Improving asthma outcomes: Clinicians' perspectives on peripheral airways.

Disease of the peripheral (or small) airways is fundamental in asthma, being closely related to symptoms (or lack of control of them), airway hyperresponsiveness, spirometric abnormalities, risk of loss of control, or exacerbations and inflammation. Current technology now allows routine measurement of peripheral airway function. Having a working concept of peripheral airways disease in asthma is arguably very useful to clinicians and beneficial to patients because it allows a more comprehensive assessment of asthma severity (rather than just symptoms alone, which is the norm), tracking of progress or deterioration, and assessing response to treatment. Oscillometry is a sensitive way to monitor the peripheral airways, whereas multiple breath nitrogen washout parameters are excellent measures of future risk. In the longer term, physiologic measurements will be crucial in research to define causes and find new disease-modifying treatments.

Development and evaluation of a tool to optimise inhaler selection prior to hospital discharge following an exacerbation of COPD.

Introduction: Rates of mortality and re-admission after a hospitalised exacerbation of COPD are high and resistant to change. COPD guidelines do not give practical advice about the optimal selection of inhaled drugs and device in this situation. We hypothesised that a failure to optimise inhaled drug and drug delivery prior to discharge from hospital after an exacerbation would be associated with a modifiable increased risk of re-admission and death. We designed a study to 1) develop a practical inhaler selection tool to use at the point of hospital discharge and 2) implement this tool to understand the potential impact on modifying inhaler prescriptions, clinical outcomes, acceptability to clinicians and patients, and the feasibility of delivering a definitive trial to demonstrate potential benefit. Methods: We iteratively developed an inhaler selection tool for use prior to discharge following a hospitalised exacerbation of COPD using surveys with multiprofessional clinicians and a focus group of people living with COPD. We surveyed clinicians to understand their views on the minimum clinically important difference (MCID) for death and re-admission following a hospitalised exacerbation of COPD. We conducted a mixed-methods implementation feasibility study using the tool at discharge, and collated 30- and 90-day follow-up data including death and re-admissions. Additionally, we observed the tool being used and interviewed clinicians and patients about use of the tool in this setting. Results: We completed the design of an inhaler selection tool through two rounds of consultations with 94 multiprofessional clinicians, and a focus group of four expert patients. Regarding MCIDs, there was majority consensus for the following reductions from baseline being the MCID: 30-day readmissions 5-10%, 90-day readmissions 10-20%, 30-day mortality 5-10% and 90-day mortality 5-10%. 118 patients were assessed for eligibility and 26 had the tool applied. A change in inhaled medication was recommended in nine (35%) out of 26. Re-admission or death at 30 days was seen in 33% of the switch group and 35% of the no-switch group. Re-admission or death at 90 days was seen in 56% of the switch group and 41% of the no-switch group. Satisfaction with inhalers was generally high, and switching was associated with a small increase in the Feeling of Satisfaction with Inhaler questionnaire of 3 out of 50 points. Delivery of a definitive study would be challenging. Conclusion: We completed a mixed-methods study to design and implement a tool to aid optimisation of inhaled pharmacotherapy prior to discharge following a hospitalised exacerbation of COPD. This was not associated with fewer re-admissions, but was well received and one-third of people were eligible for a change in inhalers.

Demystifying Dry Powder Inhaler Resistance with Relevance to Optimal Patient Care.

The selection of an inhaler device is a key component of respiratory disease management. However, there is a lack of clarity surrounding inhaler resistance and how it impacts inhaler selection. The most common inhaler types are dry powder inhalers (DPIs) that have internal resistance and pressurised metered dose inhalers (pMDIs) that use propellants to deliver the drug dose to the airways. Inhaler resistance varies across the DPIs available on the market, depending largely on the design geometry of the device but also partially on formulation parameters. Factors influencing inhaler choice include measures such as flow rate or pressure drop as well as inhaler technique and patient preference, both of which can lead to improved adherence and outcomes. For optimal disease outcomes, device selection should be individualised, inhaler technique optimised and patient preference considered. By addressing the common clinically relevant questions, this paper aims to demystify how DPI resistance should guide the selection of the right device for the right patient.

Selection of the right inhaler is important to ensure that patients with respiratory diseases get the most benefit from their treatment. Dry powder inhalers and pressurised metered dose inhalers are the most common inhaler types. Pressurised metered dose inhalers use propellants to deliver the drug to the lungs. In contrast, dry powder inhalers deliver the drug to the lungs by having internal resistance. This restricts the flow of air through the inhaler. As the patient inhales through the inhaler, the resistance against the air flow generates the power to separate the drug molecules and carry them to the lungs. While there are many factors to be considered for inhaler selection, there is often confusion around how resistance should guide selection of inhaler. With low-resistance devices, patients must inhale faster to generate the power to separate the drug molecules, which may be difficult in patients with poor lung function. With high-resistance devices, patients do not need to inhale as fast to separate the drug, and most patients can effectively use the inhaler. This article addresses the common clinically relevant questions to clarify how the internal resistance of the inhaler should be used to help guide the selection of the right device for the right patient.

