A systematic review of methods of scoring inhaler technique.

Many inhaler devices are currently used in clinical practice to deliver medication, with each inhaler device offering different benefits to overcome technique issues. Inhaler technique remains poor, contributing to reduced airway drug deposition and consequently poor disease control. Scoring inhaler technique has been used within research as an outcome measure of inhaler technique assessment, and this systematic review collates and evaluates these scoring methods. The review protocol was prospectively registered in PROSPERO (CRD42020218869). A total of 172 articles were screened with 77 included, and the results presented using narrative synthesis due to the heterogeneity of the study design and data. The most frequently used scoring method awarded one point per step in the inhaler technique checklist and was included in 59/77 (77%) of articles; however limited and varied guidance was provided for score interpretation. Other inhaler technique scoring methods included grading the final inhaler technique score, expressing the total score as a percentage/ratio, deducting points from the final score when errors were made, and weighting steps within the checklist depending on how crucial the step was. Vast heterogeneity in the number of steps and content in the inhaler technique checklists was observed across all device types (range 5-19 steps). Only 4/77 (5%) of the inhaler technique measures had undertaken fundamental steps required in the scale development process for use in real world practice. This review demonstrates the demand for a tool that measures inhaler technique and highlights the current unmet need for one that has undergone validation.

Temperature-controlled Laminar Airflow (TLA) in symptomatic severe asthma - a post hoc analysis of severe exacerbations, quality of life and health economics.

PURPOSE: Uncontrolled severe asthma constitutes a major economic burden to society. Add-ons to standard inhaled treatments include inexpensive oral corticosteroids and expensive biologics. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA; Airsonett®) could be an effective, safe and cheaper alternative. The potential of TLA in reducing severe asthma exacerbations was addressed in a recent randomised placebo-controlled trial (RCT) in patients with severe asthma (Global Initiative for Asthma (GINA) step 4/5), but the results were inconclusive. We re-analysed the RCT with severe exacerbations stratified by the level of baseline asthma symptoms and Quality of Life. METHODS: More uncontrolled patients, defined by Asthma Control Questionnaire 7 (ACQ7) > 3, EuroQoL 5-Dimension Questionnaire Visual Analogue Scale (EQ5D-VAS) ≤ 65 and Asthma Quality of Life Questionnaire (AQLQ) ≤ 4 were selected for re-analysis. The rates of severe asthma exacerbations, changes in QoL and health-economics were analysed and compared between TLA and placebo. RESULTS: The study population included 226 patients (113 TLA / 113 placebo.) The rates of severe asthma exacerbations were reduced by 33, 31 and 25% (p = 0.083, 0.073, 0.180) for TLA compared to placebo, dependent on selected control measures (ACQ7, EQ5D-VAS, AQLQ, respectively). For patients with less control defined by AQLQ≤4, the difference in mean AQLQ0-12M between TLA and placebo was 0.31, 0.33, 0.26 (p = 0.085, 0.034, 0.150), dependent on selected covariate (AQLQ, EQ5D-VAS, ACQ7, respectively). For patients with poor control defined by ACQ7 > 3, the difference in EQ5D-5 L utility scores between TLA and placebo was significant at 9 and 12 months with a cost-effective ICER. The results from the original study did not demonstrate these differences. CONCLUSION: This post hoc analysis demonstrated an effect of TLA over placebo on severe exacerbations, asthma control and health economics in a subgroup of patients with more symptomatic severe allergic asthma. The results are consistent with the present recommendations for TLA. However, these differences were not demonstrated in the full study. Several explanations for the different outcomes have been outlined, which should be addressed in future studies. FUNDING: NIHR Health Technology Assessment Programme and Portsmouth Hospitals NHS Trust.

Effect of nocturnal Temperature-controlled Laminar Airflow on the reduction of severe exacerbations in patients with severe allergic asthma: a meta-analysis.

