Extrafine inhaled corticosteroid therapy in the control of asthma

Figures & data

Table 1 Histological evidence of small airways pathology in asthma

Authors	Type of specimen	Subjects	Findings in small airways
Hamid et al^Citation12	Surgically resected lungs	6 asthma, 10 controls	Increased T cells and eosinophils in all asthmatic airways. Greater numbers of activated eosinophils in the small airways.
Kraft et al^Citation14	Transbronchial biopsy (proximal airway endobronchial and distal alveolar tissue)	11 nocturnal asthma, 10 non-nocturnal asthma	Greater number of eosinophils in nocturnal asthma alveolar tissue at 4 am as compared with non-nocturnal asthma. Greater number of eosinophils and macrophages in the nocturnal asthma alveolar tissue at 4 am as compared with 4 pm. Only alveolar tissue eosinophils correlated with the nocturnal decrement in lung function.
de Magalhães Simões et al^Citation15	Nasal mucosa, trachea, intrapulmonary airways and peribronchiolar and distal parenchyma	20 fatal asthma, 10 controls	Higher eosinophil content in all studied areas in fatal asthma. The outer wall of small membranous bronchioles is the main site of inflammatory changes in fatal asthma. There is a localized distribution of alveolar inflammation at the peribronchiolar region for mast cells and neutrophils.
Kuwano et al^Citation18	Autopsied lungs Surgically resected lungs	8 fatal asthma, 7 nonfatal asthma, 15 mild COPD, 15 controls	The membranous airways showed a gradation in wall thickening in fatal asthma > nonfatal asthma > COPD > control.
Aikawa et al^Citation20	Autopsied lungs	3 died of severe acute asthma attack, 5 died of nonstatus asthmaticus, 4 died of nonrespiratory causes (controls)	Increased goblet percent and mucus in patients who died of a severe acute asthma attack; more dominant in the peripheral airways. Mucus correlated with goblet percent in the peripheral airways.
Kuyper et al^Citation21	Autopsied lungs	93 fatal asthma, including 19 children	Cells made up a higher proportion of exudate in the small airways.
Faul et al^Citation22	Autopsied lungs	5 sudden asphyxic asthma deaths	Both proximal and distal tissues showed infiltrates of T cells, macrophages, and eosinophils, with a CD8+ T cell predominance; a high proportion of eosinophils were activated.
James et al^Citation23	Autopsied lungs	18 asthma, 23 controls	Greater wall area (epithelium, muscle, and submucosa) both in the membranous and cartilaginous airways in asthma.
Carroll et al^Citation26	Autopsied lungs	11 fatal asthma, 13 nonfatal asthma, 11 controls	Greater total and outer wall areas in the small membranous bronchioles (perimeter <2 mm) in fatal and nonfatal asthma. Structural changes occur in the large and small airways in fatal asthma, but predominantly in the small airways in nonfatal asthma.
Dolhnikoff et al^Citation27	Autopsied lungs	24 fatal asthma, 11 controls	Increased collagen I and decreased collagen III content in the small airways, increased fibronectin and MMP-1, MMP-2, and MMP-9 content at the outer area of the small airways, increased MMP content in the peribronchiolar parenchyma in asthmatics.
Mauad et al^Citation28	Autopsied lungs	15 fatal asthma, 9 controls	Increased proportion of abnormal alveolar attachments and decreased elastic fiber content in the small airways adventitial layer and in the peribronchial alveoli (but not in the distal alveoli) in fatal asthma.
Balzar et al^Citation29	Endobronchial and transbronchial/surgical biopsy tissue	20 severe asthma	The number of inflammatory cells increased toward the periphery, but the percentage of T lymphocytes, eosinophils, monocytes/macrophages, and neutrophils remained at a similar value or decreased from the large to the small airways. In contrast, mast cell number and percentage, as well as the chymase-positive phenotype increased in the small airway regions. Chymase-positive mast cells in the small airway/alveolar attachments lung region correlated positively with lung function.
Minshall et al^Citation31	Surgically resected lungs	6 asthma, 10 controls	Increased IL-5 and IL-4 mRNA-positive cells both in the large and small airways in asthmatics, but increased expression of IL-5 mRNA in the small airways as compared with the large airways.
Taha et al^Citation32	Surgically resected lungs	6 asthma, 10 controls	Increased expression of eotaxin and monocyte chemotactic protein-4 mRNA in the large and small airways of asthmatics.
Wenzel et al^Citation35	Bronchoalveolar lavage fluid Endobronchial and transbronchial biopsies	14 severe, high-dose oral glucocorticoid-dependent asthma, 12 moderate asthma, 6 controls	Higher numbers of neutrophils and elevated levels of eicosanoid mediators in severe asthma.
Andersson et al^Citation36	Bronchial and transbronchial biopsies	14 uncontrolled asthma, 8 allergic rhinitis, 8 controls	Increased alveolar mast cell density, FcɛRI expression and surface-bound immunoglobulin E in asthma.

