Objective: Baseline inhaled corticosteroid (ICS) dose may be a factor for prescribers to consider when they select a budesonide/formoterol maintenance and reliever therapy regimen for symptomatic ...asthmatics.
Methods: A 6-month randomized study compared two maintenance doses of budesonide/formoterol 160/4.5 µg, 1 × 2 and 2 × 2, plus as needed, in 8424 asthma patients with symptoms when treated with ICS ± an inhaled long-acting β2-agonist (LABA). In the total study population, 1339 (17%) were high-dose ICS (HD) users (≥1600 µg/day budesonide). This HD stratum was compared with the rest of the study population, divided into low-dose (LD; 400 µg/day) and medium-dose strata (MD; 401–1599 µg/day) with regard to severe asthma exacerbations and mean changes in five-item Asthma Control Questionnaire (ACQ5) scores from baseline.
Results: In all three strata there were fewer exacerbations in the 2 × 2 treatment groups (yearly rates 0.268, 0.172 and 0.094) than in the 1 × 2 treatment groups (yearly rates 0.232, 0.138 and 0.764). In no stratum was the difference between the treatment groups statistically significant. There was no statistically significant difference in time to the first severe exacerbation between the treatments 2 × 2 and 1 × 2 in the HD group (hazard ratio 0.944, p = 0.75). The adjusted mean changes in ACQ5 scores in the HD, MD and LD strata were −0.89, −0.61 and −0.65, respectively, with 1 × 2 treatment and −0.90, −0.74 and −0.76, respectively, with 2 × 2 treatment. In the MD and LD strata, the difference between doses was significant in favour of 2 × 2 (MD p < 0.0001; LD p = 0.004), but not in the HD stratum (p = 0.870). No difference in serious adverse events was seen.
Conclusion: Compared with the LD and MD strata, the HD stratum patients had more exacerbations and a shorter time to first exacerbation. However, there were no differences in response between the 1 × 2 and 2 × 2 groups in any of the strata. This indicates that patients using budesonide/formoterol maintenance and reliever therapy, irrespective of baseline ICS dose, can be switched to 1 × 2 with its lower steroid load. ACQ5 scores improved more in the HD stratum than in the MD and LD strata indicating, among other things, that HD patients were not overtreated at baseline.
ClinicalTrials.gov registration: NCT00463866
To identify airway pathologic abnormalities selectively associated with severe asthma, we examined 10 control subjects, 10 patients with intermittent asthma, 15 patients with mild-to-moderate ...persistent asthma, 15 patients with severe persistent asthma, and 10 patients with chronic obstructive pulmonary disease. Bronchial biopsies were assessed for epithelial integrity; subepithelial basement membrane (SBM) thickness; collagen type III deposition; eosinophil, neutrophil, and fibroblast numbers; mucous gland and airway smooth muscle (ASM) areas; SBM-ASM distance; ASM hypertrophy (increased cell size); and the expression of the contractile proteins alpha-actin, smooth muscle myosin heavy-chain isoforms, myosin light-chain kinase, and the phosphorylated form of the regulatory light chain of myosin. Neither mucosal eosinophilia nor neutrophilia, epithelial damage, or SBM thickness reflected asthma severity. In contrast, higher numbers of fibroblasts (p < 0.001), an increase in collagen type III deposition (p < 0.020), larger mucous gland (p < 0.040) and ASM (p < 0.001) areas, augmented ASM cell size (p < 0.001), and myosin light-chain kinase expression (p < 0.005) distinguished patients with severe persistent asthma from patients with milder disease or with chronic obstructive pulmonary disease. Stepwise multivariate regression analysis established that fibroblast numbers and ASM cell size were negatively associated with prebronchodilator and postbronchodilator FEV1 values in patients with asthma. We conclude that fibroblast accumulation and ASM hypertrophy in proximal airways are selective determinants of severe persistent asthma.
Omalizumab has been shown to decrease the risk of hospitalization or ED visits in patients with uncontrolled severe allergic asthma compared with placebo. This longitudinal study observed the ...conditions under which omalizumab is prescribed in real-life settings and assessed whether its use as an add-on therapy alongside standard treatments decreases the risk of severe asthmatic exacerbations.
