Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that are characterized by airflow limitation. They are distinct conditions with different causes, structural changes, and immunopathology. The pathophysiology in asthma and COPD involves not only the proximal large airways, but also the distal small airways, and thus the small airways are an important therapeutic target in the treatment of both diseases. The assessment of diseased distal small airways is challenging. Extensive disease can be present in the small airways with little abnormality in conventional pulmonary function tests. Recent advances in imaging technologies have led to better spatial resolution to assess small airways morphology non-invasively. New physiological tests have been developed to detect disease and response to therapy in regional airways. Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol particle size or using inhaler devices that emit aerosolized drug at slow inhalation flows. Large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes.
Key messages
Small airways are an important therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Extensive disease can be present in the small airways with little abnormality in conventional lung function tests.
Alveolar nitric oxide, multiple-breath nitrogen wash-out, and forced oscillation technique are sensitive non-invasive physiological tests that can identify airway responses from large and small airways.
Small airways
The small airways are classified as airways of internal diameter less than 2 mm that do not contain cartilage in their walls and extend from the 8th generation airways to the alveoli (Citation1) (). They incorporate the lung regions involving the terminal bronchus, bronchioles, alveolar ducts, and the alveolar sacs. Compared to the large (> 2 mm) airways, the cross-sectional surface area and airway volume of the small airways are far greater, yet the small airways contribute only 10% of the total airway resistance (Citation2,Citation3). Consequently, the small airways are sometimes referred to as the ‘silent zone’, as extensive disease can be present with little abnormality in conventional pulmonary function tests (Citation4).
Figure 1. Airway dimensions and physiological compartments of the tracheobronchial tree.
Pathophysiology of asthma and COPD
Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that each have characteristic structural airway features and distinctly different immunopathology (Citation5). The inflammation present in asthma and COPD involves not only the proximal large airways, but also the distal small airways and there are differences in both the nature and the distribution of the inflammation between the diseases (Citation6–8). Children with asthma have greater disease involvement of peripheral than central airways, and better understanding is needed not only in adult but also in paediatric populations regarding pathobiology, monitoring techniques, and improved targeted therapy to the small airways (Citation9).
Structurally there is an increase in airway smooth muscle mass, mucus plugging, and goblet cell hyperplasia in both large and small airways in asthma (Citation10) (). Post-mortem studies in fatal asthma reveal the outer wall of the small airways as a major site of inflammation and remodelling, whereas in the proximal large airways the inner wall is mainly affected (Citation11). The small airways inflammation can extend to involve the perivascular region of the pulmonary arteries and the peribronchiolar alveoli (Citation12), which may contribute to the observed structural alterations of decreased alveolar attachments that have been described in cases of severe fatal asthma (Citation13).
Table I. Pathophysiology, histology, and inflammatory characteristics of asthma and COPD.
In contrast, the disease in COPD predominantly involves remodelling of the small airways with features of increased airway smooth muscle, goblet cell hyperplasia, airway wall fibrosis, destruction of alveolar attachments, and associated emphysema; that is, enlargement and destruction of air spaces and lung parenchyma distal to the terminal bronchioles (Citation7) (). The classical patterns of emphysema observed in COPD are centrilobular (parenchymal destruction around the terminal bronchioles) and panlobular or panacinar (homogeneous parenchymal destruction and enlargement of airspaces), and a greater fibrotic response and mast cell infiltrate have been associated with centrilobular disease patterns. The small airways of smokers have fewer alveolar attachments than non-smokers, and the loss of alveolar attachments correlates with the amount of airway inflammation (Citation14). Disease affecting the large airways has also been shown in COPD patients and in smokers at risk of developing COPD (Citation15,Citation16).
The inflammatory cellular profile in asthma primarily involves mast cells, eosinophils and CD4 + Th2 lymphocytes, as well as macrophages and sometimes neutrophils, with evidence to support differences in the distribution of these cells along the respiratory tree (Citation6,Citation17,Citation18). The immunopathology in COPD is mainly driven by macrophages, neutrophils, and CD8+ Tc1 lymphocytes that infiltrate the airways throughout the respiratory tree (Citation19) (). Patients with similar degrees of fixed airflow obstruction show distinct pathologic and functional characteristics depending on a history of either asthma or chronic obstructive pulmonary disease (Citation20). In a study involving 46 subjects, asthmatic patients compared to those with COPD were shown to have significantly more airway eosinophils, fewer luminal neutrophils, higher ratios of CD4+/CD8+ T cells infiltrating the airway mucosa, and a thicker reticular layer of the epithelial basement membrane. Physiologically, the asthmatic patients demonstrated greater reversibility to inhaled β2-agonists and oral corticosteroids, had significantly lower residual lung volumes, greater alveolar diffusing capacity, higher exhaled nitric oxide concentrations, and lower high-resolution computed tomography scan emphysema scores compared to patients with COPD.
