Transmission of Coronaviruses

• Overview Transmission Models
  • Overview Airborne Transmission
  • Non Airborne Transmission of Respiratory Tract Pathogens
• Airborne Transmission
  • Summary Airborne Transmission
  • Objects Moving in the Air
  • Objects Transforming in the Air
  • The Fate of Particles in the Air
• Particle Dynamics in the Respiratory Tract
  • Particles Sources
  • Particles Deposition
  • Particles Clearance
  • Simulations and Experiments
• Proposal of a Dry Form Transmission for Coronaviruses
  • Summary Dry Form Transmission
  • Dry Form Transmission Model
  • Evidence for the Dry Form Transmission Model
  • Metaphor and Measures
• References
  • Epidemiological Patterns
  • Environmental Factors on Betacoronaviruses
  • Transmission Models
  • Particles in the Respiratory Tract
  • Particles in the Air
  • Airflow Theory
  • Summarized References Sources of Exhaled Particles
  • References Sources of Exhaled Particles
  • Particle Deposition at In/Exhalation
  • Transmission and Infection of Respiratory Viruses

Overview Transmission Models

Overview Airborne Transmission

Watery droplets in the air that cannot be seen, are called aerosol since it looks dissolved in the air. The main reason the distinction between droplets and aerosols is driving forces of their movement: Droplets behave like heavy balls while aerosols behave smoke-like i.e. they mostly move with the air.

Comments

• In warm climates rooms can be ventilated well, which reliably reduces and if done right mostly prevents aerosol spread. Careless use of air-conditioning enables and enhances aerosol spread.
• Aerosol and dry form transmissions increase with the amount of indoor air exchanged. Especially when deep/heavy breathing.
• The air humidity is relevant since:
  • droplets grow or shrink depending on the relative humidity -> Fate of Particles in the Air
  • The viability of coronaviruses is highest when dried (Virion Viability).
• The absolute humidity in the air is determined by the outside air temperature. Thus in heated indoor rooms the relative humidity is lower the cooler the outside temperature is.
• The dry form model is proposed here.
• for details on Actions and Sources in Particles in the Respiratory Tract and masks.

Non Airborne Transmission of Respiratory Tract Pathogens

For the time being only respiratory tract and oral pathogens are considered.

• Indirect contact transmission can occur through multiple steps: e.g. shaking dirty hands.
• Indirect contact is not very frequent for RNA viruses (RNA viruses usually don’t survive long) but to consider for DNA based life forms especially bacteria.
• Indirect contact is prevented by washing or disinfecting the hands and objects before taking them into the mouth.

Objects mediating transmission are called fomites:

Fomite

Fomite are objects through which indirect contact transmission occurs.

Fomite transmission is mostly an issue for bacteria since unlike viruses bacteria don’t need a host to replicate. So when cooking eggs which sometimes can contain salmonella and then spilling eggs or touching some object with dirty hands, some object can become salmonella contaminated. The salmonella may happily replicate on the object in question.

Airborne Transmission

Summary Airborne Transmission

Low density or very small objects follow the airflow, while heavy object fly in trajectories. The underlying physics is sketched and and examples are given. An aerosol is defined as a collection of very small particles that go with the air, droplet transmission on the other hand denotes transmission with droplets large enough they fly in trajectories. The particulates staying in the air can shrink by evaporation and growth by condensation. In dry air, evaporation can even cause particles to dry out.

Objects Moving in the Air

The movement of an object in the air depends on the ratio of its surface divided by its mass. The mass is turn is the volume times the density of the material.

S/m ratio = surface of a particle divided by its

• small S/m ratio => gravity and initial movement

  Heavy object and small surface: the acceleration is the gravity which points downwards and the horizontal movement stays constant. This results in projectile motions which are, as already Galileo knew, upside down parabolas. Examples are heavy balls in sports, rain droplets or snowballs.

• large S/m ratio => go with the air

  Light objects with large surfaces: the movement goes with the airflow since the air resistance is big compared to the weight i.e. they are carried by the air. Feathers, dust particles and dry snowflakes are examples.

Examples and movements in between:

• Feathers and balloon: Have large surface and low densities, so the S/m ratio is large and they go with the air.
• Table tennis balls are both small and have a relatively low density, so they often go with the air.
• Footballs and tennis balls mostly fly with parabolas. But strong wind can influence their movements.
• Golf balls on the other hand are less subject to the wind compared to table tennis balls. The size is similar but golf balls have a higher density.
• Shut pots are round & large and have a high density which yields a small surface to mass ration. They won’t be blown by the wind.

Material Factor

The mass calculates as density multiplied volume so

• large density => small S/m ratio

  E.g. shot puts, stones, snowballs

• small density => large S/m ratio

  E.g. table tennis ball, balloon, feathers

Form Factor

A spherical form yields the smallest surface for a fixed volume. Thus round objects have smaller ratios surface/volume than non round objects.

