An observational cohort study of interstitial lung abnormalities (ILAs) in a large Japanese health screening population (Kumamoto ILA study in Japan: KILA-J).

BACKGROUND: Interstitial lung abnormalities (ILAs) are subtle or mild parenchymal abnormalities observed in more than 5% of the lungs on computed tomography (CT) scans in patients in whom interstitial lung disease was not previously clinically suspected and is considered. ILA is considered to be partly undeveloped stages of idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This study aims to clarify the frequency of subsequent IPF or PPF diagnosis, the natural course from the preclinical status of the diseases, and the course after commencing treatment. METHODS: This is an ongoing, prospective, multicentre observational cohort study of patients with ILA referred from general health screening facilities with more than 70,000 annual attendances. Up to 500 participants will be enrolled annually over 3 years, with 5-year assessments every six months. Treatment intervention including anti-fibrotic agents will be introduced in disease progression cases. The primary outcome is the frequency of subsequent IPF or PPF diagnoses. Additionally, secondary and further endpoints are associated with the efficacy of early therapeutic interventions in cases involving disease progression, including quantitative assessment by artificial intelligence. DISCUSSION: This is the first prospective, multicentre, observational study to clarify (i) the aetiological data of patients with ILA from the largest general health check-up population, (ii) the natural course of IPF or PPF from the asymptomatic stage, and (iii) the effects and outcomes of early therapeutic intervention including anti-fibrotic agents for progressive cases of ILA. The results of this study could significantly impact the clinical practice and treatment strategy for progressive fibrosing interstitial lung diseases. TRIAL REGISTRATION NUMBER: UMIN000045149.

Associated Factors and Comorbidities of Airflow Limitation in Subjects Undergoing Comprehensive Health Examination in Japan - Survey of Chronic Obstructive Pulmonary Disease Patients Epidemiology in Japan (SCOPE- J).

Purpose: To identify associated factors of having at least one of the airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases in health examinees, and to describe the characteristics of each subgroup classified by comorbidities. Subjects and Methods: This was an observational cross-sectional survey carried out in multiple regions of Japan. Subjects aged 40 years older, undergoing comprehensive health examination, were recruited. Airflow limitation was defined as having forced expiratory volume in 1 s/forced vital capacity lower than 70%. Associated factors of having at least one of the airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases were examined by logistic regression analysis. Subgroup classification by comorbidity patterns was conducted by hierarchical cluster analysis. Results: In a total of 22,293 subjects, 1520 (6.8%) had at least one of the airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases. With this objective variable, the following explanatory variables were significantly associated: older age, higher total score in the chronic obstructive pulmonary disease assessment test (CAT) and coexistence of lung cancer (common in ever-smokers and never-smokers), higher pack-years, lower body mass index, higher C-reactive protein, without coexistence of diabetes mellitus (specific in ever-smokers), male sex, coexistence of anxiety, and sleep disorder (specific in never-smokers). Among the 1520 subjects, 1512 subjects with smoking history data were classified by comorbidity patterns into subgroups of "no comorbidities," "mixed comorbidities," "inflammatory comorbidities," "overweight," "underweight," and "chronic kidney disease." "Inflammatory comorbidities" were specific in ever-smokers, and "underweight" was specific in never-smokers. Conclusion: Several factors were identified as associated factors of having at least one of airflow limitation, chronic cough/phlegm, and currently treated respiratory diseases and they were different between ever-smokers and never-smokers. Different comorbidity patterns were observed by smoking history. These findings could provide information to assist the management of subjects with COPD or at risk for COPD in the general population.

Chronic Cough and Phlegm in Subjects Undergoing Comprehensive Health Examination in Japan - Survey of Chronic Obstructive Pulmonary Disease Patients Epidemiology in Japan (SCOPE-J).

