key: cord-1017111-ezrarusj authors: Pozzer, Andrea; Dominici, Francesca; Haines, Andy; Witt, Christian; Münzel, Thomas; Lelieveld, Jos title: Regional and global contributions of air pollution to risk of death from COVID-19 date: 2020-10-26 journal: Cardiovasc Res DOI: 10.1093/cvr/cvaa288 sha: 9905c89b5733729f428690031a5d24b22637087d doc_id: 1017111 cord_uid: ezrarusj AIMS: The risk of mortality from the coronavirus disease that emerged in 2019 (COVID-19) is increased by comorbidity from cardiovascular and pulmonary diseases. Air pollution also causes excess mortality from these conditions. Analysis of the first severe acute respiratory syndrome coronavirus (SARS-CoV-1) outcomes in 2003, and preliminary investigations of those for SARS-CoV-2 since 2019, provide evidence that the incidence and severity are related to ambient air pollution. We estimated the fraction of COVID-19 mortality that is attributable to the long-term exposure to ambient fine particulate air pollution. METHODS AND RESULTS: We characterized global exposure to fine particulates based on satellite data, and calculated the anthropogenic fraction with an atmospheric chemistry model. The degree to which air pollution influences COVID-19 mortality was derived from epidemiological data in the USA and China. We estimate that particulate air pollution contributed ∼15% (95% confidence interval 7–33%) to COVID-19 mortality worldwide, 27% (13 – 46%) in East Asia, 19% (8–41%) in Europe, and 17% (6–39%) in North America. Globally, ∼50–60% of the attributable, anthropogenic fraction is related to fossil fuel use, up to 70–80% in Europe, West Asia, and North America. CONCLUSION: Our results suggest that air pollution is an important cofactor increasing the risk of mortality from COVID-19. This provides extra motivation for combining ambitious policies to reduce air pollution with measures to control the transmission of COVID-19. Poor air quality, especially from fine particulate matter with a diameter <2.5 mm (PM 2.5 ), is one of the leading risk factors, and responsible for many excess deaths. 1, 2 The global loss of life expectancy from long-term exposure to ambient air pollution exceeds that of infectious diseases, and is comparable with that of tobacco smoking. [1] [2] [3] The mortality from COVID-19 depends on comorbidities, including conditions that increase cardiovascular risks such as arterial hypertension, diabetes mellitus, obesity, and established coronary artery disease, as well as respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), being similar to those that are influenced by air pollution. [3] [4] [5] [6] The risk of death is strongly related to age, being particularly high in those aged >70. It is also higher amongst males, economically disadvantaged populations, and in some ethnic groups. In assessing the relationships between exposures to risk factors and outcomes, potential confounders therefore need to be accounted for in the design of studies and in data analysis. These include the age distribution of the population, availability of hospital beds (and intensive care capacity), and the proportion of the population living in poverty. . A recent study, using an ecological design, assessed how environmental influences modify the severity of COVID-19 outcomes in the USA. 7 Potential confounders were identified, and statistical models were used to relate long-term exposure to ambient PM 2.5 to COVID-19 deaths. The computed mortality rate ratios (MRRs) express the relative increase in COVID-19 deaths for each microgram per cubic meter increment of PM 2.5 in ambient air. The PM 2.5 data were derived from satellite and ground-based measurements combined with atmospheric modelling, 8 and the confounders were determined from county-level censuses, homeland infrastructure, and meteorological data. Here we test the assumption that the derived MRRs are representative for the populations of other countries (China) and consider the global impact. In the present study, we apply the MRRs to estimate the excess mortality, i.e. the fraction of COVID-19 deaths that could be avoided if the population were exposed to lower counterfactual air pollution levels without fossil fuelrelated and other anthropogenic emissions. We emphasize that our results are provisional, based on epidemiological data collected up to the third week of June 2020, and a comprehensive evaluation will need to follow after the COVID-19 pandemic. In the early 2000s, the first severe acute respiratory syndrome coronavirus (SARS-CoV-1) appeared in China (Guangdong Province). The virus was zoonotic, as it originally developed in bats. 9 The World Health Organization (WHO) reported that it resulted in a SARS epidemic with >8000 cases in 26 countries, mostly in south-east Asia and in Canada. 8 The disease emerged in November 2002 and was contained in July 2003. SARS-CoV-1 and SARS-CoV-2 have many similarities, as their RNA genomes are closely related and the viruses enter the host cells by binding to the same entry receptor angiotensin-converting enzyme 2 (ACE2). 