Abbreviations: COPD, chronic obstructive pulmonary disease; CD, cluster of differentiation; IL, interleukin; MMP, matrix metalloproteinase; FcɛRI, low-affinity immunoglobulin E (IgE) receptor.

Table 2 Noninvasive tools suitable for assessment of small airways

Method	Scope	Strengths	Weaknesses
FEF25%–75%^Citation43,Citation44	Small airways obstruction Correlates with IOS and HRCT indices	Easy to perform	Too variable Influenced by central airways obstruction or lung volume alterations Fails to correlate with other parameters of air trapping or with small airway inflammation
RV/TLC^Citation43,Citation45	Air trapping Elevated in asthma, particularly in severe disease	Easy to perform	Relatively time-consuming
FVC^Citation43,Citation46,Citation47	Decreased FVC was related to air trapping; FVC correlates inversely with RV/TLC	Easy to perform	Not sensitive Assumes normal TLC
CA(NO)^Citation49^–^Citation52	Ventilation heterogeneity (particularly in severe and refractory asthma) Correlates with RV/TLC, FRC, dN2, CC/TLC, R5–R20	Good reproducibility	Back-diffusion of NO from the conducting airways
HRCT^Citation53^–^Citation58,Citation81	Ventilation heterogeneity (inspiratory CT), air trapping (expiratory CT) Negatively correlates with FEV1/FVC and FEF25%–75% and positively with RV/TLC	Sensitive Good reproducibility and objective if computerized and spirometrically controlled	Radiation Expensive
SBW, MBW tests^Citation45,Citation59^–^Citation65	Ventilation heterogeneity, air trapping, collapsibility of small airways CV and dN2 correlate with RV/TLC dN2 correlates with recurrent exacerbations and asthma control Scond predicts airway hyperresponsiveness	Sensitive, able to detect early changes in small airways Good reproducibility (if computerized)	Difficult to perform
IOS^Citation13,Citation52,Citation66^–^Citation70	Airway mechanics, small airway obstruction R5–R20 correlates with FEF25%–75% and CA(NO) Correlates with symptoms and control better than spirometry	Sensitive Able to distinguish reliably between peripheral and proximal airway effects Does not require any respiratory maneuvers	Relatively time-consuming

Abbreviations: FEF_25%–75%, forced expiratory flow at 25%–75% of forced vital capacity; IOS, impulse oscillometry; HRCT, high-resolution computed tomography; RV, residual volume; TLC, total lung capacity; FVC, forced vital capacity; CA(NO), alveolar concentration of nitric oxide; dN2, slope of Phase III of the washout curve; CC, closing capacity; R5–R20, resistance from 5 to 20 Hz; FEV₁, forced expiratory volume in one second; SBW, single-breath washout; MBW, multiple-breath washout; CV, closing volume; Scond, index of conductive airways ventilation heterogeneity; FRC, functional residual capacity.

