Parameters related to climate change may have an impact on the spread of SARS-CoV-2 by both affecting viral diffusion / viral survival outside of the host and the immunity of the population.40 The impact of temperature and humidity has been relatively well studied. For instance, according to several studies from China, low temperature, low humidity, and mild diurnal temperature range facilitate SARS-CoV-2 transmission.41-43 Yao et al. reported that COVID-19 transmission is negatively affected by higher temperature and lower relative humidity.44 In an extensive study, which was conducted in 3739 locations worldwide, between December 12, 2019, and April 22, 2020, the authors found a negative relationship between temperatures above 25°C and transmission rate of the virus, suggesting that lower temperature can induce SARS-CoV-2 infection.45 Furthermore, there was a weaker association with diurnal temperature, while a U-shaped relationship with outdoor ultraviolet (UV) exposure was noted. Together these findings suggest that changes in meteorological parameters may impact the viability of SARS-CoV-2 and transmission of the virus.

There is a lack of studies investigating the association between viral transmission and other meteorological parameters, such as wind speed and direction, and atmospheric pressure. However, Zhou et al. (2022) investigated the effect of daily average wind speed in four different states in the US. The number of confirmed COVID-19 cases in New York, California, and Texas was negatively correlated with daily average wind speed, while there was no correlation for Florida, and the authors concluded that low wind speed facilitated viral spread.46 In another study, a mild positive association of wind speed, precipitation, and air pressure with SARS-CoV-2 infection was found.45 The study by Adhikari and Yin34 showed that meteorological factors, such as wind speed, temperature, precipitation, and relative humidity, were associated with new COVID-19 cases.

Few studies investigated the mechanisms underlying the impact of meteorological factors on SARS-CoV-2 infection. Environmental conditions may affect the stability of the virus in nasal mucus and sputum. It was found that SARS-CoV-2 is more stable at low-temperature and low-humidity conditions and that warmer temperatures and higher humidity shortened its half-life.47 It has been suggested that single-stranded RNA viruses like SARS-CoV-2 are susceptible to UV inactivation6 and that a reduction in UV penetration may facilitate virus persistence in the ambient atmosphere. Furthermore, a decrease in UV is thought to reduce the synthesis of vitamin D, which has an antioxidant effect and has a positive role in a proper defence system against SARS-CoV-248. Finally, cold, and dry weather is also reported to induce susceptibility of the host immunity to the virus.49 These studies are summarised in Table 2.

In summary, epidemiological studies conducted in different countries and regions have demonstrated that there is clear evidence suggesting an association between air pollution and an increased risk for COVID-19 morbidity and mortality worldwide. Thus, an improvement in the air quality can be expected to have a positive impact on the outcomes of COVID 19. On the other hand, studies on the role of meteorological parameters on COVID 19 are lacking clear evidence. However, a limited number of studies have suggested that lower temperatures can facilitate the spread of SARS-CoV-2 that could lead to increased number of COVID 19 cases.

Italy, one of the first Western countries hit by the pandemic, has been the site of many recent epidemiological contributions (Table 1).

Veronesi et al., 50 in a prospective study in the city of Varese, were able to link citizens by residential address to 2018 average annual exposure to outdoor concentrations of air pollutants modelled using FARM, a chemical transport model. Citizens were further linked to regional datasets for COVID-19 case ascertainment. The authors found that PM2.5 was associated with a 5.1% (95% confidence interval [CI]= 2.7% to 7.5%) increase in the rate of COVID-19, corresponding to 294 additional cases per 100,000 person-years. Similar findings were observed for PM10, NO2, and NO.

Tateo et al.,51 in a study on environmental factors influencing SARS-CoV-2 spreading in North Italy, examined eight administrative areas (altogether 26 million inhabitants) and were able to demonstrate that PM matched the growth of hospitalisations in areas with low chronic particulate pollution, whilst fewer hospitalisations strongly corresponded to the higher temperature and solar radiation. They hypothesised that solar radiation alone and combined with high temperature exert an anti-SARS-CoV-2 effect, via both direct inactivation of virions and stimulation of vitamin D synthesis, improving function of the immune system.

