PROMOTING SAFE AND EFFECTIVE USE OF AEROSOL DEVICES IN COVID-19:RISKS AND SUGGESTIONS FOR VIRAL TRANSMISSION

KEYWORDS:

• Aerosols
• nebulizers
• metered-dose inhalers
• dry powder-inhalers
• soft-mist inhalers
• Covid-19
• and viral transmission

1. Promoting safe and effective use of aerosol devices in COVID-19

While aerosol devices play a crucial role in the treatment of pulmonary diseases, aerosol drug delivery is considered as a risk for viral transmission and cross-infection between patients, and healthcare professionals (HCPs) in the era of COVID-19. Although the current pandemic demands serious precautions for infection control and prevention, there is no scientific guideline for preventive measures that can be used to minimize viral transmission through aerosol devices. Therefore, evaluating each aerosol device for potential contamination, and viral transmission as well as providing strategies to use each device safely and effectively is vital in this global pandemic.

Pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), soft-mist inhalers (SMIs), and nebulizers are commonly used in the treatment of pulmonary diseases. Each aerosol device has advantages, limitations, and risks for device contamination and viral transmission (Table 1). Although there is no ranking system available in the literature that evaluates the risk of transmission with various aerosol delivery devices, the rationale behind such an evaluation system could be the treatment time, the amount of emitted dose and aerosol mass generated by the device during aerosol therapy as well as the design of the device that impacts the risk of contamination during device preparation, cleaning and maintenance. For instance, inhalers have short treatment time, deliver a lower emitted dose and generate less aerosol mass than nebulizers. Since the drug is enclosed in the inhaler, they are hard to contaminate compared to nebulizers with an open medication reservoir. Because of these rationales, it is assumed that the risk for device contamination and viral transmission with inhalers may be lower than nebulizers. However, further research is warranted to provide direct evidence on the risk of device contamination and viral transmission with various aerosol devices used in the treatment of patients with COVID-19.

Table 1. The advantages, limitations and risks for device contamination and viral transmission of aerosol devices

Devices	Advantages	Limitations	Risk for Device Contamination	Risk for Viral Transmission
pMDIs	Portable Compact Easy to use Multi-dose device Short treatment time	High oropharangeal deposition Requires hand-breath coordination Need to prime if not used recently Need to shake before use Not all medications are available	Low	Low
DPIs	Portable Compact Breath-actuated Short treatment time	Requires moderate to high inspiratory flow Some devices are single dose Susceptible to environmental humidity Not all medications are available	Low	Low
SMIs	Portable Multi-dose device Less dependence on inspiratory flow Slow velocity aerosol Long plume duration No propellant Dose indicator	Needs to be assembled initially Not breath actuated Need to prime if it is not used for several days Not all medications are available	Low	Low
Jet Nebulizer	No need for hand-breath coordination Easy to use Effective with tidal volume No need for hand-breath coordination High doses possible Dose modification possible	Less portable Requires pressurized gas source Long treatment time Device preparation needed Contamination possible Large residual volume	High	High
Mesh Nebulizer	Quiet Portable Compact No need for hand-breath coordination Easy to use Effective with tidal volume Low residual volume High dose reproducibility Dose modification possible Less drug loss during exhalation	Cost Requires device preparation Less portable	Low	Low

pMDIs offer short treatment time and multi-dose convenience with consistent and accurate dosing [1,2]. They are used with valved-holding chambers (VHCs) to improve aerosol delivery and overcome device-related issues like high oropharyngeal deposition and poor hand-breath coordination [3,4]. Also, training patients to exhale into VHCs may reduce exhaled bioaerosol dispersion to the environment [4]. Contaminating the pMDI during device preparation is less probable because the drug is enclosed in the canister. Since pMDIs are expensive and there is a shortage of pMDIs in the US, a protocol to use the same pMDI in multiple patients have been implemented. Transferring the pMDI from patient to patient is not recommended in the era of COVID-19 where strict infection control and prevention measures are required [5]. While most hospitals use personal VHCs in the common pMDI canister protocol, others disinfect the mouthpiece of the pMDI with alcohol wipes to prevent bacterial contamination. However, the effectiveness of alcohol wipes in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is unknown. Noncompliance with mouthpiece disinfection is also a problem.

Dry-powder inhalers (DPIs) are breath-actuated and overcome issues with hand-breath coordination. However, errors in using DPIs still exist due to inadequate inspiratory effort needed to deliver the drug to the patient. The inspiratory effort required for effective drug delivery varies with each DPI [6]. While forceful inspirations draw the medication from the inhaler and disperse drug particles within the respirable range, they may cause cough or airway irritation that increases the distance of exhaled air dispersion and the risk of viral transmission in the era of COVID-19 [3,4]. Therefore, DPIs should not be used in cough, and airway irritations, as well as in patients who cannot generate a high inspiratory flow rate required to use the DPI effectively. DPIs are categorized as unit-dose and multi-dose DPIs. Due to loading each capsule/blister before treatment, the unit-dose DPIs are more prone to device contamination than multi-dose DPIs in which the drug is enclosed in the inhaler.