Purpose: The purpose of this study was to estimate the prevalence of subjects with chronic cough and phlegm and describe their characteristics including the presence or absence of airflow limitation among the general population in Japan. Subjects and Methods: This was an observational cross-sectional survey targeting multiple regions of Japan. Subjects aged 40 years or above who were undergoing comprehensive health examination were recruited. The existence of chronic cough and phlegm, airflow limitation, and treatment for respiratory diseases were examined. Chronic cough and phlegm were defined as having both symptoms for at least 3 months of the year and for at least 2 consecutive years, or as receiving any treatment for chronic bronchitis at the time of recruitment. Airflow limitation was defined as forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) less than 0.7. Results: In a total of 22,293 subjects, 380 subjects (1.7%) had chronic cough and phlegm. Among these 380 subjects, 21.8% received treatment for a respiratory disease, and 11.6% had airflow limitation. Compared to subjects without both chronic cough and phlegm but with airflow limitation, subjects with chronic cough and phlegm without airflow limitation were younger, more likely to be current smokers (39.6%), and had higher total scores on a chronic obstructive pulmonary disease (COPD) assessment test (CAT). Scores of CAT questions 1-4 (cough, phlegm, chest tightness, breathlessness, respectively) were higher in subjects with chronic cough and phlegm regardless of airflow limitation. Conclusion: This study demonstrated that subjects identified to have chronic cough and phlegm in comprehensive health examination settings were symptomatic, while most of them did not receive any treatment for respiratory diseases and did not have airflow limitation. Screening subjects for chronic cough and phlegm in a comprehensive health examination followed by a detailed examination of screened subjects could be an effective approach for better management of chronic cough and phlegm. Smoking cessation should be included in the management, in consideration that around 40% of subjects with chronic cough and phlegm were current smokers.

Aspirin-exacerbated respiratory disease (AERD): Current understanding of AERD.

The characteristics in AERD are severe adult-onset asthma, eosinophilic rhinosinusitis with nasal polyposis, and CysLT overproduction. The cause of AERD have remained unclear, however the decrease in the production of PGE2 caused by the reduction in COX-2 activity is considered to main pathological mechanism of AERD. The mast cell activation and the interaction between platelets and granulocytes are lead to the CysLT overproduction and severe eosinophilic inflammation. The ongoing activation of mast cells is important key pathogenesis in not only stable AERD but exacerbated AERD by aspirin and NSAIDs. In recent years, type 2 inflammation caused by ILC2 activation in patients with AERD have been attracting attention. Omalizumab is effective option for AERD via suppression of mast cell activation and CysLT overproduction. Dupilumab improves sinus symptoms especially in patients with AERD. In near future, anti-platelet drug, CRTH2 antagonist, and anti-TSLP antibody may be useful candidates of therapeutic options in patients with AERD.

Comorbidities according to airflow limitation severity: data from comprehensive health examination in Japan.

OBJECTIVES: The present study aimed to investigate the relationship between airflow limitation (AL) severity and comorbidities in comprehensive health examination. METHODS: This cross-sectional study included 6661 men and 6044 women aged 40-89 who underwent a lung function test during medical checkups. AL was defined as forced expiratory volume in 1 s/forced vital capacity of < 0.7. Logistic regression analysis was used to assess the association between AL severity and the presence of comorbidities. RESULTS: When compared with the normal lung function group, subjects with AL had a higher prevalence of lung cancer (odd ratio (OR) 9.88, 95% confidence interval (CI) 3.88-25.14) in men, hypertension (OR 1.63, 95% CI 1.26-2.10) in women, diabetes and hyperglycemia (OR 1.23, 95% CI 1.02-1.49 in men, OR 1.61, 95% CI 1.18-2.20 in women) in men and women after adjusting for potential confounders. In men, lung cancer and MetS (the Joint Interim Statement: JIS) were significantly associated with moderate-to-very severe AL after adjustment. In women, hypertension, diabetes and hyperglycemia, MetS (JIS), and MetS (the Japanese Committee of the Criteria for MetS: JCCMS) were significantly associated with mild AL after adjustment. Hypertension was significantly associated with moderate-to-very severe AL after adjustment in women. CONCLUSIONS: Significant relationships were found between AL severity and the presence of comorbid lung cancer in men, hypertension in women, diabetes and hyperglycemia, and MetS in men and women. Knowledge of comorbidities associated with AL should be widely publicized to raise the awareness of chronic obstructive pulmonary disease (COPD).

