Data from The Asthma Report - Curated by EPG Health - Last updated 31 October 2018

The Myths and truths of inhaler therapy

For our day four highlights, the Asthma Report is pleased to bring you a summary of two sessions. Our first session looks at The Myths and truths of inhaler therapy and how inhaler device, technique and adherence are arguably more important than choice of drug.

Dr Omar Usmani, Imperial College, London started the session commenting on the importance of “ds” – device, dose, desire, drug, with the device being most important. Too many devices are available currently, and physicians are very poor at teaching technique. Undergraduate education doesn’t cover inhaler technique despite this being vital to drug delivery. GINA highlights that medication shouldn’t be adjusted until inhaler technique has been checked. Poor Inhaler technique is associated with poor health outcomes, but errors are not clearly defined. “Equivalent drug doses” are unhelpful if patients are unable to use devices. Small particles improve lung deposition and deeper penetration, and slow flow is important for penetration and deposition. Extra fine particles are more effective in systematic reviews. 

The UK Environmental Audit Committee is going to advise a switch to “low global warming potential” which currently means using dry powder inhalers (DPI) DPIs. 70% of deaths in NRAD (The National Review of Asthma Deaths, a UK wide investigation into asthma deaths, first published in 2014) were out of hospital, necessitating appropriate inhaler use and availability at home. Pulsed nebulisers allow improved delivery of nebulisers medications. Mixing inhaler devices results in poorer outcomes. 

Professor Henry Chrystyn continued the theme discussing error rates, showing 28.4% had critical errors with DPIs and 45.6% with Pressurized metered-dose inhalers (pMDIs). Without training, only 10% of patients have optimal technique. Correcting flow rate with pMDIs can improve quality of life as measured by AQLQ (The Asthma Quality of Life Questionnaire) by more than the minimally important difference. The 2017 CRITIKAL study identified critical errors in several inhaler devices, with multiple types of errors associated with significantly poorer control including failure of breath-hold and insufficient inhalation effort. Patient information leaflets are inconsistent and unclear in many cases. 

ProfessProfessor David Price completed the session with a discussion of adherence. Adherence has long been a problem, and this can be split into three phases. Firstly, initiation of treatment; secondly implementation, taking doses as recommended; and finally persistence with treatment. “Percentage” adherence doesn’t give much information on the type of non-adherence. Adherence in RCTs does not reflect real life, often because patients can’t afford treatment outside of the trial. Those in higher BTS steps (BTS/SIGN guidance on the management of asthma in adults) are more likely to be adherent, as are those with multiple exacerbations. Recent work by Professor Richard Costello with the INhaler Compliance Assessment (INCA) showing adherence and technique identifies four groups, with only 11% having both adherence and good technique. Simplified treatment regimes may help, and electronic monitoring may be useful. 

The section ended with advice on common goal setting as being vital to map both physician and patient priorities. Once daily treatment may improve adherence, but detecting and addressing it can prove challenging in practice.

Professor David Price completed the session with a discussion of adherence. Adherence has long been a problem, and this can be split into three phases. Firstly, initiation of treatment; secondly implementation, taking doses as recommended; and finally persistence with treatment. “Percentage” adherence doesn’t give much information on the type of non-adherence. Adherence in RCTs does not reflect real life, often because patients can’t afford treatment outside of the trial. Those in higher BTS steps (BTS/SIGN guidance on the management of asthma in adults) are more likely to be adherent, as are those with multiple exacerbations. Recent work by Professor Richard Costello with the INhaler Compliance Assessment (INCA) showing adherence and technique identifies four groups, with only 11% having both adherence and good technique. Simplified treatment regimes may help, and electronic monitoring may be useful.

The parting advice being around common goal setting and its importance in mapping both physician and patient priorities. Once daily treatment may improve adherence, but detecting and addressing it can prove challenging in practice.