It can be appreciated, therefore, that not only are the small airways an important therapeutic target in the treatment of both asthma and COPD, requiring inhaled drug to be adequately delivered to this lung region, but the different types of pathology and inflammatory patterns between diseases, and within each disease, may require differently targeted anti-inflammatory therapeutic strategies.
Assessing small airways disease
The assessment of diseased distal small airways is challenging (Citation21) (). Invasive techniques have been employed in patients with asthma and COPD to assess the histopathology of small airways involvement, analyse airways tissue inflammation, and determine structural remodelling, but these are unpleasant tests that have mainly been used for research purposes. Approaches have included examining resected lung specimens in patients with severe and fatal asthma (Citation6,Citation17,Citation18), assessing alveolar tissue from transbronchial biopsies (Citation22,Citation23), and distal luminal airway sampling using bronchoalveolar lavage and prolonged sputum induction (Citation24,Citation25).
Table II. Assessing small airways disease.
Imaging modalities allow non-invasive assessment of the lungs. Recent advances in technology have led to better spatial resolution to assess small airways morphology with high-resolution computed-tomography (HRCT) on expiration to measure air trapping (Citation26–28) and in the use of hyperpolarized helium with magnetic resonance lung imaging (3He-MRI) to measure gas distribution (Citation29–32). Ventilation-perfusion relationships in the peripheral lung regions have been measured with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) (Citation33), although these techniques require high-dose radiation and are not widely available. Recently, static lung CT images have been combined with computational fluid dynamics of patient-specific computer simulations to allow a more functional modelling approach to investigate small and large airways in pulmonary disease (Citation34).
Several radiological indices are used in lung CT to stratify asthma and COPD patients including bronchial dilatation (bronchiectasis), bronchial wall thickening, air trapping, emphysema, and mosaic lung attenuation (Citation26,Citation35,Citation36). These indices have been observed to be more common in asthmatic patients than in healthy subjects and to be related to asthma disease severity (Citation26,Citation37). Lung attenuation is related to asthma control, with decreased lung density in patients during asthma exacerbations (Citation38), and measuring lung attenuation during expiration better reflects pulmonary function abnormalities in patients with severe COPD (Citation39). Although air trapping is not specific to differentiate asthmatics from healthy smokers (Citation40), in COPD patients the change in air trapping between inspiratory and expiratory scans correlates closely with airway dysfunction, irrespective of the degree of emphysema (Citation41). Indeed, regional air trapping on lung CT has been used as an indirect measure of small airways function in asthmatic subjects to assess the effects of inhaled corticosteroid therapy. Short-term 4-week treatment with inhaled hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) of mass median aerodynamic diameter (MMAD) 0.8–1.2 μm significantly improved air trapping compared to conventional inhaled chlorofluorocarbon-beclomethasone dipropionate (CFC-BDP) of MMAD 3.5–4.0 μm, but there was no significant difference between the two groups in symptoms, spirometry, or methacholine response (Citation42). In contrast, two different-sized particle formulations of inhaled corticosteroid in relatively equipotent doses given for a 3-month duration showed that both the small particles of HFA-BDP and the large particles of dry-powder fluticasone propionate (DPI-FP) improved air trapping and lung attenuation to similar degrees in mild-to-moderate asthmatic patients (Citation43).
Hyperpolarized helium with magnetic resonance lung imaging (3He-MRI) advantageously allows an assessment of the lung microstructure without ionizing radiation (Citation44). Inhaled helium remains in the airways and does not transfer to the blood-stream, and the technique measures the degree to which diffusion-driven displacement of inhaled helium atoms are restricted by the airway walls. The apparent diffusion coefficient (ADC) is an important derived index that is increased in COPD patients compared to healthy subjects (Citation45), corresponds to the degree of lung destruction in emphysema (Citation46), and is increased in healthy smokers (Citation47). Significant increases in the ADC (short and long time-scale) have been observed in asthmatic patients compared to healthy subjects, with marked increases in COPD patients, where these changes most probably reflect tissue remodelling with permanent structural changes in the small airways (Citation48).
