Trends in Prevalence of Non-Valvular Atrial Fibrillation and Anticoagulation Therapy in a Japanese Region　- Analysis Using the National Health Insurance Database.

BACKGROUND: Direct oral anticoagulants (DOACs) are effective in reducing thromboembolism events in patients with non-valvular atrial fibrillation (NVAF). However, little is known about trends in NVAF prevalence and DOAC prescriptions in daily clinical practice. This study investigated the current status and trends in NVAF prevalence and DOAC prescriptions in a region of Japan.Methods and Results:Annual data for the 4 years from May 2014 to May 2017 in the Tsugaru region of Aomori Prefecture, Japan, were obtained for analysis from the Japanese National Health Insurance database ("Kokuho" database [KDB]). The prevalence of NVAF in subjects aged 40-74 years increased gradually over the 4-year study period (1,094/57,452 [1.90%] in 2014, 1,055/56,018 [1.88%] in 2015, 1,072/54,256 [1.98%] in 2016, and 1,154/52,341 [2.20%] in 2017). The proportion of NVAF patients prescribed warfarin decreased (42%, 33%, 24%, and 21% in 2014, 2015, 2016, and 2017, respectively), the proportion of those prescribed DOACs increased (30%, 42%, 50%, and 57%, respectively), and the proportion not prescribed an oral anticoagulant (OAC) decreased (28%, 25%, 26%, and 22%, respectively). However, 17% of patients with a CHADS2score ≥2 were not prescribed an OAC in 2017. CONCLUSIONS: By using the KDB we found that the prevalence of NVAF has increased gradually from 2014 to 2017. In the Tsugaru region in Japan, DOACs prescriptions increased and warfarin prescriptions decreased over the 4-year period.

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.

N,N-Dimethylaminoxy Carbonyl, a Polar Protecting Group for Efficient Peptide Synthesis.

Peptide coupling with minimal protection is one of the desired methods for the synthesis of peptides and proteins. To achieve regioselective amide bond formation, side chain protection is often essential; however, protecting groups potentially diminish peptide solubility and render the polar polyamide chain amphipathic due to their apolar nature. In this manuscript, we describe a new protecting group, N,N-dimethylaminoxy carbonyl (Dmaoc), and its use in peptide coupling reactions. The Dmaoc group has a relatively polar character compared to the Boc group, which is a conventional protecting group for the N ε-amine of Lys residues. This polar protecting group is removable by reduction in the buffer containing (±)-dithiothreitol (DTT). Furthermore, the Dmaoc group proved compatible with peptide ligation strategies featuring the activation of N-acyl diaminobenzamides (Dbz) with sodium nitrate to generate the respective benzotriazole leaving group. The Dmaoc/Dbz strategy described in this manuscript provides a new method for the chemical synthesis of peptides.

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators.

Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8-driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF.

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.

Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma.

RATIONALE: Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established. OBJECTIVES: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma. METHODS: Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte-platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections. MEASUREMENTS AND MAIN RESULTS: 8-Isoprostane levels in sputum supernatants were inversely related to LXA4 in severe asthma (r = -0.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA4 and 15-epi-LXA4 biosynthesis by peripheral blood leukocytes. LXA4 and 15-epi-LXA4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte-platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited platelet-activating factor-induced increases in leukocyte-platelet aggregates (70.8% inhibition [LXA4 100 nM], 78.3% inhibition [15-epi-LXA4 100 nM]) and 15-epi-LXA4 markedly inhibited tumor necrosis factor-α-induced increases in bronchial contraction. CONCLUSIONS: LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).

Exhaled breath condensate eicosanoid levels associate with asthma and its severity.

