Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma.

BACKGROUND: Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma. OBJECTIVE: We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design. METHODS: After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting ß-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire. RESULTS: Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) µg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P < .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/µL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab. CONCLUSION: Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.

End-point selection to determine the airway-systemic ratio of inhaled corticosteroids in asthma.

The use of adenosine monophosphate challenge and basal cortisol as short-term surrogate end points of airway-systemic effects of inhaled corticosteroids in asthma is not suitable to properly determine the clinically relevant long-term therapeutic index.

Randomized controlled trial of triple versus dual inhaler therapy on small airways in smoking asthmatics.

BACKGROUND: Smoking worsens underlying asthma inflammation and also induces resistance to inhaled corticosteroids (ICS). Small airways dysfunction measured by impulse oscillometry (IOS) is associated with worse control. OBJECTIVES: We investigated the effects on small airways of adding long-acting beta-agonist (LABA) alone or with long-acting muscarinic antagonist (LAMA) to ICS in asthmatic smokers. METHODS: Sixteen current smokers were enrolled: mean age 44 year, FEV1 84%, FEF25-75 47%, R5 158%, ACQ 1.69, 20 pack year . Patients were converted to a reference ICS as HFA-BDP during initial run-in at median dose of 800 µg/day. Open label olodaterol 5 µg od (OLO) or olodaterol 5 µg/tiotropium 5 µg od (OLO/TIO) was added to HFA-BDP for median duration of 3 weeks in a randomized cross over design, including run-in and washout periods on HFA-BDP. IOS and spirometry were measured after each treatment (BDP/OLO/TIO or BDP/OLO) and at baseline after run-in and washout (BDP). RESULTS: After chronic dosing, IOS outcomes at trough except for R20 were all significantly improved with OLO/TIO compared to OLO. For the primary end-point of total airway resistance (as R5), the mean difference (95%CI) at trough was 0.06 (0.015-0.10) kPa/l/s, peripheral airways resistance (as R5-R20) 0.03 (0.003-0.06) kPa/l/s, peripheral lung reactance area (as AX) 0.38 (0.08-0.68) kPa/l and resonant frequency (as RF) 2.28 (0.45-4.12) Hz. FEF25-75 at trough was also better with OLO/TIO vs TIO: 0.93 (0.86 - 0.95) l/s while FEV1 was not different. CONCLUSIONS: ICS/LABA/LAMA was superior to ICS/LABA on trough small airway outcomes in asthma patients who smoke.

Pragmatic evaluation of inhaled corticosteroid particle size formulations on asthma control.

BACKGROUND: Extra-fine particle formulations of inhaled corticosteroid (ICS) are associated with improved lung delivery. OBJECTIVES: A pragmatic study to assess patient-reported outcomes after switching from fine to extra-fine particle ICS in persistent asthma. METHODS: Twenty-four patients (mean age 48 year, FEV1 84%, ACQ 1.67) received 4 weeks run-in with a constant dose of fine particle ICS (mean dose 710 µg), followed by switching to an equivalent dose of extra-fine particle hydrofluoroalkane beclomethasone dipropionate (mean dose 355µg). Asthma control questionnaire (ACQ), the primary outcome and mini asthma quality of life questionnaire (mAQLQ) were measured pre- and post-run-in (baseline) and after 4 weeks and 8 weeks of switching. RESULTS: Comparing pre- vs post-run-in, there were no differences for ACQ: 1.67 vs 1.65 or AQLQ: 5.08 vs 5.34. There were mean (95%CI) improvements (P < 0.001) from baseline after 8 weeks for ACQ: -0.53 (-0.83, -0.23) and AQLQ: 0.69 (0.35, 1.04), which exceeded the minimal clinically important difference (MCID) of 0.5 for both. There were also differences (P < 0.05) in domiciliary symptoms and reliever use. There were no significant changes at 8 weeks in lung function, FeNO or blood eosinophils. CONCLUSIONS: Pragmatic switching from fine to extra-fine particle ICS at half the dose was associated with clinically relevant improvements in asthma control and quality of life, but not lung function or type 2 biomarkers.

I Say IOS You Say AOS: Comparative Bias in Respiratory Impedance Measurements.

BACKGROUND: The forced oscillation technique (FOT) measures respiratory impedance during normal tidal breathing and requires minimal patient cooperation. OBJECTIVE: To compare IOS and AOS devices in patients with asthma and COPD. METHODS: We compared two different FOT devices, namely impulse oscillometry using a loudspeaker (IOS: Jaeger Masterscreen) and airwave oscillometry using a vibrating mesh (AOS: Thorasys Tremoflo) for pre- and post-bronchodilator measurements in 84 patients with asthma and COPD. RESULTS: The overall pattern of measurement bias was for higher resistance with IOS and higher reactance with AOS, this being the case in asthma and COPD separately. There were small but significantly higher values using IOS for resistance at 5 Hz (R5) and 20(19) Hz (R20(19)). In converse, values for reactance at 5 Hz (X5), reactance area (AX) and resonant frequency (Fres) were significantly higher using AOS but to a much larger extent. The difference in AX between devices was more pronounced in COPD than in asthma. Salbutamol reversibility as % change was greater in asthma than COPD patients with AX but not FEV1. CONCLUSION: Our study showed evidence of better agreement for resistance than reactance when comparing IOS and AOS, perhaps inferring that AOS may be more sensitive at measuring reactance in patients with airflow obstruction.