Effectiveness of myAirCoach: A mHealth Self-Management System in Asthma.

BACKGROUND: Self-management programs have beneficial effects on asthma control, but their implementation in clinical practice is poor. Mobile health (mHealth) could play an important role in enhancing self-management. OBJECTIVE: To assess the clinical effectiveness and technology acceptance of myAirCoach-supported self-management on top of usual care in patients with asthma using inhalation medication. METHODS: Patients were recruited in 2 separate studies. The myAirCoach system consisted of an inhaler adapter, an indoor air-quality monitor, a physical activity tracker, a portable spirometer, a fraction exhaled nitric oxide device, and an app. The primary outcome was asthma control; secondary outcomes were exacerbations, quality of life, and technology acceptance. In study 1, 30 participants were randomized to either usual care or myAirCoach support for 3 to 6 months; in study 2, 12 participants were provided with the myAirCoach system in a 3-month before-after study. RESULTS: In study 1, asthma control improved in the intervention group compared with controls (Asthma Control Questionnaire difference, 0.70; P = .006). A total of 6 exacerbations occurred in the intervention group compared with 12 in the control group (hazard ratio, 0.31; P = .06). Asthma-related quality of life improved (mini Asthma-related Quality of Life Questionnaire difference, 0.53; P = .04), but forced expiratory volume in 1 second was unchanged. In study 2, asthma control improved by 0.86 compared with baseline (P = .007) and quality of life by 0.16 (P = .64). Participants reported positive attitudes toward the system. DISCUSSION: Using the myAirCoach support system improves asthma control and quality of life, with a reduction in severe asthma exacerbations. Well-validated mHealth technologies should therefore be further studied.

The topical study of inhaled drug (salbutamol) delivery in idiopathic pulmonary fibrosis.

BACKGROUND: Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF). METHODS: The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99mTechnetium-labelled monodisperse salbutamol (1.5 µm or 6 µm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 µg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4). RESULTS: Small monodisperse particles (1.5 µm) achieved significantly better total lung deposition (TLD, mean % ± SD) than larger particles (6 µm), where polydisperse nebulisation was poor; (TLD, 64.93 ± 10.72; 50.46 ± 17.04; 8.19 ± 7.72, respectively). Small monodisperse particles (1.5 µm) achieved significantly better lung penetration (mean % ± SD) than larger particles (6 µm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean ± SD) 0.8 ± 0.16, 0.49 ± 0.21, and 0.73 ± 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 µm and 6 µm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation. CONCLUSION: Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF. TRIAL REGISTRATION: This trial was registered on clinicaltrials.gov ( NCT01457261 ).

MyAirCoach: the use of home-monitoring and mHealth systems to predict deterioration in asthma control and the occurrence of asthma exacerbations; study protocol of an observational study.

INTRODUCTION: Asthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations and increased morbidity and mortality rates. The ability to determine and to predict levels of asthma control and the occurrence of exacerbations is crucial in asthma management. Therefore, we aimed to determine to what extent physiological, behavioural and environmental data, obtained by mobile healthcare (mHealth) and home-monitoring sensors, as well as patient characteristics, can be used to predict episodes of uncontrolled asthma and the onset of asthma exacerbations. METHODS AND ANALYSIS: In an 1-year observational study, patients will be provided with mHealth and home-monitoring systems to record daily measurements for the first-month (phase I) and weekly measurements during a follow-up period of 11 months (phase II). Our study population consists of 150 patients, aged ≥18 years, with a clinician's diagnosis of asthma, currently on controller medication, with uncontrolled asthma and/or minimally one exacerbation in the past 12 months. They will be enrolled over three participating centres, including Leiden, London and Manchester. Our main outcomes are the association between physiological, behavioural and environmental data and (1) the loss of asthma control and (2) the occurrence of asthma exacerbations. ETHICS: This study was approved by the Medical Ethics Committee of the Leiden University Medical Center in the Netherlands and by the NHS ethics service in the UK. TRIAL REGISTRATION NUMBER: NCT02774772.

