Journal of Aerosol Medicine and Pulmonary Drug Delivery

There is an urgent need to understand the risk of viral transmission during nebulizer treatment of patients with coronavirus disease 2019 (COVID-19).

To assess the risk of transmitting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS, Middle East respiratory syndrome (MERS), and influenza with administration of drugs via nebulizer.

We searched multiple electronic databases, including PubMed^®, China National Knowledge Infrastructure, Wanfang, preprint databases, and clinicaltrials.gov through December 1, 2020. Any study design in any language describing the risk of viral transmission with nebulizer treatment was eligible. Data were abstracted by one investigator and verified by a second.

We identified 22 articles: 1 systematic review, 7 cohort/case-control studies, 7 case series, and 7 simulation-based studies. Eight individual studies involved patients with SARS, five involved MERS, and one involved SARS-CoV-2. The seven cohort/case-control studies (four high risk of bias [ROB], three unclear ROB) found mixed results (median odds ratio 3.91, range 0.08–20.67) based on very weak data among a small number of health care workers (HCWs) with variable use of personal protective equipment (PPE). Case series had multiple potential contributors to transmission. Simulation studies found evidence for droplet dispersion after saline nebulization and measureable influenza viral particles up to 1.7 m from the source after 10 minutes of nebulization with a patient simulator. Study heterogeneity prevented meta-analysis.

Case series raise concern of transmission risk, and simulation studies demonstrate droplet dispersion with virus recovery, but specific evidence that exposure to nebulizer treatment increases transmission of coronaviruses similar to COVID-19 is inconclusive. Tradeoffs balancing HCW safety and patient appropriateness can potentially minimize risk, including choice of delivery method for inhaled medications (e.g., nebulizer vs. metered dose inhaler) and PPE (e.g., N95 vs. surgical mask).

Understanding the morphology of nasal airways is important in determining the nasal airway deposition of inhaled aerosol. Moreover, objective assessment of the anatomy of human nasal airways is useful to develop a database of reference or normal values as a resource to investigate anatomical abnormalities of airways. Current methods for the objective assessment of the nasal airways are either limited to very few dimensions or can only be performed by specialized researchers. Thus, the main objective of this study was to determine the correlations between the intranasal pressure gradient (Δp) and the key anatomical dimensions of the pediatric nasal airways, which could in turn allow the extrapolation of nasal airway morphology based on simple minimally invasive measurements of pressure.

The anatomical data and Δp were obtained from in vitro studies with nasal airway models of 11 infants ages 3–18 months and 13 children ages 4–14 years old. Key anatomical dimensions were identified based on both rhinology and aerosol dosimetry literature. These anatomic data, including the volume, V, surface area, A_s, length, L, and the minimum cross-sectional area of the replicas, A_min, were then analyzed for correlation with Δp and flow parameters, using Bernoulli's principle and dimensional analysis.

Strong correlations were found between Δp and A_s/L for children, and between Δp and V/A_s for infants. Additional pressure gradient correlations were developed with A_min, V/A_s, V ∕ L , and L.

The correlations identified between anatomic data and Δp have clinical implications in pediatric rhinology, suggesting that certain aspects of airway anatomy in infants and children can be predicted through the measurement of Δp. The airway dimensions, predicted using Δp measurement, may be used in tandem with aerosol nasal deposition correlations that account for nasal airway dimensions.

Inhaled corticosteroids (ICSs) are the main prophylactic treatment for asthma and are used in other diseases, including chronic pulmonary obstructive disease, yet the interaction of ICS particles with the ciliated epithelium remains unclear. The aim of this study was to investigate the earliest interaction of aerosolized fluticasone propionate (FP) particles with human ciliated respiratory epithelium.

A bespoke system was developed to allow aerosolized FP particles to be delivered to ciliated epithelial cultures by nebulization and from a pressurized metered-dose inhaler (pMDI) through a spacer with interactions observed in real time using high-speed video microscopy. Interaction with nonrespiratory cilia was investigated using steroids on brain ependymal ciliary cultures. The dissolution rate of steroid particles was determined.

FP particles delivered by aerosol attached to the tips of rapidly beating cilia. Within 2 hours, 8.7% ± 1.8% (nebulization) and 12.1% ± 2.1% (pMDI through spacer) of ciliated cells had one or more particles attached to motile cilia. These levels decreased to 5.8% ± 1.6% (p = 0.59; nebulization) and 5.3% ± 2.2% (p = 0.14; pMDI through spacer) at 24 hours. Particle attachment did not affect ciliary beat frequency (p > 0.05) but significantly (p < 0.001) reduced ciliary beat amplitude. Steroid particles also attached to the tips of motile ependymal brain cilia and also reduced beat amplitude (24 hours: >2 particles bound p < 0.001). Dissolution of FP particles was slow with only 22.8% ± 1.3% of nebulized and 12.8% ± 0.5% of pMDI-delivered drug dissolving by 24 hours.

FP particles adhere to the tips of rapidly moving cilia with significant numbers remaining bound at 24 hours, resisting the shear stress generated by ciliary beating. In vivo, this mechanism may predispose to high local drug concentrations and enhance respiratory and systemic corticosteroid exposure.

