Leukotriene antagonists as first-line or add-on asthma controller therapy

Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score =6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score =1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group

Heterogeneity of emergency treatment practices in wheezing preschool children

Aim Our aim was to survey treatment practices used for preschool children with wheezing in emergency rooms (ER) focussing on inhalation device choice and handling, face mask use, salbutamol dosing and written instructions. We sought to assess whether current protocols are in line with published evidence and guidelines. Methods This is a cross-sectional survey done in paediatric ER units located in Finnish municipalities with more than 10 000 inhabitants. Results Of the 100 units contacted, 50% responded. More than 50% of the units used nebulisers. Only 13% of the units administered salbutamol in single puffs. More than 30% of the units lacked criteria on face mask use. Poor co-operation had no effect on the dose of salbutamol in 62% of the units. Ensuring tight mask-to-face seal was included in the training in 20% of the units. A written action plan was provided to the caregivers in 28% of the units. Conclusion ER treatment guidelines for preschool children with wheezing are poorly endorsed. Research is needed to identify approaches to guideline implementation that are specific for primary care. Clinical research should focus on strengthening recommendations that are currently not embraced. ER treatment protocols need to be updated and adherence to guidelines should be re-evaluated.Peer reviewe

Early Alterations in Hippocampal Circuitry and Theta Rhythm Generation in a Mouse Model of Prenatal Infection: Implications for Schizophrenia

Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic–polyribocytidilic acid (poly I∶C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.</p> <p>Methods</p> <p>Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV₁, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV₁area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV₁and analysis of variance for AMP challenge.</p> <p>Results</p> <p>Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV₁was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response.</p> <p>Conclusions</p> <p>The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01343745">NCT01343745</a></p

Comparative effectiveness of asthma interventions within a practice based research network

<p>Abstract</p> <p>Background</p> <p>Asthma is a chronic lung disease that affects more than 23 million people in the United States, including 7 million children. Asthma is a difficult to manage chronic condition associated with disparities in health outcomes, poor medical compliance, and high healthcare costs. The research network coordinating this project includes hospitals, urgent care centers, and outpatient clinics within Carolinas Healthcare System that share a common electronic medical record and billing system allowing for rapid collection of clinical and demographic data. This study investigates the impact of three interventions on clinical outcomes for patients with asthma. Interventions are: an integrated approach to care that incorporates asthma management based on the chronic care model; a shared decision making intervention for asthma patients in underserved or disadvantaged populations; and a school based care approach that examines the efficacy of school-based programs to impact asthma outcomes including effectiveness of linkages between schools and the healthcare providers.</p> <p>Methods/Design</p> <p>This study will include 95 Practices, 171 schools, and over 30,000 asthmatic patients. Five groups (A-E) will be evaluated to determine the effectiveness of three interventions. Group A is the usual care control group without electronic medical record (EMR). Group B practices are a second control group that has an EMR with decision support, asthma action plans, and population reports at baseline. A time delay design during year one converts practices in Group B to group C after receiving the integrated approach to care intervention. Four practices within Group C will receive the shared decision making intervention (and become group D). Group E will receive a school based care intervention through case management within the schools. A centralized database will be created with the goal of facilitating comparative effectiveness research on asthma outcomes specifically for this study. Patient and community level analysis will include results from patient surveys, focus groups, and asthma patient density mapping. Community variables such as income and housing density will be mapped for comparison. Outcomes to be measured are reduced hospitalizations and emergency department visits; improved adherence to medication; improved quality of life; reduced school absenteeism; improved self-efficacy and improved school performance.</p> <p>Discussion</p> <p>Identifying new mechanisms that improve the delivery of asthma care is an important step towards advancing patient outcomes, avoiding preventable Emergency Department visits and hospitalizations, while simultaneously reducing overall healthcare costs.</p

Inhaled corticosteroids in childhood asthma: the story continues

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic–pituitary–adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses