BackgroundAsthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations.Methodology/Principal FindingsOver the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations.Conclusions/SignificanceThis study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.

The incidence and pathogenesis of right ventricular dysfunction in obstructive sleep apnoea (OSA) remains controversial. Using nuclear ventriculography, the prevalence of right ventricular dysfunction (RVD) was therefore determined in obese patients with OSA, as well as their clinical characteristics, arterial blood gas values, spirometry and sleep parameters. The reversibility of RVD was evaluated after long-term use of nasal continuous positive airway pressure (nCPAP).We studied 112 obese patients with OSA by nuclear ventriculography, 35 with RVD (Group 1), 77 without RVD (Group 2), and 14 patients without OSA as controls (Group 3). Repeat nuclear ventriculography was performed in seven patients who used nCPAP nightly for 6-24 months.The mean right ventricular ejection fractions (RVEF) were 31%, 47% and 44% in Groups 1, 2 and 3, respectively. Group 1 also had a lower left ventricular ejection fraction (LVEF) of 55 vs 63% in Group 2. The OSA groups did not differ in mean spirometric or arterial blood gas values. Group 1 had a lower mean nocturnal arterial oxygen saturation (Sa,O 2 ) of 82 vs 87% in Group 2, and a longer apnoea duration of 22.3 vs 19.2 s. All but two patients in Group 1 had either awake alveolar hypoventilation or an apnoea + hypopnoea index >40 disordered breathing events·h -1 . Repeat nuclear ventriculography after nCPAP revealed an increase in RVEF from 30 to 39%.In conclusion, right ventricular dysfunction is common in obstructive sleep apnoea, but it is reversible with nasal continuous positive airway pressure treatment and appears to be related to nocturnal oxygen desaturation. Eur Respir J., 1996, 9, 945- [8]. In patients with OSA, left ventricular failure has been demonstrated to exist in the absence of ischaemic or valvular heart disease, and to be reversible with the long-term use of nasal continuous positive airway pressure [9][10][11][12]. Pulmonary hypertension and cor pulmonale have similarly been reported to be associated with OSA [13][14][15][16], but have been attributed to coexisting chronic obstructive pulmonary disease (COPD) [14,15].In a study of 50 patients with OSA, a 12% incidence of right ventricular failure (RVF) was found on the basis of clinical examination and radiological or electrocardiographic criteria [16]. The authors suggested that a "sustained hypoxaemia and/or hypercapnia over a 24 h period" was a necessary prerequisite for the development of RVF in patients with OSA [16]. Another study of 114 OSA patients reported similar relationships between pulmonary hypertension and obstructive lung disease, but 35% of the patients with pulmonary hypertension were not found to have lower airways obstruction [17].To further define and characterize obese patients with OSA who are at increased risk of right (RVD) and left ventricular dysfunction (LVD), we prospectively investigated the sleep parameters, pulmonary function, arterial blood gas values and radionuclide ejection fractions in 126 patients. The effect of long-term treatment utilizing nCPAP on right and ...

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The acute effects of thoracentesis on arterial oxygenation were observed in 19 studies on 17 patients. Arterial blood samples were obtained prior to, immediately after, and 1 h after thoracentesis. Unpredictable changes in the arterial oxygen tension, ranging from – 22 to + 19 mm Hg were found immediately following thoracentesis. It was concluded that significant hypoxemia may result from thoracentesis due to aberration of ventilation-perfusion relationships. It is further suggested that oxygen therapy be routinely administered during and immediately after the procedure