Which size particles are infectious and for how long? CQ2 Panel (16/36)

cq2panel

In order: Moderator, Dr. Emmie de Wit, Dr. Donald Milton, Dr. Joshua L. Santarpia, Dr. Catherine Noakes, and Dr. Kanta Subbarao (bios below).

What types of environments do we need to be focusing on? We've heard a lot about healthcare studies, largely out of necessity, but what are the priority areas now?

Subbarao: We also need studies to provide scientific support for the epidemiological data in aged care facilities, meat processing plants, dental offices, cruise ships, bars, restaurants, and ultimately schools and universities as they are opening. There are questions about ventilation in lecture theaters.

In thinking about the built environment and engineering controls, how can the environment and buildings affect virus survival? Is there anything we can do to optimize prevention?

Noakes: The virus is fairly stable in aerosols. Although we don't know exactly how this translates to buildings, it's clearly stable enough since people are becoming infected. The dominant factor of what we can do is increasing the ventilation. There is some evidence that higher temperature, more humid environments are likely to be better, but within the range of parameters that are practically achievable in most buildings, ventilation is where there can be a large effect.

Meat or other chilled food processing facilities are particularly challenging. The cold, dry air allows aerosols to evaporate and then stay airborne for a longer time. It's not clear how to address this, but we should be looking around ventilation. The winter conditions worry me when it becomes colder, drier, and harder to effectively ventilate a building.

Does the data on viral persistence in air tell us anything about what to expect with COVID-19 from a seasonal perspective given the seasonality of influenza? Are there any extrapolations you are making now as we approach winter in the Northern hemisphere?

De Witt: With flu we know that the seasonality is at least partly attributable to the fact that airborne transmission is more effective in cold and dry environments. It would not be suprising to see something similar, with a bigger component of airborne transmission during the seasonal flu months. This would be a major factor if aerosols are the main route of transmission, and is we are discussing today, this is not entirely known. It could be huge or it could be minimal.

Subbarao: We are in winter here in the Southern hemisphere, and actually we haven't seen a spike in influenza or RSV, possibly due to the various preventive measures in place. However, we are seeing a lot of rhinovirus, which is interesting since it leads to the question of why rhinovirus is not impacted by the preventive measures in place.

How does the dose required for infection vary for inhalation compared to other routes?

Milton: We'd like to know, but I don't think we know anything about that yet. We know from human studies in the 40s and 60s that the dose needed for influenza was 5-10x lower by aerosol than by nose drops, and a 1000x larger dose was needed by nose drops to generate symptomatic cases. Flu is an anisotropic (prev. preferential) infection, but rhinovirus is isotropic (prev. opportunistic), and will have similar outcomes regardless of where it lands. We don't know if dose or route dominates for COVID-19.

Can studying exhaled breath help to understand superspreading events?

Santarpia: The only way we will get to the source is to capture what people are producing to inform the efficacy of different interventions. We need to determine what sort of particles people are producing from different activities (e.g. talking, breathing), and then that can feed into the infectious dose question along with where those particles get deposited.

De Witt: I'd like to see data in differences among symptomatic and asymptomatic patients since most of the data originates from hospitals where the patients typically have pneumonia and the virus comes from the lower respiratory tract. With mild or asymptomatic cases, the production is probably from outside the lungs, which would affect the viral levels being shedded as well as the other properties of the aerosol.

Santarpia & Milton: It's tough to grab people in the short time window of being presymptomatic.

Subbarao: What does it mean that there is so much virus in the saliva since this is unusual for other respiratory viruses?

Noakes: There are still questions about where the aerosol particles are generated.

Santarpia: That could change over the course of the illness, and it might be different depending on whether the patient is symptomatic. Maybe the oral cavity originating particles would be larger and contribute less to aerosol spread.

Milton: Even if the oral route is common, SARS-CoV-2 is an anisotropic (preferential) virus so that tends to result in a mild case, whereas the aerosol transmission route could be responsible for the severe cases. There is not a correlation between levels of virus in the nose or saliva and what is present in aerosols.

Noakes: You can have people who are sputum-negative, but aerosol-positive and your standard test won't pick that up.

Does the virus on a mask pose an infection risk? Could inappropriate use of a mask pose an infection risk?

Noakes: I find it hard to imagine that the risk from touching a mask after wearing it, and then touching one's face, would be higher than being indoors and breathing aerosols.

Santarpia: The exception might be in health care environments, where you know that your mask is highly contaminated so appropriate handling of PPE is critical to not causing infection. People should treat their masks as if they are dirty, and that doesn't mean you shouldn't wear it.

Why are able to sample aerosols below 10 microns with some size segregation, but how do we sample and size segragate larger aerosols (e.g. 10 to 50 microns)?

Santarpia: The bigger particles don't move well with the air stream. Larger particles are increasingly dominated by their own momentum. One approach is the use of witness paper, which changes color and enables seeing the distance of particle sprays. This approach is challenging in a hospital environment.

Is there any evidence for indirect transmission of SARS-CoV-2? i.e. exposure from surfaces that an infectious person previously contacted?

Subbarao: I am not aware of transmission by that route, but there is data on the survival of viruses on surfaces, which can be prolonged, especially at low temperatures, which makes it plausible.

Are we at a point where we can use the data on infectiousness of viral particles to model risks? We are seeing discrete risk models for community transmission based on sizes of gatherings. If the 1m or 2m transmission models are not accurate, are we still able to model transmission risk for SARS-CoV-2?

Milton: One problem with the modeling is that infectious disease models treat the contact event as a black box. This is rather different from the multi-step model being used throughout this conference. Unless we have models that take into account the various lower level processes, it is difficult to understand what's going on, or how different interventions will play out.

Noakes: The models we use work well at a nation scale where we want to know the effects of large interventions such as working from home, closing schools, or other major events. It's far more complicated within an environment. How much does hand-washing help? How much do masks help? How much does distancing help? How much does ventilation help? Models can be built out from a mechanistic perspective and a couple have been published, but it's difficult to know how accurate those models are. The viral emission rate could be a major weakness to these models since that is still unknown.

What is the methodology to evaluate virus viability from air samples?

Santarpia: The basic thing you want to see for infectivity is that the virus can replicate in cell culture. With PCR you can see if there more copies at the end than at the beginning. That was acceptable early on in the pandemic, but now people want to see plaque assays, which allows you to see spots of cell death, which is a more quantitative way to see how many infectious viruses you have in a sample. TCID50 is also common, which is where you dilute your sample until cell death no longer occurs, and this allows you to statistically determine how many viruses were likely present in the sample.

With small numbers of viruses in an aerosol (e.g. due to collection methods), these techniques become challenging. In TCID50, if there is only enough virus present to cause cell death in the neat (original, undiluted) sample, there is no way to calculate the concentration. You might have to look at more indirect methods such as increases in RNA, which lose quantitative accuracy. This has been one of the sticking points [in getting widespread recognition of the aerosol transmission pathway].

De Witt: You need a very high dose viral solution when generating an aerosol. When we generate aerosols synthetically, we are able to start with a lot, and this allows us to measure the degradation over time more accurately with TCID50.

A lot of what we are doing is risk analysis to determine interventions. Since we are focused on aerosol tranmsission, what do each of you think is a really important intervention measure for indoor exposure?

Milton: The Japanese ministry put out their "three Cs" and I'd agree with that.

  • Closed environments
  • Crowds
  • Close contact

These factors all add up and we need layers of protection. Mask, distance, and ventilation all add up as protective measures.

Noakes: I'd agree with Don [Milton]. It's important to think about context and duration. Poorly ventilated spaces where people spend a long amount of time are the problem. Passing for a few seconds in a hallway or by a desk I wouldn't say is irrelvant, but it is minor. We need masks in all those environments and to think about how to have ventilation in winter. I think we're getting away with poor ventilation in buildings because now people are able to open the windows and go outside. The minute everyone goes back into those spaces we'll see a different outcome.

Subbarao: The viral amount is a key factor and we need to think about superspreaders. How can we figure out beforehand if a person is a superspreader? The temperature, ventilation, and relative humidity are also key factors, along with the various intervention measures.

Santarpia: There is no single intervention that can do everything. We need a bit of everything. We'll probably have to get used to it. However, one thing that was noted was the lower incidence of other non-pandemic diseases so these measures are also making a difference there. Some of these things might be inherently worthwhile to think about going forward, including better ventilation in buildings, and better rules for building ventilation -- not just hospitals, labs, and modern buildings, but looking at implementing better ventilation in all sorts of indoor spaces so we can start to return to some semblance of normalcy.

De Witt: I'd agree with all the above. It's a bit tangential to the workshop, but frequent testing is also a critical aspect so that we can isolate people who are infected.

Next: Exposure to expired infectious aerosols in proximity and distance (20/36)

Previous: Effective use of face masks for COVID-19 (15/36)

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Biographies

Emmie de Wit is the Chief of the Molecular Pathogenesis Unit in the Laboratory of Virology of NIAID, where her lab focuses on emerging respiratory viruses, aiming to combine pathogenesis studies with detailed molecular analyses to identify molecular determinants of severe respiratory tract disease within the virus and the host. In 2009, she moved to the Laboratory of Virology of NIAID in Hamilton, Montana to work in the biosafety level 4 laboratory there. Here, she focused on the pathogenesis of and countermeasures against Nipah virus, the Middle East Respiratory Syndrome Coronavirus and the 1918 H1N1 influenza A virus (Spanish flu). In 2014-2015, Dr. de Wit spent 4 months in a field lab in Monrovia, Liberia in charge of patient diagnostics for several Ebola Treatment Units in the area, to help contain the devastating Ebola epidemic in Liberia. Since the emergence of COVID-19, Dr. de Wit has focused her research on SARS-CoV-2, developing animal models and using those for testing of medical countermeasures and to gain a better understanding of SARS-CoV-2 pathogenesis. Dr. de Wit received her Ph.D. in virology in 2006 from Erasmus University Rotterdam, the Netherlands where her research focused on the replication, pathogenesis and transmission of influenza A virus.