The soft-mist inhaler (SMI) provides multi-dose convenience and short treatment time. The small particle size and prolonged spray duration of the SMI reduce oropharyngeal deposition while increasing lung dose [2]. The risk of device contamination and viral transmission with SMIs is low during device preparation and treatment because the drug is enclosed in the inhaler that is discarded after the completion of all doses. However, the number of drug formulations available as SMIs is limited and the device requires some level of hand-breath coordination that may be difficult for patients with respiratory distress.

Unlike inhalers, nebulizers require power, have long treatment time, and need extensive cleaning and maintenance. Jet and mesh nebulizers are widely used in patients with pulmonary diseases. Jet nebulizers are inefficient and inexpensive compared to mesh nebulizers[7]. The highly contagious SARS-CoV-2 increased concerns on viral transmission via aerosols generated by nebulizers [5,8,9]. While some professional organizations recommend using nebulizers when applicable [10,11], others caution clinicians on using nebulizers in COVID-19 [12]. The Center of Disease Control and Prevention does not advise against the use of nebulizers but categorizes them as an unknown exposure to HCPs [13]. Some scholars believe that medical aerosols generated by nebulizers may contain pathogens [5,8,9], whereas others think that is not the case unless the device is contaminated [14]. Understanding different takes on using nebulizers in the era of COVID-19 is necessary to bridge the gap between managing COVID-19 effectively and protecting HCPs from the viral transmission. Although data on the use of aerosol devices in COVID-19 is still evolving, it is also important to review previous evidence to guide patients and clinicians who raise questions on how to use aerosol delivery devices safely and effectively in the era of COVID-19. Whereas two cohort studies reported risks associated with the use of nebulizers in SARS [15,16], another research found no direct association between them [17]. According to previous research, the risk of SARS transmission among HCPs increased by 6.6-fold with intubation and 3.1-fold with noninvasive ventilation as opposed to 0.9 with the nebulizer treatment that was not significant [18]. Additionally, a study conducted by Edwards et al reported that the delivery of isotonic saline with nebulizers can markedly decrease the number of exhaled bioaerosol particles for up to 6 hours after inhalation [19].

The nebulizer design plays an important role in device contamination and the risk of viral transmission. Due to their open design and position below the gas pathway, the patient’s secretion may drop in the reservoir of jet nebulizers. Mesh nebulizers separate the medication from the patient interface through the mesh and have less residual volume (<0.5 mL) than jet nebulizers with a residual volume of ~2 mL, which may create a hospitable environment for microorganisms to grow between treatments. Unlike mesh nebulizers, jet nebulizers operate with an external gas flow that increases exhaled air dispersion to the environment. Recently, Tang et al used a live attenuated influenza vaccine as a surrogate virus tracer and reported that aerosols spread at a decreasing concentration with increasing distance from a simulated spontaneously breathing adult in an isolation room with 12 air changes/hour [20]. They also stated that it can be an issue in home-care where airborne virus concentration may increase gradually over time [20]. Tang et al used a home nebulizer with a facemask in their study and did not attach a filter to the nebulizer to decrease exhaled air dispersion during aerosol therapy. Since the current recommendations suggest using a mouthpiece with nebulizers and attaching a filter to the exhalation port of the nebulizer to minimize exhaled bioaerosol transmission with nebulizers [3,4], the Tang et al. study is a good example of how jet nebulizers should not be used in this global pandemic. Clinicians should consider using nebulizers in a history of poor response to inhalers, inability to perform specific techniques required by inhalers, severe life-threatening respiratory diseases such as status asthmaticus, ventilator-dependent patients, and unavailable drug formulation as an inhaler. As shown in Figure 1, nebulizers should be used with a mouthpiece and a filter attached to the exhalation port of the nebulizer. Clinicians should ensure that the reservoir cap of the mesh nebulizer is closed after each use and the exhalation valve of the mouthpiece was not blocked with the attachment of the filter to the mouthpiece. To avoid this problem, a 22 mm silicon adaptor can be used between the filter and the mouthpiece of the mesh nebulizer.