The effect of body weight on distal airway function and airway inflammation.

BACKGROUND/OBJECTIVES: Obesity is a global health problem that adversely influences the respiratory system. We assessed the effects of body mass index (BMI) on distal airway function and airway inflammation. SUBJECTS/METHODS: Impulse oscillometry (IOS) as a measure of distal airway function, together with spirometry, were assessed in adults with a range of different BMIs. Airway inflammation was assessed with the fraction of exhaled nitric oxide (FeNO) and participants exhaled at various exhalation flows to determine alveolar and bronchial NO. RESULTS: In total 34 subjects were enrolled in the study; 19 subjects had a normal BMI (18.50-24.99), whilst 15 subjects were overweight (BMI 25.00-29.99), or obese (BMI ≥30). All subjects had normal spirometry. However, IOS measures of airway resistance (R) at 5Hz, 20Hz and frequency dependence (R5-20) were elevated in overweight/obese individuals, compared to subjects with a normal BMI (median (interquartile range)); 5Hz: 0.41 (0.37, 0.45) vs. 0.32 (0.30, 0.37)kPa/l/s; 20Hz: 0.34 (0.30, 0.37) vs. 0.30 (0.26, 0.33)kPa/l/s; R5-20: 0.06 (0.04, 0.11) vs. 0.03 (0.01, 0.05)kPa/l/s; p<0.05), whereas airway reactance at 20Hz was decreased in overweight/obese individuals (20Hz: 0.07 (0.03, 0.09) vs. 0.10 (0.07, 0.13)kPa/l/s, p=0.009; 5Hz: -0.12 (-0.15, -0.10) vs. -0.10 (-0.13, -0.09)kPa/l/s, p=0.07). In contrast, within-breath IOS measures (a sign of expiratory flow limitation) and FeNO inflammatory measures, did not differ between groups (p>0.05). CONCLUSIONS: Being overweight has significant effects on distal and central airway function as determined by IOS, which is not detected by spirometry. Obesity does not influence airway inflammation as measured by FeNO. IOS is a reliable technique to identify airway abnormalities in the presence of normal spirometry in overweight people.

Oscillating Positive Expiratory Pressure on Respiratory Resistance in Chronic Obstructive Pulmonary Disease With a Small Amount of Secretion: A Randomized Clinical Trial.

This study aims to evaluate the acute effects of an oscillating positive expiratory pressure device (flutter) on airways resistance in patients with chronic obstructive pulmonary disease (COPD).Randomized crossover study: 15 COPD outpatients from Asthma Lab-Royal Brompton Hospital underwent spirometry, impulse oscillometry (IOS) for respiratory resistance (R) and reactance (X), and fraction exhaled nitric oxide (FeNO) measures.Thirty minutes of flutter exercises: a "flutter-sham" procedure was used as a control, and airway responses after a short-acting bronchodilator were also assessed.Respiratory system resistance (R): in COPD patients an increase in X5insp (-0.21 to -0.33 kPa/L/s) and Fres (24.95 to 26.16 Hz) occurred immediately after flutter exercises without bronchodilator. Following 20 min of rest, a decrease in the R5, ΔR5, R20, X5, and Ax was observed, with R5, R20, and X5 values lower than baseline, with a moderate effect size; there were no changes in FeNO levels or spirometry.The use of flutter can decrease the respiratory system resistance and reactance and expiratory flow limitation in stable COPD patients with small amounts of secretions.

A novel approach to partition central and peripheral airway nitric oxide.