Physiological tests of small airways function
Conventional lung function testing
The physiological characteristics of small airways obstruction include air trapping, early airways closure, regional ventilation heterogeneity, and exaggerated volume dependence on airflow limitation, and tests that focus on these characteristics may be useful surrogates to detect and quantify small airways disease (). Spirometry undertaken in clinics is routinely used to determine obstructive lung disease and detect expiratory airflow limitation, with a reduction in the forced expiratory volume in 1 second (FEV1) relative to a preserved forced vital capacity (FVC) (Citation49). The spirometric measures of peak expiratory flow (PEF) and FEV1 mainly give an assessment of lung disease affecting proximal airways, whereas the other indices of FVC and forced expiratory flows at low lung volumes (FEF) are non-specific and insensitive to detect small versus large airway changes during expiratory airflow obstruction, as the indices may be affected by airflows and volume changes in the larger airways, have poor correlation with measures of air trapping, and show considerable variability (Citation50). Although FEF25-75 (the mean expiratory flow between 25% and 75% of FVC) has been considered an index of small airways impairment, it is highly reliant on an accurate FVC manoeuvre and measurement, and the American Thoracic Society (ATS) guidelines on lung function testing do not support FEF25-75 for determining small airways disease (Citation51). Recently, the ratio of forced expiratory volume in 3 seconds (FEV3)/FVC has been explored on airflow limitation in current smokers versus adult non-smokers, and it has been shown that the fraction of the FVC not expired in the first 3 seconds of the FVC (1-FEV3/FVC) is very useful to characterize distal expiratory airflow obstruction, in contrast to the FEF25-75 (Citation52).
The measurement of lung volumes by body plethysmography can identify air trapping and lung hyperinflation. Lung hyperinflation reflects abnormalities of expiratory airflow limitation, inspiratory muscle activity at end expiration, lung elasticity, and distal airway disease, and is said to exist when the total lung capacity (TLC) is > 120% of the predicted value, with increased functional residual capacity (FRC) and residual volume (RV) that reflect the presence of air trapping and early airway closure. As TLC is commonly increased in obstructive disease, the RV/TLC ratio is the best measure readily available to most clinicians as an indicator of air trapping (Citation53). Lung hyperinflation is observed not only in COPD patients (Citation54) but also in adult (Citation55) and paediatric (Citation56) asthmatics, and it has been shown that severe asthma patients have marked air trapping when compared to non-severe patients (Citation57). Reduction of carbon monoxide diffusing capacity (DLCO) is a functional measure of constant alveolar damage by emphysematous disease in patients with COPD.
Other physiological measurements have been advocated as identifying small airways dysfunction. Closing volume, derived from the single-breath nitrogen wash-out test (SBN2W), is a measure of early airway closure that correlates well with RV/TLC (Citation58), and enhanced small airways closure has been shown to be a phenotypic characteristic of severe asthma patients and a risk factor for disease exacerbations (Citation59). Small airways tests may predict the clinical course of disease. A retrospective analysis study found the slope of the alveolar plateau of the SBN2W predicted the risk of exacerbations in poorly controlled asthmatic patients (Citation60). In COPD patients, factors associated with small airway disease such as increased specific airway resistance and RV have been shown to be modified by inhaled bronchodilators with resulting improvements in lung volumes and exertional symptoms (Citation61). The frequency dependence of airway compliance has been used to indicate obstructed peripheral small airways, but it requires sophisticated equipment and is difficult to perform (Citation62). Indeed, many tests claim to identify small airways disease but lack specificity, are poorly reproducible, or are not predictive (Citation63,Citation64).
There is a real need for better physiological correlates of detecting changes in regional airways function. Recent approaches have focused on non-invasive physiological tests that are sensitive to, and differentiating in, the presence of disease from the small versus the large airways (Citation21). Exhaled breath nitric oxide, multiple-breath nitrogen wash-out, and forced oscillation techniques are well established physiological assessments, gaining renewed interest, which incorporate mathematical modelling to allow the tracheobronchial tree to be anatomically partitioned into conducting (airway generations 0–16, gas transport region) versus acinar (airway generations 17–23, gas exchange region) zones, from which airway responses can be identified ().
