key: cord-1036321-hu6iwoab
authors: Setti, L.; Passarini, F.; De Gennaro, G.; Barbieri, P.; Perrone, M. G.; Piazzalunga, A.; Borelli, M.; Palmisani, J.; Di Gilio, A.; PISCITELLI, P.; Miani, A.
title: The Potential role of Particulate Matter in the Spreading of COVID-19 in Northern Italy: First Evidence-based Research Hypotheses
date: 2020-04-17
journal: nan
DOI: 10.1101/2020.04.11.20061713
sha: b685cbae213e7e3eafe36505f91921754ab94dbf
doc_id: 1036321
cord_uid: hu6iwoab

Background: An epidemic model based only on respiratory droplets and close contact could not fully explain the regional differences in the spread of the recent severe acute respiratory syndrome COVID-19 in Italy, which was fast and dramatic only in Lombardy and Po Valley. On March 16th 2020, we presented a Position Paper proposing a research hypothesis concerning the association between higher mortality rates due to COVID-19 observed in Northern Italy and the peaks of particulate matter concentrations, frequently exceeding the legal limit of 50 micrograms/m3 as PM10 daily average Methods: To assess environmental factors related to the spread of the COVID-19 in Italy from February 24th to March 13th (the date when the lockdown has been imposed over Italy), official daily data relevant to ambient PM10 levels were collected from all Italian Provinces between February 9th and February 29th , taking into account the average time (estimated in 17 days) elapsed between the initial infection and the recorded COVID positivity. In addition to the number of exceedances of PM10 daily limit value, we considered also population data and daily travelling information per each Province. Results. PM10 daily limit value exceedances appear to be a significant predictor (p <0.001) of infection in univariate analyses. Less polluted Provinces had a median of 0.03 infection cases over 1000 residents, while most polluted Provinces had a median of 0.26 cases over 1000 residents. Thirty-nine out of 41 Northern Italian Provinces resulted in the category with highest PM10 levels, while 62 out of 66 Southern Provinces presented low PM10 concentrations (p<0.001). In Milan, the average growth rate before the lockdown was significantly higher than Rome (0.34 vs. 0.27 per day, with a doubling time of 2.0 days vs. 2.6), suggesting a basic reproductive number R0>6.0, comparable with the highest values estimated for China.

Severe acute respiratory syndrome known as COVID-19 disease (due to SARS-CoV-2 virus), is recognized to spread via respiratory droplets and close contacts [1] . However, this unique transmission model does not seem to explain properly the different spread observed in Italy from February 24th, 2020 to March 13rd, 2020. The huge virulence of COVID19 in the Po Valley is not comparable to the milder contagiousness observed in the central-southern regions. Demographic factors related to the ageing of the population and the possibility of infection without clinical symptoms for a quite long time -associated with the high rate of asymptomatic people that characterize COVID-19, estimated in 50-75% of infections -may only partially explain the fast spreading of the virus in Lombardy and Northern Italy [2, 3] . Cai et al (2020) reported different incubation periods in patient(s) infected in Wuhan [4] , but an epidemic model based only on respiratory droplets and close contact could not fully explain the regional differences in the spreading of the recent severe acute respiratory syndrome COVID-19 in Italy, which was fast and dramatic only in Lombardy and Po Valley.

At the same time, a number of studies have shown that airborne transmission route could spread viruses even further the close contact with infected people [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . Paules et al. (2020) highlighted that -besides close distance contacts -airborne transmission of SARS-CoV can also occur [5] . It has also been reported how for some pathogens the airborne transport can reach long distances [6] [7] [8] . Reche et al. (2018) described the aerosolization of soil-dust and organic aggregates in sea spray that facilitates the long-range transport of bacteria, and likely of viruses free in the atmosphere. In particular, virus deposition rates were positively correlated with organic aerosol <0.7 µm, implying that viruses could have longer persistence times in the atmosphere and, consequently, will be dispersed further [9] . Moreover Qin et al. (2020) analyzed the microbiome of the airborne particulate matter (PM 2.5 and PM 10 ) in Beijing over a period of 6 months in 2012 and 2013, putting in evidence a variability of the composition that depended on the months [10] . Temporal distribution of the relative abundance of the microbiome on the particulate matter (PM) showed the highest presence of viruses in January and February, just in coincidence with most severe PM pollution. Chen. et al (2017) demonstrated the relationship between short-term exposure PM 2.5 concentration and measles incidence in 21 cities in China [11] . Their meta-analyses showed that the nationwide measles incidence was significantly associated with an increase of 10 µg/m 3 in PM 2.5 levels.