Contiero et al.52 performed an ecological study of five Italian Regions (Piedmont, Lombardy, Veneto, Emilia-Romagna and Sicily), linking all-cause mortality by province (administrative entities within regions) to data on atmospheric concentrations of PM (PM2.5 and PM10) and ammonia (NH3), which are mainly produced by agricultural activities, documenting a 6.9% excess in a proxy for COVID-19 mortality for each tonne/km2 increase in NH3 emissions.

Nobile et al.53 reported that long-term exposure to air pollution (PM2.5 and NO2) was associated with COVID-19 mortality, but not with SARS-CoV-2 incidence, in a large observational population-based cohort of >1.5 million subjects in Rome.

Perone54 assessed air quality in 107 Italian provinces in the 2014-2019 period, and the association between exposure to nine outdoor air pollutants and COVID-19’s spread and related mortality in the same areas. The results showed that long-term exposure to NO2, PM2.5, PM10, benzene, benzo[a]pyrene (BaP), and cadmium (Cd) was positively and significantly correlated with the spread of COVID-19; in addition, long-term exposure to NO2, O3, PM2.5, PM10, and arsenic (As) was positively and significantly correlated with COVID-19 related mortality. In detail, PM and Cd showed the most adverse effect on COVID-19 prevalence, while PM and As showed the most relevant impact on excess mortality rate.

Falco et al.55 explored the possible beneficial effect of green areas in Spain and Italy: for both countries, a statistically significant association between COVID-19 clinical features (contagions, hospitalisations, and deaths) and the extension of public green areas (negative correlation), as well as the annual average concentrations of PM2.5 (positive correlation), clearly emerged.

Fedrizzi et al.,56 investigating a cohort of health care workers in Milan, found that a 10 μg/m3 increase in NO2 average concentration in the four days preceding nasopharyngeal swab for detecting SARS-CoV-2 was associated with a higher risk of testing positive (Incidence Rate Ratio [IRR] = 1.08, 95% CI: 1.01; 1.16). When considering a 1 μg/m3 increase in 2019 annual NO2 average, they observed a higher risk of infection (IRR: 1.02, 95%CI: 1.00; 1.03) and an increased antibody titre (IRR: 2.4%, 95%CI: 1.1; 3.6%).

The large availability of both air pollution and COVID-19 data, and the simplicity to make geographical correlations between them, led to a proliferation of ecological studies relating the levels of pollution in administrative areas to COVID-19 incidence, mortality, or lethality rates. However, the major drawback of these studies is the ecological fallacy that can lead to spurious associations. This has prompted a group of researchers from several epidemiological units, including the National Institute of Health (Istituto Superiore di Sanità) to launch the EpiCovAir study.56,57 Initially, the authors investigated the association between long-term exposure to air pollutants and the incidence of SARS-CoV-2 infections in Italy.57 A satellite-based air pollution exposure model with 1-km2 spatial resolution for entire Italy was applied and 2016-2019 mean population-weighted concentrations of PM10, PM2.5, and NO2 were calculated for each municipality, as estimates of chronic exposures. Individual records of diagnosed SARS-2-CoV-2 infections in Italy from February 2020 to June 2021 reported to the Italian Integrated Surveillance of COVID-19 were used. Updated statistical techniques were applied: principal component analysis (PCA); a mixed longitudinal ecological design with the study units consisting of individual municipalities in Italy; and generalised negative binomial models controlling for several confounders/effect modifiers. Almost 4 million COVID-19 cases in 7,800 municipalities were analysed (total population: 59,589,357 inhabitants). It was found that long-term exposure to PM2.5, PM10, and NO2 was significantly associated with the incidence rates of SARS-CoV-2 infection. In particular, incidence of COVID-19 increased by 0.3% (95%CI: 0.1%-0.4%), 0.3% (0.2%-0.4%), and 0.9% (0.8%-1.0%) per 1 μg/m3 increment in PM2.5, PM10 and NO2, respectively. Associations were higher among elderly subjects and during the second pandemic wave (September 2020-December 2020).

