Targeting the small airways with dry powder adenosine: a challenging concept

Abstract

Background: Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. Objective: We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. Design: In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min–1) and once with a high flow rate (60 l min–1). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV1 reflects the large airways, and FEF25–75%, R5-R20 and X5 reflect the small airways. Results: The four adenosine tests were not significantly different with respect to the threshold values of FEV1 (p = 0.12), FEF25–75% (p = 0.37), R5-R20 (p = 0.60) or X5 (p = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. Conclusions: In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.

Therapeutic effects of adenosine in high flow 21% oxygen aereosol in patients with Covid19-pneumonia

“…The results observed in our historical group were, therefore, in line with those reported worldwide for similar patients [ 6 ]. Our findings seem to confirm the results of the preclinical studies in mice were intra-bronchial administration of A2 receptor agonists could restore the anti-inflammatory and tissue protective effects of oxygen-dampened adenosine system [ 20 , 32 – 35 ] ( S1 Fig ). Presently, we do not have enough information to explain the effect of inhaled adenosine therapy on SARS-Cov-2 load; however, it can be hypothesized that adenosine given in hypoxic conditions is able to induce the following effects: i) to restore an appropriate virus-specific immune-response previously attenuated by the inflammatory storm; ii) to exert a direct anti-viral host effect mediated throughout the A2R pathway; iii) to convert the intracellular adenosine in pro-apoptotic metabolites (like deoxy-adenosine/deoxy-ATP) in some infected cells.…”

“…Adenosine was nebulized and dispensed by an Aerogen USB Controller linked to a high flux device with 21% FiO 2 , a flow of 60 l/m in five minutes. Inhaled adenosine dose was extrapolated from the preclinical studies in mice [ 25 , 31 – 33 ] as well as from the clinical studies using adenosine as aereosol formulation showing dose limiting efficacy over 10 mg and no adverse events in normal individuals and patients with non asthmatic disease [ 31 – 35 ]. No concomitant treatment for Covid19 including corticosteroids was allowed.…”

“…Due to the acute medical need and shortage of time, it was impossible to gain access to a synthetic A2A receptor agonists, while adenosine was already available for clinical use (Adenoscan® and Krenosin®) with a number of different applications in humans [ 31 ]. Additionally, adenosine has already been tested as an aerosol formulation (6 to 40 mg per dose), presenting an acceptable safety profile with no hemodynamic or other side-effects in normal subjects, and it is currently used to discriminate patients with small respiratory tract asthmatic disease from chronic inflammatory lung disease [ 32 – 35 ]. In this retrospective data analysis, we report on safety and efficacy of adenosine as inhalatory formulation to patients with severe Covid-19-realted interstitial pneumonitis with a PaO 2 /FiO 2 ratio <300 requiring ventilator supports as a compassionate life-saving therapeutic act.…”

Efficacy and Effect of Inhaled Adenosine Treatment in Hospitalized COVID-19 Patients

“…The administration of aerosolized adenosine has a dose-limiting efficacy >10 mg. Its use did not show adverse effects in non-asthmatic subjects ( 47 , 48 ).…”

Finally More Direct Evidence That Impulse Oscillometry Measures Small Airway Disease

“…The group from Vancouver has added analysis of actual pathology specimens from explanted lungs to further assess the smaller airways, which could be a useful addition for the current technique as well (7, 8). In addition, the modeled sites of constriction from trachea to small airways could perhaps be further validated by actually imposing constriction in patients with asthma in different parts of the bronchial tree (e.g., with small vs. large particle size bronchoprovocation agents) (9).…”