Advances in aspirin-exacerbated respiratory disease (AERD).

Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of asthma, eosinophilic nasal polyposis and a hypersensitivity to all medications that inhibit the cyclo- oxygenase (COX) -1 enzyme. Clinical history and observed aspirin provocation test remains gold standard for diagnosis of AERD. AERD patients typically have more severe asthma with airflow limitation and greater requirement for high-dose corticosteroid therapies. Over- production of cysteinyl-leukotrienes (CysLTs) and prostaglandin D2 (PGD2) correlate with the pathogenetic features of AERD, suggesting the possible involvement of mast cell activation with innate type 2 immune response. Next breakthroughs in diagnosis and treatment have been expected in the nearest futures.

Platelet activation markers overexpressed specifically in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by respiratory reactions on ingestion of COX-1 inhibitors and cysteinyl leukotriene overproduction. The hypersensitivity reaction is induced by low doses of aspirin that inhibit COX-1 in platelets. OBJECTIVE: We sought to explore the role of platelets in the pathogenesis of AERD in patients under stable conditions and during an aspirin challenge test. METHODS: Stable patients with AERD (n = 30), aspirin-tolerant asthma (ATA; n = 21), or idiopathic chronic eosinophilic pneumonia (n = 10) were enrolled. Platelet activation was estimated based on expression levels of P-selectin (CD62P), CD63, CD69, and GPIIb/IIIa (PAC-1) in peripheral platelets; percentages of circulating platelet-adherent leukocytes; and plasma levels of soluble P-selectin (sP-selectin) and soluble CD40 ligand (sCD40L). RESULTS: In the stable condition, expression of all surface markers on platelets, the percentage of platelet-adherent eosinophils, and the plasma levels of sP-selectin and sCD40L were significantly higher in patients with AERD compared with those in patients with ATA. P-selectin and CD63 expression on platelets and plasma sP-selectin and sCD40L levels were positively correlated with the percentage of platelet-adherent eosinophils. Among these markers, P-selectin expression and plasma sP-selectin levels positively correlated with urinary concentrations of leukotriene E4. Additionally, plasma sP-selectin and sCD40L levels were negatively correlated with lung function. In contrast, platelet activation markers in patients with AERD did not change during the aspirin challenge test. CONCLUSION: Peripheral platelets were activated more in patients with stable AERD compared with those in patients with stable ATA, patients with idiopathic chronic eosinophilic pneumonia, and control subjects. Platelet activation was involved in cysteinyl leukotriene overproduction and persistent airflow limitations in patients with AERD.

Differences in urinary leukotriene E4 levels and distribution of eosinophils between chronic rhinosinusitis patients with aspirin-intolerant and -tolerant asthma.

OBJECTIVE: Urinary leukotriene E4 (U-LTE4) concentrations are significantly elevated in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic features of eosinophilic rhinosinusitis and U-LTE4 concentration remains unknown. Here we examined the relationship between U-LTE4 level and eosinophil in chronic rhinosinusitis. METHODS: We measured the U-LTE4 concentrations and eosinophil counts in ethmoidal and maxillary sinuses and peripheral blood in 30 asthmatic patients (including 15 AIA patients). RESULTS: Eosinophil counts in ethmoidal sinuses and peripheral blood were markedly higher in asthmatic patients than in controls. Although there were no significant differences between eosinophil counts in maxillary and ethmoidal sinuses for ATA group, eosinophil counts were higher in ethmoidal sinus compared to that in maxillary sinus in the AIA group (P<.05). Eosinophil counts were higher in the maxillary than in ethmoidal sinuses for control patients (P<.05). Despite low correlation between eosinophil counts in peripheral blood and eosinophil counts in maxillary sinus (rs=0.4323, P<.001), moderate correlation was observed between eosinophil counts in peripheral blood and eosinophil counts in ethmoidal sinus (rs=0.5249, P<.0001). Basal U-LTE4 concentrations were higher in AIA patients than in those with aspirin-tolerant asthma. Despite low correlation between eosinophil counts and U-LTE4 concentration in maxillary sinus (rs=0.3849, P<.01), moderate correlation was observed between eosinophil counts and U-LTE4 concentrations in ethmoidal sinus (rs=0.4736, P<.001). CONCLUSION: We describe the differences in U-LTE4 and other parameters in AIA compared to ATA, and correlation among parameters. We demonstrate that eosinophil-dominant inflammation starts in ethmoidal sinus clinicopathogenetically in CRS with asthma. U-LTE4 concentration was not exclusively associated with eosinophil counts in ethmoidal sinus. Eosinophils in ethmoidal sinus may be a major production site for CysLTs, particularly in AIA. CRS with AIA is assumed to be characterized by leukotriene-eosinophil cross-interaction in ethmoidal sinus.