Figure 1. The use of filters with jet and mesh nebulizers attached to a mouthpiece

There is no evidence for viral transmission with inhalers. However, inhalers may not be the right device in patients with cognitive or neuromuscular impairment, poor hand-breath coordination, inadequate inspiratory strength, and acute respiratory failure receiving mechanical ventilation. The ventilator circuit should be kept intact to eliminate bioaerosol dispersion and viral transmission that may occur during the placement of pMDIs to the circuit [3]. Although no significant difference was found between nebulizers and inhalers in terms of the efficacy of aerosol therapy [21,22], switching from nebulizers to inhalers may cause unintended consequences like inadequate therapeutic effects, worsening disease symptoms, and poor medication adherence due to patients’ inability to use inhalers effectively [23,24]. Patients may be unable to use the pMDI effectively that requires several steps like priming, shaking, actuating the device at the onset of inspiration, slow breathing, and breath-hold for 10 sec. Using DPIs is also a challenge for patients with pulmonary diseases. Due to the excipients of DPIs, patients don’t taste the medication and complain about not receiving any drug during treatment. Some patients fail to exhale before inhaling through the DPI, and others fail to make forceful inspiration. The suboptimal technique may result in disease exacerbations and patient admission to the hospital that may increase the risk of SARS-CoV-2 exposure. Therefore, implementing strategies to improve the safe and effective use of aerosol devices is essential in this global pandemic (Table 2).

Table 2. Suggestions for safe and effective delivery of aerosolized medications with inhalers and nebulizers

Aerosol Devices	Suggestions for Effective Delivery of Aerosolized Medications	Suggestions for Safe Delivery of Aerosolized Medications
pMDIs	Use pMDIs with VHCs. Prime and shake the pMDI before therapy Exhale, actuate the pMDI at the onset of inspiration and breath-hold for 10 seconds	Train patients to exhale into the VHC to reduce exhaled bioaerosol dispersion to the environment. Use a VHC with a mouthpiece. Do not use the same pMDI in multiple patients
DPIs	Follow the manufacturer’s guidelines when using DPIs	Do not use DPIs in patients with cough or airway irritations as well as those who cannot generate a high inspiratory flow rate.
SMIs	Follow the manufacturer’s guidelines when using SMIs	Make sure the patient has some level of hand-breath coordination to use the device correctly.
Jet Nebulizers	Increase the fill volume to 4–5 ml Set the flow rate to 6–8 L/min unless the jet nebulizer is designed for a low flowrate Follow manufacturer’s recommendations to use compressor/nebulizer combination. Do not use different brands of nebulizers and compressors together to prevent deterioration in their performance.	Prefer mouthpiece instead of a facemask Attach a filter to the expiratory port of the nebulizer Remove the remaining drug solution from the nebulizer reservoir after each therapy. Rinse the nebulizer cup with distilled or sterile water Let it air dry on a clean absorbent paper towel. Replace disposable nebulizers every 24 hours
Mesh Nebulizers	Follow the manufacturer’s guidelines when using mesh nebulizers.	Prefer mouthpiece instead of a facemask Attach a filter to the expiratory port of the nebulizer Make sure that the filter does not block the exhalation valve on the mouthpiece. Using a 22 mm silicon adapter is an option to avoid such an issue. Keep the reservoir cap close after use. Clean the nebulizer based on the manufacturer’s guidelines.

All aerosol devices are not manufactured equal. Ensuring device effectiveness and safety in the era of COVID-19 depends on selecting the right device for the right patient after a careful evaluation of device features, the potential risk for device contamination, and viral transmission.

2. Expert opinion

Given the importance of disease management in the era of COVID-19, it is essential to translate the dilemma of using aerosol devices into an evaluation of not only the device but also the patient to recommend an appropriate device tailored specifically to patients’ abilities and clinical conditions. Therefore, it is vital to train patients and clinicians on the risk of contamination during device preparation and viral transmission while providing suggestions on how to use each device safely and effectively in patients with COVID-19.

Patients should continue using prescribed inhaled medications at home. If they develop symptoms of COVID-19, they should isolate themselves in well-ventilated rooms with open windows and take their inhaled medications outside on a porch, patio or in a garage to reduce exhaled air dispersion and the risk of viral transmission to other family members [4]. Wearing a mask, covering the nose and mouth with a tissue during cough and sneeze, discarding tissues in a trash can in the patient’s room, and designating a family member for the care of the patient with COVID-19 are other necessary precautions. In hospitalized patients, device selection should be based on patients’ clinical conditions. While inhalers are good options in spontaneously breathing patients who has no impairments and can perform specific breathing technique, mesh nebulizers should be preferred in patients receiving mechanical ventilation or using high flow nasal cannula [3].

Although there is no evidence showing that aerosols generated by nebulizers contain pathogens unless the nebulizer is contaminated, clinicians should exercise caution with nebulizers and protect themselves from COVID-19 through a stringent sanitization protocol and the use of personal protective equipment (PPE) during aerosol delivery to patients with known or suspected COVID-19. Aerosol therapy should be administered in negative pressure rooms and clinicians should dispose or disinfect PPE after each use.

Declaration of interest

A Ari discloses a relationship with Bayer Pharmaceuticals, ARC Medical, Sunovion Pharmaceuticals, and Aerogen. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.