Exploring facilitators and barriers in asthma management in rural, semi-urban and urban populations in Vellore, India:an interview study of patients and primary care physicians

Summary box In India, there are deficits in asthma self-management and asthma training for primary care physicians. We advocate culturally tailored interventions for patients and clinically oriented training for primary care physicians.<br/

A Charter to Fundamentally Change the Role of Oral Corticosteroids in the Management of Asthma

Asthma affects 339 million people worldwide, with an estimated 5–10% experiencing severe asthma. In emergency settings, oral corticosteroids (OCS) can be lifesaving, but acute and long-term treatment can produce clinically important adverse outcomes and increase the risk of mortality. Therefore, global guidelines recommend limiting the use of OCS. Despite the risks, research indicates that 40–60% of people with severe asthma are receiving or have received long-term OCS treatment. Although often perceived as a low-cost option, long-term OCS use can result in significant health impairments and costs owing to adverse outcomes and increased utilization of healthcare resources. Alternative treatment methods, such as biologics, may produce cost-saving benefits with a better safety profile. A comprehensive and concerted effort is necessary to tackle the continued reliance on OCS. Accordingly, a threshold for OCS use should be established to help identify patients at risk of OCS-related adverse outcomes. Receiving a total dose of more than 500 mg per year should trigger a review and specialist referral. Changes to national and local policies, following examples from other chronic diseases, will be crucial to achieving this goal. Globally, multiple barriers to change still exist, but specific steps have been identified to help clinicians reduce reliance on OCS. Implementing these changes will result in positive health outcomes for patients and social and economic benefits for societies.</p

Magmatic and geotectonic significance of Santa Elena Peninsula, Costa Rica

We present a new integrated interpretation of the geochemistry and geotectonic significance of the Santa Elena Peninsula, which is divided in three units: 1) an overthrust allocthonous unit of ultramafic and mafic rocks, the Santa Elena Nappe; 2) an autochthonous basaltic sedimentary suite, resting immediately below the overthrust, the Santa Rosa Accretionary Complex; and 3) Islas Murciélago pillow and massive basaltic flows. In the Santa Elena Nappe three petrological affinities have been recognized: 1) the ultramafic complex, that corresponds to depleted (MORB-like) mantle serpentinizated peridotites, with very low TiO2 and high Ni and Cr; 2) the pegmatitic gabbros, layered gabbros and plagiogranites and basaltic dikes with low TiO2 (0.89%). These mafic associations have geochemical signatures that suggest an island arc origin and petrographic evidences of low grade metamorphism and hydrothermal alteration. The Santa Rosa Accretionary Complex includes pelagic and volcanoclastic sediments, tuffs and alkaline magmatic rocks, originated by low degree melting of enrichment OIB mantle source, and probably related with seamount portions incorporated into the accretionary prism. Islas Murciélago pillow and massive basalts show no clear structural relationship with the rest of the units, but are geochemically similar to the dolerites of the Santa Elena Nappe. Sr, Nd, and Pb isotopic ratios of the Santa Elena Nappe and the Santa Elena Accretionary Complex samples do not correspond to the Galapagos Mantle array, and have different mantle reservoirs and geochemical characteristics than the Nicoya Complex

Temperature-controlled laminar airflow in severe asthma for exacerbation reduction (The LASER Trial):study protocol for a randomised controlled trial

Background: Asthma affects more than 5 million patients in the United Kingdom. Nearly 500,000 of these patients have severe asthma with severe symptoms and frequent exacerbations that are inadequately controlled with available treatments. The burden of severe asthma on the NHS is enormous, accounting for 80 % of the total asthma cost (£1 billion), with frequent exacerbations and expensive medications generating much of this cost.Of those patients with severe asthma, 70 % are sensitised to indoor aeroallergens, and the level of exposure to allergens determines the symptoms; patients exposed to high levels are therefore most at risk of exacerbations and hospital admissions.The LASER trial aims to assess whether a new treatment, temperature controlled laminar airflow (TLA) delivered by the Airsonett™ device, can reduce the frequency of exacerbations in patients with severe allergic asthma by reducing exposure to aeroallergens overnight.Methods: This multicentre study is a placebo-controlled, blinded, randomised controlled, parallel group trial. A total of 222 patients with a new or current diagnosis of severe allergic asthma will be assigned with a random element in a 1:1 ratio to receive either an active device for one year or a placebo device. The primary outcome is the frequency of severe asthma exacerbations occurring over a 12-month period, defined in accordance with the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. Secondary outcomes include changes in asthma control, lung function, asthma-specific and global quality of life for participants and their carers, adherence to intervention, healthcare resource use and costs, and cost-effectiveness. Qualitative interviews will be conducted to elicit participant’s and their partner’s perceptions of the treatment.Discussion: Effective measures of allergen avoidance have, to date, proved elusive. The LASER trial aims to address this. The study will ascertain whether home-based nocturnal TLA usage over a 12-month period can reduce the frequency of exacerbations and improve asthma control and quality of life as compared to placebo, whilst being cost-effective and acceptable to adults with poorly controlled, severe allergic asthma. The results of this study will be widely applicable to the many patients with allergic asthma both in the UK and internationally.Trial registration: Current controlled trials ISRCTN46346208 (Date assigned 22 January 2014).<br/

Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era.