Table 3 Changes in small airway inflammation and function as described in studies on extrafine particle sizes of ICS

Authors	Subjects	Treatment	Period	Assessment methods	Outcomes
Micheletto et al^Citation30	15 mild asthma (steroid-naïve)	CFC-BDP 1000 μg (n = 8) versus HFA-BDP 400 μg (n = 7)	12 weeks	MCh challenge	Greater increase in PD20 FEV1 to MCh while treated with HFA-BDP.
Hauber et al^Citation34	12 mild-to-moderate asthma	HFA-flunisolide 340 μg bid	6 weeks	Transbronchial and endobronchial biopsies	Reduction in eosinophils, IL-5, and eotaxin, increase in neutrophils, no change in lymphocytes either in peripheral or central airways. Improvement in lung function.
Bergeron et al^Citation76	12 mild-to-moderate asthma	HFA-flunisolide 340 μg bid	6 weeks	Transbronchial and endobronchial biopsies	Decrease in α-smooth muscle actin area in peripheral airways, which correlates with the percentage increase in FEF25%–75%. No changes in collagen deposition and TGF-β expression.
Ohbayashi^Citation77	74 moderate stable asthma	FP (n = 37) or BUD (n = 37), then switch to HFA-BDP	One year	Induced sputum	Fewer eosinophil-positive patients in both groups and reduction in sputum ECP and eotaxin.
Hoshino^Citation78	30 mild asthma	Ciclesonide 200 μg versus FP 200 μg	8 weeks	IOS Induced sputum	Ciclesonide improved resistance of small airways (R5–R20), distal reactance, reactance area, decreased late-phase sputum eosinophils, increased ACT scores and decreased rescue β2 inhalation compared with FP. No changes in spirometry indices in either group.
Cohen et al^Citation79	16 mild-to-moderate asthma	Ciclesonide 320 μg (n = 9) versus placebo (n = 7)	5 weeks	HRCT SBNW test CA(NO)	Improvements in CA(NO) and MCh-induced air trapping on HRCT as compared with placebo. No changes in other small airways parameters.
Goldin et al^Citation80	31 mild-to-moderate asthma (steroid-naïve)	CFC-BDP 100 μg bid versus HFA-BDP 100 μg bid	4 weeks	HRCT	Greater improvement in air trapping, and less marked increase in MCh-induced air trapping in the HFA-BDP group. Similar improvements in symptoms, spirometry, and PC20 MCh.
Tunon-de-Lara et al^Citation81	25 mild-to-moderate uncontrolled asthma	FP 250 μg bid versus HFA-BDP 200 μg bid	3 months	HRCT	Similar improvements in air trapping.
Yamaguchi et al^Citation82	38 mild-to-moderate asthma (steroid-naïve)	HFA-BDP 200 μg bid (n = 26) versus CFC-BDP 400 μg bid (n = 12)	12 weeks	IOS MCh challenge	Greater improvements in the resistance of small airways (R5–R20) and reactance area (AX) while treated with HFA-BDP. HFA-BDP attenuated MCh sensitivity.
Thongngarm et al^Citation83	30 uncontrolled asthma	HFA-BDP 160 μg bid (n = 20) versus CFC-FP 330 μg (n = 10) in addition to the previous treatment (moderate to high doses of ICS and other controller medications)	3 months	SBNW test	Greater improvements in CV, CV/VC and postbronchodilator FEF25%–75% while treated with HFA-BDP.
Verbanck et al^Citation84	30 stable asthma (wide range of severity)	BUD, then switch to HFA-BDP (the same dose for 6 weeks, then half dose for another 6 weeks)	12 weeks	MBNW test	With the switch to HFA-BDP, improvements in Sacin and RV in the subgroup of patients with abnormal baseline Sacin (n = 16) occurred. Although all patients presented abnormal baseline Scond, no changes were observed in this lung zone.