Small airways disease in patients with alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder, characterized by panacinar emphysema mainly in the lower lobes, and predisposes to chronic obstructive pulmonary disease (COPD) at a younger age, especially in patients with concomitant cigarette smoking. Alpha-1 antitrypsin (a1-AT) is a serine protease inhibitor that mainly blocks neutrophil elastase and maintains protease/antiprotease balance in the lung and AATD is caused by mutations in the SERPINA1 gene that encodes a1-AT protein. PiZZ is the most common genotype associated with severe AATD, leading to reduced circulating levels of a1-AT. Besides its antiprotease function, a1-AT has anti-inflammatory and antioxidative effects and AATD results in defective innate immunity. Protease/antiprotease imbalance affects not only the lung parenchyma but also the small airways and recent studies have shown that AATD is associated with small airway dysfunction. Alterations in small airways structure with peripheral ventilation inhomogeneities may precede emphysema formation, providing a unique opportunity to detect early disease. The aim of the present review is to summarize the current evidence for the contribution of small airways disease in AATD-associated lung disease.

Domiciliary Fractional Exhaled Nitric Oxide and Spirometry in Monitoring Asthma Control and Exacerbations.

BACKGROUND: Domiciliary measurements of airflow obstruction and inflammation may assist healthcare teams and patients in determining asthma control and facilitate self-management. OBJECTIVE: To evaluate parameters derived from domiciliary spirometry and fractional exhaled nitric oxide (Feno) in monitoring asthma exacerbations and control. METHODS: Patients with asthma were provided with hand-held spirometry and Feno devices in addition to their usual asthma care. Patients were instructed to perform twice-daily measurements for 1 month. Daily symptoms and medication change were reported through a mobile health system. The Asthma Control Questionnaire was completed at the end of the monitoring period. RESULTS: One hundred patients had spirometry, of which 60 were given additional Feno devices. Compliance rates for twice-daily measurements were poor (median [interquartile range], 43% [25%-62%] for spirometry; 30% [3%-48%] for Feno); at least 15% of patients took little or no spirometry measurements and 40% rarely measured Feno. The coefficient of variation (CV) values in FEV1 and Feno were higher, and the mean % personal best FEV1 lower in those who had major exacerbations compared with those without (P < .05). Feno CV and FEV1 CV were associated with asthma exacerbation during the monitoring period (area under the receiver-operating characteristic curve, 0.79 and 0.74, respectively). Higher Feno CV also predicted poorer asthma control (area under the receiver-operating characteristic curve, 0.71) at the end of the monitoring period. CONCLUSIONS: Compliance with domiciliary spirometry and Feno varied widely among patients even in the setting of a research study. However, despite significant missing data, Feno and FEV1 were associated with asthma exacerbations and control, making these measurements potentially clinically valuable if used.

A narrative review on the Synchrobreathe™: A novel breath-actuated pressurised metered-dose inhaler for the treatment of obstructive airway diseases.

Pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs), are widely used to deliver drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Incorrect use of inhalers is one of the main obstacles to achieving better clinical control. Indeed, with pMDIs, patients fail to synchronise actuation with inhalation due to a lack of coordination and with DPIs insufficient inspiratory effort compromises drug deposition in lungs. More than 50% of patients desire to switch their pMDIs and DPIs for a better device. This led to the development of pressurised breath-actuated inhalers (BAIs) with the aim of combining the beneficial features of pMDIs and DPIs and mitigating their problems. BAIs, e.g., Synchrobreathe™, are designed such that they are activated by a low inhalation effort and mechanically actuate the dose in synchrony to inspiration, thereby resolving the need to coordinate actuation with inspiration. BAIs have advantages, including ease of use, high lung deposition of medication, and greater patient preference. We discussed the design features, operating procedure, and clinical evidence of the Synchrobreathe™ device (Cipla Ltd, India), a BAI available with a wide range of drug combinations. Studies have shown that a higher number of patients (68.19%) used the Synchrobreathe™ without any error than the pMDI (56.21%), and that the vast majority of them (92%) found it easy to understand and use. The Synchrobreathe™ is an innovative, easy-to-use inhaler that may overcome many limitations associated with pMDIs and DPIs, thus potentially improving management of obstructive airway diseases and patients' quality of life.

Suboptimal Peak Inspiratory Flow and Critical Inhalation Errors are Associated with Higher COPD-Related Healthcare Costs.