BACKGROUND: The UK Severe Asthma Registry (UKSAR) is the world's largest national severe asthma registry collecting standardised data on referrals to UK specialist services. Novel biologic therapies have transformed the management of type 2(T2)-high severe asthma but have highlighted unmet need in patients with persisting symptoms despite suppression of T2-cytokine pathways with corticosteroids. METHODS: Demographic, clinical and treatments characteristics for patients meeting European Respiratory Society / American Thoracic Society severe asthma criteria were examined for 2225 patients attending 15 specialist severe asthma centres. We assessed differences in biomarker low patients (fractional exhaled nitric oxide (FeNO) <25 ppb, blood eosinophils <150/μL) compared with a biomarker high population (FeNO ≥25 ppb, blood eosinophils ≥150/µL). RESULTS: Age (mean 49.6 (14.3) y), age of asthma onset (24.2 (19.1) y) and female predominance (62.4%) were consistent with prior severe asthma cohorts. Poor symptom control (Asthma Control Questionnaire-6: 2.9 (1.4)) with high exacerbation rate (4 (IQR: 2, 7)) were common despite high-dose treatment (51.7% on maintenance oral corticosteroids (mOCS)). 68.9% were prescribed biologic therapies including mepolizumab (50.3%), benralizumab (26.1%) and omalizumab (22.6%). T2-low patients had higher body mass index (32.1 vs 30.2, p<0.001), depression/anxiety prevalence (12.3% vs 7.6%, p=0.04) and mOCS use (57.9% vs 42.1%, p<0.001). Many T2-low asthmatics had evidence of a historically elevated blood eosinophil count (0.35 (0.13, 0.60)). CONCLUSIONS: The UKSAR describes the characteristics of a large cohort of asthmatics referred to UK specialist severe asthma services. It offers the prospect of providing novel insights across a range of research areas and highlights substantial unmet need with poor asthma control, impaired lung function and high exacerbation rates. T2-high phenotypes predominate with significant differences apparent from T2-low patients. However, T2-low patients frequently have prior blood eosinophilia consistent with possible excessive corticosteroid exposure

A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial

Background: Patients with difficult-to-control asthma consume 50–60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called ‘T2-low asthma’ and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy.Methods/design: Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers.Discussion: Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct.Trial registration: ClinicalTrials.gov, NCT02717689. Registered on 16 March 2016

Effect of benralizumab in a patient with uncontrolled severe eosinophilic asthma and comorbid chronic rhinosinusitis with nasal polyps refractory to mepolizumab treatment.

Severe eosinophilic asthma is associated with a high corticosteroid burden, particularly in patients with comorbid chronic sinusitis/nasal polyps. This case study reports a 33-year-old woman who presented to the severe asthma center with uncontrolled severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Despite maximized asthma treatment, including maintenance oral corticosteroids (OCS) for 7 years, the patient experienced one to two hospitalizations per year, had daily symptoms that substantially impacted her quality of life, and elevated type 2 inflammatory markers (blood eosinophils, 0.72 × 10/L; fractional exhaled nitric oxide, 134 to 300 parts per billion). Her asthma worsened during her first pregnancy, in which she required five hospital admissions despite treatment with maintenance OCS. Mepolizumab treatment was commenced after pregnancy but showed limited efficacy (blood eosinophil levels up to 0.94 × 10/L); treatment was discontinued because of a second pregnancy. The patient's asthma worsened and resulted in four hospitalizations and an increase in monthly OCS dose. Mepolizumab was recommenced after pregnancy, but her asthma remained uncontrolled, symptoms persisted, and one hospitalization and nine OCS courses were required. The patient was switched to benralizumab treatment when it became available. Although her CRSwNP symptoms remained, benralizumab treatment resulted in a marked improvement in asthma control, zero hospitalizations, and suppressed blood eosinophil levels. Notably, the patient was successfully weaned off maintenance OCS after >11 years of treatment. In summary, these findings support the use of benralizumab as a corticosteroid-sparing treatment option in difficult-to-treat severe eosinophilic asthma refractory to mepolizumab treatment

Disconnect of type 2 biomarkers in severe asthma; dominated by FeNO as a predictor of exacerbations and periostin as predictor of reduced lung function.

BACKGROUND biomarkers of Type 2 (T2) inflammation may predict asthma control and exacerbation risk. However, the relationships between individual T2 biomarkers to exacerbations and lung function in severe asthma remain uncertain. OBJECTIVES to explore the roles played by T2 biomarkers individually and as a composite score in predicting clinical outcomes in severe asthma. METHODS unselected severe asthma patients were enrolled in this cross sectional real life study. Participants were clinically characterised and the following measurements were obtained: the frequency of exacerbations requiring oral corticosteroids (OCS), asthma control (Juniper ACQ6-7), lung function, Fraction exhaled Nitric Oxide (FeNO), peripheral blood eosinophils (PBE), and serum periostin. RESULTS A total of 115 patients were recruited [mean age 45 years (range 18-70), 80 (69.6%) females, mean forced expiratory volume in first second (FEV) %predicted was 68% ± 24.7, mean inhaled corticosteroids (ICS) 1.96 ± 0.82 mg/day. FeNO correlated significantly with PBE (r = 0.35, p = 0.0004), but not with periostin (r = 0.22, p = 0.065) and there was no significant correlation between PBE and periostin. FeNO correlation with exacerbations (r = 0.42, p = 0.0008) was stronger than PBE and periostin. A composite score of the 3 biomarkers correlated with exacerbations in a dose-dependent manner but multiple regression analysis did not confirm an added benefit. Only periostin demonstrated a significant correlation with FEV%predicted (r = -0.34, p = 0.004) with ROC-AUC 0.7. CONCLUSION FeNO demonstrated stronger correlation with asthma exacerbations than PBE or periostin with no definite added benefit from a composite score of the 3 biomarkers. Only periostin showed significant association with reduced lung function raising its potential as a biomarker of airway remodeling