Exhaled breath nitric oxide
Exhaled breath nitric oxide (NO) has been shown to be elevated in the presence of intrapulmonary inflammation (Citation65), and NO measurements are typically obtained using a single exhalation flow-rate during tidal breathing (Citation66). Exhaled NO exhibits flow-rate dependency such that, using several different exhalation flow-rates, exhaled NO may be separated into that produced from central bronchial/conducting airways (low exhalation flows) and that generated in peripheral alveolar regions (high flows), and this breathing technique allows an assessment of where the airway inflammation is more active within the pulmonary tree (Citation67). Alveolar NO concentrations have been shown to be higher in patients with alveolitis compared to those with mild-to-moderate asthma (where bronchial NO was higher), and, in those patients with alveolitis, alveolar NO correlated inversely with pulmonary diffusing capacity, whereas in the asthmatic patients bronchial NO correlated with airway hyperresponsiveness (Citation68). The central airways have been identified as the major site of NO production in patients with moderate asthma when stable and during disease exacerbations, whereas their alveolar NO concentrations were normal (Citation69). Patients with severe refractory asthma have greater alveolar NO concentrations compared to those with mild asthma, and their NO concentrations positively correlate with bronchoalveolar lavage eosinophil counts but not with sputum or bronchial wash eosinophil counts (Citation70). Alveolar NO is also closely related to parameters of peripheral airway dysfunction in patients with severe asthma, such that it is associated with uneven ventilation and air trapping (Citation71). In COPD patients, normal NO gas exchange has been observed from both large conducting and small distal airways compared with age-matched healthy controls, with absence of correlation between NO gas exchange and CT-scored emphysema and a significant reduction in only bronchial NO concentration with moderate-to-high doses of inhaled corticosteroids but not with low doses, despite the varying extents of emphysematous disease (Citation72).
Recent data highlight the role of ‘back-diffusion’ of NO into the small airways and alveoli, paradoxically leading to increased alveolar NO concentrations following treatment with inhaled corticosteroids in asthmatic subjects (Citation73). Back-diffusion of NO from the proximal large airways back into the distal small airways can be prevented by airway closure, leading to an increased total fraction of exhaled NO and decreased alveolar NO concentrations. The paradox lies in the fact that treating airways inflammation with inhaled corticosteroids may provide relief of airways obstruction (air trapping) and hence increase alveolar NO as a result of increased back-diffusion; whereas, simultaneously, treatment may reduce airways inflammation and NO production that could decrease alveolar NO concentrations. The net dynamic balance between these two physiologic processes will determine the final values of alveolar NO, but it can be appreciated that these processes give rise to the large variability of this measure in patients.
Multiple-breath nitrogen wash-out
The multiple-breath nitrogen wash-out (MBN2W) technique involves inhalation of 100% oxygen to ‘wash out’ resident airway nitrogen gas during tidal breathing and is highly reproducible (Citation74). The rate and extent of nitrogen gas exhalation from the tracheobronchial tree allows an assessment of changes in lung ventilation (ventilation heterogeneity) in the whole lung (lung clearance index), from proximal/conducting airway compartments (where gas transport is mainly convective) and from distal/acinar regions (where gas transport is mainly diffusive) (Citation75,Citation76). Patients with COPD display considerably greater base-line ventilation heterogeneity of the distal lung acinar airway compartment (Sacin) compared to patients with asthma who, in contrast, demonstrate better improvements in ventilation heterogeneity in the proximal conducting airways (Scond) and in Sacin, in response to inhaled bronchodilators (Citation76,Citation77). Even in the mildest forms of asthma, the most consistent pattern of structural impairment is located in the conductive airways (Citation78), although recent data show that peripheral acinar airway ventilation heterogeneity (Sacin) is present in asthmatic patients receiving moderate-to-high maintenance doses of inhaled corticosteroids and that this acinar structural impairment correlated with distal airway inflammation determined by alveolar NO (Citation79). MBN2W has also been shown to detect peripheral airway changes in smokers well before conventional spirometry becomes abnormal (Citation80).
Forced oscillation technique
The forced oscillation technique (FOT), or impulse oscillometry, generates oscillating pressure-flow signals of moving air during tidal breathing to determine central and peripheral lung mechanical parameters, which include airways impedance (Z), resistance (R), and reactance (X) (Citation81). FOT shows greater sensitivity for assessing inhaled β2-agonist bronchodilator reversibility compared to FEV1 in patients with airflow obstruction (Citation82). Oscillation signals at low frequencies (5 Hz) reflect changes in the small airways. Data show that the change in inspiratory-minus-expiratory reactance at 5 Hz (ΔX5Hz) is greater in COPD patients compared to asthmatics with similar degrees of airflow obstruction (FEV1 < 60% predicted), reflecting the enhanced dynamic expiratory airflow limitation observed in COPD patients (Citation83). Recently, multidimensional mathematical and statistical analyses of the dynamic fluctuations in respiratory impedance (Z) that occur over time reveal that COPD and asthmatic patients behave differently in these fluctuations, which may temptingly allow FOT data to discriminate between the two disease groups (Citation84).
