Does Air Pollution Inﬂuence COVID-19 Outbreaks?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] is the pathogen of the COVID-19 disease. COVID-19 in a in Province, The World Health Organization declared COVID-19 a Public Health Emergency of International At the it clearly appears there are remarkable di ﬀ erences in terms of the rate of spread and mortality in the outbreaks of COVID-19 in di ﬀ erent countries of the world. These di ﬀ erences important questions related to the inﬂuence of atmospheric factors, such as atmospheric on the spread of COVID-19 it is so transmissible) and on its it is erent the and, in ﬀ erent of the same country). The the What is the inﬂuence of atmospheric aerosol, and more generally, air pollution, in eliciting indirect systemic e ﬀ ects (linked to pro-inﬂammation and oxidation mechanisms of the lungs, and immunological alteration processes) increasing the

oxygen-free radical-generating activity, DNA oxidative damage, mutagenicity, and the stimulation of pro-inflammatory responses, are currently unclear. Indeed, particle size matters, and it is important to consider the role of ultrafine particles (particles with aerodynamic diameters smaller than 100 nm) on health outcomes [11,12]. The role of chemical composition influences ecotoxicity, cytotoxicity, and genotoxicity in different ways, so that different biological outcomes are expected even in cases of similar number and mass concentrations [13]. Although the interpretation of data is still uncertain, the possibility that exposure to air pollutants may contribute to increasing the vulnerability of a population to COVID-19 is plausible. However, caution should be used in translating high values of conventional aerosol metrics, such as PM 2.5 and PM 10 concentrations without chemical, physical, and biological analysis, to an increase in vulnerability or to a direct explanation of the differences in mortality observed in different countries.
Finally, it should be noted that the role of pollution was suggested to partially explain the differences in mortality observed in northern Italy compared to other regions of Italy, based on information that was available as of mid-March [14]. It must be said that the current data on mortality (and contagions) could be affected by relevant uncertainty due to the different strategies used for counting deaths related to COVID-19 and infected people. Furthermore, recent outbreaks of COVID-19 also took place in areas (Spain, the USA, the UK, France) characterized by very different pollution levels compared to northern Italy in winter (and also compared to Wuhan in China); no significant outbreaks (up to now) have been observed, fortunately, in very highly populated and polluted cities in India. This suggests that several variables are potentially involved in the spread of COVID-19 and in the current evaluation of its mortality, such as the age distribution of a population, population density, social habits, the restrictive measures applied, and meteorological conditions. All of these factors should be considered in further studies, together with atmospheric pollution, to correctly estimate the importance (weights) of each of the factors in COVID-19 spread, as recently suggested by the Italian Aerosol Society [15].
Airborne transmission of SARS-CoV-2. Is it a plausible mechanism? If so, what is the probability of occurrence in outdoor and indoor environments?
When infected people are detected, there is no way to ascertain with certainty how they were infected. The epidemiological approach to carefully track who came into contact with an infected person does not provide conclusive information on how the virus was effectively transferred. There are different possible transmission routes of the respiratory virus among humans [16] and it is difficult to estimate the relative contribution of each route. These include direct contact between infected and susceptible individuals or indirect contact mediated by a "fomite" (i.e., an object or surface that has been contaminated with the virus). Airborne transmission may occur in two distinct modes not requiring direct contact. The first mode is via large (>5 µm in diameter) virus-laden droplets released by infected individuals via a cough or sneeze; the second mode is when a susceptible individual inhales small virus-laden aerosols released during respiration or vocalism [17] or the residual solid component after the evaporation of droplets [18]. Large droplets, emitted in a cough or sneeze, are quickly stopped by the resistance of air and removed by dry deposition, mainly through gravitational settling, generally at a distance smaller than 1-1.5 m from the emission. The smaller virus-laden particles (<5 µm in diameter) related to the respiratory emissions of infected individuals could remain in the air for hours and could be transported and dispersed by winds and turbulent eddies. Therefore, it is plausible that this mechanism could contribute to the contagion, however, knowledge of several parameters is necessary to evaluate the effective probability of contagion and its weight compared to other transmission routes (direct contact, via fomites, and transmission via large droplets). Other important factors include the effective concentration and the size distribution of virus-laden aerosols in air, the chemical and biological composition of the bioaerosol, the lifetime of the virus in the aerosol, and the minimum amount of viable virus needed to be inhaled to produce infection. Further research is required to determine the characteristics of these last parameters. Recent works [19,20] demonstrated that aerosolized SARS-CoV-2 remains viable in the air with a half-life in the order of 1 h in a laboratory controlled environment, but the half-life could be different in outdoor environments in relation to meteorological conditions (temperature, relative humidity, ultraviolet radiation) that could degrade the virus [21,22]. In considering outdoor environments, Liu et al. [23] collected aerosol samples in public areas in Wuhan in February 2020 and found no detectable concentration of SARS-CoV-2 (<3 copies/m 3 ) in all but two crowded sites. This is a very low concentration compared to the typical concentration of atmospheric particles, which generally varies between 100,000,000 particles/m 3 in remote uncontaminated areas (high mountains, Antarctica) and 100,000,000,000 particles/m 3 in highly polluted urban areas [24]. Considering the typical volume of air involved in respiration, in the range of 0.5-1.5 m 3 /hour, the probability of inhalation of airborne viable virus in outdoor environments is very low.