A cohort of adult patients with uncontrolled severe asthma despite optimal treatment with inhaled and oral corticosteroids and a long-acting b 2 -agonist but no treatment with omalizumab upon entry was assembled. Risk of hospitalization or ED visits for asthma exacerbation was assessed using the Andersen-Gill extension of the Cox model for repeated events, controlling for age, sex, smoking history, BMI, gastroesophageal reflux, allergic status, allergic rhinitis, treatment, and hospitalization or ED visits for asthma in the 2 months prior to omalizumab treatment.
Overall, 163 physicians recruited 767 patients, of whom 374 took omalizumab at least once (mean observation period, 20.4 months). Omalizumab use was associated with an adjusted relative risk of 0.57 (95% CI, 0.43-0.78) for hospitalization or ED visits for asthma. In users of omalizumab, the adjusted relative risk of hospitalization or ED visits for asthma during omalizumab treatment vs nontreatment periods was 0.40 (95% CI, 0.28-0.58).
Add-on omalizumab is associated with a significantly decreased risk of hospitalization or ED visits in patients with uncontrolled severe asthma in real-life practice.
Tyrosine nitration is a post-translational protein modification with potentially significant biological implications. In the present study we demonstrate, for the first time, that tyrosine residues ...of human inducible nitric oxide synthase (NOS2) can be nitrated by peroxynitrite in vitro, leading to a decreased activity. Moreover, we show that NOS2 expressed in a skeletal muscle from septic patients is nitrated on selective tyrosine residues belonging to a canonic sequence. This phenomenon could be an endogenous mechanism of in vivo modulation of NOS2 enzymic activity.
1 Laboratoire de Cytophysiologie et Toxicologie
Cellulaire, Université Paris VII, 75251 Paris; and
2 Institut National de la Santé et de la
Recherche Médicale Unité 408, Faculté X. Bichat,
...75018 Paris, France
We have
previously shown that exposure to diesel exhaust particles (DEPs)
stimulates human airway epithelial cells to secrete the inflammatory
cytokines interleukin-8, interleukin-1 , and granulocyte-macrophage
colony-stimulating factor (GM-CSF) involved in allergic diseases. In
the present paper, we studied the mechanisms underlying the increase in
GM-CSF release elicited by DEPs using the human bronchial epithelial
cell line 16HBE14o . RT-PCR analysis has shown an increase in
GM-CSF mRNA levels after DEP treatments. Comparison of the effects of
DEPs, extracted DEPs, or extracts of DEPs has shown that the increase
in GM-CSF release is mainly due to the adsorbed organic compounds and
not to the metals present on the DEP surface because the metal chelator
desferrioxamine had no inhibitory effect. Furthermore, radical
scavengers inhibited the DEP-induced GM-CSF release, showing
involvement of reactive oxygen species in this response. Moreover
genistein, a tyrosine kinase inhibitor, abrogated the effects of DEPs
on GM-CSF release, whereas protein kinase (PK) C, PKA, cyclooxygenase,
or lipoxygenase inhibitors had no effect. PD-98059, an inhibitor of
mitogen-activated protein kinase, diminished the effects of DEPs,
whereas SB-203580, an inhibitor of p38 mitogen-activated protein
kinase, had a lower effect, and DEPs did actually increase the active,
phosphorylated form of the extracellular signal-regulated kinase as
shown by Western blotting. In addition, cytochalasin D, which inhibits the phagocytosis of DEPs, reduced the increase in GM-CSF release after
DEP treatment. Together, these data suggest that the increase in GM-CSF
release is mainly due to the adsorbed organic compounds and that the
effect of native DEPs requires endocytosis of the particles. Reactive
oxygen species and tyrosine kinase(s) may be involved in the
DEP-triggered signaling of the GM-CSF response.
granulocyte-macrophage colony-stimulating factor; 16HBE14o cells; signal transduction; reactive oxygen
species; cytokines; inflammation
Bronchial Thermoplasty (BT) is a bronchoscopic treatment for severe asthma. Following research trials there remains a need to guide BT treatment in clinical practice, specifically in the fields of ...patient assessment, selection and positioning of BT within the range of treatment modalities, BT treatment protocols and post-BT management and follow-up. Consensus statements can bridge the gap between evidence-based medicine and real world clinical practice.
We performed a modified RAND consensus analysis using a baseline list of statements derived from ATS/ERS Guidelines on Severe Asthma, Cochrane review and UK commissioning guidance. A panel of 5 European BT experts, individually scored the statements and following a day of discussion, rescored a revised final list independently.
An initial list of 132 statements, were independently scored. These were modified to 108 following group discussion. Consensus/total agreement was reached for 68 (63%) of the statements; 8 (7.4%) statements achieving total disagreement. For only 17 statements, could some form of consensus not be achieved.