10-12 About 2-14 days after infection, the systemic symptoms of both diseases are alike, and a similar fraction of patients develops severe symptoms with a mortality rate that increases strongly with advanced age. [13] [14] [15] [16] In China alone, >5000 cases of SARS-CoV-1 were reported, leading to nearly 350 fatalities. Since the exposure to ambient air pollution is associated with respiratory and cardiovascular diseases, it was hypothesized that health outcomes of SARS were aggravated by poor air quality. A study in 2003 corroborated that in parts of China with moderate levels of air pollution, the risk of dying from the disease was >80% higher compared with areas with relatively clean air, while in heavily polluted regions the risk was twice as high. 17 In 2019, the related second virus strain appeared (SARS-CoV-2) in China (Hubei Province), which also developed in bats, 4 causing COVID-19, which grew from an epidemic into a pandemic in the early part of 2020. A Chinese analysis indicated that the risk of symptomatic infection typically increases by $4% for each year of age between 30 and 60, and that the lethality is highest for individuals >60 years. 15 COVID-19 is associated with a combination of respiratory and cardiovascular complications, which may comprise myocardial infarction, heart failure, venous thrombo-embolisms, and increases in biomarkers, 18 which are also found in connection with high levels of air pollutants. 5 In a recent analysis of 5700 patients hospitalized with COVID-19 in the New York City area, the most common comorbidities were hypertension (57%), obesity (42%), and diabetes (34%), 19 representing cardiovascular risk factors that are also observed in relation to elevated PM 2.5 concentrations, 5, 20 suggesting additive or synergistic effects on the cardiovascular system. In addition, advanced age is a strong risk factor for cardiovascular disease, and the effects on immune function may be equally important for COVID-19 susceptibility. The age dependency coincides with that of excess mortality from PM 2.5 . 3, 15 The COVID-19 mortality rate has been estimated to be $4% in symptomatic cases, in part because pre-existing conditions such as cardiovascular and respiratory disorders increase the risk. 21 Considering the cardiovascular and respiratory health impacts of air pollution, the relationship to COVID-19 mortality is not unexpected. Preliminary studies addressed the influence of air pollution on COVID-19 in different regions. In China, the incidence of COVID-19 was found to be significantly enhanced by PM 2.5 , 22 while a correlation between ambient PM 2.5 and the mortality rate was also established. 23 In Italy, it was found that the high pollution concentrations that are typical for the Po valley, especially in the Lombardy region of which Milan is the capital, were associated with a high mortality rate. 24 As mentioned above, in the USA the severity of COVID-19 outcomes was linked to PM 2.5 exposure, making use of Medicare data for >60 million people and nationwide air quality measurements. 7 Data were collected for 98% of the population in 3087 of the total number of 3142 counties, of which $42% had reported COVID-19 deaths up to the third week of April 2020. The death counts relied on data from the Coronavirus Resource Center of the Johns Hopkins University. 25 The study accounted for 20 potential confounding factors including population size, age distribution, population density, time period since the beginning of the outbreak, time elapsed since the home confinements, hospital beds, number of individuals tested, meteorological conditions, and socioeconomic and risk factors such as obesity and smoking. 7 The results showed significant overlap between the causes of death in COVID-19 patients and those that lead to mortality from PM 2. 5 . The MRR, i.e. the percentage increase of COVID-19 mortality risk per mg/m 3 increase of exposure to PM 2.5 , was found to be 8%, with a 95% confidence interval of 2-15%. 7 The calculations are continually updated based on the most recent data (up to 18 June at the time of writing), showing no significant changes in the MRR in the preceding 4 months. We applied a global atmospheric chemistry general circulation model (EMAC) which comprehensively simulates atmospheric chemical and meteorological processes and interactions with the oceans and the biosphere, in the same set-up as in recent studies on climate change, air pollution, and public health. 3, 26 In addition to the standard simulation, we performed two sensitivity calculations: (i) with fossil fuel-related emissions removed and (ii) with all anthropogenic emissions removed. The model results were used to estimate the ratio of fine particulates in simulation (i) and (ii) and the standard simulation. The annual atmospheric near-surface PM 2.5 concentrations were taken from model-integrated satellite data, for the year 2019. 