Association between airflow limitation severity and arterial stiffness as determined by the brachial-ankle pulse wave velocity: a cross-sectional study.

Objective Chronic obstructive pulmonary disease (COPD) is often associated with concomitant systemic manifestations and comorbidities, such as cardiovascular disease. There are limited data regarding airflow limitation (AL) and atherosclerosis in Japanese patients, and the potential association between AL and arterial stiffness has not yet been investigated in Japanese patients. Therefore, the purpose of this study was to investigate the association between AL severity and arterial stiffness using the brachial-ankle pulse wave velocity (baPWV). Methods This cross-sectional study included 1,356 subjects aged 40-79 years without clinical cardiovascular diseases who underwent a comprehensive health screening that included spirometry, the baPWV measurement, and blood sampling during medical check-ups in 2009 at the Japanese Red Cross Kumamoto Health Care Center. AL was defined in accordance with the Global Initiative for COPD criteria (forced expiratory volume in one second / forced vital capacity of < 0.7). A cut-off baPWV value of >1,400 cm/s was used for risk prediction and screening. Results The average baPWV (SD) results were 1,578.0 (317.9), 1,647.3 (374.4), and 1,747.3 (320.1) cm/s in the patients with a normal pulmonary function, mild AL, and moderate-to-severe AL, respectively (p< 0.001). Using logistic regression models adjusted for the age, body mass index, smoking status, hypersensitive C-reactive protein levels, hypertension, hyperglycemia, and dyslipidemia, an increased baPWV (>1,400 cm/s) was significantly associated with moderate-to-severe AL compared with a normal pulmonary function (odds ratio=2.76; 95% confidence intervals, 1.37-5.55; p=0.004). Conclusion Our results indicated an association between AL and increased arterial stiffness. Arterial stiffness may therefore worsen with an increase in the severity of AL.

Aspirin-intolerant asthma (AIA) assessment using the urinary biomarkers, leukotriene E4 (LTE4) and prostaglandin D2 (PGD2) metabolites.

The clinical syndrome of aspirin-intolerant asthma (AIA) is characterized by aspirin/nonsteroidal anti-inflammatory drug intolerance, bronchial asthma, and chronic rhinosinusitis with nasal polyposis. AIA reactions are evidently triggered by pharmacological effect of cyclooxygenase-1 inhibitors. Urine sampling is a non-invasive research tool for time-course measurements in clinical investigations. The urinary stable metabolite concentration of arachidonic acid products provides a time-integrated estimate of the production of the parent compounds in vivo. AIA patients exhibits significantly higher urinary concentrations of leukotriene E(4) (LTE(4)) and 1,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor-PGDM), a newly identified metabolite of PGD(2), at baseline. This finding suggests the possibility that increased mast cell activation is involved in the pathophysiology of AIA even in a clinically stable condition. In addition, lower urinary concentrations of primary prostaglandin E(2) and 15-epimer of lipoxin A(4) at baseline in the AIA patients suggest that the impaired anti-inflammatory elements may also contribute to the severe clinical outcome of AIA. During the AIA reaction, the urinary concentrations of LTE(4) and PGD(2) metabolites, including tetranor-PGDM significantly and correlatively increase. It is considered that mast cell activation probably is a pathophysiologic hallmark of AIA. However, despite the fact that cyclooxygenease-1 is the dominant in vivo PGD(2) biosynthetic pathway, the precise mechanism underlying the PGD(2) overproduction resulting from the pharmacological effect of cyclooxygenease-1 inhibitors in AIA remains unknown. A comprehensive analysis of the urinary concentration of inflammatory mediators may afford a new research target in elucidating the pathophysiology of AIA.

