Interdependencies between respiratory viral transmission pathways

During the pandemic years, why were the globally implemented NPIs so successful in limiting the spread of a variety of respiratory viral infections, and not just SARS-CoV-2? We believe this is due to the fact that these NPIs, as mentioned above, were intended to address each of the viral transmission pathways, not just the droplet pathway. ^{Reference Ijaz, Nims, Rubino, McKinney and Gerba3} Instead of being mutually exclusive, the three virus transmission pathways (involving infectious droplets, aerosols, virus-contaminated fomites and hands) display interdependencies. ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2,Reference Killingley and Nguyen-Van-Tran4–Reference Zhang and Duchaine6} For instance, respiratory droplets produced during a human expiratory event (sneezing, coughing, talking, or breathing) can directly infect another individual who is at close range or can evaporate to form smaller droplets or aerosols. ^{Reference Leung1,Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2,Reference Killingley and Nguyen-Van-Tran4–Reference Zhang and Duchaine6} Alternatively, these droplets may experience hygroscopic growth to increase in mass. ^{Reference Leung1,Reference Killingley and Nguyen-Van-Tran4} Gravitational settling of virus-contaminated droplets may result in contamination of environmental surfaces (fomites), ^{Reference Johnson, Loehle, Zhou, Chiosonne, Palumbo and Wiegand7,Reference Geng and Wang8} which may then exchange infectious virus to the hand of an uninfected individual ^{Reference Johnson, Loehle, Zhou, Chiosonne, Palumbo and Wiegand7,Reference Geng and Wang8} leading to transfer to a susceptible mucous membrane and subsequent initiation of an infection.

Viruses deposited on environmental surfaces through settling of droplets or by exchange from contaminated hands ^{Reference Castaño, Cordts and Jalil9,Reference Tang, Mao and Jones10} may be re-aerosolized (re-suspended) through human activities such as walking, vacuuming, or flushing toilets, to contribute to airborne virus load including association with aerial particulate matter such as dust and allergens. ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2,Reference Boone, Ijaz, McKinney and Gerba11–Reference Gu, Han and Zhang14} The stability of airborne respiratory viruses depends on a number of factors, including the ambient temperature and relative humidity (RH), but also the matrix (pathophysiological, such as mucous, or non-physiological, such as PM_2.5, pollen or dust) that the virus associates with. ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2,Reference Marr and Tang15–Reference Sattar and Ijaz19}

These interdependencies, which may not be generally acknowledged, are depicted schematically in Figure 1. It is understood by the authors that more robust empirical supporting evidence for the biological significance of these proposed interdependencies must be collected. In particular, more clarity on the amounts of infectious virus (as opposed to RNA) released by an infected individual during breathing, talking, sneezing, or coughing, or re-aerosolized by mechanical activities such as vacuuming, walking, or removing clothing, must be obtained. ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2} The challenges associated with air sampling for infectious virus have been reviewed ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2} and must be overcome in order to answer many of the remaining questions on the relevance of certain of the interdependencies discussed above (especially the importance of virus re-aerosolization from fomites and the association of infectious virus with aerial particulates). Evidence of virus spread via the air/surface/hand nexus has been summarized as a workshop consensus outcome by Abney et al. ^{Reference Abney, Bloomfield and Boone20}

Figure 1. Schematic depiction of major virus transmission pathways, indicating interdependencies. Image source: ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2} CC BY 4.0. https://creativecommons.org/licenses/by/4.0/.