• roundish => small S/m ratio

  Watery particles tend to have a minimal surface and are roundish. Thus wet particles tend to fall more than dry particles.

• non roundish => large S/m ratio

  Feathers or leaves are flat and thus have large surfaces compared to their mass, so the S/m ratio is large (Remark: feathers also have a low density). These objects tend to go with the air.

Size Factor

Since the volume increases in cubic and the surface only in square of the length/diameter. Tiny objects have very large ratios and thus go with the air. An example is flour: a whole pack of flour behaves ball like, while the single flour particles fly in the air.

• larger size => smaller S/m ratio

• smaller size => larger S/m ratio

The size factor is the distinguishing point for aerosols versus droplets since both have a spherical form and consist of water. Very small water droplets, that can’t seen as single particles, move with airflow.

Classifying based on Movement

Aerosol

An aerosol is air with a collection of tiny particulates which can’t be seen and move with the air in the situation of interest.

Aerosol comes from Greek aero=air and sol=solvent, since tiny particulates can’t be seen and thus look like dissolved in the air. However an aerosol is air containing tiny particulates which in turn can contain other materials e.g. virions. Thus an aerosol is not actually dissolved but just behaves like regarding movement and visibility.

// ‘Classically’ an aerosol is defined as air with (watery) particulates smaller than 5 micro meters. The definition used here is more general and includes dry particulates and also larger droplets as long as they move with the air in the situation of interest.

The watery particles which are larger in size such that their movement is driven by gravity droplets keep their name and are called droplets:

Droplets

Droplets in the context of transmission models denote watery particles which don’t go with air but move subject to gravity and the initial movement e.g. they behave like ordinary objects thrown into the air.

// The ‘classical’ definition of droplets defines them as watery particulates with a diameter greater equal 5 micro meter.

The change both of movement and visibility is continuos and not digital as the classification border of 5 micro meter suggests. The behavior depends also on the situation:

• the respiratory tract has sharp turns and the humidity is very high so particles growth, so particles entering with a diameter of 5 micrometer don’t necessarily follow the air.
• In indoor air also particles with diameters several factors larger than 5 micro meter often stay in the air for more than half an hour.
• That water droplets fade from visibility and start flying when getting as small as a couple of micrometers is a coincidence or at least there is no obvious causal connection.

Objects Transforming in the Air

Particles staying in the air a long time, are subject to condensation and evaporation. Whether a particles growths due to condensation or shrinks due to evaporation depends on the material the particle consists of. For a certain particle composition there exists a relative humidity at which the evaporation and condensation are in an equilibrium named condeva equilibrium, at relative humidities below the particles evaporate and thus shrink and above water condensates and the particles growth (-> section Evaporation and Condensation on the page Aggregation of Atoms).

The particle composition depends on the source of exhaled particles while the air humidity depends on the locations/setting (e.g. whether heated or AC used):

• The air humidity is related to the weather and (thus) varies across the world and across the seasons.
• The material of an exhaled particle depends mainly on the source of the particle i.e. whether it is produced in the alveoli, bronchi, trachea, vocal folds, pharynx or mouth.

The Fate of Particles in the Air

Stay in the Air?

Particles which are large and heavy enough, have a small S/m ratio, so they will just fall down. Small and/or light particles have a large or intermediate S/m ratio and stay longer in the air.

Growth or Shrink?

The air humidity and the particle-composition/material determine whether particles growth (condensation) or shrink (evaporation), and if they shrink whether all water evaporates such that they dry out (efflorescence).

The Fate in Programming Style

• if S/m ratio small => fall down
• if S/m ratio intermediate or large -> stay in and move with the air =>
  • if the condeva equilibrium is on the condensation side => particles growth => fall down or reach condeva equilibrium
  • if in condeva equilibrium => size constant
  • if the condeva equilibrium is on the evaporation side => water evaporates and particles shrink =>
    • if water available => reach condeva equilibrium
    • if out of water => efflorescence

Particle Dynamics in the Respiratory Tract

Conversational remarks about how I understand the behavior of particles in the respiratory tract.

Particle deposition and clearance are relevant for Covid-19 in view of:

• infection pathway -> Transmission
• spread within the body:
  • spread in the lower respiratory tract -> Pathogenesis and infection locations
  • spread to the pharynx -> Diagnosis (swab test) and transmission
• spread out of the body -> Transmission
• depositions of medicaments for treatments -> topical treatments

Particles Sources

[in rework] This section describes when particles are generated and how they spread within the respiratory tract and out of it.