Background: Allergen avoidance is important in allergic asthma management. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA) has been shown to provide a significant reduction in the exposure to allergens in the breathing zone, leading to a long-term reduction in airway inflammation and improvement in Quality of life (QoL). Allergic asthma patients symptomatic on Global Initiative for Asthma (GINA) step 4/5 were found to benefit the most as measured by Asthma Quality of Life Questionnaire (AQLQ). However, the effect of TLA on severe asthma exacerbations is uncertain and therefore a meta-analysis was performed. Methods: Patients with severe allergic asthma (GINA 4/5) were extracted from two 1-year randomised, double-blind, placebo-controlled trials conducted with TLA. A meta-analysis of the effect on severe exacerbations was performed by negative binomial regression in a sequential manner, defined by baseline markers of asthma control (symptoms and QoL scores). Results: The pooled dataset included 364patients. Patients with more symptoms at baseline (ACT<18 or ACQ7>3; N=179), had a significant mean 41% reduction in severe exacerbations (RR=0.59 (0.38-0.90); p=0.015) in favour of TLA. Higher ACQ7 cut-points of 3.5-4.5 resulted in significant reductions of 48-59%.More uncontrolled patients based on AQLQ total and symptom domains ≤3.0 at baseline also showed a significant reduction in severe exacerbations for TLA vs. placebo ((47% (p=0.037) and 53% (p=0.011), respectively). The meta-analysis also confirmed a significant difference in AQLQ-responders ((Minimal Clinically Important Difference)≥0.5; 74% vs. 43%, p=0.04). Conclusion: This meta-analysis of individual patient data shows a beneficial effect on severe exacerbations and quality of life for TLA over placebo in more symptomatic patients with severe allergic asthma. These outcomes support the national management recommendations for patients with symptomatic severe allergic asthma. The actual effect of TLA on severe exacerbations should be confirmed in a prospective study with larger numbers of patients.

Managing complex respiratory patients in the community: an evaluation of a pilot integrated respiratory care service.

INTRODUCTION: In the UK, there is significant variation in respiratory care and outcomes. An integrated approach to the management of high-risk respiratory patients, incorporating specialist and primary care teams' expertise, is the basis for new integrated respiratory services designed to reduce this variation; however, this model needs evaluating. METHODS: To evaluate an integrated service managing high-risk respiratory patients, electronic searches for patients with asthma and chronic obstructive pulmonary disease at risk of poor outcomes were performed in two general practitioner (GP) practices in a local service-development initiative. Patients were reviewed at joint clinics by primary and secondary care professionals. GPs also nominated patients for inclusion. Reviews were delivered to best standards of care including assessments of diagnosis, control, spirometry, self-management, education, medication, inhaler technique and smoking cessation support. Follow-up of routine clinical data collected at 9-months postclinic were compared with seasonally matched 9-months prior to integrated review. RESULTS: 82 patients were identified, 55 attended. 13 (23.6%) had their primary diagnosis changed. In comparison with the seasonally adjusted baseline period, in the 9-month follow-up there was an increase in inhaled corticosteroid prescriptions of 23.3%, a reduction in short-acting ß2-agonist prescription of 33.3%, a reduction in acute respiratory exacerbations of 67.6%, in unscheduled GP surgery visits of 53.3% and acute respiratory hospital admissions reduced from 3 to 0. Only 4 patients (7.3%) required referral to secondary care. Health economic evaluation showed respiratory-related costs per patient reduced by £231.86. CONCLUSIONS: Patients with respiratory disease in this region at risk of suboptimal outcomes identified proactively and managed by an integrated team improved outcomes without the need for hospital referral.

Tuberculous syringomyelia in an HIV-infected patient: a case report.

A 37-year-old HIV-positive Gambian woman presented with spastic weakness of the right leg six years after receiving treatment for tuberculous meningitis (TBM). Magnetic resonance imaging (MRI) of the spine showed a multiloculated syrinx in the thoracic spinal cord extending from the T2 to the T11 level. Syringomyelia and syringobulbia have been reported as complications of TBM. We describe the first case of syringomyelia as an uncommon late complication of treated TBM in the setting of HIV infection. Early recognition of this rare entity may avoid irreversible neurological sequelae.

