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The Size and Culturability of Patient-Generated SARS-Cov-2 Aerosol ✉ Joshua L

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The Size and Culturability of Patient-Generated SARS-Cov-2 Aerosol ✉ Joshua L Journal of Exposure Science & Environmental Epidemiology www.nature.com/jes ARTICLE OPEN The size and culturability of patient-generated SARS-CoV-2 aerosol ✉ Joshua L. Santarpia 1,2,3,11 , Vicki L. Herrera1,2, Danielle N. Rivera3, Shanna Ratnesar-Shumate1,2, St. Patrick Reid1,2,11, Daniel N. Ackerman3, Paul W. Denton4, Jacob W. S. Martens4, Ying Fang5, Nicholas Conoan6, Michael V. Callahan7, James V. Lawler2,8, David M. Brett-Major2,9 and John J. Lowe2,10,11 © The Author(s) 2021 BACKGROUND: Aerosol transmission of COVID-19 is the subject of ongoing policy debate. Characterizing aerosol produced by people with COVID-19 is critical to understanding the role of aerosols in transmission. OBJECTIVE: We investigated the presence of virus in size-fractioned aerosols from six COVID-19 patients admitted into mixed acuity wards in April of 2020. METHODS: Size-fractionated aerosol samples and aerosol size distributions were collected from COVID-19 positive patients. Aerosol samples were analyzed for viral RNA, positive samples were cultured in Vero E6 cells. Serial RT-PCR of cells indicated samples where viral replication was likely occurring. Viral presence was also investigated by western blot and transmission electron microscopy (TEM). RESULTS: SARS-CoV-2 RNA was detected by rRT-PCR in all samples. Three samples confidently indicated the presence of viral replication, all of which were from collected sub-micron aerosol. Western blot indicated the presence of viral proteins in all but one of these samples, and intact virions were observed by TEM in one sample. SIGNIFICANCE: Observations of viral replication in the culture of submicron aerosol samples provides additional evidence that airborne transmission of COVID-19 is possible. These results support the use of efficient respiratory protection in both healthcare and by the public to limit transmission. Keywords: SARS-CoV-2; aerosol transmission; viral aerosol; human-generated aerosol Journal of Exposure Science & Environmental Epidemiology; https://doi.org/10.1038/s41370-021-00376-8 INTRODUCTION In order to classify an infectious disease as airborne, studies Since first being reported in December of 2019, Severe acute must show transmission via aerosol particles. The diameter of respiratory syndrome coronavirus 2 (SARS-CoV-2) the etiologic particles involved in airborne transmission has been actively agent of coronavirus disease 2019 (COVID-19), has rapidly debated over the course of the pandemic. Initially, historical spread across the globe. Implementing optimal infection guidance utilizing a 5 µm cut-off for airborne transmission was prevention and control (IPC) practices to mitigate disease used, but recent work [10, 11], argues that the scientific basis for spread depends upon a robust understanding of the mechan- such a cut-off is non-existent, and that a broader range of aerosol isms of transmission and relative risk of environmental and size should be considered to be involved in airborne transmission personal exposures. SARS-CoV-2 was originally considered to of disease. Therefore, there are several lines of evidence that must spread primarily by droplet and direct contact [1–3]. Similar to be demonstrated in order to establish airborne transmission: other respiratory viruses, including the closely related severe infectious aerosol that is small enough to be transported to and acute respiratory syndrome (SARS-CoV-1) and Middle East inhaled by another person must be produced by ill individuals; the respiratory syndrome, the virus can also be transmitted by infectious aerosol must be stable long enough to expose another aerosolized particles [4], mounting evidence supporting the person; and if inhaled, the viral aerosol must be capable of causing importance of airborne transmission [5–8] has resulted in infection. Experimentally, viral growth in medium from changes in CDC guidance affirming the importance of aerosol expired aerosol particles <5 µm has been detected from influenza transmission of COVID-19 [9]. infected humans [12, 13] and several studies have also 1Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA. 2Global Center for Health Security, University of Nebraska Medical Center, Omaha, NE, USA. 3National Strategic Research Institute, Omaha, NE, USA. 4Department of Biology, University of Nebraska Omaha, Omaha, NE, USA. 5Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. 6Electron Microscopy Core Facility, University of Nebraska Medical Center, Omaha, NE, USA. 7Vaccine & Immunotherapy Center, Massachusetts General Hospital, Boston, MA, USA. 8Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. 