Association among fraction of exhaled nitrous oxide,bronchodilator response and inhaled corticosteroid type

BACKGROUND:Fraction of exhaled nitrous oxide (FeNO) is a known marker of airway inflammation and a topic of recent investigation for asthma control in children.OBJECTIVE:To investigate the relationship among FeNO and bronchodilator response measured by spirometry and types of inhaled corticosteroids (ICS).METHODS:A one-year review of children tested with spirometry and FeNO in a regional pediatric asthma centre was conducted.RESULTS:A total of 183 children were included (mean [± SD] age 12.8±2.8 years). Fluticasone was used most commonly (n=66 [36.1%]), followed by ciclesonide (n=50 [27.3%]). Most children (n=73 [39.9%]) had moderate persistent asthma. Increased FeNO was associated with percent change in forced expiratory volume in 1 s (FEV₁) after bronchodilator adjusted for allergic rhinitis, parental smoking and ICS type (B=0.08 [95% CI 0.04 to 0.12]; P<0.001). Similarly, FeNO was associated with percent change in forced expiratory flow at 25% to 75% of the pulmonary volume (FEF_25–75) after bronchodilator adjusted for parental smoking and ICS type (B=0.13 [95% CI 0.01 to 0.24]; P=0.03). FeNO accounted for only 16% and 9% of the variability in FEV₁ and FEF_25–75, respectively. Mean-adjusted FeNO was lowest in fluticasone users compared with no ICS (mean difference 18.6 parts per billion [ppb] [95% CI 1.0 to 36.2]) and there was no difference in adjusted FeNO level between ciclesonide and no ICS (5.9 ppb [95% CI −9.0 to 20.8]).CONCLUSION:FeNO levels correlated with bronchodilator response in a regional pediatric asthma centre. However, FeNO accounted for only 16% and 9% of the variability in FEV₁ and FEF_25–75, respectively. Mean adjusted FeNO varied according to ICS type, suggesting a difference in relative efficacy between ICS beyond their dose equivalents.     

Inhibitory effects of glycopyrronium,formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells

BackgroundCoronavirus 229E (HCoV-229E), one of the causes of the common cold, exacerbates chronic obstructive pulmonary disease (COPD) and bronchial asthma. Long-acting muscarinic antagonists and β₂-agonists and inhaled corticosteroids inhibit the exacerbation of COPD and bronchial asthma caused by infection with viruses, including HCoV-229E. However, the effects of these drugs on HCoV-229E replication and infection-induced inflammation in the human airway are unknown.MethodsPrimary human nasal (HNE) and tracheal (HTE) epithelial cell cultures were infected with HCoV-229E.ResultsPretreatment of HNE and HTE cells with glycopyrronium or formoterol decreased viral RNA levels and/or titers, the expression of the HCoV-229E receptor CD13, the number and fluorescence intensity of acidic endosomes where HCoV-229E RNA enters the cytoplasm, and the infection-induced production of cytokines, including IL-6, IL-8, and IFN-β. Treatment of the cells with the CD13 inhibitor 2′2′-dipyridyl decreased viral titers. Pretreatment of the cells with a combination of three drugs (glycopyrronium, formoterol, and budesonide) exerted additive inhibitory effects on viral titers and cytokine production. Pretreatment of HNE cells with glycopyrronium or formoterol reduced the susceptibility to infection, and pretreatment with the three drugs inhibited activation of nuclear factor-kappa B p50 and p65 proteins. Pretreatment with formoterol increased cAMP levels and treatment with cAMP decreased viral titers, CD13 expression, and the fluorescence intensity of acidic endosomes.ConclusionsThese findings suggest that glycopyrronium, formoterol, and a combination of glycopyrronium, formoterol, and budesonide inhibit HCoV-229E replication partly by inhibiting receptor expression and/or endosomal function and that these drugs modulate infection-induced inflammation in the airway.     