Easyhaler (registered trademark by Orion Corporation) is a multidose dry powder inhaler (DPI) for the treatment of asthma and chronic obstructive pulmonary disease (COPD), designed to be simple and easy to use. Salmeterol–fluticasone propionate (S-F) Easyhaler (50/250 and 50/500 μg per dose), available in several European countries, provides combined inhaled corticosteroid and long-acting beta agonist therapy for the management of asthma and COPD. A requirement of the European Committee for Medical Products for Human Use guidelines is to demonstrate product performance under conditions that mimic real-life patient use. Therefore, our aims were to assess the robustness of the S-F Easyhaler by assessing the delivered dose (DD) and fine particle dose (FPD) throughout the inhaler lifespan and under simulated environmental stress conditions.

This was a noncomparative exploratory in vitro study. Two batches and six to nine inhalers per batch from both dose strengths were used to assess drug delivery performance over the inhaler lifespan (doses 1–60). For determining the impact of simulated environmental stress (tests for exposure of dropping, vibration, moisture, and freeze–thawing) on DD and FPD, one batch and three inhalers per batch from both dose strengths were used per test, respectively. Aerodynamic particle size distribution was evaluated during the simulated dropping and vibration tests.

DD and FPD from both dose strengths of S-F Easyhaler performance remained consistent through the inhaler lifespan and simulated environmental stress did not affect its performance. Similar DD and FPD values were observed with or without dropping, vibration, exposure to moisture, and freeze–thawing, and no inhaler breakages occurred during the simulated tests.

The in vitro performance of S-F Easyhaler at both dose strengths suggests that reliable dosing and robustness can be achieved under real-life stress conditions; S-F Easyhaler is a durable DPI for the management of asthma and COPD.

Aspergillosis is a serious fungal lung infection caused by Aspergillus spp. and is often fatal in immunocompromised patients. Current antifungal drug treatment and delivery results in modest efficacy in these patients may be due to low drug distribution to the lung. A comparison of intravenous (IV) caspofungin and lung-targeted inhaled caspofungin was conducted in rats. The goal was to determine the concentrations of drug at the site of infection and systemic distribution that leads to toxicity. This was performed to understand the difference in the in vitro activity of caspofungin and modest in vivo efficacy.

Caspofungin was delivered to rats through IV injection and nose-only inhalation. Each cohort received a single 2 mg/kg dose of drug. Plasma and tissue samples were analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) and drug levels were compared.

The lung drug level was above the minimum effective concentration for 168 hours in the inhaled group but <24 hours in the IV cohort. The lung C_max and area under curve (AUC) in the inhaled group was 20 times higher than in the IV group. Lung-targeted delivery doubled lung drug half-life compared with IV delivery. Systemic distribution to the liver and kidney was 45% lower for the inhaled cohort than the IV group of animals.

Based on pharmacokinetic and pharmacodynamic indices, lung-targeted inhaled caspofungin is likely to provide an improved therapeutic benefit without any increase in systemic toxicities. Furthermore, inhaled delivery supports a weekly dosing regimen instead of daily IV dosing.

Functional respiratory imaging (FRI) is a computational fluid dynamics-based technique using three-dimensional models of human lungs and formulation profiles to simulate aerosol deposition.

FRI was used to evaluate lung deposition of extrafine beclomethasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB) and extrafine BDP/FF delivered through pressurized metered dose inhalers and to compare results with reference gamma scintigraphy data. FRI combined high-resolution computed tomography scans of 20 patients with moderate-to-severe chronic obstructive pulmonary disease (mean forced expiratory volume in 1 second 42% predicted) with in silico computational flow simulations, and incorporated drug delivery parameters to calculate aerosol airway deposition. Inhalation was simulated using profiles obtained from real-life measurements.

Total lung deposition (proportion deposited in intrathoracic region) was similarly high for both products, with mean ± standard deviation (SD) values of 31.0% ± 5.7% and 28.1% ± 5.2% (relative to nominal dose) for BDP/FF/GB and BDP/FF, respectively. Pairwise comparison of the deposition of BDP and FF gave a mean intrathoracic BDP/FF/GB:BDP/FF deposition ratio of 1.10 (p = 0.0405). Mean intrathoracic, central and peripheral deposition ratios for BDP were 1.09 (95% confidence interval [CI]: 1.05–1.14), 0.92 (95% CI: 0.89–0.96), and 1.20 (95% CI: 1.15–1.26), respectively, and for FF were 1.11 (95% CI: 1.07–1.15), 0.94 (95% CI: 0.91–0.98), and 1.21 (95% CI: 1.15–1.27), within the bioequivalence range (0.80–1.25) for intrathoracic and central regions, and slightly exceeding the upper boundary in the peripheral region. Mean ± SD central:peripheral deposition (C:P) was 0.48 ± 0.13 for BDP/FF/GB and 0.62 ± 0.17 for BDP/FF, indicating a higher proportion of drug deposition in the small airways than in the large airways.

FRI demonstrated similar deposition patterns for extrafine BDP/FF/GB and BDP/FF, with both having a high lung deposition. Moreover, the deposition patterns of BDP and FF were similar in both products. Furthermore, the C:P ratios of both products indicated a high peripheral deposition, supporting small airway targeting and delivery of these two extrafine fixed combinations, with a small difference in ratios potentially due to mass median aerodynamic diameters.