• Larger particles i.e. droplet are mostly spread at coughing and speaking. Coughing yields mostly particles from the upper respiratory tract.
• Small particles from the lower respiratory tract (<1 micro meter) are generated from breathing alone and their generation does not require speaking or coughing. Larsson et al identified the origins by analyzing the lipid composition of the particles.
• Fabian et al describes that the number of particles exhaled is very individual. Differences greater than a factor of 500 were observed. Data indicate a positive correlation with age. 24% of participants exhaled 81% of all measured exhaled particles.
• Yan et al observed that the aerosol amount exhaled correlated both with coughing and BMI. Coughing correlated with RNA shedding. However, with breathing and speaking alone, there are small infectious aerosols exhaled too.

That small particulates are exhaled upon breathing alone from the deep lungs, combined with the observations that in the deep lungs the SARS-CoV-2 receptor ACE2 is highly available, means that Covid-19 can be transmitted with breathing alone.

Particles Deposition

This section describes how particles are deposited in the respiratory tract. These particles can originate from other locations in the respiratory tract or being inhaled from extern air.

Literature

• Heyder is a readable description
• Lindstrom explains very well the overall topic in her 40 pages long thesis.
• Park is a recent review.
• An often used model is the ICRP Model.
• This work often relies on the simulation from Kleinstreuer.
• Varghese and Gangamma show that hygroscopic growth can increase alveoli deposition of particles.

Deposition Factors

How many particles are deposited/breath out in which region in/from the respiratory tract depends on various factors:

• Breathing Pattern: Breathing volume and frequency hofemeier
• Orientation: Orientation respect to gravity i.e. wether horizontal or vertical
• Lung Diseases: Qi et al simulate that particle deposition is individual and may change in case of lung diseases.
• Particles properties such as
  • Diameter: the diameter determines the size of particles and thus how particles move in the air.
  • Form: constant for water droplets but dry particles can vary in form. Sturm simulated the deposition of non-spherical particles particles. The form factor showed to matter most for larger particles in the size of 10 micro meter. Fibers in that size were deposited early on, where as disks showed the highest deposition rate in the airway generations 20 to 25.
  • Material and Hygroscopic Growth: Zhong et al describe that the particles can be moistened upon inhale and this has an effect on depositions locations. Similarly observed by Varghese and Gangamma, Figure 4: The alveolar deposition of soluble matter (shown for salt NaCl) between 250 nm and 1000 nm is increased by the particle growth due to moistening in the lungs. In Figure 7 the simulated effect of particle growth on total deposition is compared to measurements in experiments.

Deposition Locations

The physiology of the airways is evolved that particles are absorbed and cleared out as early as possible. The heavier and larger the earlier Stuart, Balley, Kleinstreuer.

• Particles smaller than 10 micro meter enter the deep lungs Kleinstreuer 2018 Fig 12, Heyder. Between 2 and 10 micro meters the particles are deposited due to sedimentation i.e. they fall down since the breathing out airstream is not strong enough to change their direction from downwards to upwards. Starting from around 200 nano meters and below, particles are deposited due to diffusion. Particles between 200 nano meters and 2 micro meters have the lowest deposition fraction, they are deposited due to diffusion and sedimentation but not very well.
• Locations of particles depositions for different sizes both a inhale and exhale are shown in Kleinstreuer et al on page 23 are used: “Fig. 6. Particle deposition in human nasopharyngeal model: (a) nasopharyngeal; (b) tracheal; (c) generation 1; (d) generation 2; and (e) generation 3”. Especially noteworthy is that upon exhale many particles are deposited in the pharynx (which is relevant for the viral load distribution and thus for infection locations and diagnosis)
• The particles depositions aren’t equal for the left and right lung and bronchus Rahimi-Gorji, kleinstreuer2017
• Particle deposition in the alveolar regions is greatly increased upon deep inhaling hofemeier.

Particles Clearance

Methods of Clearance

• Clearance by mucus flow towards the alimentary system
• Coughing
• Clearance by macrophages in the epithelium and in the mucus[to check and cite]
• Absorption in the alveoli and clearance:
  • Locally by immune cells (mostly local macrophages)
  • Release to the blood stream
    • immune cells in the blood
    • clearance organs
  • Lymph system

Factors Influencing Clearance

• Well flowing mucus (see factors increasing the mucus flow)
• The earlier deposited the better is the mucus clearance
• Particle properties such as material (bad clearance for insoluble in the deep lungs), form, size

Simulations and Experiments

Modeling or experimentally determine the deposition rates is not easy and both simulation and experimental methods have caveats as described in the section Limitations.

Types of Experiments

In vitro

Build an artificial lung and measure: sznitman.

In vivo

Experiment types:

• A person inhales aerosols and the deposited fraction is measured.
• A person inhales some test particles and the number of absorbed particles is measured for different volumes inhaled. For small volumes, the air goes not fare into to lung and so for this part the absorption is calculated. Then the volume is increased, the adsorbed particles measured again and the next part of the lung is calculated: the previous result is subtracted and the remaining adsorption is the next deeper lung part [reference to be added].
• Experimental data on the regional deposition of radio-labelled aerosol particles can be derived from gamma camera images. The limited resolution of the planar image allows no separation between the peripheral and the bronchial airways. This separation can be done by measuring the particle clearance kinetics during the first few days after inhalation[reference to be added].

