation area less than −950Hu (LAA-950) in the whole lung was measured. Differences in visual subtypes, LAA-950, and clinical basic characteristics were compared between groups. The clinical factors influencing frequent exacerbation were determined using binary logistic regression. Finally, based on imaging and clinical factors, the receiver operating characteristic curve was used to identify the phenotype of COPD with frequent acute exacerbations. ResultsPatients with frequent exacerbations had a larger LAA-950 than those non-frequent exacerbations patients (p＜0.001). Frequent acute exacerbations were associated with worsening visual subtypes. Multivariate binary logistic regression illustrated that age, smoking status, BMI, FEV1 pred, and LAA-950 were associated with frequent exacerbations of COPD. The area under the receiver operating characteristic curve for predicting frequent exacerbations based on age, smoking status, BMI, FEV1 pred, and LAA-950 was 0.907 (p＜0.001). ConclusionThe combination of imaging and clinical characteristics reached high diagnostic efficacy in the identification of frequent acute exacerbations in patients with COPD.

Bronchiectasis exacerbation: a narrative review of causes, risk factors, management and prevention.

Bronchiectasis exacerbations are significant events in the natural course of the disease and determine long-term clinical outcomes. This review aims to discuss the definition, causes, risk factors, management and prevention of bronchiectasis exacerbations. The PubMed database was searched for relevant articles published in English between January 1990 and March 2022 using keywords "bronchiectasis" and "exacerbation". Causes of bronchiectasis exacerbation are multifactorial; it can be associated with bacterial and viral pathogens, host inflammatory responses, and external environmental effects. In addition, recent advances in bronchiectasis research highlight the phenotype of patients who are more prone to exacerbations, including those with chronic Pseudomonas aeruginosa infection, worse symptoms, greater lung inflammation and comorbid airway diseases. Once bronchiectasis exacerbations occur, antibiotics are the mainstay treatment. Preventing exacerbations is of paramount importance because frequent exacerbations are linked to a detrimental disease course and higher mortality. To prevent frequent exacerbations, clinicians should attempt to understand the risk factors for exacerbation that are amenable to therapeutic intervention: so called "treatable traits". Treatments are personalised but include improving mucociliary clearance by physiotherapy and mucoactive therapy, reducing airway infection by inhaled antibiotics, and inflammation by long-term macrolide or in specific subpopulations, inhaled corticosteroids (ICS). Novel approaches to prevent exacerbations including direct anti-inflammatory therapies are in development for bronchiectasis. Future research is needed to better manage and prevent exacerbations in patients with bronchiectasis, although recent studies have characterised frequent exacerbator phenotype and enhanced our understanding of various aspects of exacerbations.

Frequent exacerbators of chronic obstructive pulmonary disease have distinguishable sputum microbiome signatures during clinical stability.

Frequent exacerbation phenotype of chronic obstructive pulmonary disease (COPD) represents a more concerning disease subgroup requiring better prevention and intervention, of which airway microbiome provides new perspective for further exploration. To investigate whether frequent exacerbators of COPD have distinguishable sputum microbiome during clinical stability, COPD patients at high disease grades with or without frequent exacerbation were recruited for sputum microbiome analysis. Sputum samples were collected during clinical stability and underwent 16S rRNA sequencing, which was then subjected for amplicon sequence variants (ASVs)-based microbiome analysis. Our results revealed that compared with healthy controls and infrequent exacerbators, frequent COPD exacerbators have distinguishably dysbiotic sputum microbiome, as featured by fewer ASVs features, lower alpha diversity, distinct beta diversity patterns. Further taxonomic compositional analysis illustrated the structural distinctions between frequent COPD exacerbators and infrequent exacerbators at differential taxa levels and highlighted Stenotrephomonas due to its prominent elevation in frequent COPD exacerbators, providing a promising candidate for further exploration of microbiome biomarker. Moreover, we also demonstrated that frequent exacerbation phenotype is distinguishable from infrequent exacerbation phenotype with respect of functional implications. Our study demonstrated the first positive correlation between the frequent exacerbation phenotype of COPD and the sputum microbiome during clinical stability in a single-center Chinese COPD cohort and provide potential diagnostic and therapeutic targets for further investigation.