Challenge of isolated sputum cells supports in vivo origin of intolerance reaction to aspirin/non-steroidal anti-inflammatory drugs in asthma.

BACKGROUND: There is no in vitro test to diagnose aspirin-intolerant asthma (AIA). The aim of this study was to test if challenge with aspirin of sputum cells from subjects with AIA triggers the release of cysteinyl leukotrienes (CysLTs), known to be mediators of bronchoconstriction in AIA. METHODS: Sputum induction was performed at baseline and at another visit 2 h after a lysine-aspirin bronchoprovocation in 10 subjects with AIA and 9 subjects with aspirin-tolerant asthma (ATA). The isolated sputum cells were incubated for ex vivo challenge. RESULTS: Release of CysLTs by sputum cells from patients with AIA was not induced by lysine-aspirin ex vivo, neither when cells were collected at baseline nor in sputum cells recovered after lysine-aspirin-induced bronchoconstriction, whereas release of CysLTs from sputum cells was triggered by an ionophore on both occasions. However, the CysLT levels elicited by the ionophore were higher in the AIA group both at baseline (AIA vs. ATA: 3.3 vs. 1.6 ng/million cells; p < 0.05) and after the lysine-aspirin bronchoprovocation (3.9 vs. 1.7 ng/million cells; p < 0.05). This difference in the amount of CysLTs released between the groups appeared to be related to the number of eosinophils. CONCLUSIONS: Intolerance to aspirin could not be triggered in sputum cells isolated from subjects with AIA. Together with the previous inability to demonstrate intolerance to non-steroidal anti-inflammatory drugs in isolated blood cells, these results support the requirement of tissue-resident cells in the adverse reaction. However, ex vivo stimulation of sputum cells may be developed into a new test of capacity for LT release in inflammatory cells recovered from airways.

Increase in salivary cysteinyl-leukotriene concentration in patients with aspirin-intolerant asthma.

BACKGROUND: Cysteinyl-leukotrienes (CysLTs; LTC4, LTD4, and LTE4) play a considerable role in the pathophysiology of aspirin-intolerant asthma (AIA). Saliva has recently been validated as novel, simple, and noninvasive method for investigating inflammation in patients with asthma. The aim of this study is to clarify the molecular species of CysLT in saliva and to evaluate the CysLT and LTB4 concentrations in saliva in AIA patients. We also examined how the CysLT concentration in saliva reflects that of their corresponding urinary metabolite. METHODS: We preformed an analytical cross-sectional study. CysLT and LTB4 concentrations in saliva were quantified by enzyme immunoassay (EIA) following purification by high-performance liquid chromatography (HPLC). RESULTS: 1. When analyzed by EIA in combination with HPLC, saliva was found to consist of LTC4, LTD4 and LTE4 in similar amounts. 2. In saliva analysis among the three groups (AIA patients, aspirin-tolerant asthma [ATA] patients, and healthy subjects), both the concentrations of CysLTs and LTB4 were significantly higher in AIA patients than in ATA patients and healthy subjects. 3. We found significant correlations between CysLT concentration and LTB4 concentration in saliva in each group. 4. No significant correlation was found between the concentration of LTE4 in urine and that of CysLTs in saliva. CONCLUSIONS: In this study, we found higher concentrations of CysLTs and LTB4 in saliva from AIA patients than in saliva from ATA patients, suggesting that the quantification of CysLT and LTB4 concentrations in saliva may be another diagnostic strategy for AIA.

Profile of eicosanoid generation in aspirin-intolerant asthma and anaphylaxis assessed by new biomarkers.