It’s my favourite cell that affects your asthma

The next session for our report came under the title It’s my favourite cell that affects your asthma and looked at how multiple cell types contribute to asthma, but not all cells can be targeted safely. The developing theme was that more research was needed on non-eosinophil cell involvement.

Hans Jürgen Hoffmann, Aarhus University, Department of Clinical Medicine began the session discussing the role of mast cells in asthma. Mast cell progenitors, under the influence of numerous cytokines, migrate and mature in tissue to MCt, MCc or MCtc. Mast cells may progress from tryptase positive to both positive over time. Mast cells are known to be present in lung, particularly in alveoli, while asthmatic patients have been shown to have more IgE receptor positive mast cells. 

Antihistamines, LTRAs and PGD2 inhibitors together, inhibiting various mast cell products, ablate much of the allergic response. Single clone IgE against an allergen doesn’t activate mast cells, and 50:50 ratios of two clones targeting different allergen epitopes activates mast cells most effectively. 

IgE affinity affects the mast cell response, with high affinity IgE provoking a cytokine and neutrophil response, while low affinity IgE attracts monocytes/macrophages. 

Professor Florence Schelich, University of Liège, Liège presented on the role of eosinophils, their mechanisms of effect and therapeutic implications. 55% of Severe asthmatics in the Belgian Severe Asthma Registry (BSAR) were eosinophilic. Eosinophils degranulate, releasing cationic proteins including MBP, EPX, ECP and EDN. These contribute to bronchospasm, epithelial damage and vascular permeability. 

Two populations of eosinophils can be found, inflammatory and regulatory. Asthmatics have similar numbers of rEos but far more iEos. Sputum eosinophils correlate with increased symptoms, mainly driven by the group with high blood and sputum eos. Increase and decrease in sputum eosinophilia is associated with worsening and improvement in symptoms respectively. Sputum eosinophil variability with high eosinophils is associated with rapid decline in lung function. BHR is associated with eosinophilia and inversely with neutrophilia. Eosinophil derives MBP is known to impair M2 receptors, which leads to more acetylcholine release into the airway smooth muscle and therefore more bronchoconstriction. Eosinophils have been found bound to nerves in cases of fatal asthma, and eosinophils lead to increased airway nerve growth.

Professor Jodie Simpson of University of Newcastle discussed the role of the neutrophil in asthma. Neutrophils are capable of cytokine release, phagocytosis, oxidant release and NET formation. IL-17 is inversely correlates with PC20, but not much evidence is available about neutrophils and bronchial hyper responsiveness. Neutrophilia is associated with impaired airflow and low FEV1. Exacerbations correspond with increased neutrophils in the airways. Airway neutrophilia is more common with reflux and rhinosinusitis, and results in more IL-1b, elastase and IL-8, and less microbe diversity. CXCR2 antagonists were trialled but not in neutrophil specific groups. Anti-TNFa has been trialled but not in neutrophilic disease again. Macrolides have both antimicrobial and anti-inflammatory effects, but have no effect on sputum cell count however data from AMAZES does show less TNFa and IL-8 after azithromycin. Data suggests that neutrophil migration in older adults is less direct, and therefore results in more elastase release and potentially therefore damage. Hypersegmented neutrophils are more common in airway diseases.

Finally, Innate Lymphoid Cells and the epithelium were discussed by Professor Cezmi Akdis, Director of the Swiss Institute of Allergy and Asthma. He considered how cultured bronchial epithelial cells have a very low resistance in asthma compared to healthy controls and this may be attributable to inflammation. Both Type 2 and non-Type 2 inflammation open tight junctions IL-C2s seem to be very important in murine models although human data is scarce to date. IL-C2s open tight junctions resulting in a drop in air lung interface resistance, particularly with IL-33. Knockout mouse studies show epithelial barriers remain intact in the absence of ILCs but are not affected by T or B cell presence. Surfactants and detergents found in cleaning products can be shown to damage the epithelial barrier.

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