Purpose: To assess the relationship between suboptimal Peak Inspiratory Flow (sPIF), inhalation technique errors, and non-adherence, with Healthcare Resource Utilisation (HCRU) in Chronic Obstructive Pulmonary Disease (COPD) patients receiving maintenance therapy via a Dry Powder Inhaler (DPI). Patients and methods: The cross-sectional, multi-country PIFotal study included 1434 COPD patients (≥40 years) using a DPI for maintenance therapy. PIF was measured with the In-Check DIAL G16, and sPIF was defined as a typical PIF lower than required for the device. Inhalation technique was assessed by standardised evaluation of video recordings and grouped into 10 steps. Patients completed the "Test of Adherence to Inhalers" questionnaire. HCRU was operationalised as COPD-related costs for primary healthcare, secondary healthcare, medication, and total COPD-related costs in a 1-year period. Results: Participants with sPIF had higher medication costs compared with those with optimal PIF (cost ratio [CR]: 1.07, 95% CI [1.01, 1.14]). Multiple inhalation technique errors were associated with increased HCRU. Specifically, "insufficient inspiratory effort" with higher secondary healthcare costs (CR: 2.20, 95% CI [1.37, 3.54]) and higher total COPD-related costs (CR: 1.16, 95% CI 1.03-1.31). "no breath-hold following the inhalation manoeuvre (<6 s)" with higher medication costs (CR: 1.08, 95% CI [1.02, 1.15]) and total COPD-related costs (CR 1.17, 95% CI [1.07, 1.28]), and "not breathing out calmly after inhalation" with higher medication costs (CR: 1.19, 95% CI [1.04, 1.37]). Non-adherence was not significantly associated with HCRU. Conclusion: sPIF and inhalation technique errors were associated with higher COPD-related healthcare utilisation and costs in COPD patients on DPI maintenance therapy.

Clinimetric analysis of outcome measures for airway clearance in people with cystic fibrosis: a systematic review.

BACKGROUND: Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy. OBJECTIVES: To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF. DESIGN AND METHODS: A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required. RESULTS: No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified. DISCUSSION AND CONCLUSION: This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essential. REGISTRATION: This systematic review was registered on the PROSPERO database (CRD42020206033).

The Role of Viral Infections on Severe Asthma Exacerbations: Present and Future

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Reference equations for oscillometry and their differences among populations: a systematic scoping review.

Respiratory oscillometry is gaining global attention over traditional pulmonary function tests for its sensitivity in detecting small airway obstructions. However, its use in clinical settings as a diagnostic tool is limited because oscillometry lacks globally accepted reference values. In this scoping review, we systematically assessed the differences between selected oscillometric reference equations with the hypothesis that significant heterogeneity existed between them. We searched bibliographic databases, registries and references for studies that developed equations for healthy adult populations according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A widely used Caucasian model was used as the standard reference and compared against other models using Bland-Altman and Lin's concordance correlational analyses. We screened 1202 titles and abstracts, and after a full-text review of 67 studies, we included 10 in our analyses. Of these, three models had a low-to-moderate agreement with the reference model, particularly those developed from non-Caucasian populations. Although the other six models had a moderate-to-high agreement with the standard model, there were still significant sex-specific variations. This is the first systematic analysis of the heterogeneity between oscillometric reference models and warrants the validation of appropriate equations in clinical applications of oscillometry to avoid diagnostic errors.

Real-World Impact of Nonclinical Inhaler Regimen Switches on Asthma or COPD: A Systematic Review.

BACKGROUND: Switching inhaler regimens can be driven by poor disease control but also by nonclinical factors, such as cost and environmental impact. The consequences of switching for nonclinical reasons are largely unclear. OBJECTIVE: To systematically review the real-world consequences of switching inhaler regimens for nonclinical reasons in asthma and/or chronic obstructive pulmonary disease patients. METHODS: Embase, MEDLINE, EBM Reviews, and EconLit were searched to November 21, 2020. Conference searches and reference checking were also performed. Real-world studies of asthma and/or chronic obstructive pulmonary disease patients undergoing a switch in inhaler regimen for any reason apart from clinical need were included. Two reviewers screened and extracted data. Key outcomes included symptom control, exacerbations, and patient-doctor relationships. RESULTS: A total of 8,958 records were screened and 21 studies included. Higher-quality (matched comparative) studies were prioritized. Five matched studies (6 datasets) reported on symptom control: 5 datasets (n = 7,530) with unclear patient consent reported improved disease control following switching, and 1 dataset (n = 1,648) with non-consented patients reported significantly worsened disease control. Three matched studies (5 datasets, n = 10,084) reported on exacerbation rate ratios; results were heterogeneous depending on the definition used. Two studies (n = 137) reported that switching inhaler regimens could have a negative impact on the doctor-patient relationship, especially when the switches were non-consented. Study quality was generally low. CONCLUSIONS: Switching inhaler regimens is a complex issue that can have variable clinical consequences and can harm the patient-doctor relationship. Limited high-quality evidence was identified, and study designs were heterogeneous. A robust framework is needed to guide the personalized switching of inhalers.