Weekend admission and mortality from acute exacerbations of chronic obstructive pulmonary disease in winter.

Historically, acute medical staffing numbers have been lower on weekends and in winter numbers of medical admissions rise. An analysis of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) admissions to Portsmouth Hospitals over a seven-year period was undertaken to examine the effects of admission on a weekend, of winter, and with the opening of a medical admissions unit (MAU). In total, 9,915 admissions with AECOPD were identified. Weekend admissions accounted for 2,071 (20.9%) of cases, winter accounted for 3,026 (30.5%) admissions, and 522 (34.4%) deaths. Adjusted odds ratio (OR) for death on day 1 after winter weekend admission was 2.89 (95% confidence interval (CI) 1.035 to 8.076). After opening the MAU, the OR for death day 1 after weekend winter admission fell from 3.63 (95% CI 1.15 to 11.5) to 1.65 (95% CI 0.14 to 19.01). AECOPD patients have an increased risk of death after admission over a weekend in winter and this effect was reduced by opening a MAU. These findings have implications for the planning of acute care provision in different seasons.

Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids.

BACKGROUND: There is evidence of activation of the extrinsic coagulation cascade in the asthmatic airway, and both plasma and locally derived factors may be involved. The hypothesis that the normal haemostatic balance of healthy airways sampled by sputum induction favours fibrin formation in asthmatic airways, and that inhaled corticosteroids (ICS) and plasma exudation influence this balance, was tested. METHODS: ELISA and activity assays were used to measure alpha(2)-macroglobulin (an index of plasma leakage) and coagulation factors in hypertonic saline-induced sputum of 30 stable subjects (10 controls, 10 with moderate asthma and 10 with severe asthma). Additionally, the moderate cohort were weaned off their ICS, followed by further sputum induction 5 days after cessation of steroids. RESULTS: ICS wean induced a significant rise in plasminogen (median (interquartile range (IQR)): 13.92 (6.12-16.17) vs 4.82 (2.14-13.32) ng/ml; 95% CI 0.003 to 8.596, p = 0.0499) and tissue plasminogen activator (tPA; 5.57 (3.57-14.35) vs 3.88 (1.74-4.05) ng/ml; 95% CI 0.828 to 9.972, p = 0.0261) levels in sputum, such that tPA in untreated moderate asthma was significantly (p = 0.0029) higher than normal (2.14 (0.0-2.53) ng/ml). Subjects with severe asthma had significantly more alpha(2)-macroglobulin (p = 0.0003), tissue factor (p = 0.023), plasminogen activator inhibitor (p = 0.0091), thrombin-activatable fibrinolysis inhibitor (p = 0.0031) and fibrin degradation products (p = 0.0293) in their sputum than control subjects. CONCLUSION: Untreated moderate asthma is associated with increased fibrinolysis that is corrected by ICS. Severe asthma and high dose corticosteroid therapy is associated with a profibrinogenic, antifibrinolytic environment in the airways. This study suggests that inhibition of fibrin deposition in severe asthma may be a therapeutic approach.

The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial.