Donald K. Milton is a Professor of Environmental and Occupational Health at the University of Maryland School of Public Health. He is a Diplomat of the American Boards of Internal and Preventive (Occupational) Medicine and a Fellow of the International Society for Indoor Air Quality and Climate. He has served on the editorial boards of Applied Environmental Microbiology, Indoor Air, and BMC Public Health, on the NIOSH NORA Indoor Environment Team, and chaired the ACGIH Bioaerosols Committee. Dr. Milton’s research focuses on infectious disease aerobiology and exhaled breath. His work lead to the recognition that influenza patients can shed infectious virus into aerosols without coughing and that surgical mask worn by infected cases can reduce the aerosol release of influenza and seasonal coronaviruses. Dr. Milton earned a B.S. in Chemistry from the University of Maryland Baltimore County, an M.D. from Johns Hopkins, and a Dr.P.H. (Environmental Health) from Harvard School of Public Health.

Joshua L. Santarpia is the Research Director for Counter WMD programs at the National Strategic Research Institute, Associate Professor of Microbiology and Pathology, and Program Director for Biodefense and Health Security Degree Program at the University of Nebraska Medical Center. He has held past positions at the Edgewood Chemical and Biological Center, the Johns Hopkins University Applied Physics Laboratory, and was most recently a distinguished staff member at the Sandia National Laboratories. His work is generally in the field of aerobiology, the study of airborne microorganisms. He has worked extensively on RDT&E and OT&E efforts for biological sensors for both DoD and DHS. He has developed building and facility sensing networks for biological detection in numerous facilities. He has developed aerosol measurement tools, including those for unmanned aerial vehicles and for biodetection/collection activities. He has worked extensively to understand optical and other signatures that can be used to detect and identify biological aerosol and studied how those signatures change over time. He has developed novel methods to study bioaerosol hazard in medical environments, and studies for private companies to determine potential aerosol hazards of medical devices in operating rooms. Dr. Santarpia is trained in aerosol physics, atmospheric chemistry and microbiology. His peer reviewed research focuses largely on the fate biological aerosols in the atmosphere, detection of biological aerosols and atmospheric chemistry of biological and anthropogenic particles. He has contributed to several books on the characterization and measurement of biological aerosols in the environment.

Cath Noakes is a Professor of Environmental Engineering for Buildings in the School of Civil Engineering at the University of Leeds. She is a chartered mechanical engineer with a background in fluid dynamics, and significant expertise in ventilation and indoor air quality. Her research group conduct experimental and modelling based studies, with a strong focus on ventilation for health including exploring the transport of airborne pathogens and effectiveness of engineering approaches to controlling infectious disease transmission. She has been an investigator on projects funded by EPSRC, Department of Health, MRC, AHRC and CDC which have allowed her to work with researchers across a wide range of disciplines. She has over 100 peer reviewed journal and conference papers and has co-authored design guidance for CIBSE and the Department of Health. Cath is the Deputy-Director of Leeds Institute for Fluid Dynamics and the Co-Director of the EPSRC Centre for Doctoral Training in Fluid Dynamics. She currently sits on the UK government Scientific Advisory Group for Emergencies (SAGE) as part of the COVID response where she chairs the Environment and Modelling Group. Dr. Noakes received her PhD in Mechanical Engineering from the University of Leeds.

Kanta Subbarao is Director of the WHO Collaborating Centre for Reference and Research on Influenza and Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity. Dr. Subbarao was appointed Director of the WHO Collaborating Centre for Reference and Research on Influenza and Honorary Professorial Fellow in the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity in 2016. Her research is focused on newly emerging viral diseases of global importance including seasonal and pandemic influenza, severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS) and now COVID-19. Her research includes the study of virus biology and pathogenesis, immune responses to infection and vaccination, development and preclinical and clinical evaluation of vaccines and evaluation of antiviral drugs. She is an internationally recognised leader in the field of emerging respiratory viruses and is an elected Fellow of the American Academy of Microbiology and the Infectious Diseases Society of America and is a member of the American Society of Microbiology, American Society for Virology and Australasian Virology Society. She serves on the Editorial Boards of PLoS Pathogens, mBio and Cell Host and Microbe. In response to the COVID-19 pandemic, she has been invited to serve on international panels on animal models and vaccine safety (CEPI, WHO and American Society for Microbiology). Prior to her arrival in Melbourne, she was Chief of the Emerging Respiratory Viruses Section of the Laboratory of Infectious Diseases, NIAID, National Institutes of Health (NIH) in the United States from 2002-2016 and chief of the Molecular Genetics Section of the Influenza Branch at the US CDC from 1997-2002. Dr. Subbarao is a virologist and a physician with specialty training in paediatric infectious diseases. She received her M.B.B.S. from Christian Medical College, Vellore in India and trained in pediatrics at Cardinal Glennon Children’s Hospital in St Louis and pediatric infectious diseases at the University of Oklahoma Health Sciences Center, where she also completed an M.P.H. in epidemiology. She received postdoctoral training in the Laboratory of Infectious Diseases, NIAID, NIH.

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