Is Inhaler Technique Adequately Assessed and Reported in Clinical Trials of Asthma and Chronic Obstructive Pulmonary Disease Therapy? A Systematic Review and Suggested Best Practice Checklist.

BACKGROUND: Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies. OBJECTIVE: To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD. METHODS: Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents. RESULTS: Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist. CONCLUSIONS: Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps.

Lung Deposition of Inhaled Extrafine Beclomethasone Dipropionate/Formoterol Fumarate/Glycopyrronium Bromide in Healthy Volunteers and Asthma: The STORM Study.

Background: An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation. Methods: This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m (81mKr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 µg radiolabeled using technetium-99 m [99mTc]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; 99mTc aerosol C/P/81mKr gas C/P). Results: All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean ± standard deviation intrapulmonary deposition was 25.50% ± 6.81%, not significantly different to that in healthy volunteers (22.74% ± 9.19%; p = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 ± 0.07 and 0.49 ± 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 ± 0.25 and 1.06 ± 0.25, respectively, with sC/P ratios of 1.80 ± 0.40 and 1.94 ± 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated. Conclusions: This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition. Clinical Trial Registration number: NCT03795350.

European Respiratory Society Guidelines for the Diagnosis of Asthma in Adults.

Although asthma is very common affecting 5-10% of the population, the diagnosis of asthma in adults remains a challenge in the real world that results in both over- and under-diagnosis. A task force (TF) was set up by the European Respiratory Society to systematically review the literature on the diagnostic accuracy of tests used to diagnose asthma in adult patients and provide recommendation for clinical practice.The TF defined eight PICO (Population, Index, Comparator, and Outcome) questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach, The TF utilised the outcomes to develop an evidenced-based diagnostic algorithm, with recommendations for a pragmatic guideline for everyday practice that was directed by real-life patient experiences.The TF support the initial use of spirometry followed, and if airway obstruction is present, by bronchodilator reversibility testing. If initial spirometry fails to show obstruction, further tests should be performed in the following order: FeNO, PEF variability or in secondary care, bronchial challenge. We present the thresholds for each test that are compatible with a diagnosis of asthma in the presence of current symptoms.The TF reinforce the priority to undertake spirometry and recognise the value of measuring blood eosinophils and serum IgE to phenotype the patient. Measuring gas trapping by body plethysmography in patients with preserved FEV1/FVC ratio deserves further attention. The TF draw attention on the difficulty of making a correct diagnosis in patients already receiving inhaled corticosteroids, the comorbidities that may obscure the diagnosis, the importance of phenotyping, and the necessity to consider the patient experience in the diagnostic process.

Relationship between Peak Inspiratory Flow and Patient and Disease Characteristics in Individuals with COPD-A Systematic Scoping Review.

Optimal delivery of medication via dry powder inhalers, the most commonly prescribed inhaler type, is dependent on a patient achieving a minimum level of inspiratory flow during inhalation. However, measurement of peak inspiratory flow (PIF) against the simulated resistance of a dry powder inhaler is not frequently performed in clinical practice due to time or equipment limitations. Therefore, defining which patient characteristics are associated with lower PIF is critically important to help clinicians optimize their inhaler choice through a more personalized approach to prescribing. The objective of this scoping review was to systematically evaluate patient and disease characteristics determining PIF in patients with chronic obstructive pulmonary disease (COPD). Medline, Cochrane and Embase databases were systematically searched for relevant studies on PIF in patients with COPD published in English between January 2000 and May 2021. The quality of evidence was assessed using a modified Grading of Recommendations Assessment, Development and Evaluation checklist. Of 3382 citations retrieved, 35 publications were included in the review (nine scored as high quality, 13 as moderate, nine as low, and four as very low). Factors correlating with PIF in >70% of papers included both patient characteristics (lower PIF correlated with increased age, female gender, shorter height, decreased handgrip and inspiratory muscle strength, and certain comorbidities) and disease characteristics (lower PIF correlated with markers of lung hyperinflation, lower peak expiratory flow [PEF] and increased disease severity). Other factors correlating with adequate/optimal or improved PIF included education/counseling and exercise/inspiratory muscle training; impaired physical function and errors in inhalation technique/non-adherence were associated with low/suboptimal PIF. In conclusion, clinicians should measure PIF against the simulated resistance of a particular device wherever possible. However, as this often cannot be done due to lack of resources or time, the patient and disease characteristics that influence PIF, as identified in this review, can help clinicians to choose the most appropriate inhaler type for their patients.

Measuring Peak Inspiratory Flow in Patients with Chronic Obstructive Pulmonary Disease.

Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)-a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)-are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.