Exome and Sputum Microbiota as Predictive Markers of Frequent Exacerbations in Chronic Obstructive Pulmonary Disease.

Frequent acute exacerbations are the leading cause of high rates of hospitalization and mortality in chronic obstructive pulmonary disease (COPD). Despite the enormous worldwide medical burden, reliable molecular markers for effective early diagnosis and prognosis of acute exacerbations are still lacking. Both the host genetics and airway microbiome are known to play potential roles in the pathogenesis of frequent exacerbations. Here, we performed whole exome sequencing (WES) and 16S rRNA gene sequencing to explore the interaction between these two factors and their implications in the pathogenesis of frequent exacerbations. We collected peripheral blood (n = 82), sputum samples (n = 59) and clinical data from 50 frequent-exacerbation phenotype (FE) COPD patients and 32 infrequent-exacerbation phenotype (IE) as controls. Based on filtering the deleterious sites, candidate mutated genes shared only in FE patients and did not occur in the IE group were identified. Microbiota analysis revealed significant differences in bacterial diversity and composition between FE and IE groups. We report the underlying pathogenic gene including, AATF, HTT, CEP350, ADAMTS9, TLL2 genes, etc., and explore their possible genotypic-phenotypic correlations with microbiota dysbiosis. Importantly, we observed that AATF gene mutations were significantly negatively correlated with microbial richness and diversity. Our study indicated several deleterious mutations in candidate genes that might be associated with microbial dysbiosis and the increased risk of frequent acute exacerbations in COPD patients. These results provide novel evidence that exomes and related microbiomes may potentially serve as biomarkers for predicting frequent acute exacerbations in COPD patients.

Kronik Obstrüktif Akciğer Hastalığında Fenotiplere Göre Kanda ve İdrarda Biyobelirteçlerin Karşılaştırılması: Kesitsel Araştırma

Objective: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. Biomarkers have been recognized as an important tool in assessing COPD patients. In this study, we aimed to investigate the possible relationship between certain biomarkers and different COPD phenotypes. Material and Methods: Between January 1, 2017-December 31, 2017, a total of 85 patients who were admitted to the Çanakkale Onsekiz Mart University Faculty of Medicine Hospital Chest Diseases Outpatient Clinic with a diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease 2017 Guidelines were included in this study. All patients filled in the COPD Assessment Test and modified Medical Research Council questionnaires. Patients were divided into 4 phenotypes: emphysema, chronic bronchitis, frequent exacerbation, and asthma COPD overlap syndrome (ACOS). Levels of C-reactive protein (CRP), desmosine, fibronectin, eotaxin, and interleukin (IL)-2 were measured and compared between the phenotypes. Results: The mean age was 64.56 years and 92.9% of the study population were males. Of 85 patients, 43 had emphysema, 13 had frequent exacerbation, 15 had chronic bronchitis, and 14 had ACOS phenotype. Blood fibronectin, eotaxin, and urine desmosine levels were significantly lower in patients with ACOS phenotype compared to the other phenotypes. In patients with the frequent exacerbation phenotype, the CRP level was significantly higher than that of the other three phenotypes. The IL-2 levels were similar in all phenotypes. Conclusion: Our study results suggest that these biomarkers may be useful in the differential diagnosis of COPD phenotypes.

Characterization Associated with the Frequent Severe Exacerbator Phenotype in COPD Patients.

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease with exacerbations causing hospitalizations, morbidity, and mortality. COPD exacerbation causes a substantial health impact, and its subtypes might differ in prognosis and treatment response.MethodsThis study evaluated the factors of COPD exacerbations and explored the probabilities of frequent severe COPD exacerbations. Categorical and continuous variables between groups were compared. The hazard ratio (HR) and the probability of no hospital readmission were also estimated.ResultsA total of 617 COPD patients were enrolled and comprised the frequent exacerbator (N = 226) and the non-frequent exacerbator (N = 391) groups. The frequent exacerbator group significantly displayed a higher eosinophil count (EC; p=0.004), a higher percentage of the frequent severe acute exacerbation history before the index hospitalization (IH; p < 0.001), a lower FEV1 value (p=0.001), and a higher triple combination inhaler prior and following the IH (p < 0.001 and p=0.002) than the non-frequent exacerbator one. Increasing age (aOR of 1.02), higher EC (aOR of 1.09), and lower FEV1 value (aOR of 0.72) were significantly associated with an increased hospital readmission risk. The readmission rate and risk were higher in patients with a history of frequent severe acute exacerbation (aHR of 3.38) than those without severe acute exacerbation. Cases treated with the triple combination inhaler before the IH had a higher readmission rate and risk than non-users.ConclusionPatients with EC ≥2%, FEV1 <50%, or frequent severe acute exacerbation history before the IH have a higher risk of being diagnosed with a frequent exacerbator phenotype. Besides, higher age, triple combination inhaler before the IH, and smoking might be independently correlated with the frequent readmission risk within 1-year post-exacerbation. A better comprehension of the COPD exacerbation mechanism may further identify the best course of preventative strategy and lead to novel interventions.

Development and multimodal characterization of an elastase-induced emphysema mouse disease model for the COPD frequent bacterial exacerbator phenotype

ABSTRACT Chronic obstructive pulmonary disease (COPD) patients undergo infectious exacerbations whose frequency identifies a clinically meaningful phenotype. Mouse models have been mostly used to separately study both COPD and the infectious processes, but a reliable model of the COPD frequent exacerbator phenotype is still lacking. Accordingly, we first established a model of single bacterial exacerbation by nontypeable Haemophilus influenzae (NTHi) infection on mice with emphysema-like lesions. We characterized this single exacerbation model combining both noninvasive in vivo imaging and ex vivo techniques, obtaining longitudinal information about bacterial load and the extent of the developing lesions and host responses. Bacterial load disappeared 48 hours post-infection (hpi). However, lung recovery, measured using tests of pulmonary function and the disappearance of lung inflammation as revealed by micro-computed X-ray tomography, was delayed until 3 weeks post-infection (wpi). Then, to emulate the frequent exacerbator phenotype, we performed two recurrent episodes of NTHi infection on the emphysematous murine lung. Consistent with the amplified infectious insult, bacterial load reduction was now observed 96 hpi, and lung function recovery and disappearance of lesions on anatomical lung images did not happen until 12 wpi. Finally, as a proof of principle of the use of the model, we showed that azithromycin successfully cleared the recurrent infection, confirming this macrolide utility to ameliorate infectious exacerbation. In conclusion, we present a mouse model of recurrent bacterial infection of the emphysematous lung, aimed to facilitate investigating the COPD frequent exacerbator phenotype by providing complementary, dynamic information of both infectious and inflammatory processes.

Analysis of vaccination characteristics and influencing factors of influenza vaccine and pneumococcal vaccine in patients with frequent acute exacerbation phenotype COPD.

article: Analysis of vaccination characteristics and influencing factors of influenza vaccine and pneumococcal vaccine in patients with frequent acute exacerbation phenotype COPD - Panminerva Medica 2021 Jul 09 - Minerva Medica - Journals

Burden of Disease Among Exacerbating Patients with COPD Treated with Triple Therapy in Spain.

BackgroundThe cost of chronic obstructive pulmonary disease (COPD) in Spain has been studied from different perspectives, but parameters such as the patient’s phenotype have seldom been considered. Our aim was to describe the disease burden of COPD patients with frequent exacerbator phenotype, treated with triple therapy.MethodsAn observational, multicenter study was carried out from December 2017 to November 2018 in pulmonology services among patients ≥40 years with COPD confirmed diagnosis receiving triple therapy (ICS/LAMA/LABA) and history of ≥2 moderate or ≥1 severe exacerbation in the 12 months prior to the inclusion visit. COPD-related healthcare resources were collected over a 12-months period prior to the inclusion visit: pharmacological and non-pharmacological treatments, medical and ER visits, hospitalizations, tests and productivity loss. Costs were updated to €2019. Patients were classified according to blood eosinophil levels: <150 cells/µL and ≥150 cells/µL.ResultsA total of 306 patients were included (77.1% men), with mean age of 69.9 years. Mean COPD exacerbation rate was 2.5/patient/year and 51.3% of patients had ≥150 cells/µL eosinophil level. On average, for the total population, COPD-related visits/patients/year were 6.2. Resource use in moderate exacerbation was higher in patients with eosinophils ≥150 cells/µL, whereas in severe exacerbation was higher in patients with eosinophils <150cells/µL. According to eosinophil levels, total annual mean (SD) costs/patient accounted for €8382 (9863) and €5144 (5444) for patients with eosinophils <150 cells/µL and ≥150 cells/µL, respectively.ConclusionThe impact of exacerbating COPD patients treated with triple therapy in Spain is large, especially among those with eosinophils <150 cells/µL.

