SARS-CoV-2, the novel coronavirus that causes COVID-19, emerged in China in late 2019 and rapidly reached pandemic status. The virus displays tropism for the respiratory system, causing symptoms that range from an acute respiratory syndrome, manifested in mild form in the vast majority of cases, and progressing in some cases to an extremely severe and rapidly developing type of pneumonia with major respiratory failure, evolving to death ¹1. World Health Organization. Coronavirus disease (COVID-19) pandemic. https://www.who.int/emergencies/diseases/novel-coronavirus-2019 (acessado em 14/Abr/2020).
https://www.who.int/emergencies/diseases... .

The following are known risk factors for more severe outcomes, including the need for admission to intensive care and/or mechanical ventilation and death: age 65 years or older; long-term institutional care; chronic obstructive pulmonary disease; moderate to severe asthma and oxygen-dependent; severe or decompensated cardiac disease; decompensated hypertension; chromosomal diseases or suppressed immune status; end-stage renal disease; high-risk pregnancy; severe obesity at any age (BMI > 40); and other clinical conditions such as liver disease ²2. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; [Epub ahead of print].^,33. Ministério da Saúde. Guia de Vigilância Epidemiológica. Emergência de saúde pública de importância nacional pela doença pelo coronavírus 2019. Vigilância integrada de síndromes respiratórias agudas, doença pelo coronavírus 2019, influenza e outros vírus respiratórios. https://www.saude.gov.br/images/pdf/2020/April/06/GuiaDeVigiEp-final.pdf (acessado em 14/Abr/2020).
https://www.saude.gov.br/images/pdf/2020... . COVID-19 may also involve endothelial dysfunction, potentially leading to severe coagulopathies and thromboses ⁴4. Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, Santulli G. Is COVID-19 an endothelial disease? Clinical and basic evidence. Preprints 2020; 2020040204. https://www.preprints.org/manuscript/202004.0204/v1.
https://www.preprints.org/manuscript/202... .

However, it is possible that an important risk factor for COVID-19 has not been included thus far in the global guidelines for control of the pandemic, namely smoking.

Smokers are part of the risk group for COVID-19. One can infer the group’s increased risk of infection to the extent that smokers tend to hold smoking products to their mouths (whether conventional cigarettes or electronic smoking devices - ESDs) without adequate prior hand hygiene.

Waterpipes, which are highly popular in the younger population (who generally share the mouthpieces), facilitate SARS-CoV-2 transmission ⁵5. WHO Framework Convention on Tobacco Control. Increased risk of COVID-19 infection amongst smokers and amongst waterpipe users. https://untobaccocontrol.org/kh/waterpipes/covid-19/ (acessado em 31/Mar/2020).
https://untobaccocontrol.org/kh/waterpip... . The World Health Organization (WHO) expressed concern over the potential spread of COVID-19 through the use of tobacco products ⁵5. WHO Framework Convention on Tobacco Control. Increased risk of COVID-19 infection amongst smokers and amongst waterpipe users. https://untobaccocontrol.org/kh/waterpipes/covid-19/ (acessado em 31/Mar/2020).
https://untobaccocontrol.org/kh/waterpip... . The literature indicates that diseases such as influenza, oral herpes, and tuberculosis are transmitted through waterpipe mouthpieces ⁶6. Instituto Nacional de Câncer José Alencar Gomes da Silva. Narguilé: o que sabemos? Rio de Janeiro: Instituto Nacional de Câncer José Alencar Gomes da Silva; 2019.. The characteristics of electronic smoking devices allow shared use, and the ESDs should thus also be classified as products that contribute to SARS-CoV-2 infection.

Another relevant factor is the risk of smokers suffering burns when lighting a cigarette or handling a waterpipe after hand hygiene with alcohol in gel, a highly flammable product.

As for the harms from COVID-19 infection, smoking increases the risk of lung damage. Smoking is related to bronchiolitis (generally asymptomatic), various types of pneumonia, chronic bronchitis, pulmonary emphysema, tuberculosis, and lung cancers, leading to decline in lung function ⁷7. U.S. Department of Health and Human Services. The health consequences of smoking: 50 years of progress. A report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services; 2014..

