key: cord-0991504-clp07n7v authors: Magfira, N.; Helda, H. title: Correlation Between Adult Tobacco Smoking Prevalence and Mortality of Coronavirus Disease-19 Across The World date: 2020-12-03 journal: nan DOI: 10.1101/2020.12.01.20241596 sha: ce7ac057a5c84951fe8b7d4af4954ea139a3a6f0 doc_id: 991504 cord_uid: clp07n7v Background and aim Coronavirus disease 2019 (COVID-19) is a global pandemic spreading worldwide. Limited studies showed that smokers were at higher risk of having severe complications and higher mortality. This study aims to analyze the possible correlation between adult tobacco smoking prevalence and COVID-19 mortality all over the world. Methods This is a correlation study, we conducted a linear regression to analyse the correlation between smoking prevalence data in adults and COVID-19 Case Fatality Ratio (CFR) in countries with 1000 confirmed COVID-19 cases on May 3, 2020. Results Seventy-five country included with median CFR 3.66%. There are no relationships between adult male or female smoking prevalence with COVID-19 mortality in all over the countries. The multivariate analysis showed p-values of 0.823 and 0.910 for male and female smoking prevalence respectively. However, in lower-middle-income countries (LMIC), there is a positive correlation between the prevalence of adult male smoking with the lethality of COVID-19. Each percentage point increase in adult male smoking prevalence caused a CFR of COVID-19 increase by 0.08% (95% CI 0.00%-0.15%, p=0.041). Conclusions A correlation was found between the prevalence of adult male smoking and the CFR of COVID-19 in lower middle-income countries. Based on these findings, strengthening tobacco control policies is needed to reduce the impact of the COVID-19 pandemic especially in LMIC. Further researches are still needed. Respiratory Syndrome Coronavirus-2 (SARS CoV-2). 1 COVID-19 has resulted in a public health emergency and an unprecedented economic crisis. On March 11, 2020 , the World Health Organization (WHO) declared COVID-19 as a global pandemic. As of May 3 rd , 2020 (the date of the latest data availability for this study) the disease has been infecting 3,349,786 people and causing 238,628 death. 2 There is no clear light on when the COVID-19 pandemic will end. Studies show that it will take at least a decade to restore the social and economic conditions to their former state. 3 Policies that effective, efficient, and provide broad effects on COVID-19 impact need to consider, one of it was applying social restriction. Following those policy, the time spent indoors are lengthened and those made the risk of harmful use of tobacco smoking increased. 4 As we all know, smoking is main common risk factor of morbidity and mortality of various non-communicable diseases. We have also known that COVID-19 fatalities are higher among people with pre-existing conditions. 5 In a study that predicted the 90-day mortality rate from viral pneumonias in hospitalized patients, smokers were twice as likely to die compared with those who did not smoke. 6 Recent studies show smoking increases the risk of developing severe symptoms and increases the risk of in-hospital mortality. A meta-analysis by Zhao et al. showed that there was a significant relationship between smoking and the severity of COVID-19, OR 2.0 (95% CI 1.3-3.1). 7 Studies by Zheng et.al and Guo et.al. also showed the same, smoking increased the risk of severe symptoms and mortality by twofold compared with those who did not smoke. 8 9 By contrast, some researchers suggest a protective effect of smoking and COVID-19 based on epidemiologic data that were not controlled for age and comorbidities. 10 Preliminary meta-analysis based on Chinese patients suggest that active smoking does not apparently seem to be significantly associated with enhanced risk of progressing towards severe disease in However, all studies included in this meta-analysis were limited in China. In response to recent published possibility of smokers paradox, the centers for disease control and prevention and the World Health Organization recommend against smoking to reduce the risk of harm from the disease. 12 Knowing that COVID-19 is a newly identified disease, the link between tobacco smoking and COVID-19 needs further research. Here we describe the correlation of adult tobacco smoking prevalence and the mortality of COVID-19 in all over the world. This is a correlation study using pooled data from all over the world. To investigate the correlation between adult smoking prevalence and COVID-19 mortality, only countries who had 1000 total confirmed cases by May 3rd, 2020 included. A minimum confirmed case was required because extremely low case may reflect inadequate testing. Countries with no available data on adult smoking prevalence were excluded from this study. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Case Fatality Ratio for each country was measured by dividing total deaths to the total confirmed case in percent. Attack rate was measured by dividing total confirmed case/ 100,000 population. We performed spearman correlation analysis to analyze the correlation between adult tobacco smoking prevalence and mortality of COVID-19. Multivariate analysis was conducted by performing linear regression analysis to evaluate the relationship incorporating the studied variables (attack rate, health expenditure, prevalence of population above 65, and comorbidity). Many factors might influence the CFR of COVID-19 including a country's standard of medical care. 14 To account for that we performed sub-analysis according to country Gross National Income per capita in 2018. We divided countries into two categories: low and lower-middleincome countries (LMIC) with an income below 3.995 dollars and upper-middle (UMIC) to highincome countries (HIC) with an income above 3.995 dollars. By May 3rd, 2020, 89 countries had more than 1000 total confirmed cases of COVID-19. However, only 75 countries whose data on adult tobacco smoking prevalence available. This study includes 15 (20%) LMIC, 22 (29.33%) UMIC, and 38 (50.67%) HIC (Appendix 1). By that, All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. Figure 1A ). We also found there is significant positive correlation between the prevalence of adult female smoking and CFR of COVID-19. The Spearman's rank correlation coefficient was 0.3005 (p=0.009, Figure 1B ). All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. ; https://doi.org/10.1101/2020.12.01.20241596 doi: medRxiv preprint preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. ; https://doi.org/10.1101/2020.12.01.20241596 doi: medRxiv preprint preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. In UMIC and HIC, we found a significant negative correlation between the prevalence of adult male smoking and CFR of COVID-19. The Spearman's rank correlation coefficient was -0.4472 (p=0.000). We also found there is significant positive correlation between the prevalence of adult female smoking prevalence and CFR of COVID-19. The Spearman's rank correlation coefficient was 0.2706 (p=0.037). However, there are no significant relationship seen between adult male and female smoking prevalence with CFR of COVID-19 in UMIC and HIC when including the confounding variable (table 2) . To best of our knowledge, this is the most comprehensive study to analyse the correlation of adult female and male smoking prevalence with the lethality of COVID-19 in all over the world using pooled data from 75 countries. The global spread of tobacco use has been long known to have an impact on human health. However, only few studies available explaining how tobacco impacts COVID-19 patients. Our study showed there are no relationships between adult male or female smoking prevalence with COVID-19 mortality in all over the countries. The multivariate analysis showed pvalues of 0.823 and 0.910 for male and female smoking prevalence respectively. However, in lower-middle-income countries (LMIC), there is a positive correlation between the prevalence of adult male smoking with the lethality of COVID-19. Each percentage point increase in adult male smoking prevalence caused a CFR of COVID-19 increase by 0.08% (95% CI 0.00%-0.15%, p=0.041). Our study has some potential limitation to be discussed, first, we received the data of COVID-19 from situation reports by WHO, the number of deaths and cases might not always reflect the exact situation since there are differences in how different Governments across countries identifying infected cases. Second, in our report, we performed sub-analysis by All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. ; https://doi.org/10.1101/2020.12.01.20241596 doi: medRxiv preprint categorizing countries according to their GNI per capita. However, there are still many factors that can influence the lethality of COVID-19 in which we do not control. Thus, including prevalence of other related comorbidities such as chronic kidney disease, heart disease, stroke, respiratory disease, malignancy and autoimmune conditions. We also did not include weather parameters situation of each countries which may contribute to In bivariate analysis, we found a significant negative correlation between prevalence of adult male smoking and CFR of COVID-19 in all over the world also in sub-analysis UMIC and HIC groups. However, after adjusting with other variables there are no significant correlations found. Some studies reported active smokers are under represented among COVID-19 patients and there is also a study that show protective effect of smoking in COVID-19 mortality. 16 17 Those studies lead to widespread claim that smoking maybe protective against COVID-19. 