Peak-Inspiratory-Flow-Rate Guided Inhalation Therapy Reduce Severe Exacerbation of COPD.

Optimal peak inspiratory flow rate (PIFR) is crucial for inhalation therapy in patients with chronic obstructive pulmonary disease (COPD). However, little is known about the impact of PIFR-guided inhalation therapy on the clinical outcomes among patients with varying severities of COPD. A PIFR-guided inhalation therapy, including PIFR assessment and PIFR-guided inhaler education, was introduced in a pay-for-performance COPD management program in National Taiwan University Hospital. Among 383 COPD patients, there was significant reduction in incidence of severe acute exacerbation in the PIFR-guided inhalation therapy (PIFR group) than conventional inhaler education (control group) (11.9 vs. 21.1%, p = 0.019) during one-year follow-up. A multivariable Cox’s proportional-hazards analysis revealed that the PIFR-guided inhalation therapy was a significant, independent factor associated with the reduced risk of severe exacerbation (adjusted hazard ratio = 0.49, 95% confidence interval, 0.28–0.84, p = 0.011). Subgroup analysis found PIFR-guided inhalation therapy was more beneficial to patients with older age, short body stature, COPD stage 1&2, group C&D (frequent exacerbation phenotype), and using multiple inhalers. This study showed the PIFR-guided inhalation therapy significantly reduced the incidence of severe acute exacerbation than conventional inhaler education in patients with COPD. Careful PIFR-assessment and education would be crucial in the management of COPD.

Long-Term Azithromycin Maintenance Treatment in Patients with Frequent Exacerbations of Chronic Obstructive Pulmonary Disease.

Macrolides are effective in reducing the number of exacerbations in COPD patients with the frequent exacerbator phenotype. Our study did not show a persistent effect of azithromycin on exacerbation frequencies after more than one year of usage.

Airway bacterial and fungal microbiome in chronic obstructive pulmonary disease

Little is known about airway mycobiome, and its relationship with bacterial microbiome in chronic obstructive pulmonary disease (COPD). Here we report the first simultaneous characterization of sputum bacterial and fungal microbiome in 84 stable COPD and 29 healthy subjects, using 16S ribosomal DNA and fungal internal transcribed spacer DNA sequencing. Ascomycota predominated over Basidiomycota in fungal microbiome both in COPD patients and healthy controls. Meyerozyma, Candida, Aspergillus and Schizophyllum were most abundant at the genus level. There was a significant inverse correlation between bacterial and fungal microbial diversity, both of which altered in opposite directions in COPD patients versus controls, and in frequent versus non-frequent exacerbators. An enhanced bacterial-fungal ecological interaction was observed in COPD patients, which was characterized by higher proportion of co-occurrence intrakingdom interactions and co-exclusive interkingdom interactions. In COPD, four mutually co-occurring fungal operational taxonomic units (OTUs) in Candida palmioleophila, Aspergillus and Sordariomycetes exhibited co-exclusive relationships with other fungal OTUs, which was specifically present in frequent exacerbators but not in non-frequent exacerbators. The perturbed bacterial-fungal interactions in COPD were associated with increased airway inflammatory mediators such as IL-6 and IL-8. The disruption of airway bacterial-fungal community balance, characterized by the loss of commensal bacterial taxa and enriched pathogenic fungal taxa, is implicated in COPD. The emergence of pathogenic fungi such as Candida and Aspergillus could be a marker for the frequent exacerbator phenotype. The airway mycobiome is an important cofactor mediating pathogenic infection and host inflammation in COPD.

Increased mortality associated with frequent exacerbations in COPD patients with mild-to-moderate lung function impairment, and smokers with normal spirometry

BackgroundThe burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown. MethodsWe categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7). ResultsAmong 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25–3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21–1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26–4.01). ConclusionsIn COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.