Other recent studies have also reported associations between PM and infectious diseases (e.g., influenza, hemorrhagic fever with renal syndrome): inhalation could bring PM deep into the lung and virus attached to particles may invade the lower part of respiratory tract directly, thus enhancing the induction of infections, as demonstrated by Sedlmaier et al (2009) [12] . Zhao et al. (2018) showed that the majority of the positive cases of highly pathogenic avian influenza (HPAI) H5N2 in Iowa (USA) in 2015 might have received airborne virus, carried by fine PM, from infected farms both within the same State and from neighboring States [13] . The condensation and stabilization of the bioaerosol, generating aggregates with atmospheric particles from primary (i.e. dust) and secondary particulate, has been indicated as mechanisms able to transport airborne bacteria and viruses to distant regions, even by the inter-continent- [15] ; Brown et al (1935) found that the most severe measles epidemic in the United States occurred in Kansas in 1935 during the Dust Bowl period [16] .

Coming to recent specific studies, laboratory experiments of Van Doremalen et al. (2020) indicated that airborne and fomite transmission of SARS-Cov-2 is plausible, since the virus can remain viable and infectious in aerosol for hours [17] . Field measurement by Liu et al. (2020) showed evidence of coronavirus RNA in air sampled in Wuhan Hospitals and even in ambient air in close proximity during COVID-19 outbreak, pointing at the airborne route as a possible important pathway for contamination, that should have a further confirmation [18] . Santarpia et. al. reported the presence of airborne SARS-Cov-2 in air sampled at the Nebraska University Hospital [19] , while -at the opposite -some negative evidence of virus presence in air reported by Ong et al. (2020) come from explicitly poor sampling scheme [20] . A research carried out by the Harvard School of Public Health seems to confirm an association between increases in particulate matter concentration and mortality rates due to COVID-19

[21]. On March 16 th 2020, we have released an official Position Paper highlighting that there are enough evidence to consider airborne route as a possible additional factor for interpreting the anomalous COVID-19 outbreaks notified in the Northern Italy, known to be one of the European areas characterized by highest PM concentration [22, 23] . Data that led to the publication of the Position Paper are presented in this article, and are expected to trigger the interest of the research community at working on this topic.

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The copyright holder for this preprint this version posted April 17, 2020. .

We have analyzed daily data relevant to ambient PM 10 levels, urban conditions and virus incidence from all Italian Provinces, in order to reliably determine the association between PM pollution level and the initial spread of COVID-19. PM 10 daily concentration levels were collected by the official air quality monitoring stations of the Regional Environmental Protection Agencies, ARPA), publicly available on their websites. The number of PM 10 infected people for each Province from February 24 th to March 13 th (the date when the lockdown was decided) was that reported on the official Government website, updated with daily frequency [24] . PM 10 exceedances were collected between February 9 th and February 29 th , taking into account the lag period, which is the average time elapsed between the initial infection and the diagnosis. To investigate how high PM 10 concentrations (above the daily limit value) might relate to infection diffusion, we performed an exploratory analysis considering the recursive binary partitioning tree approach, as implemented into the party package [25] of R [26] .

Besides PM 10 daily limit value exceedances we considered several further covariates related to the different Provinces: population absolute frequencies; population densities (n° inhabitants/km 2 ); the absolute frequencies of people daily travelling as estimated by the Italian National Institute of Statistics [3] , and its proportion with respect to the overall Province population. As response variable we considered the infection rate of the disease, expressed as a proportion obtained binding together into a single two-dimensional vector both the number of COVID-19 cases and the rest of the Province population. We have performed statistical inferences analyses on Milan and Rome data, in order to observe the potential association between PM levels and COVID-19 spreading in big cities located in different geographic areas and with remarkable differences in PM 10 exceedances, presenting at the same time quite similar urbanization, life style, population, ageing index, and number of commuters.

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The copyright holder for this preprint this version posted April 17, 2020. .

The spatial distribution of ambient PM 10 exceedances between Italian cities was geographically heterogeneous and it is presented in Fig. 1a . The highest numbers of exceedances were generally located in Northern Italian Regions, while zones with a lower contagion were sited in Central and Southern

Regions. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 17, 2020. . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 17, 2020. . In order to observe the effect of the particulate matter in big cities having quite similar urbanization, l style, population and number of commuters, Milan and Rome were chosen, finding out that the presen of the first infected people was similar on February 25 th : 8 and 3 infected persons in Milan and Rom respectively. However, we considered as the first day of spread for both cities when in Rome the infect persons was about 6 on March 1st (Figure 4 ).