Then, the authors aimed to investigate the association between long-term exposure to air pollutants and mortality among 4 million COVID-19 cases in Italy.58 They used the same COVID population and methods for attributing air pollution exposures and for statistical analysis, adding a generalised propensity score (GPS) approach to an extensive list of area-level covariates to account for major determinants of the spatial distribution of COVID-19 case-fatality rates. Overall, case-fatality rates increased by 0.7% [95% CI: 0.5%, 0.9%], 0.3% (95% CI: 0.2%, 0.5%), and 0.6% (95% CI: 0.5%, 0.8%) per 1μg/m3 increment in PM2.5, PM10, and NO2, respectively. Associations were higher among elderly subjects during the first (February 2020-June 2020) and the third (December 2020-June 2021) pandemic waves. They estimated that ∼8% of COVID-19 deaths were attributable to pollutant levels above the WHO 2021 air quality guidelines.

In summary, the recent epidemiological contributions from Italy have consistently reported a relationship of air pollution exposure with several health outcomes linked to COVID-19.

Fewer studies were conducted in Portugal, mostly involving indoor air quality and the effects of lockdown or modelling air pollutants in cities. There is not yet a large epidemiological study to assess the effects of outdoor air pollutants on COVID-19 incidence or mortality.

Indeed, there has been an important nationwide study to evaluate the effects of the 2020 lockdown on air quality.59 This study evaluated air pollution changes across all of Portugal (68 stations) considering all urban, suburban, and rural zones. PM10, PM2.5, NO2, SO2, and ozone were analysed in the pre-, during, and post-lockdown period (January-May 2020) and, for a comparison, also in 2019. NO2 was the most reduced pollutant in 2020, which coincided with decreased traffic. A significant drop (15-71%) in traffic-related NO2 was observed specifically during the lockdown period, 55% for the largest and most populated region in the country. The PM was affected to a lesser degree, with substantial differences found for largely populated areas (Lisbon region ∼ 30%; North region, up to 49%); during lockdown, traffic-related PM dropped 10-70%. PM10 daily limit was exceeded 50% less in 2020, with 80% of exceedances before the lockdown period. SO2 decreased by 35%, due to suspended industrial productions, whereas ozone concentrations slightly (though not significantly) increased (83 vs. 80 µg m-3).

Interestingly, a systematic review of the impact of COVID 19 pandemic on air quality was published by Portuguese authors in 2022.60 A total of 114 studies that quantified the impact of the COVID-19 pandemic on air quality through monitoring were selected from three databases. The authors found that, although using different methodologies, some studies reported a temporary air quality improvement during the lockdown. More studies are still needed, comparing different lockdown, and lifting periods and, in other areas, for a definition of better-targeted policies to reduce air pollution.

Another study aimed to understand the influence of industries (including steelworks, lime factories, and industry of metal waste management and treatment) on the air quality of the urban-industrial area of Seixal (Portugal), during the first period of national lockdown due to COVID-19, whereas local industries kept their normal working schedule.61 The impact of the industries located in the study area on local air quality was identified (namely, the steelworks), confirming the concerns of the local population. The authors deemed that this valuable information is essential to improve future planning and optimize the assessment of particulate matter levels by reference methods.

In summary, the epidemiological studies from Portugal specifically focused on impact of lockdowns on air quality, and it was found that decreases in traffic and industrial activities led to an improvement in the air quality. It would be useful to realize a large epidemiological study to assess the effects of outdoor air pollutants on COVID-19 incidence or mortality.