AIM: Tumour necrosis factor alpha (TNFalpha) is a cytokine recognised as a therapeutic target in chronic inflammatory diseases. METHODS: A randomised, double blind, placebo controlled parallel group trial is reported of etanercept (an IgG1-TNF p75 receptor fusion protein), administered once weekly for 12 weeks in 39 patients with severe corticosteroid refractory asthma. Efficacy was measured by change from the pretreatment baseline in Asthma Related Quality of Life (AQLQ) and Asthma Control (ACQ) Questionnaire scores (the primary endpoints), lung function, peak expiratory flow (PEF) and bronchial hyperresponsiveness (BHR). Sputum and serum inflammatory cells and cytokines, serum albumin and C reactive protein (CRP) as biomarkers of inflammation were also assessed. RESULTS: There was a small but significant difference in reduction of ACQ scores between treatment and placebo (-1.11 (95% CI -1.56 to -0.75) and -0.52 (95% CI -0.97 to -0.07), respectively, p = 0.037). There was no significant difference in improvements in AQLQ scores, lung function, PEF, BHR or exacerbation rates between the groups. Minor adverse events, including injection site pain and skin rashes, were more frequent with etanercept. There was a significant reduction in sputum macrophages and CRP, and increases in serum TNFalpha and albumin following treatment, but not in other laboratory parameters. CONCLUSION: Etanercept therapy over 12 weeks demonstrated only a small but significant improvement in asthma control and systemic inflammation, as measured by serum albumin and CRP. Larger randomised, placebo controlled trials are required to clarify the role of TNFalpha antagonism in subjects with severe refractory asthma.

Increased frequency of detection of Chlamydophila pneumoniae in asthma.

Previous studies have suggested that chronic Chlamydophila pneumoniae infection may play a role in the pathogenesis of asthma. However, most studies have been based on serology and have been unable to differentiate acute from chronic infection. The present authors assessed the presence of acute and chronic C. pneumoniae infection in 74 spouse pairs, each consisting of one atopic asthmatic and one nonatopic nonasthmatic. Nasal secretions were sampled every 2 weeks from October to December and actively replicating C. pneumoniae infection was detected by specific RT-PCR. C. pneumoniae was detected in 31 out of 709 samples analysed, 23 (6.4%) were positive in 362 samples from asthmatic participants and in eight out of 347 (2.3%) samples from their normal spouses (with a significant difference in infection rates, 95% confidence interval: 4.2%, 1.2-7.2%). A total of 16 (22%) asthmatic and seven (9%) normal participants were positive at least once during the study. These data confirm that Chlamydophila pneumoniae infection is detected more frequently among asthmatic participants than normal control participants. Further studies are required to confirm whether infections are also present in the lower airway and whether Chlamydophila pneumoniae infection plays a role in disease pathogenesis.

Personal exposure to nitrogen dioxide (NO2) and the severity of virus-induced asthma in children.

BACKGROUND: A link between exposure to the air pollutant nitrogen dioxide (NO2) and respiratory disease has been suggested. Viral infections are the major cause of asthma exacerbations. We aimed to assess whether there is a relation between NO2 exposure and the severity of asthma exacerbations caused by proven respiratory viral infections in children. METHODS: A cohort of 114 asthmatic children aged between 8 and 11 years recorded daily upper and lower respiratory-tract symptoms, peak expiratory flow (PEF), and measured personal NO2 exposures every week for up to 13 months. We took nasal aspirates during reported episodes of upper respiratory-tract illness and tested for infection by common respiratory viruses and atypical bacteria with RT-PCR assays. We used generalised estimating equations to assess the relation between low (<7.5 microg/m3), medium (7.5-14 microg/m3 ), and high (>14 microg/m3) tertiles of NO2 exposure in the week before or after upper respiratory-tract infection and the severity of asthma exacerbation in the week after the start of an infection. FINDINGS: One or more viruses were detected in 78% of reported infection episodes, and the medians of NO2 exposure were 5 (IQR 3.6-6.3), 10 (8.7-12.0), and 21 microg/m3 (16.8-42.9) for low, medium, and high tertiles, respectively. There were significant increases in the severity of lower respiratory-tract symptom scores across the three tertiles (0.6 for all viruses [p=0.05] and >2 for respiratory syncytial virus [p=0.01]) and a reduction in PEF of more than 12 L/min for picornavirus (p=0.04) for high compared with low NO2 exposure before the start of the virus-induced exacerbation. INTERPRETATION: High exposure to NO2 in the week before the start of a respiratory viral infection, and at levels within current air quality standards, is associated with an increase in the severity of a resulting asthma exacerbation.

Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection.