8, 27 The horizontal resolution is 0.01 by 0.01 degrees, corresponding to a grid size of $1 km  1 km. The near-surface concentrations of PM 2.5 for fossil fuel-related and all anthropogenic emissions are estimated by scaling this data set to the ratios (i) and (ii) obtained with the EMAC model simulations. To estimate the relative risk (RR or hazard ratio) of excess COVID-19 mortality from the long-term exposure to air pollution, we used the exposureresponse function of the WHO, 28 . RR is a function of the concentration of air pollutants, which specifies annual average exposure dependent on location (grid cell) derived from the data mentioned above. X is the pollutant (PM 2.5 ) and X 0 is the pollutant threshold concentration below which exposure does not have implications for public health. Both b and X 0 are estimated by fitting to data from the literature with a least square method (Figure 1) . We adopted the threshold PM 2.5 concentration (X 0 ) from Burnett et al. 2 (i.e. < 2.4 lg/m 3 PM 2.5 ), forcing the curve fitting into this range. We tested different exposure-response functions, e.g. of Burnett et al., 2 and values for X 0 , and find that the results are not sensitive to these assumptions. Because the COVID-19 mortality rate ratio due to air pollution, based on data in the USA alone, 7 may not represent countries with very high fine particle concentrations (associated with a lack of observations in such regions), we investigated the effect of including data from the enhanced mortality rate derived for the Chinese SARS epidemic in 2003. 17 We make the assumption that SARS and COVID-19 mortality are similarly affected by long-term exposure to air pollution. Since the analysis for SARS was based on the Chinese Air Pollution Index (API), we converted the API to PM 2.5 concentrations following empirical relationships from the literature. 29, 30 The large uncertainty range in the fitting function to a large degree derives from those in these relationships (black squares and ranges in Figure 1 ). In spite of uncertainties, the curves for the USA only and those that include the Chinese results are almost identical, providing confidence in the function derived for conditions in the USA only. We calculated RR globally using PM 2.5 distributions calculated under the standard scenario. The attributable fraction (AF) of COVID-19 mortality to air pollution is calculated from the RR by AF = 1 -1/RR. From the globally distributed, gridded AFs, we aggregated into regional and country-level AFs, weighted according to the population density, in order to account for the varying population distributions within regions and countries. The population data for the year 2020 were obtained from the NASA Socioeconomic Data and Applications Center (SEDAC), hosted by the Columbia University Center for International Earth Science Information Network (CIESIN). 31 Our definition of AF does not imply a direct cause-effect relationship between air pollution and COVID-19 mortality (although it is possible). Instead it refers to relationships between the two, direct and indirect, i.e. by aggravating comorbidities that could lead to fatal health outcomes of the virus infection. To estimate the AF from exposure to ambient PM 2.5 to COVID-19 mortality, we used the epidemiological data from the USA (red curve in Figure 1 ). The chronic exposure to PM 2.5 in the years prior to the COVID-19 outbreak was estimated on the basis of satellite observations over the year 2019. The anthropogenic and fossil fuel-related fractions were calculated with the global EMAC model. Here we focus on anthropogenic and fossil fuel-related PM 2.5 to determine the impact of potentially avoidable air pollution on COVID-19 mortality. Figure 2 and Table 1 present the average fractions of COVID-19 mortality attributed to the exposure to PM 2.5 pollution, both globally and regionally. Table S1 (available as Supplementary material online) lists the results for all countries. To account for the different population distributions within countries, e.g. between rural and urban areas, the averages have been weighted accordingly. In regions with strict air quality standards and relatively low levels of air pollution, such as Australia, the attributable fraction by human-made air pollution to COVID-19 mortality is found to be a few percent only. Relatively high fractions occur in parts of east Asia ($35%), central Europe ($25%), and eastern USA ($25%). The country-level contribution to COVID-19 that we find for China, i.e. 27% (95% confidence interval 13 -47%), agrees well with that found for the SARS epidemic in 2003. 