Determining the route of transmission of the SARS-CoV-2 was very crucial to stop the pandemic. The common transmission routes of SARS-CoV-2 include person to-person, direct exposure with cough, sneeze, and droplet inhalation within a range of approximately 1.8 m and transmission through contact with oral, nasal, and eye mucous membrane.62 However, small particles with a larger viral load can be transferred to a distance up to 10 m from the source of emission in an indoor environment.62 Environmental factors including temperature, humidity, and ultraviolet radiation, such as sunlight, are also thought to impact the viability of the virus and its infectiousness over time.63

As epidemiological studies suggested a positive association between air pollution including PM pollution and SARS-CoV-2 infection, it was thought that PM may also act as a carrier for the virus in the outdoor environment. Indeed, previous studies found that influenza virus could be transported by ambient particles.63 Setti and colleagues collected ambient PMs in Bergamo, Italy, and analysed for the presence of SARS-CoV-2 RNA. They found that the particles can contain SARS-CoV-2 RNA in most of collected samples.15 In Turkey, Kayalar and co-workers detected SARS-CoV-2 RNA in approximately 10% of PM samples of various sizes collected in 10 different cities, especially in places where virus spread was common, such as hospital gardens and city centres.16 However, whether these virus particles are infectious or not remains to be determined. Adsorption of the SARS-CoV-2 on airborne dust and PM may be the contributors to the long-range transport of the virus.64

Receptor recognition is the first step of viral infection, and it has been reported that angiotensin-converting enzyme II (ACE2) is the main cell receptor binding SARS CoV-2.65,66 This enzyme is involved in the renin-angiotensin system (RAS) regulating blood pressure and inflammation. RAS system has 2 pathways oppositely running: the first one is Angiotensin-converting enzyme (ACE)/Angiotensin II peptide (Ang II)/Angiotensin II type 1 receptor (AT1R), which induces pro-inflammatory cytokine (IL-6, TNF-α) release; the second pathway is ACE2 -> Angiotensin 1-7 peptide (Ang1-7) -> Mas receptor, which has anti-inflammatory properties. In the absence of SARS-CoV-2, ACE2 cleaves AngII into Ang1-7 and inhibits the AT1R. Occupation of ACE2 by SARS-CoV-2 binding causes downregulation of receptor and is deemed to shift the pathway in favour of the Ang II axis which leads to an inflammatory response.65 ACE2 receptor is largely expressed in vascular endothelium, respiratory epithelium, alveolar monocytes, and macrophages.66-68 Alveolar type 2 (AT2) cells show the highest ACE2 expression in the lung.69 Moreover, viral entry requires cleavage of spike protein after receptor binding by cellular proteases to allow the fusion of cellular and viral membranes. Transmembrane protease, serine 2 (TMPRSS2) is the major protease utilised by SARS-CoV-2.66-70

Studies demonstrated upregulation of ACE2 and TMPRSS2 proteins because of PM exposure possibly inducing the entry of SARS-CoV-2 into the host cell. Sagawa and co-workers treated mice with PM for 24 hours and showed elevated ACE2 and TMPRSS2 expression in the alveolar regions, especially in AT2 cells.18 A recent study conducted with mice exposed to PM2.5 revealed a 40% increase in ACE2 protein expression in mice lungs.71 According to the “double hit hypothesis” by Frontera et al.,17 chronic exposure to PM2.5, in places such as Northern Italy and the Hubei province of China, caused upregulation of ACE2, as an initial protective mechanism to induce anti-inflammatory pathways. However, ACE2 expression also facilitated viral penetration into the cell that caused viral load increases in the cell. This, in turn, caused depletion of the ACE-2, leading to acute lung injury. The authors suggested that a high level of NO2 in the ambient air caused a second hit, resulting in a severe form of COVID-19.