BACKGROUND: Several studies have linked air pollution by nitrogen dioxide (NO(2)) with increased hospital admissions for asthma in children. Exacerbations of asthma in children are often precipitated by upper respiratory infections. It is therefore possible that NO(2) increases the risk of airways obstruction when asthmatic children develop upper respiratory infections. METHODS: To test this hypothesis a sample of 114 asthmatic children aged 7-12 years were followed for a total of up to 13 months. Probable upper respiratory infections were identified by consensus review of daily symptom diaries, and episodes of airways obstruction from serial records of peak expiratory flow (PEF). Personal exposures to NO(2) were measured with Palmes tubes that were changed weekly. Generalised estimating equations were used to assess the relative risk (RR) of an asthmatic exacerbation starting within seven days of an upper respiratory infection according to estimated NO(2) exposure during the one week period from two days before to four days after the onset of the infection. RESULTS: The children were followed for an average of 34 weeks during which 318 upper respiratory infections and 224 episodes of reduced PEF were diagnosed. PEF episodes were much more likely to occur in the seven days following the onset of an upper respiratory infection than at other times. Estimated exposures to NO(2) at the time of infections were generally low (geometric mean 10.6 microg/m(3)). Compared with exposures of < or = 8 microg/m(3), exposures of >28 microg/m(3) were associated with a RR of 1.9 (95% confidence interval 1.1 to 3.4) for the development of an asthmatic episode within seven days of an infection. CONCLUSIONS: The findings give some support to the hypothesis that NO(2) increases the risk of asthmatic exacerbations following respiratory infections, even at relatively low levels of exposure. Further studies in populations with higher exposures would be useful.

Personal exposures of children to nitrogen dioxide relative to concentrations in outdoor air.

OBJECTIVES: To investigate the relation between fluctuations in personal exposure to nitrogen dioxide (NO(2)) in school children and changes in outdoor NO(2) concentrations. METHODS: 114 Asthmatic school children aged 7-12 years were recruited from the Southampton area. Weekly average personal exposures to NO(2) were measured over a 13 month period with passive diffusion tubes. At the same time, outdoor NO(2) concentrations were monitored at a fixed site in the centre of Southampton. Correlations between weekly personal exposures and mean outdoor concentrations during the same periods were examined. RESULTS: Mean duration of follow up was 32 weeks. Measurements of weekly mean personal NO(2) exposures were generally low and ranged from 2.47 to 1751 [corrected] micrograms/m(3) with a geometric mean of 60 [corrected] micrograms/m(3). Substantial variation in personal exposures occurred between children and more especially within individual children from week to week. Daily outdoor concentrations of NO(2) ranged from 15.2 to 105.2 [corrected] micrograms/m(3), with a geometric mean of 43.4 [corrected] micrograms/m(3). There was no evidence of seasonal variation in outdoor concentrations. No significant correlation was found between each child's weekly mean personal exposures to NO(2) and mean outdoor concentrations for the corresponding periods. CONCLUSION: At low outdoor NO(2) concentrations, fluctuations in NO(2) in outdoor air as measured at a central monitoring station do not contribute importantly to variations in personal exposure when averaged over a week.

Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study.

