Components of the Chronic Obstructive Pulmonary Disease Assessment Test Associated with the Exacerbation of Severe Chronic Obstructive Pulmonary Disease Patients.

INTRODUCTION: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) score is widely used for evaluating the health status of patients diagnosed with COPD. The aim of this study was to identify which components of the CAT are associated with exacerbations in severe COPD patients. METHODS: Using data from the Korean COPD Subgroup Study (KOCOSS), we identified 3,440 COPD patients, among which 1,027 patients are classified as having severe COPD based on spirometry results. The CAT scores on 8 items were evaluated and classified into respiratory and non-respiratory categories. We analyzed the association between CAT item scores and moderate-to-severe exacerbations during study enrollment and the following years. RESULTS: Patients with a history of moderate-to-severe exacerbations had higher scores on non-respiratory CAT components. Longitudinal CAT scores on all items after enrollment were higher in the moderate-to-severe exacerbation group. Additionally, the frequency of severe exacerbations was associated with specific CAT components related to limited activities, confidence leaving home, sleeplessness, and energy. CONCLUSIONS: This study revealed that the non-respiratory CAT component scores were statistically significant factors for predicting the moderate-to-severe exacerbation of severe COPD patients. Non-respiratory symptoms and functional limitations should be considered in patients with severe COPD. Interventions, such as pulmonary rehabilitation, may be needed to improve patients' overall well-being and prevent exacerbations.

Development of a daily predictive model for the exacerbation of chronic obstructive pulmonary disease.

Acute exacerbation (AE) of chronic obstructive pulmonary disease (COPD) compromises health status; it increases disease progression and the risk of future exacerbations. We aimed to develop a model to predict COPD exacerbation. We merged the Korean COPD subgroup study (KOCOSS) dataset with nationwide medical claims data, information regarding weather, air pollution, and epidemic respiratory virus data. The Korean National Health and Nutrition Examination Survey (KNHANES) dataset was used for validation. Several machine learning methods were employed to increase the predictive power. The development dataset consisted of 590 COPD patients enrolled in the KOCOSS cohort; these were randomly divided into training and internal validation subsets on the basis of the individual claims data. We selected demographic and spirometry data, medications for COPD and hospital visit for AE, air pollution data and meteorological data, and influenza virus data as contributing factors for the final model. Six machine learning and logistic regression tools were used to evaluate the performance of the model. A light gradient boosted machine (LGBM) afforded the best predictive power with an area under the curve (AUC) of 0.935 and an F1 score of 0.653. Similar favorable predictive performance was observed for the 2151 individuals in the external validation dataset. Daily prediction of the COPD exacerbation risk may help patients to rapidly assess their risk of exacerbation and will guide them to take appropriate intervention in advance. This might lead to reduction of the personal and socioeconomic burdens associated with exacerbation.

Clinical aspects of severe cutaneous adverse reactions caused by beta-lactam antibiotics: A study from the Korea SCAR registry.

Background: Although beta-lactams are 1 of the major causative agents of severe cutaneous adverse reactions (SCAR), their epidemiology and clinical aspects have been poorly studied. This study aimed to investigate the characteristics of SCAR caused by beta-lactams in the Korean SCAR registry. Methods: We retrospectively analyzed beta-lactam-induced SCAR cases collected from 28 tertiary university hospitals in Korea between 2010 and 2015. The SCAR phenotypes included Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap, and drug reaction with eosinophilia and systemic symptoms (DRESS). Beta-lactams were classified according to their chemical structures: penicillins, cephalosporins, and carbapenems. The causative beta-lactams, clinical and laboratory features, treatments, and outcomes were evaluated. Results: Among the 275 antibiotic-induced SCAR cases, 170 patients developed SCAR induced by beta-lactams. Beta-lactam antibiotic-induced SCAR showed more frequent SJS/TEN compared to SCAR induced by non-beta-lactam antibiotics (SJS/TEN/SJS-TEN overlap/DRESS: 36.5/11.2/5.9/46.5% vs. 23.8/10.5/2.9/62.9%, P = 0.049). Cephalosporin was the most common culprit drug. Particularly, 91 and 79 patients presented with SJS/TEN and DRESS, respectively. The odds ratio (OR) for poor prognosis, such as sequelae and death, was significantly increased in subjects with SJS-TEN overlap and TEN and carbapenem as culprit drug in the multivariate analysis (OR, 35.61; P = 0.016, OR, 28.07; P = 0.006, OR 30.46; P = 0.027). Conclusion: Among antibiotic-induced SCAR, clinical features were different depending on whether the culprit drug was a beta-lactam antibiotic or SCAR type. The poor prognosis was related to SJS-TEN overlap, TEN type, and carbapenem as the culprit drug.