In silico

Theoretical simulations model the respiratory tract and mostly use the laws of fluid dynamics to calculate the airflow. An often used model is the ICRP Model.

• Traditional methods: Model the respiratory tract as a static pipe system and do the physics Stuart 84, ICRP by Bailey. Usually some differential equations are fitted and these equations are often solved/simulated with a computer-based approach e.g. Monte Carlo methods.
• Recent approaches model the respiratory tract accurately in 3D and make use of advances in computational fluid dynamics: Kleinstreuer 18, Qi, Rahimi-Gorji, Zhong18.

Limitations of Experiments

The airflow in the lung has variations and is complicated Tsuda, Bailey. Often good agreement for modeling methods compared to in vivo measurements are achieved, however many parameters have to be estimated and thus overfitting could occur. Usually many simplifications of relevant factors both for respiratory tract and particles are taken i.e. the simulations are done for round constant size droplets and the respiratory tract is modelled as a static pipe system. Usually not modelled are:

• The softness and dynamics of the respiratory system, modelled in darquenne.
• Particle shape (taken into account in sturm).
• Condensation and material (both considered in Zhong18).

Proposal of a Dry Form Transmission for Coronaviruses

That’s the chapter this page started.

Summary Dry Form Transmission

A dry form transmission model for Betacoronaviruses is proposed. Betacoronaviruses survive best in dry form, this makes a dry form transmission possible and also likely to occur since evolutionary drive is needed to develop this ability.

The transmission models described in the literature - a recent recommended review is Herfst - for viruses are:

• Contact (direct and indirect via fomites)
• Droplets
• Aerosols

this new model is added:

• Dry form aerosol transmission

Larger droplets behave like balls and are transmitted only over short distances. Watery particles between 2 to 100 micrometers move with the air and can stay quite long in the air, however they still tend to spread local both in time and space - an example is the scent of a cooking soup - and less often reach the deep lungs. On the other hand tiny dry particulates behave dust/smoke like - smoke is a collection of tiny dry particulates diffusing around - so they move with the air and stay in the air even longer. Dry particulates have a potentially more infectious lung deposition and less clearance.

Epidemiological Evidence

Clusters of severe betacoronavirus diseases (MERS, SARS, severe Covid) are nearly always observed in settings with dry indoor air, as discussed in the chapter Spread Analyses.

Biological Evidence

Properties of the Respiratory Tract

The described properties of dry form transmission explain best the transmission yielding to infections of the deep lungs which are a hallmark of severe diseases caused by the betacoronaviruses Sars-CoV-1, MERS and Sars-Cov-2. Remark: SARS-2 infecting the upper or middle respiratory tract can be transmitted with droplets/fomites (Disease Pattering).

• Small, not round and dry particulates have a high probability to deposit in the lower respiratory tract.
• The immune system protection against viruses is lower in the deep lungs than at other locations in the respiratory tract, since the immune system there is less trained to deal with viruses.
• the absolute number of cells infectable by betacoronaviruses is highest in the lungs:
  • SARS-CoV-1/2: susceptible cells for SARS-CoV-1/2 replication are found throughout the respiratory tract but the largest surface is in the lower respiratory tract.
  • MERS: the cells susceptible to MERS infections are in the lower respiratory tract lower respiratory tract as obligate entry point.

Viability of Virions

The viability of virions is highest when dried (Virion Viability).

Aerosol Science

The larger the ratio of the surface to the mass, the more the particulates go with the air. For tiny dry particulates the ratio is larger than for roundish droplets. Roundish droplets if small enough still move with the air, but less than tiny dry particulates.

Medical Evidence

Viral load and tissue damage indicate that MERS and SARS-1 infect primarily the lower respiratory tract. SARS-2 infections are especially dangerous if they reach the lower respiratory tract (which can result in severe pneumonia similar as observed for MERS and SARS-1 infections).

• the observed viral load in different tissue indicate that MERS and SARS-1 infect primarily the lower respiratory tract. The observed viral loads of severe SARS-2 infections are highest in the lower respiratory tract in severe cases (Viral Load).
• Tissue damage for SARS-1/2 and MERS infection is observed in the lower respiratory tract.

The pieces of evidence indicate that aerosol and the proposed dry form are relevant transmission pathways.

Smoke is a metaphor for the aerosol and dry form aerosol transmission. Based on smoke-like aerosol transmission expected spread situations are discussed. Measures for controlling the Sars-CoV-2 transmission are outlined. Key is ventilation of indoor spaces and wearing a suitable mask in risky indoor spaces.

Dry Form Transmission Model

[in rework]

The virus is attached to dry particulates or even just as a single virion particle. These dry particles smoke like fly around or in the case of tiny particulates diffuse smoke like around.