We examined the feasibility of using induced sputum to evaluate the airway inflammatory response to natural acute respiratory virus infections. We recruited eight asthmatics and nine healthy subjects on Day 4 of a cold. Viral infection was confirmed in six of the asthmatics (influenza A or B) and six of the healthy subjects (influenza A, rhinovirus, adenovirus, respiratory syncytial virus, and coronavirus). In the subjects with confirmed virus infection, five of the asthmatics had an objective exacerbation of asthma during the cold. Their sputum on Day 4 showed a high median total cell count of 19.7 x 10(6) cells/ml with a modest neutrophilia (58. 5%) and high levels of interleukin-8 (IL-8) (16,000 pg/ml), eosinophilic cationic protein (ECP) (1,880 microgram/L) and very high levels of fibrinogen (250 mg/L). In contrast, the proportion (1.3%) and absolute number of eosinophils was low. IL-2 levels were within the normal range, whereas IL-5 and interferon gamma were under the limit of detection of the assays. In the healthy subjects with a confirmed virus infection the sputum findings were qualitatively similar but significantly less prominent. Sputum IL-8 on Day 4 was strongly correlated with neutrophils (rs = 0.8, p < 0.001). This correlation was also significant when each group was analyzed separately. On Day 21 there was a fall in the absolute number of neutrophils and in ECP and fibrinogen levels in both groups. Similar results were found in the two asthmatic and three healthy subjects with a cold of comparable severity but in whom viral infection was not confirmed. We conclude that induced sputum examination can be used to study the effects of natural colds and influenza on the airways of the lungs. The results also suggest that natural colds, on Day 4, cause neutrophilic lower airway inflammation that is greater in asthmatics than in healthy subjects. The greater inflammatory response in asthmatics may be due to the changes associated with trivial eosinophilia or to the different viruses involved.

Toxicological mechanisms underlying oxidant pollutant-induced airway injury.

The health effect of atmospheric pollution is causing increasing public concern. Several controlled human-exposure studies have clearly. shown that oxidant pollutants, including ozone, nitrogen dioxide, and diesel exhaust, induce an acute inflammatory response in human airways. The main component of this response involves the influx of polymorphonuclear leukocytes (PMN) and is mediated via the upregulation of transcription factors NF-kappa B, AP-1, and NF-IL6; leukocyte-endothelial adhesion molecules, and chemokine secretion, including IL-8 and Gro-alpha. The results of recent studies also suggest that short-term exposure to ozone leads to neurogenic inflammation by causing damage to the bronchial epithelium and stimulating subepithelial sensory nerves to release substance P. In addition, such exposures lead to the consumption of endogenous antioxidants that are present in the airway lining fluid. Studies in asthmatics have shown that oxidant pollutants, including ozone and nitrogen dioxide, induce PMN influx in the airways and potentiate responses to inhaled aero-allergens. This article will review various studies addressing the toxicological mechanisms underlying oxidant pollutant-induced airways injury.

Exposure to nitrogen dioxide (NO2) and respiratory disease risk.

Epidemiological evidence suggests that exposure to nitrogen dioxide (NO2) through the use of unvented gas cookers in homes is associated with respiratory symptoms. Toxicological evidence, mainly in animal models, suggests that NO2 may increase the susceptibility to infection by viruses and bacteria. This review examines the evidence and proposes mechanisms whereby such exposure may occur, in particular how NO2 may aggravate respiratory symptoms in the presence of coexistent infection.

Development and application of a general purpose ambulatory monitor.

This paper details the development and application of a multi-channel, general purpose, lightweight, portable monitor. The monitor is constructed with separate analogue and digital circuitry so that a dedicated analogue board may be developed for each new application with the same general purpose digital board, the latter requiring only changes to the firmware. At the heart of the digital circuit is an Arizona Microchip PIC 16C64 microcontroller, which can communicate with a computer via a serial port and perform both simple and relatively complex data analysis prior to storing data in memory. The low-power design enables the circuit to operate for potentially longer than a week on one set of batteries. Designed with medical applications in mind, preliminary data from three studies utilising the monitor are described. These include measurements of bladder pressure, personal exposure to pollutant gases and body temperature. The studies demonstrate the system's versatility in a variety of investigations requiring different signal processing and sampling protocols. It is hoped that, in the future, this ambulatory device will contribute to the diagnosis, treatment and understanding of a wide variety of disease conditions.

Molecular mediators of asthma: current insights.

With advances in molecular biology, the complex inflammatory events that underlie asthma are being unraveled. The players are diverse, involving two populations each of mast cells and helper T cells, eosinophils, bronchial endothelial and epithelial cells, and an array of vasoactive and bronchoactive mediators. The clinical message is already clear: Treat the inflammation early.