BACKGROUND: It has recently demonstrated that a free radical-mediated pathway generates prostaglandins (PGs) and the corresponding prostaglandin enantiomers (ent-PGs). Aspirin-intolerant asthma and anaphylaxis accompany PGD(2) overproduction, possibly associated with mast cell activation via the COX pathway. However, free radical-mediated PG generation in the pathophysiology of these diseases, which can be demonstrated by measuring urinary ent-PGF(2)alpha, has not been reported. OBJECTIVES: To evaluate the characteristic profile of eicosanoid generation via the COX and/or free radical-mediated pathway underlying aspirin-intolerant asthma and anaphylaxis. METHODS: A comparative group analysis consisted of asthma (n = 17) and anaphylaxis (n = 8, none with aspirin-induced anaphylaxis) cases. Urinary eicosanoid concentrations were quantified as follows: 2,3-dinor-9alpha,11beta-PGF(2) by gas chromatography-mass spectrometry; leukotriene E(4), 9alpha,11beta-PGF(2), and PGs by enzyme immunoassay. RESULTS: 2,3-Dinor-9alpha,11beta-PGF(2) is a more predominant PGD(2) metabolite in urine than 9alpha,11beta-PGF(2). At baseline, the aspirin-intolerant asthma group (n = 10) had significantly higher leukotriene E(4) and lower PGE(2) concentrations in urine than the aspirin-tolerant asthma group. During the reaction, the urinary concentrations of leukotriene E(4) and PGD(2) metabolites correlatively increased, but with markedly different patterns of the mediator release, in the aspirin-intolerant asthma group and the anaphylaxis group, respectively. The urinary PGD(2) metabolites and primary PGs were significantly decreased in the aspirin-tolerant asthma group. Urinary ent-PGF(2)alpha concentrations were significantly increased in the anaphylaxis group but not the aspirin-intolerant asthma group. CONCLUSIONS: When assessed by urinary 2,3-dinor-9alpha,11beta-PGF(2), PGD(2) overproduction during aspirin-intolerant bronchoconstriction was clearly identified, regardless of COX inhibition. It is evident that free radical-mediated PG generation is involved in the pathophysiology of anaphylaxis.

CD203c expression on human basophils is associated with asthma exacerbation.

BACKGROUND: CD203c is a basophil cell surface marker used to diagnose and monitor various allergic diseases, but its relationship to asthma is not clear. OBJECTIVE: We determined whether CD203c expression levels are associated with stable and exacerbated asthma. METHODS: We used flow cytometry to compare spontaneous expression levels of surface markers on basophils from patients with stable or exacerbated asthma and from healthy subjects. Longitudinal changes in these expression levels were measured after basophil stimulation by IgE-dependent or IgE-independent mechanisms and compared with patients' asthma status. RESULTS: Spontaneous expression levels of CD203c were significantly higher on basophils from patients with asthma exacerbation than patients with stable asthma or healthy subjects. In contrast, no differences in spontaneous expression levels of CD63 or CD69 were observed among the 3 groups. Anti-IgE-induced expression of CD203c significantly increased in basophils during asthma exacerbation (P = .005). Low concentrations of Dermatophagoides pteronyssinus or IL-3 induced higher expression levels of CD203c during asthma exacerbation than during clinical improvement; induction of CD203c expression by these antigens therefore correlates with asthma control. In the patients with clinical improvement, there was a correlation between spontaneous CD203c expression levels and the percent predicted values of FEV(1) (r = -0.761; P = .022). CONCLUSION: Asthma exacerbation was accompanied by increased expression of CD203c on basophils that decreased significantly during remission. Basophil expression levels of CD203c might therefore be used to monitor asthma in patients.

Hyperleukotrieneuria in patients with allergic and inflammatory disease.