9Department of Epidemiology, University of Nebraska Medical Center, Omaha, NE, USA. 10Department of Environmental, Agricultural and Occupational Health, University of ✉ Nebraska Medical Center, Omaha, NE, USA. 11These authors contributed equally: Joshua L. Santarpia, St. Patrick Reid, John J. Lowe. email: [email protected] Received: 23 March 2021 Revised: 28 July 2021 Accepted: 29 July 2021 J.L. Santarpia et al. 2 demonstrated culture of SARS-CoV-2 aerosol collected near was performed using Invitrogen Superscript III Platinum One-Step infected indivuals [14, 15], thus demonstrating the infectious Quantitative rRT-PCR System. Each rRT-PCR run included a positive nature of the expired particles. SARS-CoV-2 generated aerosols synthetic DNA control and a negative, no template, control of nuclease have been shown to retain infectivity for several hours in the free water. Reactions were set up and run with initial conditions of 10 min at 55 °C and 4 min at 94 °C then 45 cycles of 94 °C for 15 s and 58 °C for 30 absence of sunlight [16, 17], and extensive contamination of ™ ™ s, on a QuantStudio 3 (Applied Biosytems , Inc) with the reaction mix and COVID-19 patient care areas with SARS-CoV-2 genomic RNA – primers and probe targeting the E gene of SARS-CoV-2 [20, 28] (details suggest that aerosol dissemination of virus may occur [18 20]. In provided in Table S2). Each sample was run in triplicate. addition, recent clusters of COVID-19 cases linked to a church To quantify the virus present in each sample from the measured Ct choir practice in Washington, U.S.A. and a restaurant values obtained from the rRT-PCR, a standard curve was developed using in Guangzhou, China are suggestive of airborne transmission RNA extracted from a known quantity of SARS-CoV-2 virus (BEI_ USA-WA1/ [21, 22]. Finally, the primary receptor of SARS-CoV-2 for infection is 2020) cultivated in Vero E6 cells (using the same method described below understood to be ACE2 [23], which is expressed throughout the for environmental samples). A five-log standard curve was run in triplicate 2 human respiratory tract, indicating that inhalation would be a beginning at a concentration of 1 × 10 pfu/mL, as determined by plaque assay. The data were fit with the exponential function: compatible route of infection. In April 1, 2020, letter to the White House Office of Science and pfu À : Ã Equivalent Viral Titer ¼ 6:0E9 Ã e 0 707 Ct (1) Technology Policy, the National Academy of Medicine Standing mL Committee on Emerging Infectious Diseases, and 21st Century fi fi Health Threats recommended further research into the role of In the equation, Ct is the cycle time where ampli cation is de nitively infectious aerosols in the spread of SARS-CoV-2 [24]. The work above the background. The same cycle threshold was used for all rRT-PCR runs in this study. Equation 1 was used to convert measured Ct values to an presented here demonstrates that aerosols containing SARS-CoV-2 equivalent viral titer (e-pfu) for each sample. This calibration with extracted RNA exist in particle modes that are produced during respiration, viral RNA more accurately represents the RNA that can be recovered from vocalization, and coughing; and that RNA-containing aerosols virus through the extraction and reverse-transcriptase processes, which are <5 µm in diameter contain infectious SARS-CoV-2 virions. The not accurately captured using a synthetic DNA control. However, e-pfu infectious nature of aerosol collected in this study, taken with may not accurately represent the number of copies associated with a virion the other lines of evidence presented, illustrates that airborne in an environmental sample, as compared to one grown in cell culture. transmission of COVID-19 is possible, and that infectious aerosol Therefore, the number of RNA copies/mL as a function of viral titer (pfu/ may be produced without coughing. mL) was determined for this culture. A synthetic DNA control for the SARS- CoV-2 E gene (Integrated DNA Technologies, Iowa, USA) that had an initial 1234567890();,: concentration of 2 × 108 copies/mL was diluted and assayed via qPCR using identical assay conditions as RNA extracted from the viral culture METHODS (see above). The number of copies per pfu from cell culture was compared Sample collection over five orders of magnitude in concentration, with Ct values from 23 to Aerosol sampling was conducted around six patients in five rooms in two 38, and the average was calculated to be 1.35 × 106 ± 6.29 × 105 RNA wards (referred to as Ward 5 and Ward 7) on three separate days in April of copies/pfu. This was then used to determine the RNA copies/L of air in 2020 (Table S1). Ward 7 was operated with individual rooms at negative collected samples. pressure to the hallway, while rooms in Ward 5 could not be individually isolated. In the case of Ward 5, the entire ward was put into negative airflow with the rest of the floor. In Ward 7, ventilation, heating and cooling Cell culture and detection of viral replication are controlled centrally. In Ward 5, each rooms has central ventilation and Vero E6 cells were used to culture SARS-CoV-2 virus from environmental there is a local fan coil unit in each room for heating and cooling.
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