Studies suggest that air pollutants induce the susceptibility of human beings to viral infections by altering the host immune defence system.72 Mouse studies found that exposure to diesel exhaust induced respiratory syncytial virus (RSV) gene expression in mice infected with the virus.73 It is known that short-term exposure to pollutants causes a pro-inflammatory response together with elevated reactive oxygen species (ROS) production inducing apoptosis, while long-term exposure can be a reason for immune dysregulation leading to different diseases. It has been confirmed that the innate immune capacity of alveolar macrophages is reduced in extremely polluted city populations because of the relative amount of phagocytosed PM.74 For instance, a study containing co-culture of RSV-infected bronchial epithelial cells and PM10 exposed macrophages showed that viral antigen uptake in macrophages in response to the virus dropped to half compared to the control macrophages.75 T-cell-mediated adaptive immune response is an essential part of the continuance of the clearing and suppression of viral infections in the long term. However, viral infections (including COVID-19) may lead to decreased production of T cells, natural killer cells, and interferon (IFN)-γ secretion by CD4+ T lymphocytes.76,77 Regarding air pollution, PM was found to have a reducing effect on IFN-β, a key antiviral cytokine, by affecting its promoter activity, and subsequent transcription. Additionally, diesel exhaust particles (DEP), which are present in ambient atmosphere as ultrafine particles, attenuated IL-2 and IFN-γ production by peripheral blood T lymphocytes causing defective immune status.78 These processes would influence the pathogenicity of SARS-CoV-2. Mice experiments showed that PM can cause alveolar collapse due to bio-mechanical changes occurring in surfactant function. Surfactant deficiency causes acute respiratory distress syndrome (ARDS). Hence, people living in places with higher PM concentrations could have more severe COVID-19 infection due to dysfunctional surfactants, together with ARDS.74

Airway epithelium forms the first line of defence against inhaled insults, including infectious agents. It has been shown that pollutants disrupt the epithelial barrier integrity through occludin reduction in plasma membranes and dissociation of Zonula occludens (ZO)-1, which may allow higher levels of SARS-CoV-2 entry into the host cell. In fact, SARS-CoV-2 itself may cause decreased epithelial barrier integrity, together with impaired tight junctions. Dysfunctional barrier can increase the risk for COVID-19 morbidity. Studies of air pollutants reported that O3 and NO2 increased permeability of human primary bronchial epithelial cell cultures, and that cells from asthmatic subjects were more susceptible to this process. Disrupted muco-ciliary clearance is also one of the significant reasons for an inadequate immune defence system.77 Earlier studies by Bayram et al. demonstrated that DEP could decrease ciliary beat frequency (CBF) and induce release of inflammatory mediators, while modulating cell cycle progression and apoptosis of human airway epithelial cells in several studies.79-81 Recent animal model and in vitro studies showed that the ciliary structure is shortened and deteriorated due to SARS-CoV-2 infection, thus causing changes in ciliary function leading to impaired muco-ciliary clearance in airways.82

Another aspect focuses on microbiome diversity and how it is altered in SARS-CoV-2-infected individuals. Microbiota of the respiratory tract is an essential part of immunity development since birth; it is known that environmental factors like pollutants have an alteration effect on the diversity of these organisms.77 RNA sequencing research, conducted in the US with COVID-19 patients and a control group, demonstrated differences in diversity and abundance of some bacterial species in the upper respiratory tract microbiome, in which viral and bacterial interaction can influence the viral load, host immune response, and acute severity.83Fig. 1 demonstrates mechanisms underlying the interaction between air pollution and SARS-CoV-2 infection at cellular level.

Fig. 1.

Mechanisms underlying the interaction between air pollution and SARS-CoV-2 infection at cellular level. Air pollutants disrupt the epithelial barrier integrity together with reducing ciliary beat frequency that impairs mucociliary clearance and facilitates the viral entry. Air pollutants also augment the entry of SARS-CoV-2 by inducing the expression of the angiotensin converting enzyme (ACE)2 receptor. Furthermore, they induce the production of reactive oxygen species (ROS) in the host cell, which could lead to cellular injury and apoptosis. Viral proliferation together with increased levels of ROS triggers cellular damage that could lead to severe clinical conditions such as acute respiratory distress syndrome (ARDS). IFN, interferon; TMPRSS2, Transmembrane protease, serine 2. (The figure is original and was created using BioRender.com).

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In summary, studies investigating mechanisms underlying the interaction between air pollution and SARS-CoV-2 infection have suggested that air pollutants can induce the expression of several proteins, which modulate cellular entry of the virus. Furthermore, air pollutants-induced mucociliary dysfunction, epithelial barrier disruption, oxidative stress and inflammatory changes within the cell may also enhance viral proliferation and cellular injury by SARS-CoV-2. However, there is a lack of evidence demonstrating the direct interaction of air pollutants with SARS-CoV-2, and further in vitro and in vivo mechanistic studies are clearly needed.