BACKGROUND: The relationship between anti-inflammatory lipoxins and proinflammatory leukotrienes might be important in the pathobiology and severity of asthma. OBJECTIVE: We sought to investigate whether exhaled breath condensate (EBC) lipoxin and leukotriene measurements can noninvasively characterize the asthmatic diathesis and its severity. METHODS: We measured lipoxin A4 (LXA4) and leukotriene B4 (LTB4) levels in EBC collected from patients with asthma of different severities and from healthy control subjects. RESULTS: EBC LXA4 and LTB4 levels are increased in asthmatic patients compared with those seen in healthy control subjects (LXA4: 31.40 vs 2.41 pg/mL EBC, respectively [P < .001]; LTB4: 45.62 vs 3.82 pg/mL EBC, respectively [P < .001]). Although levels of both eicosanoids are increased in asthmatic patients, the LXA4/LTB4 ratio decreases with increasing asthma severity. It is 41% lower in patients with severe versus moderate asthma (0.52 vs 0.88, P = .034). EBC LXA4 levels correlate with the degree of airflow obstruction measured by using FEV1 (r = 0.28, P = .018). An LXA4 cutoff value of 7 pg/mL EBC provides 90% sensitivity and 92% specificity for the diagnosis of asthma (area under the curve, 0.96; P < .001). An LTB4 cutoff value of 11 pg/mL EBC provides 100% sensitivity and 100% specificity for the diagnosis of asthma (area under the curve, 1; P < .001). CONCLUSIONS: Proresolving and proinflammatory eicosanoids are generated in the airways of all asthmatic patients. The proportion of proresolving compounds decreases with asthma severity. These findings support the role for EBC eicosanoid measurements in the noninvasive diagnosis of asthma and suggest that proresolving eicosanoid pathways are dysregulated in patients with severe asthma.

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.

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.

Increased serum ADAM8 concentration in patients with drug-induced eosinophilic pneumonia-ADAM8 expression depends on a the allergen route of entry.

BACKGROUND: ADAM8 (a disintegrin and a metalloprotease 8) has been linked to asthma and eosinophilic pneumonia (EP). ADAM8 cleaves a variety of substrates and is a sheddase for CD23, the low affinity IgE receptor. The concentration of soluble ADAM8 (sADAM8) is increased in bronchoalveolar lavage fluid (BALF) from patients with smoking-induced acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP), but not drug-induced EP (Drug-EP). In AEP, the BALF sADAM8 concentration significantly correlates with the soluble CD23 concentration (sCD23). METHODS: To evaluate the involvement of ADAM8 in the pathogenesis of eosinophilic pneumonia, we measured the concentrations of sADAM8 and its substrate, soluble CD23 (sCD23), in serum from patients with AEP, CEP, and Drug-EP. We also measured the change in the sADAM8 concentration after a provocation test. RESULTS: In contrast to the BALF findings, serum sADAM8 concentrations were increased in Drug-EP (mean+/-SEM; 639.6+/-49.15) and serum ADAM8 levels correlated positively with the serum sCD23 levels in patients with Drug-EP (P=0.0080, R(2)=0.8465). Serum sADAM8 concentrations were also increased in AEP (409+/-76.91) and CEP (644.7+/-87.03). Serum ADAM8 concentrations were also elevated after the provocation test. CONCLUSION: Serum ADAM8 concentrations were elevated in Drug-EP, although the sADAM8 concentrations were not increased in the BALF in Drug-EP. Thus, the pathogenesis of AEP and Drug-EP may be distinct with regard to allergen exposure; AEP may be caused by the inhalation of antigens, whereas Drug-EP may be caused by bloodstream antigens. These findings indicate that ADAM8 levels reflect the route of eosinophilic inflammation in EP.

Changes in exhaled nitric oxide measured by two offline methods predict improvements in bronchial hyperresponsiveness after inhaled steroid therapy in Japanese adults with asthma.

BACKGROUND: The fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. No studies have examined the relationship between the change in FeNO levels measured offline and changes in bronchial hyperresponsiveness (BHR) in asthmatic patients treated with inhaled corticosteroids (ICS). The objective of this study was to investigate the relationship between the change in FeNO levels measured offline and the change in BHR to acetylcholine in asthmatic patients taking ICS. METHODS: The study population comprised 41 ICS-treated asthmatics from our outpatient clinic. We measured FeNO levels by two methods -with a Sievers kit ("FeNOs") and with a kit from the Center for Environmental Information Science, Japan ("FeNOc") at baseline and after 1 year of regular treatment. We also used spirometry to test BHR to acetylcholine (PC(20Ach)). RESULTS: The mean of duration of observation was 406 days. There were significant relationships between DeltalogPC(20Ach) and logPC(20Ach) (r = -0.877, P < 0.001), FeNOs (r = 0.465, P = 0.002), and FeNOc (r = 0.524, P = 0.004) at baseline, but not with age, the dose of ICS, FEV(1), or %FEV(1). Moreover, there was a significant relationship between DeltalogPC(20Ach) and DeltaFeNOs (r = -0.386, P = 0.013) and DeltaFeNOc (r = -0.473, P = 0.004), but not with DeltaFEV(1). CONCLUSIONS: Changes in FeNOs and FeNOc correlated with improvements in BHR to acetylcholine in adult asthmatics after ICS therapy. Our findings suggest that offline monitoring of FeNO will facilitate the management of bronchial asthma in patients treated with ICS.