Coronaviruses virions keep viability in dry form and the viability is even highest when dried (chapter Virion Viability), so dry form transmission is possible in theory.

The newly proposed infection:

• Dry particulates in air with virions -> Respiratory Tract (LRT including the lungs entry likely)

where Dry Particulate is a small particulate with one or more viruses attached or possibly viruses attached to each other.

The above infection pathway is in addition to the known aerosol/droplet pathways:

• Aerosol with virus in air -> Respiratory Tract (lower or upper respiratory tract)
• Droplet with virus in air -> Respiratory Tract (likely URT, LRT unlikely)

Aerosols containing particulates and dry particulates can convert to each other in the air:

• Dry Particulates -> Small Aerosol containing a Particulate (more likely in humid air, particulates act as condensation nuclei)
• Dry Particulates <- Small Aerosol containing a Particulate (more likely in dry air)

and smaller aerosol can convert to larger (see e.g. Figure 3 (C) and (D) in Yang):

• Small Aerosol <-> Large Aerosol/Droplets (in dry air equilibrium tends to the left, in humid to the right)

The larger tend to fall to the ground since their movement is driven more by gravity (described for example in tellier).

Infectious aerosols can get into the air from the lower or upper respiratory tract through breathing, coughing or speaking (section exhaling particles).

Dry particulates get into the air either by the above conversion from aerosols, directly from an infected lung [to be searched/calculated if this is possible, work in progress] or from dirt. Dirt can be from sedimented air particles or from faeces. [to check: vacuum cleaner particle filter size]. [to be checked if dirt is/can be relevant and what kind of dirt //likely not relevant due virion decay]

Evidence for the Dry Form Transmission Model

Evidence from Biological Properties

For severe betacoronavirus diseases nearly always the lower respiratory tract is involved (always in ARDS) (chapter Disease Pattering).

As described in particles deposition only aerosols and tiny dry particulates enter the lower respiratory tract, with dry particulates having a higher chance of deposition.

• MERS likely requires lower respiratory tract entry for successful infection. Lower respiratory tract entry likely is also needed for SARS-Cov-1.
• There are several Disease Patterns observed resulting from SARS-Cov-2 infections and severe Covid is mostly associated with an early lower respiratory tract involvement (early morning saliva, sputum and BALF viral load predict disease progression in hospitalized patients while NPS do not (Chapter Viral Load)).

That in swab tests there are viruses in the nose and the mouth is caused by breathing them up and/or local replication.

• Kleinstreuer et al have shown that upon exhale particles are deposited in the nose.
• The upper respiratory tract is used to fight viruses and so infections limited to the upper respiratory tract are not virulent and infections starting in the upper respiratory tract rarely develop virulent (chapter Disease Pattering).

Evidence from observed Spread Patterns

Particles produced when speaking or coughing explain well the observed spread patterns for middle and upper respiratory tract infections, they are often spread between close contacts. However, the spread patterns betacoronaviruses diseases involving the lungs are better explained by dust-like spreading: In confined settings without special protection reproduction numbers, have been observed Mizumoto. Which is not very likely to observe with the droplet transmission model. Since the movement of droplets is affected by gravity and therefore their concentration in the air quite rapidly decreases (see model section). The movement of dry dust, on the other hand, is less affected by gravity and therefore remains longer in the air. The majority of spreading has been observed in indoor spaces. In theses settings dry dust like spreading is possible.

The observed spread pattern for SARS-CoV-2 and other respiratory viruses are described on the page Spread Analyses:

• The transmission patterns observed for SARS-2, SARS-1 and MERS show that severe lung infections are primarily transmitted in dry air.
• SARS-2 transmission are observed in setting with humid air but less than in dry air. Transmission in humid air yield mostly mild diseases and the fatality rate is much lower in situations with humid air than in settings with dry air. The latter is consistent with the observation that dry particulates likely have a higher alveoli deposition rate which

Metaphor and Measures

Avoiding the droplet spread is like avoiding somebody’s reek of alcohol, avoiding aerosols/dry particulates on the other hand corresponds to avoiding a smoker’s smoke. The latter is much more difficult since smoke remains in the air long and move around with the air stream. Just smelling would be the theoretical possibility of an infection. But for the odds to be in two digits percentages, one needs likely to be that close that the cloths start smelling. Another form of dry particulates in air is dust. In dry air dust can stay in the very long and travel long distances.

This yields either avoiding ‘Sars-CoV-2 smoke’ or filtering out particulates. The filter filters ideally above a few hundreds nanometers (Sars-CoV-2 is about between 80-150 nm; but often several virions stick together or are attached to some organic material [to check and cite]). Keeping the smoke metaphor in mind, then indoor ventilation and indoor wearing a mask are key. Outdoors is no worry for Sars-CoV-2 however, the air is diluted and sun light destroys virions (Chapter Virion Viability). Measures in more detail are found in Protection Measures.

