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.

[The methodological aspects of nasal and exhaled nitric oxide levels in adult Japanese asthmatics].

BACKGROUND: Because both allergic rhinitis and asthma are caused by eosinophilic airway inflammation, using the same method to measure the eosinophilic inflammation of both the upper and lower airway would be advantageous. The levels of nitric oxide in exhaled air (FeNO) and nasal air (nNO) are useful as noninvasive markers of eosinophilic airway inflammation. Although the off-line method of measuring these parameters is easier and more useful than the on-line method, studies using the off-line method are rare in Japan. METHODS: In Study 1, we measured the levels of nNO and FeNO in 9 healthy controls and 9 subjects with allergic rhinitis, to validate the methodology for using the off-line method to measure nNO. In Study 2, we measured the nNO and FeNO levels of and performed spirometry on 69 stable asthmatics treated with inhaled corticosteroid. RESULTS: In Study 1, nNO levels were significantly increased in patients with allergic rhinitis compared with healthy subjects (31.0 [20.8 to 41.2] versus 7.4 [0.0 to 14.8] ppb {median [95% confidence interval]}, p=0.018). The 69 patients with asthma that comprised the study population in Study 2 were classified as asthmatics with rhinitis (treatment-naïve, n=14; treated with antiallergic drugs, n=11; treated with intranasal corticosteroid, n=19) and asthmatics without rhinitis (n=15). Although FeNO did not differ among groups, nNO was significantly increased in treatment-naïve asthmatics with rhinitis compared with patients with asthma only (26.5 [17.1 to 35.9] versus 8.0 [-1.1 to 17.1] ppb, p=0.033). CONCLUSION: nNO levels measured by the off-line method are useful markers of allergic rhinitis.

[Cutoff point of the fraction of exhaled nitric oxide (FeNO) with the off-line method for diagnosing asthma and the effect of smoking on FeNO].

Evidences have shown that the fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. There is no study to show the FeNO cutoff point for detecting asthma and the influence of smoking, measured by the Sievers Bag collection kit. The study population comprised 60 steroid-naive asthmatic patients (BA) (32 non-smokers, 28 smokers) and 59 patients with chronic cough (CC) without asthma (42 non-smokers, 17 smokers) in our outpatient clinic. We measured FeNO levels, spirometory, bronchial hyperresponsiveness against acetylcholine, and other parameters. The levels of FeNO were significantly increased in asthmatics compared with subjects with chronic cough. According to the ROC curve, the cutoff point of FeNO was 30 ppb (AUC = 0.83, sensitivity 78.1%, specificity 73.5%, p < 0.001) in non-smokers. The levels of FeNO in smokers were not significantly different from those in non-smokers, both bronchial asthma and chronic cough subjects. But the cutoff point of FeNO was 40 ppb (AUC = 0.65, sensitivity 67.8%, specificity 70.6%, p = 0.012). In conclusion, the cutoff point of FeNO was 30 ppb in non-smokers and 40 ppb in smokers. In smokers, FeNO measurement was less useful.

[The effect of inhaled corticosteroid on the fraction of exhaled nitric oxide (FeNO) with off-line method in adult Japanese asthmatics].

BACKGROUND: The fraction of exhaled nitric oxide (FeNO) is a useful marker of asthma control. The FeNO measurement with our offline method using SIEVERS bag collection kit may be more affordable, but there have been no studies to show the effect of anti-asthmatic therapy on FeNO with our offline method. METHODS: The study population comprised 36 steroid-naïve asthmatics at our outpatient clinic. We treated them according to asthma prevention and management guideline 2006, Japan. We also measured eNO levels by our offline method and spirometory on baseline, 4weeks, and 12 weeks of treatment. RESULTS: All asthmatics were symptom-free on 12 weeks of treatment. The levels of FeNO FEV1/FVC were significantly decreased on 4 weeks and 12 weeks of treatment, compared with that on first visit. We classified the subjects into two groups; (A) FEV1/FVC <70% (n=11) or (B) FEV1/FVC > or =70% (n=25) on baseline. In (A) group, the level of FeNO and FEV1/FVC were significantly improved on 4 and 12 weeks of treatment. In (B) group, on 4 weeks of treatment, the level of FEV1/FVC was significantly increased but the level of FeNO was not significantly changed. On 12 weeks of treatment, the levels of FeNO was significantly decreased, but the level of FEV1/FVC was not significantly changed. CONCLUSION: The levels of FeNO were decreased by antiasthmatic therapy, so that offline monitoring of eNO will facilitate the management of bronchial asthma in patients treated with these drugs.

[The methodological aspects of off-line sampling of exhaled air for nitric oxide measurement in Japanese].

The measurement of exhaled nitric oxide (eNO) is a non-invasive biomarker of bronchial inflammation. Despite the usefulness of eNO measurement, NO analyzers are too expensive for widespread use by general practitioners. In comparison, the off-line (bag collection) method of eNO measurement may be more useful. In Japan, however, there have been few studies about eNO in asthmatics using the off-line method. This study shows methodological aspects of the off-line method. Briefly, with a SIEVERS bag collection kit, we recommend that the flow rate and pressure level of exhaled air should be 70 ml/sec and 10 cm H2O, respectively and that the sampled air should be measured within 12 hours.

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.