Developmental endothelial locus-1 as a potential biomarker for the incidence of acute exacerbation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Despite the high disease burden of chronic obstructive pulmonary disease (COPD) and risk of acute COPD exacerbation, few COPD biomarkers are available. As developmental endothelial locus-1 (DEL-1) has been proposed to possess beneficial effects, including anti-inflammatory effects, we hypothesized that DEL-1 could be a blood biomarker for COPD. OBJECTIVE: To elucidate the role of plasma DEL-1 as a biomarker of COPD in terms of pathogenesis and for predicting acute exacerbation. METHODS: Cigarette smoke extract (CSE) or saline was intratracheally administered to wild-type (WT) and DEL-1 knockout (KO) C57BL/6 mice. Subsequently, lung sections were obtained to quantify the degree of emphysema using the mean linear intercept (MLI). Additionally, plasma DEL-1 levels were compared between COPD and non-COPD participants recruited in ongoing prospective cohorts. Using negative binomial regression analysis, the association between the plasma DEL-1 level and subsequent acute exacerbation risk was evaluated in patients with COPD. RESULTS: In the in vivo study, DEL-1 KO induced emphysema (KO saline vs. WT saline; P = 0.003) and augmented CSE-induced emphysema (KO CSE vs. WT CSE; P < 0.001) in 29 mice. Among 537 participants, patients with COPD presented plasma log (DEL-1) levels lower than non-COPD participants (P = 0.04), especially non-COPD never smokers (P = 0.019). During 1.2 ± 0.3 years, patients with COPD in the lowest quartile of Log(DEL-1) demonstrated an increased risk of subsequent acute exacerbation, compared with those in the highest quartile of Log(DEL-1) (adjusted incidence rate ratio, 3.64; 95% confidence interval, 1.03-12.9). CONCLUSION: Low DEL-1 levels are associated with COPD development and increased risk of subsequent COPD acute exacerbation. DEL-1 can be a useful biomarker in patients with COPD.

Metabolic Fingerprinting Uncovers the Distinction Between the Phenotypes of Tuberculosis Associated COPD and Smoking-Induced COPD.

Background: Although smoking is considered the main cause of chronic obstructive pulmonary disease (COPD), several other risk factors, including pulmonary tuberculosis (TB), contribute significantly to disease causation, particularly in developing countries. However, the underlying pathogenesis of TB-associated COPD (T-COPD) is unclear. Moreover, the need for prompt diagnosis and treatment of T-COPD to decrease the future burden of inflammation is underestimated. This study aimed to identify distinctive endogenous metabotypes of T-COPD, compared to smoking-associated COPD (S-COPD). Methods: Cross-sectional metabolomic analyses and clinical examinations of serum samples were performed for three groups of 168 male subjects: T-COPD (n = 59), S-COPD (n = 70), and healthy normal controls (n = 39). To retain a broad spectrum of metabolites, we performed technically distinct analyses (global metabolomic profiling using LC-QTOFMS and targeted analyses using LC-MS/MS). Results: Higher levels of IL-6 and C-reactive protein and St. George Respiratory Questionnaire scores were seen in the T-COPD group, compared to those in the S-COPD group. Global metabolomic profiling showed elevated metabolites, including arachidonic and eicosanoic acids, in the T-COPD group. Typical changes in tryptophan catabolism were observed through targeted profiling. Additionally, in the T-COPD group, kynurenine was elevated, and serotonin levels were reduced; therefore, indoleamine dioxygenase (IDO)/tryptophan hydroxylase (TPH) activities were dysregulated. Correlation analyses showed that changes in oxylipins were positively correlated with serum levels of IL-6 and C-reactive protein. Conclusion: Patients with TB-related COPD have enhanced inflammatory responses that may be linked to fatty acid pathways and tryptophan catabolism, which could be novel therapeutic targets for T-COPD.