References

Epidemiological Patterns

• le

  The Lancet Editoral COVID-19: protecting health-care workers www.thelancet.com Vol 395 March 21, 2020 https://doi.org/10.1016/S0140-6736(20)30644-9

• mizumoto

  Kenji Mizumoto, Gerardo Chowell Transmission potential of the novel coronavirus(COVID-19) on board the diamond Princess Cruises Ship, 2020 https://doi.org/10.1016/j.idm.2020.02.003

• honein

  Temet M. McMichael et al. Epidemiology of Covid-19 in a Long-Term Care Facility in King County, Washington This article was published on March 27, 2020, at NEJM.org. https://doi.org/10.1056/NEJMoa2005412

• Dudas 2017

  MERS-CoV spillover at the camel-human interface Gytis Dudas, Luiz Max Carvalho, Andrew Rambaut, Trevor Bedford; elifesciences.org Summary of Dudas et al in the chapter hypotheses about nidovirales.

Environmental Factors on Betacoronaviruses

• chan

  (summarized on the virion viability page) K. H. Chan, J. S. Malik Peiris, S. Y. Lam, L. L. M. Poon, K. Y. Yuen, and W. H. Seto The Effects of Temperature and Relative Humidity on the Viability of the SARS Coronavirus Hindawi Publishing Corporation Advances in Virology Volume 2011, Article ID 734690, 7 pages https://doi.org/10.1155/2011/734690

• lin

  LIN, K., YEE-TAK FONG, D., ZHU, B., & KARLBERG, J. (2006). Environmental factors on the SARS epidemic: Air temperature, passage of time and multiplicative effect of hospital infection. Epidemiology and Infection, 134(2), 223-230. https://doi.org/10.1017/S0950268805005054

Transmission Models

• tellier

  Tellier R. (2006). Review of aerosol transmission of influenza A virus. Emerging infectious diseases, 12(11), 1657–1662. https://doi.org/10.3201/eid1211.060426 (seems broken)
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372341/

• herfst

  Kutter JS1, Spronken MI1, Fraaij PL2, Fouchier RA1, Herfst S3. Transmission routes of respiratory viruses among humans. Curr Opin Virol. 2018 Feb;28:142-151. https://doi.org/10.1016/j.coviro.2018.01.001. Epub 2018 Jan 17.

• Yang

  Yang W, Marr LC (2011) Dynamics of Airborne Influenza A Viruses Indoors and Dependence on Humidity. PLoS ONE 6(6): e21481. https://doi.org/10.1371/journal.pone.0021481

Particles in the Respiratory Tract

• kleinstreuer 2018

  Arun V Kolanjiyil, Clement Kleinstreuer, Nicole C Kleinstreuer, Wellington Pham and Ruxana T Sadikot Mice-to-men comparison of inhaled drug-aerosol deposition and clearance. Respiratory Physiology & Neurobiology. https://doi.org/10.1016/j.resp.2018.11.003

Particles in the Air

• morawska2006

  Morawska, L. (2006), Droplet fate in indoor environments, or can we prevent the spread of infection?. Indoor Air, 16: 335-347. https://doi.org/10.1111/j.1600-0668.2006.00432.x

• Yang

  Yang W, Marr LC (2011) Dynamics of Airborne Influenza A Viruses Indoors and Dependence on Humidity. PLoS ONE 6(6): e21481. https://doi.org/10.1371/journal.pone.0021481

Airflow Theory

• sznitman

  Rami Fishler, Philipp Hofemeier, Yael Etzion, Yael Dubowski & Josué Sznitman Particle dynamics and deposition in true-scale pulmonary acinar models. Sci Rep 5, 14071 (2015). https://doi.org/10.1038/srep14071

• stuart

  B O Stuart Deposition and clearance of inhaled particles. Environ Health Perspect. 1984 Apr; 55: 369–390. https://doi.org/10.1289/ehp.8455369

• tsuda

  Tsuda A1, Rogers RA, Hydon PE, Butler JP. Chaotic mixing deep in the lung. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10173-8. Epub 2002 Jul 15. https://doi.org/10.1073/pnas.102318299

Summarized References Sources of Exhaled Particles

Summary Yan 2018

Jing Yan, Michael Grantham, Jovan Pantelic, P. Jacob Bueno de Mesquita, Barbara Albert, Fengjie Liu, Sheryl Ehrman, Donald K. Milton, EMIT Consortium Aerosol shedding of infectious influenza virus Proceedings of the National Academy of Sciences Jan 2018, 115 (5) 1081-1086; https://doi.org/10.1073/pnas.1716561115

Methods

• Participants: 142 students with PCR confirmed influenza and who filled a questionary (age, BMI, vaccination status, …)
• Investigation:
  • “… 218 paired nasopharyngeal (NP) and 30-minute breath samples (coarse >5-μm and fine ≤5-μm fractions) on days 1–3 after symptom onset.
  • “We assessed viral RNA copy number for all samples and cultured NP swabs and fine aerosols.”

