Are there any guidelines supporting the use of metered dose inhalers (MDIs) versus nebulizers regarding infection transmission?

Introduction
Inhaled medication is the cornerstone of managing respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).1,2 Delivery of inhaled medications generally occurs through aerosol generation with the use of inhalers, such as pressurized metered dose inhalers (MDI), soft mist inhalers, or dry powder inhalers, or nebulizers.3 Each strategy has its own advantages and disadvantages. Inhalers are compact and portable, but patient coordination is required for proper inhalation technique. Nebulizers require no specific inhalation technique or coordination, so may be a more suitable route of medication delivery in infants, young children, and other individuals physically unable to use inhalers. However, nebulizers themselves can be bulky and nonportable, and medication delivery can be time consuming. Additionally, drug delivery via nebulization can be inefficient, as the majority of aerosols generated are released into the environment during expiration rather than making it to the lung. Conversely, an MDI with or without a spacer is a closed system, where medications are deposited directly into the lungs and oropharyngeal region after each actuation.

The rise of coronavirus disease 2019 (COVID-19) pandemic raised particular concern about the risk of transmitting infectious particles from nebulizers of infected individuals to family members, caregivers, and healthcare providers.4,5,6 Since COVID-19 spreads primarily through aerosolization of the virus, aerosol generating medication delivery has been theorized to increase infection transmission, making clinicians question whether nebulizers, an open medication reservoir, should be avoided in favor of MDIs, an enclosed portable inhaler, due to potentially less risk of viral transmission, despite a lack of published evidence on the topic.7 Since the beginning of COVID-19, multiple government agencies and professional organizations have conducted literature reviews and research on the risk of infection transmission via nebulizers to provide clarification on safe use of inhaled medications.2,4,8-11 The purpose of this article is to summarize guidelines and consensus recommendations on the use of nebulized and inhaled medications regarding infection transmission.

Guidelines
The most targeted, relevant guideline found in a literature search focused on infection transmission mitigation and was published by the COPD Foundation Nebulizer Consortium (CNC) in 2023.4 The CNC was developed initially in 2020, in response to the COVID-19 pandemic to assess the safety and highlight potential risk of aerosol-generating procedures in caring for patients with infectious respiratory disease. The consortium is comprised of scientists and healthcare professionals from academic medical centers, including Massachusetts General Hospital, Rush University, and University of North Carolina, among others, representatives from COPD Foundation, Centers for Disease Control and Prevention, American College of Chest Physicians, industry (Theravance Biopharma, Aerogen, etc.), and patient advocates.12 This narrative review and subsequent guidance statements were informed by a systematic review, including relevant articles published between 2000 and 2022.4

Based on the evaluated studies, no causal relationship was found between nebulized therapy and infection transmission, and additional studies are needed to better quantify risk of transmission from nebulizers.4 Additionally, none of the identified studies were able to verify virus viability via the dispersed aerosols after nebulization. Notably, when guidelines for personal protective equipment (PPE) were followed appropriately, there were no reports of increased transmission risk, per the studies included. Based on the evidence, CNC recommends nebulizer use should not be discouraged when clinically indicated and stresses the importance of adherence to recommended safety precautions. Several mitigation strategies for enhancing the safety of nebulized drugs were proposed and CNC provides guidance statements to help clinicians decrease transmission risk when a nebulizer is indicated, both in the health care setting and home environment. Guidance statements where committee authors have at least 50% agreement are summarized in Tables 1 and 2. Notable mitigation strategies outlined by the committee include limiting nebulizer use only to patients where a clear benefit is demonstrated and the use of an MDI is impossible or ineffective, using a vibrating mesh nebulizer over other types of nebulizers (such as jet nebulizers), when possible, and using a filtered mouthpiece over a face mask if able.

Table 1. CNC guidance statements for nebulizer drug delivery in the health care setting.4
Guidance statement Consensus of committee
Health care workers should wear protective masks, preferably an N95 respirator when caring for patients with respiratory infections.aStrongly agree
If a patient can do so effectively, a mouthpiece with an attached filter should be preferred over a face mask.Strongly agree
Healthcare workers should adhere to aseptic technique when loading nebulized medications.Strongly agree
Patients should exhale through the mouthpiece and keep the interface in place while nebulizer is active.Strongly agree
Attaching a proprietary filterb to the expiratory limb of the ventilator circuit to trap emitted aerosol is recommended.Strongly agree
If a mouthpiece is inappropriate, a face mask with a scavenger system or exhalation filter can be used.Strongly agree
When using jet nebulizers, the use of disposablec is preferred over reusable.Agree
Important considerations for nebulized medication delivery include negative-pressure rooms, disposing of used equipment, and maintaining appropriate distance from the patient.aAgree
aCDC guidance includes considerations about pathogens, device instructions, availability of negative pressure rooms, and other available space, using a layered approach to reduce exposure.
bDefined as a filter required for use with a specific ventilator that cannot be substituted easily with any other filter.
cRefers to 1-time use or use in a single patient for up to 24 hours.
Abbreviations: CDC=Centers for Disease Control and Prevention; CNC=COPD Foundation Nebulizer Consortium
Table 2. CNC guidance statements for nebulizer drug delivery in the home environment.4
Guidance statement Consensus of committee
Instructions for cleaning and disinfecting devices from manufacturer must be strictly adhered.Strongly agree
Patients/caregivers should adhere to aseptic technique when loading medications.Strongly agree
Nebulization treatment should be administered near an open window or where the air is not recirculated into the house.Agree
Using a mouthpiece is preferred over a face mask. If a face mask is necessary, use with exhalation filters.Agree
Air purifiers can be utilized.Agree
When using jet nebulizers, the use of disposablea is preferred over reusable.Agree
aRefers to 1-time use or use in a single patient for up to 24 hours.
Abbreviations: CNC=COPD Foundation Nebulizer Consortium

The CNC guideline also acknowledged that other professional organizations and government entities put forth recommendations or guidance statements regarding nebulizer use during the COVID-19 pandemic.4 Some of the current recommendations from those organizations are summarized in Table 3 below. In general, most organization recommendations align with CNC guidance statements, in the context of their practice settings, with appropriate use of PPE stressed by multiple organizations.

Table 3. Recommendations from other organizations.2,8-11
OrganizationsYearRecommendations
GINA22023In areas where COVID-19 is moderate or high, nebulizers should be avoided when possible, during acute asthma attacks due to the increased risk of infection dissemination. A pressurized MDI via a spacer, with a mouthpiece or tightly fitting face mask is preferred.

If a nebulizer is required in a setting where COVID-19 infection is possible, infection control procedures should be adhered to.
NIH
COVID-19 treatment guidelines8		2023Advise non-hospitalized patients with COVID-19 to avoid the use of nebulized medications in the presence of others to avoid aerosolization of SARS-CoV-2.
GOLDa,92022When possible, inhalers should be used instead of nebulizers. When nebulizer therapy is essential, a mesh nebulizer should be used to keep the circuit intact and prevent transmission of COVID-19. The risk of infection transmission at home can be lowered when nebulized therapy is used in the absence of others or in places near windows or in increased air circulation areas.
Surviving Sepsis Campaign, international102021It is recommended that healthcare professionals performing aerosol-generating procedures on patients with COVID-19 in the ICU use fitted respirator masks as opposed to surgical masks, in addition to other appropriate PPE.

Aerosol-generating procedures for this population should be performed in a negative-pressure room.
ACAAI112020Administer nebulized medication in a location where air is not recirculated into the home to minimize exposure risk to others.
a2023 GOLD guidelines do not mention use of nebulizers in the context of infection transmission.1
Abbreviations: ACAAI=American College of Allergy, Asthma, & Immunology; COVID-19=coronavirus disease 2019; GINA=Global Initiative for Asthma; GOLD=Global Initiative for Chronic Obstructive Lung Disease; ICU=intensive care unit; MDI=metered dose inhaler; NIH=the National Institute of Health; PPE=personal protective equipment.

Additional literature
Since the publication of the CNC guideline, 2 additional studies specifically focusing on the risks of infection transmission associated with nebulizer therapy have been published.13,14 Important aspects of the studies are summarized in table 4 below. Both studies were small, single arm cohort studies to determine viral load in aerosols emitted with nebulization in patients with COVID-19. After sampling aerosol droplets released from nebulization, samples from 2 out of 10 patients in Thibon et al (2013) and 2 out of 13 patients in Gohli et al (2022) tested positive for SARS-CoV-2, highlighting the risk of viral dissemination during nebulization. No information was obtained on viral viability and infection control measures were not described. These studies reinforce the importance of precautions against airborne infections when administering nebulizer therapy, including appropriate PPE and other infection control measures.

Table 4. Summary of additional studies not included in the systematic review.13,14
Study DesignSubjectsInterventionsResultsConclusionLimitations
Thibon 202313
Prospective cohort study		Patients (N=10) with moderate or severe COVID-19 (defined as pneumonia without oxygen or respiratory failure). Patients had to be able to perform 10-minute nebulization session with a mouthpiece.All patients received nebulization via a jet nebulizer, and 2 samplings were performed to assess the presence of SARS-CoV-2 RNA in residual aerosols.None of the 10 aerosol samples were conclusively positive to SARS-CoV-2; 2 of the 10 samples were slightly positive to SARS-
CoV-2 (<103 copies/mL)		The study confirmed the risk of SARS-CoV-2 dissemination during nebulizationSmall study sample size
RT-PCR can detect the presence of viral load in the aerosols but not the viability of the virus
No PPE descriptions were described, and clinical outcomes of present healthcare workers were not collected
Gohli 202214
Prospective cohort study		Adults (n=13) with COVID-19 admitted to wardAir samples were collected from patient isolation rooms prior to and during nebulization sessions.2 of 13 samples collected during nebulization were positive for SARS-CoV-2 by RT-PCR. No samples collected prior to nebulization were positive for SARS-CoV-2The study demonstrated an increased risk of SARS-CoV-2 dissemination during nebulizationSmall study sample size
Samples were collected after patients had been ill for a long period of time, so viral loads may have declined compared to more recent illness.
Abbreviations: COVID-19=coronavirus disease 2019; PPE=personal protective equipment; RNA=ribonucleic acid; RT-PCR= reverse transcription–polymerase chain reaction.

