In vitro model for investigating aerosol dispersion in a simulated COVID-19 patient during high-flow nasal cannula treatment.

The use of high-flow nasal cannula in the treatment of COVID-19 infected patients has proven to be a valuable treatment option to improve oxygenation. Early in the pandemic, there were concerns for the degree of risk of disease transmission to health care workers utilizing these treatments that are considered aerosol generating procedures. This study developed an in vitro model to examine the release of simulated patient-derived bioaerosol with and without high-flow nasal cannula at gas flow rates of 30 and 50 L/min. Aerosol dispersion was evaluated at 30 and 90 cm distances. Reduction of transmission risk was assessed using a surgical facemask on the manikin. Results indicated that the use of a facemask facilitated a 94-95% reduction in exhaled aerosol concentration at 30 cm and 22-60% reduction for 90 cm distance across both gas flow rates. This bench study confirms that this in vitro model can be used as a tool to assess the risk of disease transmission during aerosol generating procedures in a simulated patient and to test factors to mitigate the risk.

Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis.

Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 µm as measured by cascade impaction, and a volumetric median diameter of 4.09 µm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB.

Cellular Immunotherapy and the Lung.

The new era of cellular immunotherapies has provided state-of-the-art and efficient strategies for the prevention and treatment of cancer and infectious diseases. Cellular immunotherapies are at the forefront of innovative medical care, including adoptive T cell therapies, cancer vaccines, NK cell therapies, and immune checkpoint inhibitors. The focus of this review is on cellular immunotherapies and their application in the lung, as respiratory diseases remain one of the main causes of death worldwide. The ongoing global pandemic has shed a new light on respiratory viruses, with a key area of concern being how to combat and control their infections. The focus of cellular immunotherapies has largely been on treating cancer and has had major successes in the past few years. However, recent preclinical and clinical studies using these immunotherapies for respiratory viral infections demonstrate promising potential. Therefore, in this review we explore the use of multiple cellular immunotherapies in treating viral respiratory infections, along with investigating several routes of administration with an emphasis on inhaled immunotherapies.

Evaluation of Aerosol Drug Delivery Options during Adult Mechanical Ventilation in the COVID-19 Era.

Drug delivery devices used for aerosol therapy during mechanical ventilation to ease the symptoms of respiratory diseases provide beneficial treatment but can also pose challenges. Reflecting the significant changes in global guidance around aerosol usage and lung-protective ventilation strategies, seen in response to the COVID-19 pandemic, for the first time, we describe the drug delivery performance of commonly used devices under these conditions. Here, vibrating mesh nebuliser (VMN), jet nebuliser (JN) and pressurised metered-dose inhaler (pMDI) performance was assessed during simulated adult mechanical ventilation. Both standard test breathing patterns and those representatives of low tidal volume (LTV) ventilation with concurrent active and passive humidification were investigated. Drug delivery using a VMN was significantly greater than that with a JN and pMDI for both standard and LTV ventilation. Humidification type did not affect the delivered dose across all device types for standard ventilation. Significant variability in the pMDI dosing was evident, depending on the timing of actuation and the adapter type used. pMDI actuation synchronised with inspiration resulted in a higher delivered drug dose. The type of adapter used for pMDI actuation influenced drug delivery, with the highest dose observed using the CombiHaler.

In vitro evaluation of disposable transport ventilators with combination aerosol therapy.

BACKGROUND: The COVID-19 pandemic has highlighted the need for alternative short-term, reliable means to aid in the treatment of patients requiring ventilatory support. Concurrent aerosol drug delivery is often prescribed to such patients. As such, this study examines one such short-term option, the disposable gas-powered transport ventilator to effectively deliver aerosol therapy. Factors such as aerosol generator type, patient breathing pattern, humidification and nebuliser position within the respiratory circuit were also examined. METHODS: Aerosol drug delivery characterisation was undertaken using two different disposable transport ventilators (DTVs). Two different nebuliser types, a closed circuit vibrating mesh nebuliser (VMN) and an open circuit jet nebuliser (JN), at different locations in a respiratory circuit, proximal and distal to an endotracheal tube (ETT), with and without passive humidification, were evaluated in simulated adult and paediatric patients. RESULTS: Placement of a nebuliser proximal to the ETT (VMN: 25.19%-34.15% and JN: 3.14%-8.92%), and the addition of a heat and moisture exchange filter (VMN: 32.37%-40.43% and JN: 5.60%-9.91%) resulted in the largest potential lung dose in the adult patient model. Irrespective of nebuliser position and humidification in the respiratory circuit, use of the VMN resulted in the largest potential lung dose (%). A similar trend was recorded in the paediatric model data, where the largest potential lung dose was recorded with both nebuliser types placed proximal to the ETT (VMN: 8.12%-10.89% and JN: 2.15%-3.82%). However, the addition of a heat and moisture exchange filter had no statistically significant effect on the potential lung dose (%) a paediatric patient would receive (p>>0.05). CONCLUSIONS: This study demonstrates that transport ventilators, such as DTVs, can be used concurrently with aerosol generators to effectively deliver aerosolised medication in both adult and paediatric patients.

Nebuliser Type Influences Both Patient-Derived Bioaerosol Emissions and Ventilation Parameters during Mechanical Ventilation.

COVID-19 may lead to serious respiratory complications which may necessitate ventilatory support. There is concern surrounding potential release of patient-derived bioaerosol during nebuliser drug refill, which could impact the health of caregivers. Consequently, mesh nebulisers have been recommended by various clinical practice guidelines. Currently, there is a lack of empirical data describing the potential for release of patient-derived bioaerosol during drug refill. This study examined the release of simulated patient-derived bioaerosol, and the effect on positive end expiratory pressure during nebuliser refill during mechanical ventilation of a simulated patient. During jet nebuliser refill, the positive end expiratory pressure decreased from 4.5 to 0 cm H2O. No loss in pressure was noted during vibrating mesh nebuliser refill. A median particle number concentration of 710 particles cm-3 above ambient was detected when refilling the jet nebuliser in comparison to no increase above ambient detected when using the vibrating mesh nebuliser. The jet nebuliser with the endotracheal tube clamped resulted in 60 particles cm-3 above ambient levels. This study confirms that choice of nebuliser impacts both the potential for patient-derived bioaerosol release and the ability to maintain ventilator circuit pressures and validates the recommended use of mesh nebulisers during mechanical ventilation.