Findings

• “We recovered infectious virus from 52 (39%) of the fine aerosols and 150 (89%) of the NP swabs with valid cultures.”
• Predictors of viral RNA shedding: (Table 3 and Table S4 in the paper)
  • “Fine- and coarse-aerosol viral RNA were positively associated with body mass index and number of coughs and negatively associated with increasing days since symptom onset in adjusted models.”
  • Fine-aerosol viral RNA shedding was positively associated with influenza vaccination in the current and/or prior season for influenza A (Table S4.).
  • “NP swab viral RNA was positively associated with upper respiratory symptoms and negatively associated with age but was not significantly associated with fine- or coarse-aerosol viral RNA or their predictors.”
  • “Sneezing was rare, and sneezing and coughing were not necessary for infectious aerosol generation.”

Discussion

• “We defined symptoms as upper respiratory (runny nose, stuffy nose, sneezing, sore throat, and earache), lower respiratory (chest tightness, shortness of breath, and cough), and systemic (malaise, headache, muscle/joint ache, fever/sweats/ chills, and swollen lymph nodes).”
• “Our findings, that upper and lower airway infection are independent and that fine-particle exhaled aerosols reflect infection in the lung, opened a pathway for a deeper understanding of the human biology of influenza infection and transmission.”

Methods Details

• Participants:
  • “We recruited volunteers with acute respiratory illness on the University of Maryland–College Park campus and surrounding community from December 2012 through March 2013.”
  • 355 volunteers with respiratory disease symptoms were tested for influenza. 156 were tested positive for influenza (4 with aerosol only). Finally 142 cases completed the questions.

References Sources of Exhaled Particles

• olin

  Bake, B., Larsson, P., Ljungkvist, G. et al. Exhaled particles and small airways. Respir Res 20, 8 (2019). https://doi.org/10.1186/s12931-019-0970-9

• larsson

  Per Larsson, Björn Bake, Anita Wallin, Oscar Hammar, Ann-Charlotte Almstrand, Mona Lärstad, Evert Ljungström, Ekaterina Mirgorodskaya, Anna-Carin Olin, The effect of exhalation flow on endogenous particle emission and phospholipid composition, Respiratory Physiology & Neurobiology,Volume 243,2017,Pages 39-46,ISSN 1569-9048, https://doi.org/10.1016/j.resp.2017.05.003

• fabian

  Patricia Fabian, Sc.D.,1 Joseph Brain, S.D.,1 E. Andres Houseman, Sc.D.,2 James Gern, M.D.,3 and Donald K. Milton, M.D., Dr.PH.1,4 Origin of Exhaled Breath Particles from Healthy and Human Rhinovirus Infected Subjects JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 24, Number 3, 2011 a Mary Ann Liebert, Inc. Pp. 137–147 https://doi.org/10.1089/jamp.2010.0815

• lindstedt

  Broberg E, Andreasson J, Fakhro M, et al. Mechanically ventilated patients exhibit decreased particle flow in exhaled breath as compared to normal breathing patients. ERJ Open Res 2020; 6: 00198-2019 https://doi.org/10.1183/23120541.00198-2019

• milton 2013

  Milton, D. K., Fabian, M. P., Cowling, B. J., Grantham, M. L., & McDevitt, J. J. (2013). Influenza virus aerosols in human exhaled breath: particle size, culturability, and effect of surgical masks. PLoS pathogens, 9(3), e1003205. https://doi.org/10.1371/journal.ppat.1003205

• morawska

  Johnson, Graham & Morawska, Lidia & Ristovski, Zoran & Hargreaves, M. & Mengersen, K. & Chao, Christopher & Wan, Man-Pun & Li, Yuguo & Xie, Xiaojian & Katoshevski, David & Corbett, Shay. (2011). Modality of human expired aerosol size distributions. Journal of Aerosol Science - J AEROSOL SCI. 42. 839-851. https://doi.org/10.1016/j.jaerosci.2011.07.009.

Particle Deposition at In/Exhalation

• lindstrom

  Lindström Bagge, Maria. (2004). Particles in small airways: mechanisms for deposition and clearance & Pharmacokinetic assessment of delivered dose to the lung. https://openarchive.ki.se/xmlui/handle/10616/37702

• bailey

  The New ICRP Model for the Respiratory Tract M.R. Bailey Radiation Protection Dosimetry, Volume 53, Issue 1-4, 1 May 1994, Pages 107–114, https://doi.org/10.1093/rpd/53.1-4.107

• heyder 2004

  Joachim Heyder Deposition of Inhaled Particles in the Human Respiratory Tract and Consequences for Regional Targeting in Respiratory Drug Delivery Proc Am Thorac Soc Vol 1. pp 315–320, 2004 www.atsjournals.org https://doi.org/10.1513/pats.200409-046TA