Conclusion
Multiple professional organizations have published guidance related to infection transmission risk with nebulization. Studies evaluated in these guidelines have found no causal relationship between nebulized therapy and infection transmission, and additional studies are needed to better quantify risk of transmission from nebulizers. None of the identified studies were able to verify virus viability after nebulization. Based on these studies, the major consensus across guidelines was to not withhold nebulizer therapy if clinically indicated. In general, organizations recommend the use of an MDI in a patient with COVID-19 if possible. However, if nebulizer therapy is indicated, mitigation strategies and appropriate use of PPE and infection control measures are recommended by all organizations, both in the healthcare environment or home environment. Notably, when guidance for PPE were followed appropriately in clinical studies, there were no reports of increased transmission risk, per the systematic review conducted by CNC. Based on the evidence, nebulizer use should not be discouraged when clinically indicated and adherence to recommended safety precautions is critical to reduce the risk of infection transmission.

References

  1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report. 2023. Accessed December 26, 2023. https://goldcopd.org/2024-gold-report/
  2. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention: 2023 update. Updated July 2023. Accessed December 26, 2023. https://ginasthma.org/2023-gina-main-report/
  3. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56(6):600-612. doi:10.1046/j.1365-2125.2003.01893.x
  4. Biney I, Ari A, Barjaktarevic IZ, et al. Guidance on mitigating the risk of transmitting respiratory infections during nebulization by the COPD Foundation Nebulizer Consortium. Chest. 2023;S0012-3692(23)05708-2. doi:10.1016/j.chest.2023.11.013
  5. Sethi S, Barjaktarevic IZ, Tashkin DP. The use of nebulized pharmacotherapies during the COVID-19 pandemic. Ther Adv Respir Dis. 2020;14:1753466620954366. doi:10.1177/1753466620954366
  6. Institute of Safe Medication Practices (ISMP). Revisiting the need for MDI common cannister protocols during the COVID-19 pandemic. March 26, 2022. Accessed December 26, 2023. https://www.ismp.org/resources/revisiting-need-mdi-common-canister-protocols-during-covid-19-pandemic
  7. Lavorini F, Usmani OS, Dhand R. Aerosol delivery systems for treating obstructive airway diseases during the SARS-CoV-2 pandemic. Intern Emerg Med. 2021;16(8):2035-2039. doi:10.1007/s11739-021-02812-x
  8. Therapeutic management of nonhospitalized adults with COVID-19. National Institutes of Health. Updated November 2, 2023. Accessed December 26, 2023. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/nonhospitalized-adults–therapeutic-management/
  9. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for prevention, diagnosis and management of COPD: 2022 Report. 2022. Accessed December 26, 2023. https://staging.goldcopd.org/2022-gold-reports-2/
  10. Alhazzani W, Evans L, Alshamsi F, et al. Surviving Sepsis Campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: first update. Crit Care Med. 2021;49(3):e219-e234. doi: 10.1097/CCM.0000000000004899
  11. Important COVID-19 information for those with asthma and/or allergies. American College of Allergy, Asthma, & Immunology. Published May 1, 2020. Accessed December 26, 2023. https://acaai.org/news/important-covid-19-information-for-those-with-asthma-and-or-allergies/
  12. COPDF nebulizer consortium. COPD Foundation. Updated October 25, 2023. Accessed December 26, 2023. https://www.copdfoundation.org/Research/Research-Projects-and-Consortia/COPDF-Nebulizer-Consortium.aspx
  13. Thibon C, Vecellio L, Belkhir L, et al. There is a risk of spread during a nebulization session in a patient with COVID-19. J Aerosol Med Pulm Drug Deliv. 2023;36(5):268-274. doi:10.1089/jamp.2023.0010
  14. Gohli J, Brantsæter AB, Bøifot KO, et al. SARS-CoV-2 in the air surrounding patients during nebulizer therapy. Can J Infect Dis Med Microbiol. 2022;9297974. doi:10.1155/2022/9297974

Prepared by:
Vinh Thai, PharmD
PGY1 Pharmacy Resident
University of Illinois at Chicago College of Pharmacy

Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2024

The information presented is current as of December 26, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.