BACKGROUND: Determining the site of airways inflammation may lead to the targeting of therapy. Nitric oxide (NO) is a biomarker of airway inflammation and can be measured at multiple exhalation flow rates to allow partitioning into bronchial (large/central airway maximal nitric oxide flux [J'awno]) and peripheral (peripheral/small airway/alveolar nitric oxide concentration [Cano]) airway contributions by linear regression. This requires a minimum of three exhalations. We developed a simple and practical method to partition NO. METHODS: In 29 healthy subjects (FEV1, 97% ± 3% predicted), 13 patients with asthma (FEV1, 90% ± 4% predicted), 14 patients with COPD (FEV1, 59% ± 3% predicted), and 12 patients with cystic fibrosis (CF) (FEV1, 60% ± 3% predicted), we measured the area under the curve of the NO concentration/exhalation time plot (AUC-NO) at exhalation flow rates of 50, 100, 200, and 300 mL/s. We determined the change of the total AUC-NO production (ΔAUC-NO) among the four different exhalation flow rates and compared these levels to Cano and J'awno indices measured conventionally by linear regression. RESULTS: The change in AUC-NO between increasing exhalation flow rates of 50 to 200 mL/s (ΔAUC-NO50-200) was strongly correlated with J'awno in all patient groups as follows: healthy subjects (r = 0.94, P < .001), patients with asthma (r = 0.98, P < .001), patients with COPD (r = 0.93, P < .001), and patients with CF (r = 0.74, P < .05). In all subjects, AUC-NO at an exhalation flow rate of 200 mL/s (AUC-NO200) correlated with Cano (r = 0.69, P < .01). CONCLUSIONS: The bronchial production of NO can be determined by measuring ΔAUC-NO50-200, whereas AUC-NO200 measures its peripheral concentration. This approach is simple, quick, and does not require sophisticated equipment or mathematical models.

Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma.

BACKGROUND: Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders. METHODOLOGY/PRINCIPAL FINDINGS: Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-α induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC(50) values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r = -0.65; p<0.0005) and with decreased FEV(1) (% predicted) (r = 0.6; p<0.0005). A p38α/ß inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV(1) and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s. CONCLUSIONS/SIGNIFICANCE: p38MAPKα/ß is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/ß inhibitor in the future.

Comparing lung regions of interest in gamma scintigraphy for assessing inhaled therapeutic aerosol deposition.

BACKGROUND: Two-dimensional gamma scintigraphy is an important technique used to evaluate the lung deposition from inhaled therapeutic aerosols. Images are divided into regions of interest and deposition indices are derived to quantify aerosol distribution within the intrapulmonary airways. In this article, we compared the different approaches that have been historically used between different laboratories for geometrically defining lung regions of interest. We evaluated the effect of these different approaches on the derived indices classically used to assess inhaled aerosol deposition in the lungs. Our primary intention was to assess the ability of different regional lung templates to discriminate between central and peripheral airway deposition patterns generated by inhaling aerosols of different particle sizes. METHODS: We investigated six methods most commonly reported in the scientific literature to define lung regions of interest and assessed how different each of the derived regional lung indices were between the methods to quantify regional lung deposition. We used monodisperse albuterol aerosols of differing particle size (1.5, 3, and 6 µm) in five mild asthmatic subjects [forced expiratory volume in 1 sec (FEV(1)) 90% predicted] to test the different approaches of each laboratory. RESULTS: We observed the areas of geometry used to delineate central (C) and peripheral (P) lung regions of interest varied markedly between different laboratories. There was greater similarity between methods in values of penetration index (PI), defined as P/C aerosol counts normalized by P/C krypton ventilation counts, compared to nonnormalized C/P or P/C aerosol count-ratios. Normalizing the aerosol deposition P/C count-ratios by the ventilation P/C count-ratios, reduced the variability of the data. There was dependence of the regional lung deposition indices on the size of the P region of interest in that, as P increased, C/P count-ratios decreased and P/C count-ratios increased, whereas PI was less affected by variations in the P area. We found particle size, itself, strongly influenced the indices of regional aerosol deposition such that C/P count-ratios increased with increasing particle size for each method and conversely, P/C count-ratios and PI decreased. CONCLUSIONS: Different approaches used to determine pulmonary regions of interest and quantify aerosol deposition produce different results. Our research highlights a genuine need for a consensus to standardize the methodology to facilitate data comparison between laboratories on aerosol deposition.

Predicting the clinical effect of a short acting bronchodilator in individual patients using artificial neural networks.