Clinical features of 89 patients with autoimmune hepatitis in Nagasaki Prefecture, Japan

We examined the clinical characteristics of 89 patients with autoimmune hepatitis (AIH) in Nagasaki Prefecture, Japan, and assessed the usefulness of a provisional scoring system for the diagnosis of AIH proposed by the International Autoimmune Hepatitis Group in 1993. The majority of patients were middle-aged women in their fifties. All patients showed a hepatitic picture. Forty-three patients (48%) had an insidious or chronic onset, while 34 (38%) had an acute onset, and 12 (14%) had liver cirrhosis at presentation. Seventy-nine patients (89%) were positive for antinuclear antibody (ANA), and 5 (6%) were positive for antibody to the hepatitis C virus (anti-HCV). The prognosis was good, with 90% 3-year survival, and most patients responded well to treatment with corticosteroids. The international scoring system was useful for the diagnosis of AIH in most of our patients; the percentages of patients with definite and probable AIH were 48% and 47%, respectively. However, certain factors, such as negative ANA, positive antimitochondrial antibody, concurrent infection with hepatitis B or C virus, and insufficient response to treatment precluded the diagnosis of AIH in some patients. Whether these patients were indeed "true" AIH patients is not clear at present, and further investigation of such patients may be useful for a better understanding of AIH. (Received: June 26, 1998; accepted: Oct. 23, 1998)     

Management of patients with chronic hepatitis B

Better understanding of hepatitis B virus (HBV) replication and the natural history and immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action, is the basis for better therapeutic strategies against chronic hepatitis B. Substantial experience has now been accumulated in the use of some of these drugs, and an Asia-Pacific Consensus has been reached on indications for their use. The goals of therapy and aspects of general management will be reviewed here. Among currently available drugs, alpha-interferon therapy gives a response rate (hepatitis B e antigen (HBeAg) seroconversion) of 30-40% compared with 10-20% in matched controls, but patients with lower alanine aminotransferase (ALT), higher HBV-DNA, and immunosuppressed patients have a poorer response, and alpha-interferon can be dangerous in cirrhosis. Meta-analysis of four controlled trials also suggests that thymosin-alpha1 is effective, but more studies are needed. Lamivudine has been most extensively studied. It is effective in terms of HBV-DNA loss, ALT normalization, HBeAg seroconversion, and improvement in histology, as well as being well tolerated. After 1 year of treatment, HBeAg seroconversion rate increased with higher pretherapy ALT levels, suggesting that patients with stronger endogenous antiviral defenses to kill hepatocytes harboring covalently closed circular DNA have a better response to direct antiviral effects. Lamivudine is also beneficial in HBeAg negative chronic hepatitis B, and patients with decompensated cirrhosis and HBV replication. However, genotypic-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutations start to emerge after 9-10 months of lamivudine therapy, and their incidence increases more quickly than the HBeAg seroconversion rate durating prolonged therapy. Thus the benefits of long-term lamivudine must be balanced against concern about YMDD mutations, and the durability of treatment response. There are encouraging preliminary results for adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/nucleotide analogs in the early stages of appraisal; entecavir and adefovir dipivoxil appear effective in patients with YMDD mutants. Further development of new drugs and new strategies, such as combination or sequential therapy, may help to better achieve the goals of treatment for chronic hepatitis B in the new century.     

Determination of the cutoff values of Th2 markers for the prediction of future exacerbation in severe asthma: An analysis from the Hokkaido Severe Asthma Cohort Study