The consensus document could be applied to guide BT clinical practice and used to serve as a minimum acceptable level of assessment for BT, drive the development of clinical practice protocols and help define quality indicators
Reactive oxygen species are strongly implicated in diaphragmatic dysfunction during sepsis. We investigated whether the heme oxygenase (HO) pathway, which is a powerful protective cellular system, ...protects the diaphragm against oxidative stress and contractile failure during sepsis. A basal expression of both the inducible and constitutive HO protein isoforms (HO-1 and HO-2, respectively) was found in the diaphragm. Enhanced HO-1 expression in diaphragmatic myocytes was observed 24 h after Escherichia coli endotoxin (lipopolysaccharide, LPS) inoculation and remained elevated for at least 96 h. Enhanced HO-1 expression was also observed in the rectus abdominis and soleus muscles and in the left ventricular myocardium of endotoxemic animals. Diaphragmatic HO-2 expression was not modified by endotoxin. Diaphragmatic HO activity exhibited a biphasic time course characterized by a transient decrease during the first 12 h followed by a significant increase at 24 h, corresponding to HO-1 induction. Diaphragmatic force was significantly reduced 24 h after LPS, concomitantly with muscular oxidative stress. Administation of an inhibitor of heme oxygenase activity, zinc protoporphyrin IX (ZnPP-IX), further impaired muscular oxidative stress and contractile failure. By contrast, increased levels of HO-1 expression obtained by pretreatment of rats with hemin, a powerful inducer of HO-1, completely prevented LPS-mediated diaphragmatic oxidative stress and contractile failure. This protective effect was reversed by ZnPP-IX. These results show an important protective role for the HO pathway against sepsis-induced diaphragmatic dysfunction, which could be related to its antioxidant properties.
La transplantation pulmonaire (TxP) constitue le traitement ultime de l’insuffisance respiratoire terminale et concerne environ 400 patients par an en France. Les indications de TxP restent dominées ...par la fibrose pulmonaire et la bronchopneumopathie chronique obstructive. La TxP est une activité complexe qui fait appel à de nombreuses expertises et soulève plusieurs problématiques menaçant potentiellement son efficience et sa pérennité. Parmi celles-ci, l’adéquation entre l’offre et la demande de greffons pulmonaires, l’organisation du prélèvement et de la greffe, la vitalité de la recherche clinique et translationnelle en TxP. L’Académie nationale de médecine souhaite dans ce rapport : (1) faire un état des lieux de l’activité de TxP en France et de la recherche clinique et fondamentale adossée à cette activité, en appréciant les points forts et les points faibles de chaque item ; (2) proposer des recommandations pour optimiser l’activité et des pistes d’amélioration. Ce rapport, qui couvre les données actuelles connues dans la thématique de la TxP en France, met en lumière les principales problématiques en relation avec cette activité parmi lesquelles la lourde organisation de la TxP, la préservation limitée du greffon et la fragilisation des équipes. Il avance des propositions portant sur le soin et la recherche visant à optimiser et garantir la poursuite et le développement de cette pratique pour les années à venir, avec notamment l’encouragement l’ouverture de plateforme mutualisée de conditionnement des greffons ou la création d’un réseau réunissant les centres de transplantation pulmonaires français.
Lung transplantation (LTx) constitutes the ultimate treatment for end-stage respiratory failure and concerns around 400 patients per year in France. The indications for LTx remain dominated by pulmonary fibrosis and chronic obstructive pulmonary disease. LTx is a complex activity which calls upon numerous expertises and raises several issues potentially threatening its efficiency and sustainability. Among these, the match between supply and demand for lung allografts, the organization of harvesting and transplantation, and the vitality of clinical and translational research in LTx. The National Academy of Medicine wishes in this report: (1) to take stock of the LTx activity in France and the clinical and fundamental research linked to this activity, assessing the strong points and weak points of each item; (2) propose recommendations to optimize the activity and avenues for improvement. This report, which covers the current data known in the area of LTx in France, highlights the main issues related to this activity, including the cumbersome organization of LTx, the limited preservation of the graft and the weakening of the teams. It puts forward proposals relating to care and research aimed at optimizing and guaranteeing the continuation and development of this practice for the years to come, with in particular the encouragement of the opening of a shared platform for packaging allografts or the creation of a network bringing together French lung transplant centers.
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