Abbreviations: CFC, chlorofluorocarbon; BDP, beclomethasone dipropionate; HFA, hydrofluoroalkane; MCh, methacholine; PD₂₀ FEV₁, dose of methacholine required to produce a 20% fall in the forced expiratory volume in one second; bid, twice a day; IL-5, interleukin-5; FP, fluticasone propionate; HRCT, high-resolution computed tomography scan; FEF_25%–75%, forced expiratory flow at 25%–75% of forced vital capacity; TGF-β, transforming growth factor beta; BUD, budesonide; ECP, eosinophil cationic protein; IOS, impulse oscillometry; R5–R20, resistance from 5 to 20 Hz; X5, reactance at 5 Hz; AX, reactance area; ACT, Asthma Control Test; SBNW, single-breath nitrogen washout; CA(NO), alveolar concentration of nitric oxide; PC₂₀ MCh, the provocation concentration of methacholine causing a 20% reduction in FEV₁; ICS, inhaled corticosteroids; CV, closing volume; VC, vital capacity; MBNW, multiple-breath nitrogen washout; Sacin, index of acinar airways ventilation heterogeneity; RV, residual volume; Scond, index of conductive airways ventilation heterogeneity.

Table 4 Clinical outcomes as described by some studies on extrafine particle sizes of ICS

Authors	Subjects	Treatment	Period	Assessment methods	Outcomes
Juniper et al^Citation85	473 stable asthma	CFC-BDP 400–1600 μg, then switch to half dose HFA-BDP (n = 354)	12 months	AQLQ Pulmonary function tests	Greater improvements in AQLQ scores while treated with HFA-BDP. No difference in lung function parameters, symptoms, or β2-agonist use.
Worth et al^Citation86	209 moderate-to-severe asthma	HFA-BDP 800 μg (n = 111) versus BUD 1600 μg (n = 98)	8 weeks	Symptoms Pulmonary function tests	Greater improvements in the percentage of days with no experience of shortness of breath, chest tightness or wheeze, nights without sleep disturbance, and daily asthma symptoms while treated with HFA-BDP. No difference in FEV1, PEF, or β2-agonist use.
Tatsis et al^Citation87	40 moderate asthma or COPD	BUD 400 μg bid or FP 250 μg bid, then switch to HFA-BDP 200 μg (n = 20)	8 weeks	Symptoms Pulmonary function tests	Greater improvements in respiratory symptoms, spirometric values, and β2-agonist use while treated with HFA-BDP.
Boulet et al^Citation88	141 moderate-to-severe asthma	HFA-BDP 800 μg (n = 70) versus CFC-BDP 1500 μg (n = 71)	6 months	Symptoms Pulmonary function tests	Onset of the first exacerbation tended to occur later and asthma symptoms tended to decrease while treated with HFA-BDP. Similar pulmonary function. Similar systemic safety.
Barnes et al^Citation89	Large primary care database for asthma patients	HFA-BDP (n = 3140) versus CFC-BDP (n = 9162)	1 year	Asthma control Exacerbation rate	Patients receiving HFA-BDP are more likely to achieve asthma control.
Huchon et al^Citation90	645 uncontrolled moderate-to-severe asthma	HFA-BDP 200 μg/formoterol 12 μg bid (fixed combination) versus CFC-BDP 500 μg bid and formoterol 12 μg bid, or CFC-BDP 500 μg bid	24 weeks	Primary outcome: morning PEF Secondary outcomes: pulmonary function test symptoms, control, exacerbations	Similar improvements in PEF while using single inhaler HFA-BDP/formoterol or while using separate traditional inhalers. HFA-BDP/formoterol was superior for asthma control and also with reference to the percentage of symptom-free days.
Müller et al^Citation91	111 moderate-to-severe asthma	HFA-BDP/formoterol (n = 53) versus FP/ salmeterol (n = 25) or BUD/formoterol (n = 33)	Cross-sectional real-life study	Asthma control	Better asthma control total score, daytime symptom score, and rescue medication use score; lower mean daily ICS dose while treated with HFA-BDP/formoterol.

Abbreviations: CFC, chlorofluorocarbon; BDP, beclomethasone dipropionate; HFA, hydrofluoroalkane; AQLQ, Asthma Quality of Life Questionnaire; BUD, budesonide; FEV₁, forced expiratory volume in one second; PEF, peak expiratory flow; COPD, chronic obstructive pulmonary disease; bid, twice a day; FP, fluticasone propionate; ICS, inhaled corticosteroids.

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