Targeting drugs to the small airways
Inhaled drug administration is the foundation in the management of respiratory disease, yet existing inhaler devices are inefficient as scarcely 20% of the drug reaches the lungs, and the wasted part of the drug dose may give rise to side-effects (Citation85). Indeed, most devices emit aerosolized drug with a particle size between 2 and 6 μm MMAD (during in-vitro testing known as the fine particle fraction (FPF)) that mainly deposits drug in the proximal conducting airways (Citation86). Inhaled β2-agonists, muscarinic-antagonists, and corticosteroids are the mainstay of drug therapy in patients with asthma and COPD (Citation87,Citation88). A major limiting factor in the clinical benefit provided by current devices may be poor delivery of inhaled drug to the inaccessible diseased peripheral small airways, and it is intuitive that the key to successful treatment is to target accurately drug to the diseased lung regions.
Systemic (oral, parenteral) delivery of anti-inflammatory therapy may achieve therapeutic targeting of the peripheral small airways over and above regular inhaled administration, although data are limited and there is greater potential for adverse effects. The addition of oral prednisone to asthmatics receiving high-dose inhaled corticosteroids (ICS) was effective in attenuating small airways inflammation with improvements in alveolar NO concentrations (Citation70,Citation89). However, in contrast, studies involving oral anti-leukotriene antagonists added to standard ICS therapy did not produce an improvement in alveolar NO (Citation90,Citation91).
Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung sites may improve the clinical response, and this can be achieved by controlling the aerosol characteristics in the inhalation device and/or the patient's breathing parameters during device–patient interaction (). Of the aerosol characteristics, drug particle size is the most important that determines the site and distribution of inhaled drug deposition within the lungs.
Figure 2. Properties influencing the lung deposition of medical aerosols.
Using lung scintigraphy, it has been shown that altering aerosol drug particle size can direct inhaled therapy to different airway regions in the lungs of asthmatic patients, where large (6 μm and 3 μm) radio-labelled salbutamol particles achieved greater proximal airways deposition compared to smaller particles (1.5 μm) that preferentially deposited in distal lung regions (Citation92). The larger β2-agonist particles produced greater bronchodilation than the smaller particles, and it was reasoned they were better targeted to their therapeutic site of action, the airway smooth muscle, which is greater in the proximal conducting rather than the distal acinar airways. However, the smaller particles achieved greater total lung deposition, lower oropharyngeal deposition, were less affected by changes in patient inhalation flow, and achieved better penetration into the distal airways compared to the larger particles. It was additionally observed that slower patient inhalation flows achieved better improvements in spirometric measures than fast inhalation of aerosol (Citation92). The significance of the aerosol science of altering drug particle size and inhalation flow is being recognized and translated into new pharmaceutical formulations and inhalation devices for clinical patient use.
New drug formulations and device technologies
It is apparent that inhaled drug needs to be directed not only to large but also small airways in the management of patients with asthma and COPD, and this requires improvements in aerosol delivery technology. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol MMAD and improved inhaler devices that emit aerosolized drug at slower inhalation flows.
Pharmaceutical formulations that incorporate newer propellants such as hydrofluoroalkane (HFA) have been developed with ultrafine small drug particles (∼1 μm MMAD) in pMDI devices, where improved total lung deposition has been observed compared to older chlorofluorocarbon (CFC) propellant devices. These formulations are available for long-acting β2-agonists (formoterol), corticosteroids (beclomethasone dipropionate (BDP), ciclesonide, flunisolide), and fixed combinations of drug (BDP/formoterol, ciclesonide/formoterol) (Citation50).