Effects of a Mixture of Ivy Leaf Extract and Coptidis rhizome on Patients with Chronic Bronchitis and Bronchiectasis.

BACKGROUND: Hederacoside C from ivy leaf dry extracts (HH) and berberine from Coptidis rhizome dry extracts (CR) can be combined (HHCR) as a herbal product. Previous studies have demonstrated that HHCR has antitussive and expectorant effects in animal models of respiratory disease. However, the therapeutic effects of HHCR on respiratory diseases in humans have not been well-studied. Therefore, we aimed to clarify the effectiveness of HHCR in patients with chronic bronchitis and bronchiectasis. METHODS: This was a multicenter (10 university teaching hospitals), open-label, prospective, single-arm, observational study. Consecutive patients with chronic bronchitis and bronchiectasis were included. Patients were orally treated with HHCR daily for 12 weeks. St. George's Respiratory Questionnaire (SGRQ) scores and bronchitis severity scores (BSS) were measured at baseline and at the end of the 12-week study. RESULTS: In total, 376 patients were enrolled, of which 304 were finally included in the study, including 236 males and 68 females with a median age of 69 years (range: 37-88 years). After 12 weeks of HHCR treatment, there was a significant improvement in SGRQ score (baseline, 32.52 ± 16.93 vs. end of study, 29.08 ± 15.16; p < 0.0001) and a significant reduction in BSS (baseline, 7.16 ± 2.63 vs. end of study, 4.72 ± 2.45; p < 0.0001). During the study, 14 patients concomitantly used an inhaled corticosteroid and 83 patients used an inhaled bronchodilator. HHCR also had significant positive effects on these patients in terms of SGRQ score and BSS. No serious adverse drug reactions occurred during HHCR treatment. CONCLUSIONS: treatment with HHCR improved the SGRQ score and BSS in patients with chronic bronchitis and bronchiectasis. HHCR may be a new therapeutic option for chronic bronchitis and bronchiectasis. Large-scale, randomized, double-blind, placebo-controlled clinical trials are warranted.

Association between plasma interleukin-33 level and acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: The role of interleukin (IL)-33 in patients with chronic obstructive pulmonary disease (COPD) has not been well elucidated. The aim of this study is to analyze the association between plasma IL-33 level and acute exacerbation of COPD. METHODS: Plasma IL-33 was measured in 62 COPD patients during their stable state. Patients were prospectively followed up for 1 year. The expression of IL-33 was measured in lung tissue obtained from 38 patients who underwent surgery. RESULTS: The number of exacerbations was significantly higher in the high plasma IL-33 group compared with the low plasma IL-33 group. On Poisson regression analysis, high plasma IL-33 was associated with increased risk of exacerbation (incidence rate ratio = 2.166, P = 0.043). The expression of IL-33 in the lung was higher in COPD patients than in controls. The expression of IL-33 was significantly correlated with smoking pack years (R = 0.45, P < 0.01) and Forced expiratory volume in 1 s (%) (R = - 0.58, P < 0.01). CONCLUSION: The plasma level of IL-33 in patients with COPD was significantly associated with the risk of exacerbation in prospective follow up. The expression of IL-33 in the lung was positively correlated with smoking and negatively correlated with lung function.

A Nationwide Study of Severe Cutaneous Adverse Reactions Based on the Multicenter Registry in Korea.

BACKGROUND: Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking. OBJECTIVE: To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry. METHODS: SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record. RESULTS: A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms. CONCLUSION: Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.

Clinical Characteristics of Chronic Obstructive Pulmonary Disease in Female Patients: Findings from a KOCOSS Cohort.

Purpose: The prevalence of chronic obstructive pulmonary disease (COPD) in females has increased, changing the concept of COPD as a disease mostly limited to males. In this study, the clinical characteristics of COPD in females were investigated. Patients and Methods: The study was based on a multicenter cohort of COPD patients recruited from 54 medical centers in South Korea. Sex-based differences in general characteristics, exposure risk factors, depression scores, results of pulmonary function tests, COPD exacerbation, symptom scores, and radiologic findings were evaluated. Sex-related differences in the annual FEV1 change over 5 years were analyzed in a linear mixed model. Results: Of the 2515 patients enrolled in this study, 8.1% were female. Female patients who had a higher BMI and a lower level of education were less likely to be smokers, were more exposed to passive smoking/biomass, and were more depressed compared to males. The rates of bronchiectasis, previous childhood respiratory infection, and asthma were higher in females. Female patients also had more symptoms and a poorer exercise capacity than males, but no significant differences were observed in terms of exacerbations. Radiologic findings revealed that male patients had worse emphysema, and female patients had worse bronchiectasis, as determined based on chest X-ray and computed tomography findings. On pulmonary function tests, female patients had less obstruction and less annual FEV1 loss over 5 years. Conclusion: This study revealed differences in the clinical parameters between male and female patients with COPD, including general characteristics, disease characteristics, and clinical outcomes.

Validation of Previous Spirometric Reference Equations and New Equations.

BACKGROUND: Pulmonary functions are interpreted using predicted values from reference equations that vary with ethnicity, gender, age, height, and weight. The universally used Choi's reference equations are not validated for Korean populations, and the purpose of this study was to validate them and develop new reference equations. METHODS: Subjects with normal spirometry and chest radiographs, no co-morbidities, and non-smokers, from the Korean National Health and National Examination Survey (KNHANES)-VI were enrolled (n = 117). Intraclass correlation coefficient (ICC) was assessed for reliability of reference equations. New reference equations were developed using linear regression analysis. Differences between observed and predicted values were assessed to compare the reference equations from Choi's, Global Lung Function Initiative 2012, KNHANES-IV, and newly developed equations. RESULTS: The ICC of Choi's reference equations was 0.854 (P < 0.001). The new reference equations for men were: forced vital capacity (FVC) (L) = - 4.38775 - 0.01184 × age + 0.05547 × height, forced expiratory volume - 1 second (FEV1) (L) = - 2.40147 - 0.02134 × age + 0.04103 × height; and for women: FVC (L) = - 3.09063 + 0.003904 × age + 0.038694 × height; FEV1 (L) = - 1.32933 - 0.00872 × age + 0.02762 × height. The differences between the predicted and observed means were largest in Choi's equations, but lowest in the new equations with highest goodness of fit. CONCLUSION: Because Choi's reference equations presented larger differences from the observed values, despite reliability, and the new reference equations showed better goodness of fit, we suggest the latter for Korean populations.

Severe Cutaneous Adverse Reactions to Antiepileptic Drugs: A Nationwide Registry-Based Study in Korea.

PURPOSE: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) to antiepileptic drug (AED), are rare, but result in significant morbidity and mortality. We investigated the major culprit drugs, clinical characteristics, and clinical course and outcomes of AED-induced SCARs using a nationwide registry in Korea. METHODS: A total of 161 patients with AED-induced SCARs from 28 referral hospitals were analyzed. The causative AEDs, clinical characteristics, organ involvements, details of treatment, and outcomes were evaluated. We compared the clinical and laboratory parameters between SJS/TEN and DRESS according to the leading causative drugs. We further determined risk factors for prolonged hospitalization in AED-induced SCARs. RESULTS: Carbamazepine and lamotrigine were the most common culprit drugs causing SCARs. Valproic acid and levetiracetam also emerged as the major causative agents. The disease duration and hospital stay in carbamazepine-induced SJS/TEN were shorter than those in other AEDs (P< 0.05, respectively). In younger patients, lamotrigine caused higher incidences of DRESS than other drugs (P= 0.045). Carbamazepine, the most common culprit drug for SCARs, was associated with a favorable outcome related with prolonged hospitalization in SJS (odds ratio, 0.12; 95% confidence interval, 0.02-0.63, P= 0.12), and thrombocytopenia was found to be a risk factor for prolonged hospitalization in DRESS. CONCLUSION: This was the first large-scale epidemiological study of AED-induced SCARs in Korea. Valproic acid and levetiracetam were the significant emerging AEDs causing SCARs in addition to the well-known offending AEDs such as carbamazepine and lamotrigine. Carbamazepine was associated with reduced hospitalization, but thrombocytopenia was a risk factor for prolonged hospitalization. Our results suggest that the clinical characteristics and clinical courses of AED-induced SCARs might vary according to the individual AEDs.

Risk of acute exacerbations in chronic obstructive pulmonary disease associated with biomass smoke compared with tobacco smoke.

BACKGROUND: Risk of exacerbations in chronic obstructive pulmonary disease (COPD) associated with biomass smoke has not been well addressed, although biomass smoke is similar in composition to tobacco smoke. METHODS: To investigate whether the risk of exacerbations in COPD associated with biomass smoke differs from that in COPD associated with tobacco smoke, we recruited patients with COPD from two Korean multicenter prospective cohorts. In a multiple linear regression model, the standardized regression coefficient (ß) of biomass smoke exposure ≥25 years was most similar to that (ß') of tobacco smoke exposure ≥10 pack-years (ß = - 0.13 and ß' = - 0.14). We grouped patients with COPD into four categories based on the above cut-offs: Less Tobacco-Less Biomass, Less Tobacco-More Biomass, More Tobacco-Less Biomass, and More Tobacco-More Biomass. The main outcome was the incidence of moderate or severe exacerbations. RESULTS: Among 1033 patients with COPD, 107 were included in Less Tobacco-Less Biomass (mean age: 67 years, men: 67%), 40 in Less Tobacco-More Biomass (mean age: 70 years, men: 35%), 631 in More Tobacco-Less Biomass (mean age: 68 years, men: 98%), and 255 in More Tobacco-More Biomass (mean age: 69 years, men: 97%). The incidence rates of exacerbations were not significantly different between Less Tobacco-More Biomass and More Tobacco-Less Biomass (adjusted incidence rate ratio, 1.03; 95% confidence interval, 0.56-1.89; P = 0.921). No interaction between sex and tobacco and biomass smoke was observed. When propensity score matching with available covariates including age and sex was applied, a similar result was observed. CONCLUSIONS: Patients with COPD associated with biomass smoke and those with COPD associated with tobacco smoke had a similar risk of exacerbations. This suggests that patients with COPD associated with biomass smoke should be treated actively.

Longitudinal change of FEV1 and inspiratory capacity: clinical implication and relevance to exacerbation risk in patients with COPD.

BACKGROUND AND OBJECTIVE: FEV1 is the gold standard for assessment of COPD. We compared efficacy of FEV1, inspiratory capacity (IC), and IC to total lung capacity (TLC) ratio in the evaluation of COPD and their association with exacerbation. METHODS: We analyzed the association of dyspnea severity, quality of life status, and lung function with lung function measurements and exacerbation risk in 982 patients enrolled in the Korea COPD Subgroup Registry and Subtype Research study. Exacerbation and longitudinal lung function change were evaluated in 3 years' follow-up. RESULTS: The FEV1, IC, and IC to TLC ratio showed comparable negative correlations with dyspnea severity and quality of life status, and positive correlation with exercise capacity. In patients with >2 events/year, annual rate of change in FEV1 and IC tended to decline more rapidly in those with FEV1 <50% than in those with FEV1 >50% (-14.46±19.40 mL/year vs 12.29±9.24 mL/year, P=0.213; -4.75±17.28 mL/year vs -78.05±34.16 mL/year, P=0.056 for FEV1 and IC, respectively), without significance. CONCLUSION: Longitudinal changes in IC and FEV1 were not significantly associated with exacerbation risk.