Studies in animal and human cells suggest that tobacco increases the severity of infectious diseases such as influenza, increasing viral replication through suppression of antiviral mechanisms and alterations in cytokine patterns in cells with a central role in innate mucosal immunity ⁵5. WHO Framework Convention on Tobacco Control. Increased risk of COVID-19 infection amongst smokers and amongst waterpipe users. https://untobaccocontrol.org/kh/waterpipes/covid-19/ (acessado em 31/Mar/2020).
https://untobaccocontrol.org/kh/waterpip... . Smoking also increases the expression of angiotensin converting enzyme-2 (ACE-2), a known SARS-CoV-2 receptor ⁸8. Brake SJ, Barnsley K, Lu W, McAlinden KD, Eapen MS, Sohal SS. Smoking upregulates angiotensin-converting enzyme-2 receptor: a potential adhesion site for novel coronavirus SARS-CoV-2 (Covid-19). J Clin Med 2020; 9:E841..

Smoking is related to endothelial dysfunction and elevated concentrations of free radicals, just as microbial infections like COVID-19 ⁹9. Evora PRB, Baldo CF, Celotto AC, Capellini VK. Endothelium dysfunction classification: why is it still an open discussion? Int J Cardiol 2009; 137:175-6.. It is plausible that COVID-19 damages a smoker’s previously injured endothelium. However, smoking cessation significantly improves impaired endothelial function ¹⁰10. U.S. Department of Health and Human Services. Smoking cessation: a report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services; 2020..

COVID-19 patients display high C reative protein (CRP) and D-dimer levels ⁶6. Instituto Nacional de Câncer José Alencar Gomes da Silva. Narguilé: o que sabemos? Rio de Janeiro: Instituto Nacional de Câncer José Alencar Gomes da Silva; 2019.^,77. U.S. Department of Health and Human Services. The health consequences of smoking: 50 years of progress. A report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services; 2014.. These diagnostic markers of thrombosis are also altered in smokers ¹¹11. Das I. Raised C-reactive protein levels in serum from smokers. Clin Chim Acta 1985; 153:9-13.^,1212. Lee AJ, Fowkes GR, Lowe GD, Rumley A. Determinants of fibrin D-dimer in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1995; 15:1094-7.. One study found disseminated intravascular coagulation in 71% of fatal cases of COVID-19 compared to 0.4% in survivors ¹³13. Cai G. Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. Preprints 2020; 2020020051. https://www.preprints.org/manuscript/202002.0051/v2.
https://www.preprints.org/manuscript/202... . High D-dimer levels (> 1μg/L) at hospital admission increase the odds of evolution to death by 18 times ¹⁴14. Vardavas CI, Nikitara K. COVID-19 and smoking: a systematic review of the evidence. Tob Induc Dis 2020; 18:20.^,1515. Cai H. Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir Med 2020; 8:e20.. The mechanism of these complications is still unknown, but they suggest the relevance of smoking’s impact on the endothelium and COVID-19.

Although one metanalysis found no association between smoking and more serious outcomes of COVID-19 ¹⁴14. Vardavas CI, Nikitara K. COVID-19 and smoking: a systematic review of the evidence. Tob Induc Dis 2020; 18:20., the most robust study with the largest sample found a relationship between smoking and worse progression of the disease ¹⁵15. Cai H. Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir Med 2020; 8:e20.. Preprint articles have suggested that smoking is a risk factor for severe manifestations of COVID-19 ¹³13. Cai G. Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. Preprints 2020; 2020020051. https://www.preprints.org/manuscript/202002.0051/v2.
https://www.preprints.org/manuscript/202... ^,1616. Alqahtani JS, Oyelade T, Aldhahir AM, Alghamdi SM, Almehmadi M, Alqahtani AS, et al. Prevalence, severity and mortality associated with COPD and smoking in patients with COVID-19: a rapid systematic review and meta-analysis. medRxiv 2020; 27 mar. https://www.medrxiv.org/content/10.1101/2020.03.25.20043745v1.
https://www.medrxiv.org/content/10.1101/... . A more recently published meta-analysis also indicates that smoking is a risk factor for worse prognosis in COVID-19 ¹⁷17. Patanavanich R, Glantz SA. Smoking is associated with COVID-19 progression: a meta-analysis. medRxiv 2020; 16 abr. https://www.medrxiv.org/content/10.1101/2020.04.13.20063669v1.
https://www.medrxiv.org/content/10.1101/... .