Artificial neural networks were used in this study to model the relationships between in vitro data, subject characteristics and in vivo outcomes from N=18 mild-moderate asthmatics receiving monodisperse salbutamol sulphate aerosols of 1.5, 3 and 6 µm mass median aerodynamic diameter in a cumulative dosing schedule of 10, 20, 40 and 100 µg. Input variables to the model were aerodynamic particle size (APS), body surface area (BSA), age, pre-treatment forced expiratory volume in one-second (FEV(1)), forced vital capacity, cumulative emitted drug dose and bronchodilator reversibility to a standard salbutamol sulphate 200 µg dose MDI (REV(%)). These factors were used by the model to predict the bronchodilator response at 10 (T10) and 20 (T20) min after receiving each of the 4 doses for each of the 3 different particle sizes. Predictability was assessed using data from selected patients in this study, which were set aside and not used in model generation. Models reliably predicted ΔFEV(1)(%) in individual subjects with non-linear determinants (R(2)) of ≥ 0.8. The average error between predicted and observed ΔFEV(1)(%) for individual subjects was <4% across the cumulative dosing regimen. Increases in APS and drug dose gave improved ΔFEV(1)(%). Models also showed trends towards improved responses in younger patients and those having greater REV(%), whilst BSA was also shown to influence clinical effect. These data show that APS can be used to discriminate predictably between aerosols giving different bronchodilator responses across a cumulative dosing schedule, whilst patient characteristics can be used to reliably estimate clinical response in individual subjects.

Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma.

RATIONALE AND OBJECTIVES: Patients with severe asthma have a poor therapeutic response to corticosteroid therapy, and corticosteroid responsiveness cannot be easily measured in these patients. We hypothesized that this poor response is associated with a reduced effect of corticosteroids to inhibit cytokine release from activated peripheral blood mononuclear cells (PBMCs). METHODS: Patients with severe asthma were defined by American Thoracic Society criteria. We compared the suppression of LPS-induced cytokine release (monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein [MIP] 1alpha, RANTES, tumor necrosis factor alpha, interleukin 1beta (IL-1beta), IL-8, IFN-gamma, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) by dexamethasone from PBMCs of patients with severe asthma (n = 16), patients with nonsevere asthma (n = 19), and normal volunteers (n = 10). RESULTS: There was no difference in baseline spontaneous or stimulated release of these cytokines among groups. LPS-induced release of 10 cytokines was less suppressed by dexamethasone (10(-6) M) in patients with severe asthma compared with patients with nonsevere asthma, with statistical significance achieved for IL-1beta (p < 0.03), IL-8 (p < 0.03), and MIP-1alpha (p < 0.003), and borderline significance for IL-6 (p = 0.054). There was less difference between the two groups for dexamethasone at 10(-8) M. Nuclear histone deacetylase (HDAC) and histone acetyltransferase activities were reduced in patients with severe asthma compared with patients with nonsevere asthma (p < 0.01). HDAC activity reduction correlated directly to the degree of steroid insensitivity of GM-CSF (r = 0.57, p < 0.01) and IFN-gamma (r = 0.56, p < 0.05) release. Reduction in histone acetyltransferase activity related to corticosteroid use rather than asthma severity. CONCLUSIONS: Patients with severe asthma have diminished corticosteroid sensitivity of PBMCs when compared with patients with nonsevere asthma, associated with a reduction in HDAC activity that parallels the impaired corticosteroid sensitivity.

Formoterol attenuates neutrophilic airway inflammation in asthma.

STUDY OBJECTIVES: Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting beta2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While beta2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo. DESIGN: In a double-blind randomized crossover study, we evaluated the effects of 4 weeks of treatment with formoterol (Turbuhaler), 24 microg bid, compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients. Therapy with budesonide (administered via Turbuhaler), 400 microg bid for 4 weeks, was added at the end as a "gold standard" antiinflammatory effect comparison. PATIENTS: We studied 15 steroid-naïve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma. RESULTS: Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production. CONCLUSIONS: Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations.