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Type-2/eosinophilic inflammation plays a pivotal role in asthma. The identification of severe type-2/eosinophilic asthma is important for improving the management of patients with asthma. Therefore, efforts to develop non-invasive biomarkers for type-2/eosinophilic airway inflammation have been made during this decade. Currently, fraction of exhaled nitric oxide (FeNO) and serum periostin levels are considered markers of type-2/eosinophilic inflammation in asthma. However, a single-marker approach has limited the ability to diagnose severe type-2/eosinophilic asthma accurately and predict disease outcomes precisely. The present article reviews the utility of FeNO and serum periostin levels in a single-marker approach and in a multiple-marker approach in identifying patients with severe type-2/eosinophilic asthma. Furthermore, based on a sub-analysis of the Kinki Hokuriku Airway disease Conference (KiHAC), geno-endo-phenotypes of patients were stratified into four groups according to the FeNO and serum periostin levels.

Background: Inhalation studies suggested “protective” roles of exogenous prostaglandin E2, but the clinical relevance of endogenous prostanoids in asthma is poorly known. The objective of this study is to measure sputum levels of prostanoids in asthmatic patients to correlate with clinical indices. Methods: Mild (n = 41) or moderate-to-severe (19) asthmatics and 27 normal controls were examined for pulmonary function (FEV1 and mid-forced expiratory flow), sputum cell differentials, and sputum levels of prostaglandins D2, E2, F2α, and thromboxane B2 measured by sandwich enzyme immunoassay. Results: Each prostanoid level did not differ among the three groups. Sputum number of bronchial epithelial cells was greater in moderate-to-severe asthmatics than in the other two groups, suggesting epithelial desquamation. Levels of prostaglandin F2α, D2, and thromboxane B2 positively correlated with the severity of airflow obstruction in the 60 asthmatic patients, whereas prostaglandin E2 levels were unrelated to pulmonary function. The ratio of combined “contractile” prostanoids (prostaglandin D2/prostaglandin F2α/thromboxane B2) to prostaglandin E2 was 2.5-fold greater in moderate-to-severe asthmatics than in controls (p = 0.001) or in mild asthmatics (p = 0.0002) but did not differ between the latter two groups. In the two asthmatic groups combined, this ratio positively correlated with the sputum number of epithelial cells. The combined “contractile” prostanoids levels positively correlated with prostaglandin E2 levels in controls and in mild asthmatics but not in moderate-to-severe asthmatics. Conclusions: An imbalance in production, breakdown, or both between prostaglandin E2 and other prostanoids possibly due to epithelial damage may be involved in the pathogenesis of moderate-to-severe asthma.

Background: Gastroesophageal reflux disease (GERD) is known as a common comorbidity of asthma and chronic cough. The impact of GERD symptoms on cough-specific quality of life (QoL) in patients with asthmatic cough is poorly understood. The aim of this study is to determine the association of GERD symptoms with cough-specific quality of life in patients with cough variant asthma (CVA) using the Leicester Cough Questionnaire (LCQ). Methods: A total of 172 consecutive patients (121 females) with mean cough duration of 45.1 months (range 2–480 months) completed the Japanese version of the LCQ. The Frequency Scale for the Symptoms of Gastroesophageal reflux was administered to assess symptoms of acid-reflux and dysmotility. A range of clinical variables that may determine cough-specific QoL (LCQ) were estimated. Results: The mean LCQ scores was 12.9 (SD 3.5), consistent with severe impairment in QoL. Female gender, symptoms of gastroesophageal dysmotility, sensitization to allergens (house dust and Japanese cedar pollen) and the number of sensitized allergens were associated with lower LCQ scores (i.e. impaired cough-specific QoL) in univariate regression analysis. Acid-reflux symptoms, airway hyperresponsiveness, fractional exhaled nitric oxide, and sensitization to molds were unrelated to the LCQ score. After adjustment for gender, symptoms of gastroesophageal dysmotility was the only significant determinant of impaired cough-specific QoL accounting for 23% of the variance. Conclusions: Cough-specific QoL is severely impaired in patients with CVA. Symptoms of gastroesophageal dysmotility are an independent predictor of cough-specific QoL of patients with CVA.

Patients with asthma show a steeper age-related decline in pulmonary function than healthy subjects, which is often alleviated after the initiation of treatment with inhaled corticosteroids (ICS). However, there still are patients who develop irreversible airflow limitations despite receiving adequate ICS treatment. The identification of the characteristics of such patients and biomarkers of progression for airflow limitation, a functional consequence of airway remodeling, is considered important in the management of asthma. A variety of biomarkers are associated with the forced expiratory volume in 1 s (FEV1) in asthma in a cross-sectional fashion. However, few biomarkers are known to reflect the decline in pulmonary function, particularly in patients with asthma who receive ICS treatment. Recently periostin, a matricellular protein that prolongs Th2/eosinophilic inflammation and reflects airway remodeling, was reported to be detected in serum. In a Kinki Hokuriku Airway disease Conference multicenter cohort study, we demonstrated that among several serum markers, high serum periostin level, particularly ≥95 ng/mL, was the only marker associated with a greater annual decline in FEV1 and a decline in FEV1 of ≥30 mL-yr-1∙A variant (rs9603226) of the POSTN gene that encodes periostin was also involved in the frequency of a decline in FEV1 of ≥30 mL-yr-1. Our results suggest that the serum periostin level is a useful marker reflecting pulmonary function decline in patients with asthma receiving ICS.

Background: The character or timing of chronic cough is considered to be unpredictable for diagnosing its cause. However, the associations of cough triggers with cough pathophysiology remains unknown. Methods: We developed a closed questionnaire listing 18 triggers that were reported by ≥1% of 213 patients in a retrospective survey. Using this questionnaire, patients with cough-predominant or cough-variant asthma (n = 140) and those with non-asthmatic cough (54) were asked whether their cough was induced by the listed triggers. Associations of triggers with causes of cough, airway sensitivity to inhaled methacholine, exhaled nitric oxide (NO) levels, number of sensitizing allergens, and scores from gastroesophageal reflux (GER) questionnaires were examined. Factor analysis was used to categorize variables, including the 12 most common cough triggers, diagnosis of asthmatic cough, airway sensitivity, and exhaled NO levels. Results: "Cold air" and "fatigue/stress" induced cough more often in asthmatic coughers than in non-asthmatic coughers. "Spices" and "meals" induced cough more frequently in GER-coughers (n = 19). Patients who marked "cold air" as the trigger were more sensitive to inhaled methacholine and showed higher exhaled NO levels than those who did not mark this trigger. The "post-nasal drip" trigger was associated with elevated exhaled NO levels, and this association was mainly exhibited by patients with cough-predominant asthma. The triggers "pollen" and "mold smell" were associated with a number of sensitizing allergens. The number of triggers was weakly associated with GER scores. By factor analysis, "cold air," "fatigue/stress," asthmatic cough, airway hypersensitivity, and elevated NO levels were categorized into the same factor. Conclusions: Several cough triggers may reflect the pathophysiology of prolonged or chronic cough.

Background: Despite the fact that bronchioles are involved in asthma, there have been limited asthmatic cases showing marked centrilobular opacities on computed tomography (CT) chest scans. Systemic corticosteroids have been administered in such cases, but the efficacy of extra-fine particle inhaled corticosteroids has not been assessed. Case Summary: A previously healthy 64-year-old man presented with a four-month history of productive cough and progressive dyspnea despite a combination therapy with inhaled salmeterol (50 μg bid) and fluticasone (500 μg bid), sustained-release theophylline, and pranlukast because of suspicion of asthma. Physical examination revealed wheezing at the end of forced expiration. High resolution CT chest scan showed diffuse centrilobular opacities, bronchiectatic changes, and bronchial wall thickening. Transbronchial lung biopsy, bronchoalveolar lavage fluid, and transbronchial biopsy all showed predominant eosinophil infiltrates, suggesting that eosinophilic inflammation across the entire airway tree caused the abnormal CT findings. Alveolar fraction of exhaled nitric oxide level, a non-invasive marker of eosinophilic peripheral airway inflammation, was also elevated. Because he refused systemic corticosteroids, inhaled ciclesonide (400 μg bid) and inhaled tiotropium were added on to his current medication under careful observation. His symptoms, pulmonary function and CT findings promptly improved, and he had fully recovered at follow-up. Discussion: Extra-fine particle inhaled corticosteroids could be an alternative approach in centrilobular opacities caused by eosinophilic peripheral airway inflammation.

ABSTRACT: Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory disorders involving obstructive airway defects. There have been many discussions on their similarities and differences. Although airflow limitation expressed as forced expiratory volume in one second (FEV1) has been considered to be the main diagnostic assessment in both diseases, it does not reflect the functional impairment imparted to the patients by these diseases. Therefore, multidimensional approaches using multiple measurements in assessing disease control or severity have been recommended, and multiple endpoints in addition to FEV1 have been set recently in clinical trials so as not to miss the overall effects. In particular, as improving symptoms and health status as well as pulmonary function are important goals in the management of asthma and COPD, some patient-reported measurements such as health-related quality of life or dyspnea should be included. Nonetheless, there have been few reviews on the long-term clinical course comparing asthma and COPD as predicted by measurements other than airflow limitation. Here, we therefore analyzed and compared longitudinal changes in both physiological measurements and patient-reported measurements in asthma and COPD. Although both diseases showed similar long-term progressive airflow limitation similarly despite guideline-based therapies, disease progression was different in asthma and COPD. In asthma, patient-reported assessments of health status, disability and psychological status remained clinically stable over time, in contrast to the significant deterioration of these parameters in COPD. Thus, because a single measurement of airflow limitation is insufficient to monitor these diseases, multidimensional analyses are important not only for disease control but also for understanding disease progression in asthma and COPD. KEY WORDS: asthma, COPD, longitudinal survey, multidimensional analysis, patient-reported outcome

Physiological differences and similarities in asthma and COPD are documented based on respiratory function testing. (1) The airflow reversibility is usually important for the diagnosis of asthma. However, patients with long disease histories may have poor reversibility. The reversibility test in COPD is useful for predicting the treatment response. (2) In some of the stable asthmatic patients without attack, the concave downslope of flow- volume curve is present. In severe COPD, the flow in the second half of the curve is smaller than that of rest- breathing. (3) Inspiratory capacity (IC) is a good estimator of air trapping and of predicting the exercise capacity in COPD or persistent asthma. (4) Peak expiratory flow (PEF) can be an important aid in both diagnosis and monitoring of asthma. PEF is not used in COPD because the main disorder is in the peripheral airway. (5) Measurements of airway responsiveness may help to a diagnosis of asthma. However, many COPD cases also have it. (6) Impulse oscillation system (IOS) revealed that the predominant airway disorders in asthma and COPD are central and peripheral respiratory resistance, respectively. However, some asthma patients have larger values of peripheral component. (7) Dlco reflects the extent of pathological emphysema and it is useful for the follow-up of COPD, whereas Dlco is not decreased in asthma. (8) The patient with widened A-aDO2 and alveolar hypoventilation may lead to the life threatening hypoxia in severe asthma attack or severe COPD. When PaCO2 overcomes PaO2, the patient should immediately be treated by mechanical ventilation.