• park

  Vu Khac Hoang Bui, Ju-Young Moon, Minhe Chae, Duckshin Park and Young-Chul Lee Prediction of Aerosol Deposition in the Human Respiratory Tract via Computational Models: A Review with Recent Updates Atmosphere 2020, 11, 137; https://doi.org/10.3390/atmos11020137

Computational Simulations

• varghese

  Varghese, S.K. and Gangamma, S. (2006). Particle Deposition in Human Respiratory Tract: Effect of Water-Soluble Fraction. Aerosol Air Qual. Res. 6: 360-379. https://doi.org/10.4209/aaqr.2006.07.0004

• kleinstreuer 2018

  Arun V Kolanjiyil, Clement Kleinstreuer, Nicole C Kleinstreuer, Wellington Pham and Ruxana T Sadikot Mice-to-men comparison of inhaled drug-aerosol deposition and clearance. Respiratory Physiology & Neurobiology. https://doi.org/10.1016/j.resp.2018.11.003

• kleinstreuer 2017

  Arun V. Kolanjiyila, Clement Kleinstreuer Computational Analysis of Aerosol-Dynamics in a Human Whole-Lung Airway Model https://dx.doi.org/10.1016/j.jaerosci.2017.10.001

• qi

  Baihua Zhang, Shouliang Qi, Yong Yue, Jing Shen, Chen Li, Wei Qian and Jianlin Wu Particle Disposition in the Realistic Airway Tree Models of Subjects with Tracheal Bronchus and COPD Hindawi BioMed Research International Volume 2018, Article ID 7428609, 15 pages https://doi.org/10.1155/2018/7428609

• zhong 2018

  Xiaole Chen, Clement Kleinstreuer, Wenqi Zhong, Yu Feng & Xianguang Zhou (2018) Effects of thermal airflow and mucus-layer interaction on hygroscopic droplet deposition in a simple mouth–throat model, Aerosol Science and Technology, 52:8, 900-912, https://dx.doi.org/10.1080/02786826.2018.1476751

• rahimi-gorji

  Mohammad Rahimi-Gorji, Tahereh B. Gorji n, Mofid Gorji-Bandpy Details of regional particle deposition and airflow structures in a realistic model of human tracheobronchial airways: two-phase flow simulation https://dx.doi.org/10.1016/j.compbiomed.2016.04.017 0010-4825/& 2016 Elsevier Ltd. All rights reserved.

• hofemeier

  Philipp Hofemeier, Kenishiro Koshiyama, Shigeo Wada, and Josué Sznitman One (sub-)acinus for all: Fate of inhaled aerosols in heterogeneous pulmonary acinar structures Eur J Pharm Sci. 2018 February 15; 113: 53–63. https://doi.org/10.1016/j.ejps.2017.09.033

• sturm

  Robert Sturm A Computer Model for the Simulation of Nonspherical Particle Dynamics in the Human Respiratory Tract Hindawi Publishing Corporation Physics Research International Volume 2012, Article ID 142756, 11 pages https://doi.org/10.1155/2012/142756

• darquenne

  BY C. DARQUENNE*, L. HARRINGTON AND G. K. PRISK Alveolar duct expansion greatly enhances aerosol deposition: a three-dimensional computational fluid dynamics study Phil. Trans. R. Soc. A (2009) 367, 2333–2346 https://doi.org/10.1098/rsta.2008.0295

Experiments

• rissler

  Rissler, Gudmundsson, Nicklasson, Swietlicki, Wollmer, Löndahl. Deposition efficiency of inhaled particles (15-5000 nm) related to breathing pattern and lung function: an experimental study in healthy children and adults. Jonas K. F. Jakobsson, Johan Hedlund, John Kumlin, Per Wollmer & Jakob Löndahl Part Fibre Toxicol. 2017 Apr 8;14(1):10. doi: 10.1186/s12989-017-0190-8. https://doi.org/10.1186/s12989-017-0190-8

Transmission and Infection of Respiratory Viruses

• kikkert

  Marjolein Kikkert Innate Immune Evasion by Human Respiratory RNA Viruses J Innate Immun 2020;12:4–20 https://doi.org/10.1159/000503030

• pierret

  Reiman JM, Das B, Sindberg GM, Urban MD, Hammerlund MEM, et al. (2018) Humidity as a non-pharmaceutical intervention for influenza A. PLOS ONE 13(9): e0204337. https://doi.org/10.1371/journal.pone.0204337

• myatt

  Myatt, T. A., Kaufman, M. H., Allen, J. G., MacIntosh, D. L., Fabian, M. P., & McDevitt, J. J. (2010). Modeling the airborne survival of influenza virus in a residential setting: the impacts of home humidification. Environmental health : a global access science source, 9, 55. https://doi.org/10.1186/1476-069X-9-55