BackgroundWe recently reported that severe asthma patients with frequent exacerbations showed high blood eosinophil counts (Eo) and fractions of exhaled nitric oxide (FeNO) compared with non-exacerbators. However, we did not determine exact cutoff values related to exacerbation. The aim of this study was to determine the cutoff values of Eo and FeNO that could be related to the exacerbation of severe asthma. We also aimed to confirm the clinical utility of Th2 markers related to exacerbation.MethodsThis study included 105 severe asthma patients who completed a three-year follow-up of a severe asthma cohort study, including smokers. Three Th2 markers were selected, viz., Eo, FeNO, and positive atopic status. Regarding Eo and FeNO, we determined the cutoff values for the definition of “positive” Th2 features using receiver operating characteristic curve analyses, based on the comparisons between frequent exacerbators and other patients.ResultsThe cutoff values for positive Th2 features were Eo ≥ 250 cells/μL and FeNO ≥31 ppb. Sixteen patients (15.2%) had no Th2 features, 40 (38.1%) had one, 25 (23.8%) had two, and 24 (22.9%) had three. A high number of positive Th2 features was significantly associated with exacerbation frequencies over three years (p < 0.05). Similarly, compared to patients with one or no Th2 features, those with three Th2 features had a significantly higher probability of having more than one exacerbation (p < 0.05).ConclusionsThe cutoff values determined in the current analysis were good predictors of future exacerbations in severe asthma patients.     

Efficacy and safety of benralizumab in Japanese patients with severe,uncontrolled eosinophilic asthma

Background

In the Phase III CALIMA trial, benralizumab significantly reduced asthma exacerbations, increased lung function, and alleviated symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate the efficacy and safety of benralizumab for Japanese patients in the CALIMA trial.

Outcome of coronavirus-associated severe acute respiratory syndrome using a standard treatment protocol

OBJECTIVE: There is so far no consensus on the optimal treatment strategy for the coronavirus-associated severe acute respiratory syndrome (SARS). We aimed to analyse the outcomes of a standard treatment strategy comprising antibiotics, a combination of ribavirin, a 3-week step-down course of corticosteroids, and the possibility of pulsed methylprednisolone rescue in the event of deterioration. METHODOLOGY: This was a prospective cohort study performed at a major public-funded hospital in Hong Kong. Eighty-eight World Health Organisation/Centers for Disease Control and Prevention probable cases of SARS (97% laboratory-confirmed) were treated with a standard protocol previously reported. Seventy-one patients treated de novo were analysed in detail with regard to time to clinical stabilization after combination treatment, requirement of additional therapy (pulsed methylprednisolone; assisted ventilation); and final outcomes (recovery, mortality). RESULTS: The mean age was 42. Twenty-one patients (24%) had comorbidities. Three of 71 treated de novo recovered with antibiotics alone. The remaining 68 received combination treatment at a mean of 5.8 days after symptom onset, of whom 30 subsequently required pulsed methylprednisolone rescue (independent predictors: older age and higher LDH) and 18 required assisted ventilation (independent predictors: older age, higher oxygen requirement and creatinine level). Their median time to clinical stabilization was 8.0 days after combination treatment (independent predictor for longer time to stabilization: median age of 41 or above). Common complications were hyperglycaemia (58%), pneumo-mediastinum/thoraces (13%), psychiatric manifestations (7%) and ventilator-associated pneumonia (2%). One patient (1%) died of SARS-related respiratory failure. All-cause mortality was 3.4%, occurring in patients aged > 65 years only. None of the discharged survivors required continuation of oxygen therapy. CONCLUSIONS: This standard treatment protocol resulted in overall satisfactory outcomes. Randomized controlled trial is suggested to confirm its efficacy.     

IL-6对小鼠肾上腺皮质细胞系Y1合成皮质醇的影响

目的：探讨白介素6（IL-6）对小鼠肾上腺皮质细胞系Y1合成皮质醇能力及合成过程中类固醇急性调节蛋白（STAR）相关基因表达的影响。方法：100ng·ml^-1 IL-6单独或联合10^-9mol·L^-1促肾上腺皮质激素（ACTH）处理Y1细胞后,台盼蓝拒染法检测细胞活力,放免法检测细胞皮质醇合成量,实时荧光定量PCR法检测StAR mRNA表达水平。结果：IL-6单独或联合ACTH处理Y1细胞后,皮质醇合成量增加（P〈0．05）,同时StAR mRNA表达水平上升（P〈0．05）。结论：IL-6可单独或联合ACTH通过促进StARm RNA表达增强Y1细胞合成皮质醇的能力。