A more holistic outlook on respiratory viral transmission

The fact that the NPIs implemented during the SARS-CoV-2 pandemic were so effective at limiting respiratory virus spread in general, and not just SARS-CoV-2, ^{Reference Ijaz, Nims, Rubino, McKinney and Gerba3} is consistent with, but not necessarily proof of, a hypothesis that the transmission of respiratory viruses depends on pathways in addition to respiratory droplet transmission. Viral infection transmission may best be viewed as resulting from a dynamic virus spread from infected individuals to susceptible individuals by a spectrum of physical states of active respiratory emissions, instead of the current paradigm that emphasizes separate dissemination by respiratory droplets, aerosols, or by contaminated fomites. For instance, the holistic outlook recognizes the exposure risk associated with the short-distance, short-time exposure to larger respiratory droplets that theoretically ^{Reference Leung1,Reference Marr and Tang15,Reference Henriques, Jia and Aleixo21} contain a higher concentration of viral particles that have been exposed to less time for inactivation within the droplet matrix. Alternatively, the holistic outlook acknowledges that viruses may persist (remain infectious) for some time in aerosols. ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2,Reference Smither, Eastaugh, Findlay and Lever17,Reference Karim, Ijaz, Sattar and Johnson-Lussenburg18} For instance, the infectivity half-life of SARS-CoV-2 aerosolized in physiological (artificial saliva), or non-physiological (tissue culture medium) matrices has been reported to be 42 and 75 minutes, respectively, at 40–60% RH. ^{Reference Smither, Eastaugh, Findlay and Lever17} The extensive literature on persistence of SARS-CoV-2 on surfaces has been reviewed by Ijaz et al. ^{Reference Ijaz, Nims and Zhou22} As an example, the half-life of the virus deposited on plastic or stainless-steel surfaces in the presence of a physiological matrix (human sputum or mucus or an organic soil load) has been reported to be 3.1 or 29 hours, respectively. ^{Reference Matson, Yinda and Seifert23,Reference Kasloff, Strong, Funk and Cutts24} On LabSkin, the half-life of SARS-CoV-2 has been reported to be 2.8 to 17.8 hours, depending upon the temperature. ^{Reference Pitol, Venkatesan, Richards, Hoptroff, Majumdar and Hughes25}

This persistence of infectious virus in air and on surfaces suggests that long-distance, extended-time transmission through infectious respiratory viral particles associated with aerosols (either derived from droplets or from re-aerosolization from contaminated fomites) also might lead to infection of susceptible persons sharing indoor spaces with an infected individual. Finally, the exposure risk associated with indirect transmission from fomites to new hosts involves more than the simple exchange among contaminated surfaces to hands to susceptible host mucous membranes (ie, the surface/hand/mucous membrane nexus). The recognition ^{Reference Ijaz, Sattar, Nims, Boone, McKinney and Gerba2,Reference Tang, Mao and Jones10–Reference Goforth, Boone and Clark12} that re-aerosolization of viruses from fomites to aerosols occurs may necessitate reassessment of the risk associated with the indirect (ie, fomite) transmission pathway.

Approaches for mitigation of risk should consider each of the relevant transmission pathways

As mentioned above, different NPIs may apply to different transmission pathways (reviewed in reference 2). For instance, the wearing of a face mask or respirator is intended to mitigate risk of transmission of respiratory viruses through the droplet route, especially when worn by presymptomatic, asymptomatic, or symptomatic individuals. To a certain degree, these masks or respirators may help to mitigate risk of acquiring an infection through inhalation of airborne viruses, in general (ie, viruses in droplets or aerosols). However, these devices also reduce the frequency of face touching, thereby reducing the risk of exposure of oral and nasal mucosa to virus transmitted via the hands by touching contaminated fomites. Air decontamination within indoor spaces may mitigate risk associated with airborne respiratory viruses, either associated with droplets or with aerosols and whether associated with respiratory excretions/secretions originating from an infected person or with environmental dust, pollen, or other pollutants such as PM_2.5. This may be accomplished through use of air-sanitization technologies, or by increasing the room ventilation by opening of windows and/or increasing the rate of air exchange ^{Reference Allen and Ibrahim26} through heating and air ventilation system upgrades. Crowded indoor spaces favor, for a variety of reasons, the accumulation of viruses in air and on environmental surfaces, hence the advisability of restrictions in school, business, and hospitality venues during outbreaks and pandemics. Risk of indirect exposure to viruses through the hand/surface/mucous membrane nexus is best mitigated through increasing the frequency of hand washing or use of appropriate hand-sanitizing agents. In addition, the accumulation of viruses on environmental surfaces may be reduced through the targeted use of surface hygiene agents, implementation of surfaces with continuous disinfecting characteristics, ^{Reference Ikner and Gerba27} or the use of air sanitization technologies. ^{Reference Boone, Betts-Childress, Ijaz, McKinney and Gerba28} Remaining mindful of the potential for re-aerosolization of viruses through human activities is necessary for mitigating exposure risk associated with each of the transmission pathways. Even the removal of personal protective equipment such as face masks or respirators, gloves, or gowns may lead to virus re-aerosolization. ^{Reference Licina and Nazaroff29,Reference Kvasnicka, Cohen Hubal, Siegel, Scott and Diamond30}

