Long-term future risk of severe exacerbations: Distinct 5-year trajectories of problematic asthma.

BACKGROUND: Assessing future risk of exacerbations is an important component of asthma management. Existing studies have investigated short- but not long-term risk. Problematic asthma patients with unfavorable long-term disease trajectory and persistently frequent severe exacerbations need to be identified early to guide treatment. AIM: To identify distinct trajectories of severe exacerbation rates among "problematic asthma" patients and develop a risk score to predict the most unfavorable trajectory. METHODS: Severe exacerbation rates over five years for 177 "problematic asthma" patients presenting to a specialist asthma clinic were tracked. Distinct trajectories of severe exacerbation rates were identified using group-based trajectory modeling. Baseline predictors of trajectory were identified and used to develop a clinical risk score for predicting the most unfavorable trajectory. RESULTS: Three distinct trajectories were found: 58.5% had rare intermittent severe exacerbations ("infrequent"), 32.0% had frequent severe exacerbations at baseline but improved subsequently ("nonpersistently frequent"), and 9.5% exhibited persistently frequent severe exacerbations, with the highest incidence of near-fatal asthma ("persistently frequent"). A clinical risk score composed of ≥2 severe exacerbations in the past year (+2 points), history of near-fatal asthma (+1 point), body mass index ≥25kg/m2 (+1 point), obstructive sleep apnea (+1 point), gastroesophageal reflux (+1 point), and depression (+1 point) was predictive of the "persistently frequent" trajectory (area under the receiver operating characteristic curve: 0.84, sensitivity 72.2%, specificity 81.1% using cutoff ≥3 points). The trajectories and clinical risk score had excellent performance in an independent validation cohort. CONCLUSIONS: Patients with problematic asthma follow distinct illness trajectories over a period of five years. We have derived and validated a clinical risk score that accurately identifies patients who will have persistently frequent severe exacerbations in the future.

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.

Factors Associated with Frequent Exacerbations in the UK Severe Asthma Registry.

BACKGROUND: Frequent exacerbations are an important cause of morbidity in patients with severe asthma. OBJECTIVE: Our aim was to identify factors associated with frequent exacerbations in a large well-characterized severe asthma population and determine whether factors differed in patients treated with and without maintenance oral corticosteroids (OCS). METHODS: Adults with severe asthma from specialized asthma centers across the United Kingdom were recruited to the UK Severe Asthma Registry. Demography, comorbidities and physiological measurements were collected. We conducted univariable and multivariable logistic regression analyses to identify factors associated with frequent exacerbations, defined as 3 or more exacerbations treated with high-dose systemic corticosteroids in the past year. RESULTS: Of 1,592 patients with severe asthma from the UK Severe Asthma Registry, 1,137 (71%) were frequent exacerbators and 833 (52%) were on maintenance OCS. The frequent exacerbators were more likely to be ex-smokers, have gastroesophageal reflux disease, higher Asthma Control Questionnaire-6 (ACQ-6) score, and higher blood eosinophilia. Multivariable regression analyses showed ACQ-6 score greater than 1.5 (odds ratio [OR] 4.25; P < .001), past smoking history (OR 1.55; P = .024), and fractional exhaled nitric oxide greater than 50ppb (OR 1.54; P = .044) were independently associated with frequent exacerbations. Past smoking history correlated with frequent exacerbations only in patients on maintenance OCS (OR 2.25; P = .004), whereas ACQ-6 score greater than 1.5 was independently associated with frequent exacerbations in those treated with and without maintenance OCS (OR 2.74; P = .017 and OR 6.42; P < .001, respectively). CONCLUSIONS: Several factors were associated with frequent exacerbations in a large UK severe asthma registry population. High ACQ-6 score had the strongest association with frequent exacerbations irrespective of maintenance OCS status.

Clinical characteristics of chronic bronchitic, emphysematous and ACOS phenotypes in COPD patients with frequent exacerbations.

PURPOSE: Chronic bronchitis (CB), emphysematous (EM) and asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) phenotypes in COPD are well recognized. This study aimed to investigate distinguishing characteristics of these phenotypes in COPD patients with frequent exacerbations (FE). PATIENTS AND METHODS: A retrospective study was carried out. COPD patients with acute exacerbations were consecutively reviewed from November 2015 to October 2016. Patients were divided into FE and infrequent exacerbations (iFE) subgroups. RESULTS: A total of 142 eligible COPD subjects were reviewed. In the CB phenotype subgroup, age, body mass index, forced expiratory volume in 1 second (FEV1) % predicted, COPD assessment test (CAT), modified Medical Research Council breathlessness measurement (mMRC) dyspnea scale, emphysema scores and arterial carbon dioxide pressure (PaCO2) were significantly different in subjects with FE when compared to those in subjects with iFE of CB. In the EM phenotype subgroup, age, CAT, mMRC scores and history of COPD were different in subjects with FE when compared to those in CB subjects with iFE. Multivariate analysis indicated that FEV1% predicted (odds ratio [OR] =0.90, P=0.04) and PaCO2 (OR =1.22, P=0.02) were independent risk factors for FE in COPD with CB phenotype, and CAT (OR =2.601, P=0.001) was the independent risk factor for FE in COPD with EM phenotype. No significant differences in characteristics were observed in ACOS phenotype subgroups with FE or iFE. CONCLUSION: In CB or EM phenotypes, COPD patients with FE present several differential clinical characteristics compared to patients with iFE, while the characteristics of ACOS phenotype in patients with FE need more investigation.