Use of inhaled fluticasone propionate to control respiratory manifestations of relapsing polychondritis.

Effective management of respiratory tract involvement is very important in improving the prognosis of relapsing polychondritis (RPC). This case report describes a 19-year-old patient with RPC, who required frequent hospitalization due to recurrent exacerbations of airway obstruction. Use of high-dose fluticasone propionate effectively reduced the amount of oral corticosteroid necessary to control inflammation of the airway mucosa and dramatically decreased the patient's obstructive airway impairment. This report is the first illustrating the effectiveness and safety of inhaled corticosteroids in the control of the respiratory manifestations of RPC.

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.

[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.

Differences in regulatory T cells between Churg-Strauss syndrome and chronic eosinophilic pneumonia with asthma.

BACKGROUND: Chronic eosinophilic pneumonia (CEP) with asthma precedes the onset of Churg-Strauss syndrome (CSS) in half of all patients with CSS. It is not known what determines whether patients with CEP after asthma will have CSS. OBJECTIVE: We examined whether activation of regulatory T cells in patients with CEP inhibits CSS development and is otherwise involved in the mechanism of CSS disease. METHODS: In patients with CSS (n = 38), CEP with asthma (n = 20), and general adult asthma (n = 108), we examined the number of CD4(+)CD25(+) T cells in peripheral blood, as well as levels of expression of the cytokines IL-2, IL-5, IL-10, and TGF-beta by CD4(+)CD25(+) T cells, CD4(+)CD25(-) T cells, or both. RESULTS: At disease onset, patients with CSS, unlike patients with CEP, had significantly fewer CD4(+)CD25(+) T cells than patients with any step of asthma. CD4(+)CD25(+) T cells producing IL-10 were rarely detected in patients with CSS at disease onset or relapse, whereas the numbers of IL-10-producing T cells in patients with CEP were high at disease onset. There were fewer CD4(+)CD25(-) T cells producing IL-2 in patients with CSS before treatment than in patients with CEP at disease onset. The proportions of CD4(+)CD25(+) T cells producing IL-10 and CD4(+)CD25(-) T cells producing IL-2 in patients with CSS increased at remission. CONCLUSIONS: Maintenance of the numbers of regulatory T cells in patients with CEP with asthma might inhibit CSS development through the action of cytokines, such as IL-10 and IL-2, produced by CD4(+)CD25(+) or CD4(+)CD25(-) T cells. This might be part of a mechanism that influences progression and prognosis in these diseases.

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.

Prognosis of adult asthma after normalization of bronchial hyperresponsiveness by inhaled corticosteroid therapy.

BACKGROUND: Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory drugs for adult asthma and can improve not only clinical symptoms but also bronchial hyperresponsiveness (BHR). However, the prognosis of adult asthma has not been well studied, and it remains to be elucidated precisely how long treatment with ICSs should be continued once clinical remission is achieved. OBJECTIVES: We examined whether ICS use could be withdrawn or reduced without exacerbation of disease. METHODS: We retrospectively studied 374 adult patients with asthma to determine which factors predicted the elimination or reduction of ICS treatment without exacerbations of disease after the achievement of normalized BHR to acetylcholine. The patients were classified into three groups: Group 1 had symptoms within 6 months of normalization and needed to continue therapy; group 2 received the equivalent of >or= 400 microg fluticasone propionate until BHR normalization, did not have symptoms in the 6 months after normalization, and then had their doses of ICSs halved; and group 3 received the equivalent of