The situation is different in indoor environments, for example, hospitals, in which there are several infected individuals in restricted spaces and, eventually, poor air exchange and/or mechanical ventilation/conditioning. In these cases, the source is more intense, the dispersion due to turbulence and consequent dilution is more limited in confined spaces, and meteorological environmental conditions like temperature, relative humidity, and UV radiation are more stable, creating an environment that is more favorable to the survival of the virus. Indoor measurements showed widespread presence of viral RNA in the air in isolation rooms where patients with SARS-CoV-2 were receiving care [25]. This indicates that viral particles can be spread airborne in indoors via bioaerosols; however, the presence of an RNA sequence is not a clear signal of its viability. The authors reported that finding infectious virus has proved elusive and that further experiments are needed to determine viral activity in the collected samples. An analysis by Liu et al. [23] of aerosol samples in two hospitals in Wuhan showed the highest concentrations in patient care areas (in toilet facilities about 19 copies/m 3 ) and in medical staff areas in personal protective equipment removal rooms (18-42 copies/m 3 ). A fraction of these particles was in the fine size range (0.2-1 µm), potentially able to to remain in the air for a longer time compared to coarse fractions, thus being more suitable for airborne transmission. Furthermore, in indoor environments, it could be relevant the deposition of these particles on surfaces representing an increased risk of transmission via fomites. Therefore, the risk of contagion via airborne virus-laden aerosols could be higher in specific indoor environments compared to outdoors. Additional research is necessary, both in indoor and outdoor environments, to investigate the aerosolization of SARS-CoV-2 during respiration and speech, the concentrations and size distribution of the virus in air for different conditions, as well as physico-chemical and biological properties, lifetime, and infectivity of the bioaerosol containing virus.

Concluding Remarks
SARS-CoV-2 is highly transmissible (with more than 1.3 million people infected in the world at the time of this writing) and lethal (more than 76,000 reported deaths at present). Exposure to air pollution could increase vulnerability and have detrimental effects on the prognosis of patients affected by the COVID-19. However, the relative weight of air pollution, compared to other confounders, is still to be determined.
Caution should be used in translating high values of conventional metrics, such as PM 2.5 and PM 10 concentrations, into a direct measure of vulnerability. Airborne transmission mediated by virus-laden aerosols emitted during expiration and speech is plausible in specific environments. Current knowledge indicates a low probability in outdoor environments and an increase in probability in specific indoor environments, like hospitals and areas where patients are quarantined. In these environments, it is advisable to mitigate the risk for vulnerable people via using periodic ventilation of environments, decontaminations of surfaces and air conditioning systems, and appropriate technologies for mechanical ventilation/conditioning in order to limit the circulation of virus-laden bioaerosols in air.
The stakes for the world are enormous, and the results of robust research studies are urgently needed in order to provide information that could help in developing strategies for facing the current pandemic as well as future pandemics. Our recommendations for future research focus on (but are not limited to) the investigation, both outdoors and indoors, of airborne transmission routes, lifetimes and dynamics, dosimetry and infection thresholds within the human body, and the physical/chemical/biological/toxicological/virological properties of virus-laden bioaerosol particles, with all of these factors properly adjusted for a wide number of potential confounders. This research should come from a multidisciplinary approach involving a strong collaboration between traditionally distinct disciplines of science, and in particular, virologists, epidemiologists, toxicologists, physicians, aerobiologists, aerosol scientists, and meteorologists.
Author Contributions: D.C. and F.C. contributed to conceptualization and writing. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.