Factors influencing pharmacological treatment in COPD: a comparison of 2005 and 2014.

Introduction: The aim was to investigate how the pattern of pharmacological treatment in Swedish patients with chronic obstructive pulmonary disease (COPD) has changed over a decade, and to identify factors associated with treatment. Methods: Data on patient characteristics and pharmacological treatment were collected using questionnaires from two separate cohorts of randomly selected primary and secondary care patients with a doctor's diagnosis of COPD in central Sweden, in 2005 (n = 1111) and 2014 (n = 1329). Cross-tabulations and chi-square tests were used to compare maintenance treatment in 2005 and 2014, and to investigate the distribution of treatment by the 2017 Global Initiative for Obstructive Lung Disease (GOLD) ABCD groups. Multinomial logistic regression was used to analyze associations with the major types of recommended treatments: bronchodilator therapy, combined long-acting beta-2-antagonists (LABA) + inhaled corticosteroids (ICS), and triple inhaled therapy. Results: The proportion of patients with no maintenance treatment, with only LABA + ICS, and with sole ICS statistically significantly decreased (36 vs. 31%, 16 vs. 12% and 5 vs. 2%, respectively), and the proportion with triple inhaled therapy statistically significantly increased (29 vs. 40%). In 2014, triple inhaled therapy was the most common treatment in all GOLD groups except group A. In 2014, previous frequent exacerbations [OR (95% CI) 2.34 (1.62 to 3.36)], worse COPD Assessment Test score [1.07 (1.05 to 1.09)], female sex [2.13 (1.56 to 2.91)], and access to a specific responsible doctor [1.95 (1.41 to 2.69)] were associated with triple inhaled therapy. Current smoking [0.40 (0.28 to 0.57)] and overweight [0.62 (0.41 to 0.93)] were inversely associated with triple inhaled therapy. Conclusions: Over the last decade, triple inhaled therapy has increased, and no maintenance treatment, ICS, or LABA + ICS has decreased. Triple inhaled therapy is the most common treatment and is associated with previous exacerbations, higher symptom level, female sex, and having a specific responsible doctor.

COPD management costs according to the frequency of COPD exacerbations in UK primary care.

BACKGROUND: The economic burden of chronic obstructive pulmonary disease (COPD) exacerbations is significant, but the impact of other sources on the overall cost of COPD management is largely unknown. We aimed to estimate overall costs for patients experiencing none, one, or two or more exacerbations per year in the UK. METHODS: A retrospective cohort of prevalent COPD patients was identified in the Clinical Practice Research Datalink UK database. Patients with information recorded for at least 12 months before and after cohort entry date were included (first prevalent COPD diagnosis confirmed by spirometry on/after April 1, 2009). Patients were categorized as having none, one, or two or more moderate-to-severe COPD exacerbations in the 12 months after cohort entry and further classified by the Global initiative for chronic Obstructive Lung Disease (GOLD) category of airflow obstruction and the Medical Research Council dyspnea scale. Study outcomes included counts of general practitioner interactions, moderate-severe COPD exacerbations, and non-COPD hospitalizations. Estimated resource use costs were calculated using National Health Service reference costs for 2010-2011. RESULTS: The cohort comprised 58,589 patients (mean age 69.5 years, mean dyspnea grade 2.5, females 46.6%, current smokers 33.1%). The average total annual per patient cost of COPD management, excluding medications, was £2,108 for all patients and £1,523, £2,405, and £3,396 for patients experiencing no, one, or two or more moderate-to-severe exacerbations, respectively. General practitioner interactions contributed most to these annual costs, accounting for £1,062 (69.7%), £1,313 (54.6%), and £1,592 (46.9%) in patients with no, one, or two or more moderate-to-severe exacerbations, respectively. CONCLUSION: Disease management strategies focused on reducing costs in primary care may help reduce total COPD costs significantly.

The Overlap Syndrome of Asthma and COPD

The asthma-COPD overlap syndrome presents itself in patients where the asthma is not controlled despite seemingly appropriate measures or a patient who is a smoker and treated as COPD but also has asthmatic features. The asthma-COPD overlap syndrome is more common in the elderly. Such patients are of importance to diagnose because they have a high disease burden compared to asthma alone or COPD alone. Patients with both asthma and COPD should be identified earlier, as these patients have an increased risk for frequent exacerbations and therefore their treatment and follow-up should be optimised before hospital discharge. Also rehabilitation immediately after an exacerbation has been shown to be safe and effective to prevent further exacerbations requiring hospitalisation.