17 The largest country-average fractions are found in the Czech Republic, Poland, China, North Korea, Slovakia, Austria, Belarus, and Germany, all above 25% (Supplementary material, Table S1 ). Globally, anthropogenic air pollution contributes $15% (7 -33%) to COVID-19 mortality, which could have been largely prevented, for example by adopting the air quality regulations applied in Australia (annual PM 2.5 limit of 8 mg/m 3 ). The global mean contribution of fossil fuel use to the anthropogenic fraction is $56%, being highest in North America (83%), West Asia (75%), and Europe (68%) ( Table 1) . Both the air pollutant PM 2.5 and the SARS-CoV-2 virus enter the lungs via the bronchial system (portal organ), with potential systemic health impacts through the blood circulation. Both PM 2.5 and SARS-CoV-2 cause vascular endothelial dysfunction, oxidative stress, inflammatory responses, thrombosis, and an increase in immune cells. [32] [33] [34] [35] [36] The SARS-CoV-2 infection facilitates the induction of endothelial inflammation in Figure 1 Exposure-response dependencies, based on a log-normal relationship 28 . The relative risk (or hazard ratio), from which the attributable fraction has been derived, is based on mortality rate ratios attributed to air pollution in the COVID-19 pandemic 7 and the SARS epidemic 17 , indicated by the black bullet and squares, respectively. The triangle represents the threshold concentration below which PM 2.5 does not have health implications 2 . The red curves depict the function fitted to the data from COVID-19 in the USA only 7 , plus the threshold 2 (triangle and bullet). The blue curves depict the function fitted to all data 2,7,17 . The colored ranges show the 95% confidence intervals, which are wider after including the SARS-related results (blue), mostly due to uncertainty from converting Chinese API's into PM 2.5 COVID-19 mortality attributable to air pollution several organs as a direct consequence of viral cytotoxic effects and the host inflammatory response, which can aggravate pre-existing chronic respiratory and vascular (coronary) dysfunction, and cause lung injury by alveolar damage, as well as stroke and myocardial infarction by inducing plaque rupture. 37 Potential common pathophysiological mechanisms of increased risk thus relate to endothelial injury 33, 38 and pathways that regulate immune function. 39, 40 Further, there are strong indications of increased susceptibility to viral infections from exposure to air pollution. [41] [42] [43] [44] [45] [46] Lung injuries, including the life-threatening acute respiratory distress syndrome and respiratory failure, as well as acute coronary syndrome, arrhythmia, myocarditis, and heart failure, were shown to be clinically dominant, leading to critical complications of COVID- 19. 47,48 Recent studies in China, the USA, as well as Europe indicate that patients with cardiovascular risk factors or established cardiovascular disease and other comorbid conditions are predisposed to myocardial injury during the course of COVID- 19. 19,46,49-52 From the available information, it thus follows that air pollution-induced inflammation leads to greater vulnerability and less resiliency, and the pre-conditions increase the host vulnerability. Air pollution causes adverse events through myocardial infarction and stroke, and it is an additional factor capable of increasing blood pressure, while there is emerging evidence for a link with type 2 diabetes and a possible contribution to obesity and enhanced insulin resistance. 36 Bronchopulmonary and cardiovascular pre-conditions, including hypertension, diabetes, coronary artery disease, cardiomyopathy, asthma, COPD, and acute lower respiratory illness, all negatively influenced by air pollution, lead to a substantially higher mortality risk in COVID- 19 . Furthermore, it seems likely that fine particulates prolong the atmospheric lifetime of infectious viruses, thus favouring transmission. 53 It is possible that future research will reveal additional pathways that mediate the relationship between air pollution and the risk of death from COVID- 19 . Our results indicate that the long-term exposure to high levels of fine particulate matter is a significant cofactor that influences the severity of COVID-19 outcomes. Since PM 2.5 in China and the USA, from which epidemiological data have been used, is dominated by anthropogenic sources that are potentially preventable, we focus our analysis on this fraction of PM 2. 5 . The good agreement of our results for the USA and China is in line with recent studies, showing that the association between air pollution and excess mortality is valid for many different countries. 2, 55 Nevertheless, the calculations of RRs (hazard ratios) and the AF to mortality rely on the use of data from an ecological study design that has limitations, even though 19 county-level variables and one state-level variable, some of which are more important than air pollution, were considered as potential confounders in the analysis-and the PM 2.5 exposure data have been extensively cross-validated. 7 However, we acknowledge that residual confounding cannot be excluded. While cross-sectional ecological studies do not allow conclusions about causeeffect relationships, the biological mechanisms of air pollution-related disorders, acting as comorbidities in COVID-19, are well documented. 