Cysteinyl leukotrienes (CysLTs: leukotrienes C(4), D(4), and E(4)) have long been implicated in the pathogenesis of asthma and several allergic diseases. LTE(4) has been identified as a major metabolite of LTC(4), and urinary LTE(4) (U-LTE(4)) is considered as the most reliable analytic parameter for monitoring the endogenous synthesis of CysLTs. From recent studies on the U-LTE(4) associated with adult stable asthma we identified four factors for hyperleukotrieneuria, namely, aspirin intolerance, eosinophilic nasal polyposis (ENP), vasculitis, and severe asthma. In ENP, there is prominent infiltration of eosinophils in the sinus and polyp tissues, which is linked to adult asthma and aspirin sensitivity, and ENP is the most important factor for the overproduction of CysLTs in asthmatics. We also demonstrated that anaphylaxis and eosinophilic pneumonia (EP) are associated with a marked increase in the U-LTE(4) concentration. Under these disease conditions, U-LTE(4) may be one of the candidate biomarkers. Moreover, the changes in U-LTE(4) concentrations may provide valuable information concerning therapeutic targets.

Increase in inflammatory mediator concentrations in exhaled breath condensate after allergen inhalation.

BACKGROUND: Although a number of studies have been carried out to examine the baseline concentrations of inflammatory mediators in asthmatic patients, the clinical utility of exhaled breath condensate (EBC) in allergen-induced bronchoconstriction has not yet been clarified. OBJECTIVE: We examined whether the release of inflammatory mediators can be detected in EBC after allergen-induced bronchoconstriction in asthmatic patients. METHODS: We quantified mast cell-associated mediators in EBC and their corresponding urinary metabolites before and after allergen inhalation. RESULTS: Early asthmatic responses (EARs) caused significant increases in the concentrations of cysteinyl leukotrienes (CysLTs; median, 10.4 vs 99.0 pg/mL; P < .0001) and prostaglandin D(2) (PGD(2); median, 2.26 vs 8.72 pg/mL; P = .0077), but not that of histamine, from baseline concentrations. Significant increases in the concentrations of urinary leukotriene E(4) and 9alpha, 11beta-prostaglandin F(2) were detected in patients with EARs. However, the percentage increases in the concentrations of CysLTs and PGD(2) in EBC did not correlate with those of their corresponding urinary metabolites. The increases in concentrations of CysLTs and PGD(2) in EBC in patients with EARs correlated with each other and correlated with the extent of decrease in FEV(1). An insignificant difference in tyrosine concentration before and after the inhalation test demonstrated that errors caused by dilution of inflammatory mediators are negligibly small in EBC collected over a short period. CONCLUSION: In patients with allergen-induced EARs, pulmonary generation of mast cell-associated mediators can be evaluated by quantifying CysLTs and PGD(2) in EBC, suggesting that the quantification of EBC mediators might be useful in monitoring acute asthmatic airway inflammation.

Treatment for Churg-Strauss syndrome: induction of remission and efficacy of intravenous immunoglobulin therapy.

Churg-Strauss syndrome (CSS) is characterized by the presence of asthma, eosinophilia, and small-vessel vasculitis with granuloma. It is a distinct entity, as determined from all classifications of systemic vasculitis. The poor prognostic factors in CSS are renal insufficiency, cardiomyopathy, severe gastrointestinal (GI) tract, and central nervous systems (CNS) involvement. The initial management of CSS should include a high dose of a corticosteroid: prednisone at 1 mg/kg/day or its equivalent for methylprednisolone with tapering over 6 months. In patients with severe or rapidly progressing CSS, the administration of methylprednisolone pulse at 1 g/body/day for 3 days is recommended. When corticosteroid therapy does not induce remission, or when patients have poor prognostic factors, immunosuppressive cytotoxic therapy is indicated. However, some patients with severe CSS often show resistance to conventional treatment. We think that IVIG therapy is a hopeful candidate for second-line treatment for CSS patients, particularly in the case of neuropathy and/or cardiomyopathy, which are resistant to conventional therapy. However, there is not much evidence supporting the effectiveness of IVIG in CSS, and the mechanisms underlying the action of IVIG remain unclear. Now we are performing clinical trials of IVIG therapy for CSS patients who are resistant to conventional treatment, through a nationwide double-blinded placebo-controlled study in Japan.

Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma.

Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control interferon-gamma (IFN-gamma) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter -1993T-->C SNP, which is in linkage disequilibrium with a synonymous coding 390A-->G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA; P = 0.004, P(c) = 0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P = 0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the -1993T-->C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the -1993 position, resulting in increased transcriptional activity of the TBX21 gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-gamma) production in human airways of individuals with the -1993T-->C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.

Urinary eicosanoid and tyrosine derivative concentrations in patients with vasculitides.

BACKGROUND: Vasculitides are classified on the basis of the type of cell involved, namely, eosinophilic vasculitides such as Churg-Strauss syndrome (CSS) and noneosinophilic vasculitides. However, knowledge on inflammatory mediators and oxidative tissue damage associated with vasculitides is insufficient. OBJECTIVE: We measured the urinary concentrations of inflammatory mediators and tyrosine derivatives to assess biomarkers associated with the pathophysiology of vasculitides. METHODS: Urine was collected from 9 patients with CSS during acute exacerbation and during clinical remission, 24 patients with rheumatoid arthritis in stable condition, and 8 patients with vasculitis diseases (VDs) during acute exacerbation. Leukotriene E 4 (LTE 4 ), 9alpha,11beta prostaglandin F 2 , and eosinophil-derived neurotoxin (EDN) concentrations were determined by enzyme immunoassay. 3-Bromotyrosine (BrY) and 3-chlorotyrosine (ClY) concentrations were determined by gas chromatography-mass spectrometry. RESULTS: The urinary LTE 4 , EDN, BrY, and ClY concentrations were significantly higher in the patients with CSS during acute exacerbation than in healthy control subjects and, except for urinary ClY concentration, significantly decreased during clinical remission. The urinary EDN and BrY concentrations were significantly higher in patients with CSS during acute exacerbation than in patients with VD during acute exacerbation. Only urinary LTE 4 concentration was significantly different between the patients with rheumatoid arthritis in stable condition and the patients with VD during acute exacerbation. CONCLUSION: Oxidative tissue damage caused by eosinophil peroxidase is a pathophysiological characteristic of eosinophil-associated diseases such as CSS. Urinary LTE 4 concentration may reflect a pathophysiological event involved in eosinophilic and noneosinophilic vasculitides. Cysteinyl-leukotriene pathways are potential therapeutic targets for small-vessel vasculitides.

Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria): Involvement of chronic hyperplastic rhinosinusitis with nasal polyposis.

BACKGROUND: The urinary leukotriene E4 (U-LTE4) concentration is significantly increased in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic factors of asthma and the U-LTE4 concentration remains undetermined. OBJECTIVE: We sought to examine the clinical features of asthmatic patients with increased excretion levels of U-LTE4 (hyperleukotrienuria). METHODS: We measured the U-LTE4 concentrations in 137 asthmatic patients (including 64 patients with AIA) who were in clinically stable condition. A U-LTE4 concentration of 150 pg/mg creatinine or greater (mean U-LTE4 + 3 SDs of normal healthy control subjects) was indicative of hyperleukotrienuria. RESULTS: The basal concentration of U-LTE4 was significantly higher in the patients with AIA than in those with aspirin-tolerant asthma (ATA; median, 227.2 vs 90.3 pg/mg creatinine; P <.01). Compared with normal leukotrienuria in the patients with AIA, hyperleukotrienuria in the patients with AIA was associated with older age and decrease in pulmonary function. On the other hand, compared with normal leukotrienuria in the patients with ATA, hyperleukotrienuria in the patients with ATA was associated with severe asthma and chronic hyperplastic rhinosinusitis with nasal polyposis (CHRS/NP), which are well-known symptoms of the aspirin triad, as well as hypereosinophilia and anosmia. The patients with ATA with CHRS/NP excreted U-LTE4 at significantly high concentrations. There were significant decreases in the U-LTE4 concentrations before and after the sinus surgery in both the AIA and ATA groups (P <.05). CONCLUSION: Cysteinyl leukotrienes are not strictly associated with aspirin intolerance itself but rather with clinical features, such as CHRS/NP, that are similar to those seen in AIA. CHRS/NP might be involved in cysteinyl leukotriene overproduction in asthmatic patients.