17 However, knowing that early in pandemic there was a race to publish, this is likely resulted in aberrant and non-standardized data collection and poor statistical analysis which can lead to erroneous conclusion. Both of the studies were not having quite variables to control the relationship. Reports of the protective effects of smoking on COVID-19 are unfounded. There are no anyway the results of previous studies be an indicator to start or continue smoking. In 2015, it was estimated that 80% of smokers all over the world live in the low-and lowmiddle-income-countries. 18 Our study showed that in LMIC there is a positive correlation between the prevalence of adult male smoking with COVID-19 mortality. The result was also significant after adjustment with other variables. Each percentage point increase in adult male smoking prevalence caused CFR of COVID-19 increase by 0.08% (95% CI 0.00%-0.15%, p=0.041). Some mechanisms on how smoking interact with COVID-19 outcomes are; smokers have increased gene expression of Angiotensin Enzyme 2 (ACE2), a known receptors of SARS CoV-2 than previous smokers and non-smokers. 19 It leads to an increase in vasoconstriction, vascular permeability, inflammation, and acute lung injury. 20 There is also evidence more circulating ACE2 in men which provides evidence for gender-based variations in disease severity. 21 Smoking increase the risk of lung damage by destroying ciliated epithelium and disrupts its function which protects the lungs through the production of mucus and rapid clearance of pathogens. 19 22 Smoking has been shown to up-regulate inflammation through activation of nuclear factor kappalight-chain-enhancer of activated B cells, tumor necrosis factor-a, IL-1beta, and neutrophils. Smoking has been reported to down-regulate CXCL-10, a chemokine that is important for the recruitment of macrophages, neutrophils and natural killer cells, minimizing the capacity of the innate immune system to suppress viral replication. 23 In LMIC, due to the rising population including a large youth population, growing incomes and prosperity, and relatively poor tobacco control, the prevalence of adult male smoking was higher compared to UMIC/HIC. 18 Other than that, the results might be influenced by several factors like limited testing of COVID-19 in the LMIC group. This can be proven from mean attack rate value which is only 7.13 at LMIC while at UMIC/HIC it can reach 93.55. Also, there are different capacity of the country to managed the disease that could influenced the outcome. In HIC the policies on tobacco control is well established. 18 The battle against tobacco use should All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. ; https://doi.org/10.1101/2020.12.01.20241596 doi: medRxiv preprint continue, no other risk factors are as immediately modifiable as smoking. Gas exchange, lung function, and blood circulation, improve quickly after smoking cessation. 19 Strengthening tobacco control policies and assisting smokers to successfully and permanently quit are needed. In conclusion, a correlation was found between the prevalence of adult male smoking and the CFR of COVID-19 in LMIC. Based on these findings, strengthening tobacco control policies and assisting smokers to successfully and permanently quit are needed to reduce the impact of the COVID-19 pandemic especially in LMIC. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. ; https://doi.org/10.1101/2020.12.01.20241596 doi: medRxiv preprint Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle Coronavirus disease (COVID-19) Situation Report -104. 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International Diabetes Federation Correlation between universal BCG vaccination policy and reduced mortality for COVID-19 All rights reserved. No reuse allowed without permission. perpetuity the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted Factors associated with COVID-19-related death using OpenSAFELY Is there a smoker's paradox in COVID-19? Tobacco Control Progress in Low and Middle Income Countries in Comparison to High Income Countries COVID-19 e tabagismo: uma relação de risco Coronavirus Disease 2019 and Smoking: How and Why We Implemented a Tobacco Treatment Campaign SARS-CoV-2 COVID-19 susceptibility and lung inflammatory storm by smoking and vaping Long-Term Cigarette Smoke Exposure in a Mouse Model of Ciliated Epithelial Cell Function Smoking decreases the response of human lung macrophages to double-stranded RNA by reducing TLR3 expression All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 3, 2020. ; https://doi.org/10.1101/2020. 12 perpetuity.preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint inThe copyright holder for this this version posted December 3, 2020. ; https://doi.org/10.1101/2020.12.01.20241596 doi: medRxiv preprint