Adherence to the GOLD Guideline in COPD Management of South Korea: Findings from KOCOSS Study 2011-2018.

The guidelines for chronic obstructive pulmonary disease (COPD) treatment are important for the management of the disease. However, studies regarding the treatment adherence to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines have been scarce in Korea. Therefore, to examine the adherence to the GOLD guidelines, we examined the patterns of prescribed medication in COPD patients from 2011 to 2018. Patients were classified as having been appropriately and inappropriately treated (overtreatment or undertreatment) for the GOLD group. Appropriate medical therapy was defined as using the first choice or alternative choice drug recommended in the GOLD guidelines. Inappropriate therapy was classified as overtreatment or undertreatment in accordance with the categorization in the GOLD guidelines. According to treatment of 2011 GOLD guidelines, there was inappropriate treatment in 52.3% in group A, 47.3% in group B, 56.3% in group C, and 17.8% in group D. According to treatment of 2017 GOLD guidelines, there was inappropriate treatment in 66.7% in group A, 45.3% in group B, 14.3% in group C, and 24.0% in group D. The common type of inappropriate COPD treatment is overtreatment, with inhaled corticosteroid (ICS) containing regimens. In conclusions, adherence to the GOLD guideline by the pulmonologist in clinical practice is still low in Korea. Therefore, we need better strategies to both optimize the use of the guidelines and adhere to the guidelines as well.

Difference in systemic inflammation and predictors of acute exacerbation between smoking-associated COPD and tuberculosis-associated COPD.

PURPOSE: Tuberculosis-associated COPD (T-COPD) has clinical characteristics similar to those of smoking-associated COPD (S-COPD), such as dyspnea, sputum production, and acute exacerbation (AE). However, the degree of systemic inflammation and prognosis might be different because of difference in the pathophysiology. The aim of this study was to compare the lung function, systemic inflammatory markers, and their impacts on AE in patients with S-COPD and T-COPD. PATIENTS AND METHODS: We performed a multicenter cross-sectional cohort study. We evaluated clinical characteristics, pulmonary function tests, levels of inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and IL-6, and the association of these markers with AE in patients with S-COPD and T-COPD. RESULTS: Patients with T-COPD included more women and had lesser smoking history and higher St George Respiratory Questionnaire score than did patients with S-COPD. Although the FEV1 of both groups was similar, FVC, vital capacity, total lung capacity, and functional residual capacity were lower in patients with T-COPD than in those with S-COPD. CRP, ESR, and IL-6 levels were significantly higher in patients with T-COPD compared to patients with S-COPD. According to a multivariate logistic regression analysis, FEV1 was a significant factor predicting AE in S-COPD, and IL-6 was a significant factor predicting AE in T-COPD. IL-6 level greater than 2.04 pg/mL was a cutoff for predicting exacerbation of T-COPD (sensitivity 84.8%, specificity 59.3%, P<0.001). CONCLUSION: Patients with T-COPD have higher levels of inflammatory markers, and IL-6 has a predictive value for AE in T-COPD.

Decreased serum club cell secretory protein in asthma and chronic obstructive pulmonary disease overlap: a pilot study.