Significance

The World Health Organization has highlighted the point that it is difficult to separate potential direct and indirect exposure modes in establishing virus transmission relevancy, ³¹ and this difficulty contributes greatly to the debate mentioned above regarding the relative importance of the various transmission pathways. Bringing infected and noninfected individuals (including pre or asymptomatic cases) into proximity necessarily increases the opportunities for indoor air contamination with droplets/aerosols, subsequently contaminating fomites within the immediate area. Stated another way, the same factors that increase exposure risk associated with one of the virus transmission pathways necessarily increase the risk associated with the other pathways. Realizing the various interdependencies holistically among the different pathways, it is more challenging to proactively determine the most important factors for virus transmission and, therefore, the optimal bundle of NPIs to use for exposure risk mitigation.

A more holistic outlook on virus transmission is also informed by the concept of a continuum of sizes for droplets and aerosols, and the importance of residence time over which viruses remain airborne and infectious in droplets, aerosols, and particulate matter. The particulates of concern include gravitationally settled particles, which contaminate environmental surfaces, as well as those potentially becoming re-aerosolized from those surfaces ending up as airborne viruses that might be inhaled or land on and secondarily contaminate other environmental surfaces.

It would be beneficial to public health if individual and group biases regarding the perceived importance of the various virus transmission pathways could be set aside and a more holistic outlook encompassing the truly multimodal nature of respiratory virus dissemination could be acknowledged more broadly. In this manner, a science-based public health advisory decision-making process that takes into account the interdependencies discussed here might be implemented. In a practical sense, the global responses to the SARS-CoV-2 pandemic correctly considered most of the modes of transmission discussed herein during implementation of regionally mandated NPIs intended to limit viral dissemination. This should be considered going forward and taken into account in the messaging from health authorities, to limit confusion about sources of transmission risk.

The World Health Organization has recently ³¹ done a comprehensive job of acknowledging the various transmission modes for SARS-CoV-2. Their risk assessment methodology takes into account: [1] the opinion that most respiratory viruses spread through zoonotic transmission, direct (body surface-to-body surface) contact and indirect contact (fomite) transmission, direct deposition (droplet) transmission, and inhalation (short-range) or airborne (long range, aerosol) transmission; [2] acknowledgment that persistence of infectious virus in air is dependent on factors such as the matrix with which the virus is associated, temperature, RH, and ultraviolet radiation; [3] the relatively low minimum human infectious dose for SARS-CoV-2 of ∼10 tissue culture infectious doses (TCID₅₀); [4] the challenges associated with sampling of indoor air and fomites for recovering infectious SARS-CoV-2; and [5] the relationship between empirically determined in-air concentrations of SARS-CoV-2 RNA versus infectious SARS-CoV-2. We believe that this is a step in the right direction. Until we have definitive data to rule out one or more of the transmission modalities, considering the potential interdependencies among the various modalities, we should not discount the importance of any specific modalities and associated NPIs in our official public health messaging.