HFA-ciclesonide (1.1 μm MMAD) achieved 52% lung deposition in a study involving mild asthmatics (Citation93). In healthy volunteers, 53% lung deposition was seen with HFA-BDP (0.9 μm MMAD) compared to 4% deposition with larger-size CFC-BDP (3.5 μm MMAD) (Citation94). HFA-BDP was shown to achieve similar efficacy in FEV1 as observed with CFC-BDP using much lower drug doses in asthmatic patients (Citation95). The fixed drug combination of HFA-BDP/formoterol (1.3 μm MMAD) has been shown to achieve consistent total lung deposition (TLD) between different patient populations irrespective of airway disease severity: healthy subjects (TLD 34%; FEV1 112% predicted), asthmatics (TLD 31%; FEV1 75% predicted), and COPD patients (TLD 33%; FEV1 44% predicted) (Citation96). HFA-BDP/formoterol was also observed to be sufficiently distributed to both the large and small airways with approximately two-thirds of drug to central airways and approximately one-third delivered to peripheral airways. Randomized double-blind studies have shown that HFA-BDP/formoterol pMDI was not inferior to the fixed combination of HFA-salmeterol/fluticasone propionate pMDI and budesonide/formoterol dry powder inhaler (DPI) in spirometric measures, clinical symptoms, and asthma control (Citation97,Citation98).
There is some evidence to suggest targeting drug therapy improves measures of small airways dysfunction; however, decisive large clinical trials are needed. In asthmatic patients, specific FOT indices of small airways improved with inhaled HFA-BDP treatment compared to CFC-BDP, and similar observations on FOT were noted in a separate study with HFA-ciclesonide compared to DPI fluticasone propionate (Citation99,Citation100). Acinar ventilation heterogeneity determined by MBN2W improved when asthmatics were switched from DPI-budesonide (large particle sized drug) to pMDI HFA-BDP (small particle sized drug) (Citation101). In asthmatics, HFA-ciclesonide was shown to significantly decrease alveolar NO (Citation102), whereas, in contrast, DPI-fluticasone propionate decreased bronchial NO but had no effect on alveolar NO (Citation103).
A propellant-free inhaler device, Respimat™ (Boehringer-Ingelheim, Germany), has been developed that generates aerosolized drug as a slow-moving fine cloud that is emitted over a long duration. In-vitro testing shows the device delivers a FPF at least twice as high as most CFC-pMDIs and DPIs (Citation104). For aqueous and ethanolic drug solutions emitted from the device, the MMAD is smaller compared to conventional devices, being 2 μm and 1 μm, respectively. In-vivo gamma-scintigraphy studies show greater total lung deposition with the device (45%) compared to CFC-pMDI and spacer (26%) using the corticosteroid flunisolide in healthy subjects (Citation105), and greater total lung deposition (52%) compared to DPI-budesonide (29%) using the corticosteroid budesonide in asthmatics (Citation106), where, importantly, a more peripheral lung distribution of drug was observed compared to the DPI inhaler. In COPD patients with poor pMDI technique, higher total lung deposition was achieved with the device (37%) compared to CFC-pMDI (21%) using a combination drug formulation of short-acting β2-agonist and short-acting muscarinic-antagonist (Citation105). In the United Kingdom, the Respimat device is clinically available with a long-acting muscarinic-antagonist, tiotropium, at a daily dose of 5 μg for use in COPD patients (Citation107). Tiotropium is also available in a DPI device, HandiHaler™ (Boehringer-Ingelheim), at a higher 18 μg daily dose where total lung deposition is only 20% of the filling dose in healthy subjects and COPD patients (Citation108), although data show that both of the devices (slow-moving cloud device and DPI device at their daily prescribed clinical dose of tiotropium), achieve similar plasma pharmacokinetic drug profiles in COPD patients (Citation109).
However, paradoxically, the role of the more efficient slow-moving cloud device versus the less efficient DPI HandiHaler in delivering tiotropium to the lungs has received considered attention (Citation110). Three clinical trials of 1 year's duration have each reported an increase in mortality with the Respimat-tiotropium device compared to placebo, whereas in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) prospective clinical trial of 4 years’ duration, there was no increase in mortality with the HandiHaler-tiotropium device compared to placebo (Citation111). The Federal Drug Administration in the United States has currently not approved the Respimat device, and in a recent commentary highlighted the importance of delivery devices as critically important components to achieve the therapeutic effect of inhaled drug in the lungs (Citation110). A large prospective safety study comparing the two device formulations is currently in progress to evaluate further these findings.
Summary
Future studies are needed, particularly in patients with severe asthma and COPD, to determine whether the improvements in distal lung deposition and small airways function with ultrafine particles and new device technologies are translated into clinically significant patient outcomes such as improved control of symptoms, better health-related quality of life, fewer drug adverse effects, and decreased hospital exacerbations.
Declaration of interest: The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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