(b) Distribution of the average daily PM 10 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 17, 2020. . https://doi.org/10.1101/2020.04.11.20061713 doi: medRxiv preprint

The incidence growth rate in Italy was 0,19 per day with a doubling time close to 3.6 days in according with Sanche et al. (2020) who showed a growth rate of infection of COVID-19 in Wuhan, Hubei Province (China) on January 2020 close to 0.21-0.30 per day with a doubling time of 2.3-3.3 [27] . The basic reproductive number (R 0 ), estimated by the researchers, was 5.7 consistently with a "super-spread event"

by an airborne droplet transmission as described by Wellings and Teunis (2004) for the epidemic curves for Sever Acute Respiratory Sindrome (SARS) during the outbreak on February-June 2003 in Hong Kong, Vietnam, Singapore and Canada [28] . In Rome the growth rate before the lockdown measures (March 13 th ) was 0,27 per day with a doubling time of 2.6 days that were comparable with a "superspread event" as described for SARS. In Milan the growth rate was significantly higher, close to 0.34 per day with a doubling time of 2.0 days, and suggests a R 0 value higher than 6.0 quite similar to the epidemic transmission by airborne droplets observed for measles (known to be around 12-18) [29] and to the highest R 0 estimates documented for China, ranging from 1.4 to 6.49 with a mean of 3.28 and a median of 2.79 (Wuhan: 2.55-2.68; Hubei Province: 6.49; China: 2.2-6.47) [30] .

Based on the available literature [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] , there is enough evidence to consider the airborne route, ant specifically the role of particulate matter, as a possible additional infection "boosting" factor for interpreting the anomalous COVID-19 outbreaks observed in the Northern Italy -known to be one of the European areas characterized by the highest PM concentration [1] . Airborne transmission is certainly more effective in indoor environments, with little ventilation, but it must be considered that the Po Valley, by its atmospheric stability, closely resembles a confined environment and that long-distance virus transport is favored by high concentration of dusts. However, the highly diluted nature of viral bioaerosol in ambient air has been considered a major impediment to viral aerobiological detection -including the investigation of viral interactions with other airborne particles -despite bioaerosol is a well-known factor for the virus transmission via airborne. Recently, Groulx et al. (2018) , using an in vitro PM concentrator, suggested that the interaction between airborne viruses and airborne fine particulate matter influence viral stability and infectivity [31] . The stability of aerosol and condensation reactions occur frequently in atmosphere, as organic aerosol change the properties (hygroscopicity, toxicity, optical properties) of other aerosol [32] .

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The copyright holder for this preprint this version posted April 17, 2020. . https://doi.org/10.1101/2020.04.11.20061713 doi: medRxiv preprint Cruz-Sanchez et al. (2013) demonstrated that Respiratory Syncytial virus (RSV) exposed to black carbon, in the form of India ink, prior to co-aerosolization in vitro, and then deposited on a cell substrate, increased viral infectivity [33] . In areas of high vehicle traffic, many different pollutants arising from a variety of sources coexist (car or truck exhausts, emissions from heating installations, etc.) [34] , which present a particulate matter emissions containing carbon, ammonium, nitrate and sulfate.

Our findings showed that high frequency of PM 10 concentration peaks (exceeding 50 µg/m 3 ) result in a spread acceleration of COVID-19, suggesting a "boost effect" for the viral infectivity. We found significance differences both in PM 10 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 17, 2020. . https://doi.org/10.1101/2020.04.11.20061713 doi: medRxiv preprint Further experimental studies could confirm the possibility that particulate matter may act as a "carrier"

for the viral droplet nuclei, impressing a boost effect for the spreading of the viral infection, as it has been shown for other viruses. Recent studies [36] and recommendation [37] about increased social distancing indicate that a recommended interpersonal distance of significantly more than one meter and usage of personal masks [38] are advisable prevention measures.

It must also be pointed out that long term exposures to high levels of particulate matter itself chronically impair human health and possibly influence clinical course of infections acquired by already debilitated individuals, especially in most vulnerable age groups. Indeed, according to 2005 WHO guidelines, annual average concentrations of PM10 should not exceed 20 μ g/m3 (compared to current EU legal limits of 40 μ g/m3) and PM2.5 should not exceed 10μg/m3 (compared to current EU legal limits of 25 μ g/m3) [39] .

Moreover, the exposure-effect relationship between fine particulate matter and health damages is not of linear type, so that it is not really possible to set a threshold below which is foreseeable a complete absence of damage to human health [39] .

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The copyright holder for this preprint this version posted April 17, 2020. . https://doi.org/10.1101/2020.04.11.20061713 doi: medRxiv preprint

The available literature on the role of airborne transmission, and this first preliminary observation of consistent association between the number of COVID-19 infected people and PM 10 peaks, points out the opportunity of a further computational and experimental research on this route of transmission, and the potential role of PM on viral spread and infectivity (in addition to the possibility of regarding PM levels as an "indicator" of the expected impact of COVID-19 in most polluted areas). There is the rational for carrying out experimental studies specifically aimed at confirming or excluding the presence of the SARS-CoV-2 and its potential virulence on particulate matter of Italian cities as well as at European and international level.

Urgent actions must be adopted to counteract climate changes and the alteration of ecosystems that might trigger new and unexpected threats to human health such as that of COVID-19, which we are so dramatically experiencing worldwide.

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