PURPOSE: Improvement in the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO), and identification of biomarkers for phenotype recognition will encourage good patient care by providing optimal therapy. We investigated club cell secretory protein (CC-16), a protective and anti-inflammatory mediator, as a new candidate biomarker for diagnosing ACO. PATIENTS AND METHODS: We performed a multicenter cohort study. A total of 107 patients were divided into three groups - asthma, COPD, and ACO - according to the Spanish guidelines algorithm, and enrolled into the study. Serum CC-16 levels were measured using commercial ELISA kits. RESULTS: Serum CC-16 levels were the lowest in patients with ACO. Low serum CC-16 levels were a significant marker for the ACO even after adjustment for age, sex, and smoking intensity. Serum CC-16 levels were positively correlated with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25%-75% of FVC, FEV1/FVC, vital capacity, and diffusing capacity of the lung for carbon monoxide, and were negatively correlated with smoking amount (pack-years), bronchodilator response, fractional residual capacity, residual volume, and number of exacerbations per year. FEV1 and serum CC-16 levels were significantly lower in patients with frequent exacerbations. CONCLUSION: Serum CC-16 has the potential to be a biomarker for ACO diagnosis and also treat frequent exacerbations in patients with chronic inflammatory airway diseases.

Elevated interleukin-6 and bronchiectasis as risk factors for acute exacerbation in patients with tuberculosis-destroyed lung with airflow limitation.

BACKGROUND: Patients with tuberculosis-destroyed lungs (TDLs), with airflow limitation, have clinical characteristics similar to those of patients with chronic obstructive pulmonary disease (COPD). Acute exacerbation is an important factor in the management of TDL. Therefore, the aim of this study was to investigate the factors associated with acute exacerbations in patients with stable TDL with airflow limitation. METHODS: We evaluated the clinical characteristics, such as lung function, image findings, and serum laboratory findings, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin (IL)-6, in patients with TDL with chronic airflow limitation (n=94). We evaluated the correlation of these parameters with acute exacerbation. RESULTS: We found that patients with exacerbation were more likely to have bronchiectasis than those without exacerbation (patients with exacerbation, 66.7%; patients without exacerbation, 30.5%; P=0.001). CRP and IL-6 levels were significantly higher in patients with exacerbation than in those without exacerbation (P=0.001 and P<0.001, respectively). Bronchiectasis [OR, 3.248; 95% confidence interval (CI), 1.063-9.928; P=0.039] and elevated IL-6 levels (OR, 1.128; 95% CI, 1.013-1.257; P=0.028) were the most important parameters associated with acute exacerbation in patients with TDL with airflow limitation. CONCLUSIONS: Patients with bronchiectasis and high IL-6 levels may require more intensive treatment to prevent acute exacerbation.

Increased urinary l-histidine in patients with asthma-COPD overlap: a pilot study.

Purpose: Asthma-COPD overlap (ACO) is heterogeneous in nature and requires a unified diagnostic approach. We investigated the urinary levels of l-histidine, a precursor of histamine related to inflammatory responses, as a new candidate biomarker for diagnosing this condition. Patients and methods: We performed a prospective multicenter cohort study with retrospective analysis of 107 patients, who were divided into three groups: asthma, COPD, and ACO, according to the Spanish guidelines algorithm. Urinary l-histidine levels were measured using liquid chromatography-mass spectrometry. High-resolution metabolomic analysis, coupled with liquid chromatography-mass spectrometry and followed by multivariate statistical analysis, was performed on urine samples to discriminate between the metabolic profiles of the groups. Results: Urinary l-histidine levels were significantly higher in patients with ACO than in those with asthma or COPD, but the subgroups of ACO, classified according to disease origin, did not differ significantly. High urinary l-histidine level was a significant factor for the diagnosis of ACO even after adjusting for age, sex, and smoking amount. Among patients with airflow obstruction, the urinary l-histidine levels were elevated in patients with a documented history of asthma before the age of 40 years or bronchodilator responsiveness ≥400 mL; bronchodilator responsiveness ≥200 mL of forced expiratory volume in 1 second and exceeding baseline values by 12% on two or more visits; blood eosinophil count ≥300 cells·mm-3; and frequent exacerbations (P < 0.05). Conclusion: Urinary l-histidine could be a potential biomarker for ACO, regardless of the diversity of diagnostic definitions used.