56, 57 Recent studies in England and The Netherlands corroborate the positive relationships between air pollution and the number of COVID-19 cases, hospital admissions, and mortality. [58] [59] [60] The reported MRRs for PM 2.5 range from 1-7% to 13-21% (we applied 2-15%), which confirms the significant role of air pollution but emphasizes the large uncertainty ranges. Furthermore, our approach is likely to realistically approximate the contribution of fossil fuels and other anthropogenic sources to the total excess deaths through long-term ambient PM 2.5 air pollution exposure. We reiterate that the data used for China are associated with substantial uncertainty, and underly the assumption that comorbidity and mortality from air pollution in COVID-19 are the same as in SARS. Nonetheless, using these data does not change the results, providing confidence in the robustness of our findings. We emphasize that the data relevant to the present study are from upper-middle and highincome countries, and the representativeness of our results for lowincome countries may be limited, and uncertainties are likely to exceed the 95% confidence intervals. It is expected that in countries with high levels of aeolian dust, e.g. in Africa and West Asia, PM 2.5 pollution is also a cofactor but with less contribution from human activities. Household air pollution is also likely to be important, being of particular relevance in low-income countries. 61 It will be critical to collect epidemiological evidence from many regions with different socio-economic and environmental conditions, to support analyses of the COVID-19 pandemic and investigate the role of environmental factors. The uncertainty ranges that accompany our results are considerable but, taking into account the biological plausibility of the relationship and the strong evidence of the impact of air pollution on conditions that are known to increase COVID-19 mortality, they can nevertheless inform policy decisions. A new, though preliminary, finding of the present study is that a significant fraction of worldwide COVID-19 mortality is attributable to anthropogenic air pollution, of which $50 -60% is related to fossil fuel use ($70 -80% in Europe, West Asia, and North America). This represents potentially avoidable, excess mortality. The links between economic activity, traffic, energy use, and public health have been illustrated by the strong reduction of air pollution in many locations during the lockdown measures. 62, 63 There is ample evidence for a relationship between shortterm exposure to PM 2.5 and adverse health effects, including excess mortality from cardiovascular and respiratory diseases. 55 While it is in principle possible to disentangle the acute from the chronic outcomes from short-and long-term exposure to air pollution, 64 at this stage it is difficult to make that distinction for PM 2.5 -induced comorbidity and mortality from COVID-19. Generally, short-term associations between air pollution and mortality are substantially less than those from long-term exposure, due to the more persistent, cumulative effects from the latter. 65 By relating air pollution anomalies to short-term health outcomes during the COVID-19-induced societal lockdown, it was found that in China alone >4600 excess deaths may have been avoided. 62 This can be viewed as a health co-benefit from the containment measures, which may reduce air pollution-induced COVID-19 mortality. Such benefits could also be achieved after the COVID-19 lockdown. Both perspectives of air pollution during the pandemic underscore the important role of fossil fuel-related and other anthropogenic emissions. Our results suggest the potential for substantial benefits from reducing air pollution exposure even at relatively low PM 2.5 levels. Refinement of the exposure-response relationship and reducing uncertainties will require additional data analyses, including from large cohort studies as the COVID-19 pandemic evolves, but may appear too late to guide Regional percentages of COVID-19 mortality attributed to fossil fuel-related and all anthropogenic sources of air pollution decision-making. A lesson from our environmental perspective of the COVID-19 pandemic is that the quest for effective policies to reduce anthropogenic emissions, which cause both air pollution and climate change, needs to be accelerated. The pandemic ends with the vaccination of the population or with herd immunity through extensive infection of the population. However, there are no vaccines against poor air quality and climate change. The remedy is to mitigate emissions. The transition to a green economy with clean, renewable energy sources will further both environmental and public health locally through improved air quality and globally by limiting climate change. 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Globally $50-60% of the attributable, anthropogenic fraction is related to fossil fuel use, and 70-80% in Europe/West Asia/North America Supplementary material is available at Cardiovascular Reseach online. We thank the Mainz Heart Foundation for continuous support. T Conflict of interest: none declared. The data underlying this article will be shared upon reasonable request to the corresponding author.