Smokers with COVID-19 have 3.25 higher odds of developing severe forms of the disease when compared to non-smokers ¹⁸18. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J M 2020; 382:1708-20..

Despite the plausibility that these complications are due to the impacts of smoking, some studies have failed to report a relationship between smoking and progression of COVID-19.

The possible explanations for these conflicting findings may be found in the article by Szklo ¹⁹19. Szklo AS. Associação entre fumar e progressão para complicações respiratórias graves em pacientes com Covid-19. Rev Bras Cancerol 2020; 66:e-03974., including incorrect identification of smokers, economic vulnerability, heightened attention to exposure to the virus, and less presence due to tobacco-free environments laws. Additional factors could be the definition of smokers used in the studies (e.g., defining users of electronic cigarettes as non-smokers and time since last tobacco use) and information bias, considering that verbal communication is limited between health professionals, family members, and patients with more serious cases of COVID-19.

There is no study correlating progression of COVID-19 and use of ESDs. However, animal studies with electronic cigarettes have demonstrated altered lipid homeostasis in alveolar macrophages and epithelial cells, besides decreased immunity to viral agents ²⁰20. Madison MC, Landers CT, Gu B-H, Chang C-Y, Tung H-Y, You R, et al. Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine. J Clin Invest 2019; 129:4290-304..

Human study, reported that electronic cigarette users showed changes in protein profile linked to innate immune defense in airway secretions, inducing changes similar to those observed in conventional cigarettes smokers ²¹21. Reidel B, Radicioni G, Clapp PW, Ford AA, Abdelwahab S, Rebuli ME, et al. E-cigarette use causes a unique innate immune response in the lung, involving increased neutrophilic activation and altered mucin secretion. Am J Respir Crit Care Med 2018; 197:492-501..

Independent studies suggest that the byproducts of heated tobacco lead to alterations in lung cell homeostasis ²²22. Sohal SS, Eapen MS, Naidu VGM, Sharma P. IQOS exposure impairs human airway cell homeostasis: direct comparison with traditional cigarette and e-cigarette. ERJ Open Res 2019; 5:00159-2018. and endothelial injury ²³23. Nabavizadeh P, Liu J, Havel CM, Ibrahim S, Derakhshandeh R, Jacob III P, et al. Vascular endothelial function is impaired by aerosol from a single IQOS HeatStick to the same extent as by cigarette smoke. Tob Control 2018; 27 Suppl 1:s13-9.. Both conventional and electronic cigarettes may also increase the expression of the ACE-2 viral receptor ⁸8. Brake SJ, Barnsley K, Lu W, McAlinden KD, Eapen MS, Sohal SS. Smoking upregulates angiotensin-converting enzyme-2 receptor: a potential adhesion site for novel coronavirus SARS-CoV-2 (Covid-19). J Clin Med 2020; 9:E841..

Thus, the alterations and lung damage caused by tobacco products and ESDs can be considered risk factors for the more severe manifestations and progression of COVID-19.

With the arrival of the COVID-19 pandemic, uncertainties concerning the future and social isolation measures are associated with preoccupation towards the disease. In this scenario, people may develop emotional responses that interfere negatively in their self-efficacy, since they feel emotionally vulnerable to face a real threat, being able to appeal to inappropriate strategies, such as smoking, in an attempt to reduce emotional imbalance ²⁴24. Salvetti MG, Pimenta CAM. Dor crônica e a crença de auto-eficácia. Rev Esc Enferm USP 2007; 41:135-40..

Although there are no data on smoking and relapse during epidemics, studies have suggested that smokers exposed to natural disasters tend to smoke more than unexposed smokers ²⁵25. Huh J, Timberlake DS. Do smokers of specialty and conventional cigarettes differ in their dependence on nicotine? Addict Behav 2009; 34:204-11. and that former smokers are more likely to relapse ²⁶26. Lanctot JQ, Stockton MB, Mzayek F, Read M, McDevitt-Murphy M, Ward K. Effects of disasters on smoking and relapse: an exploratory study of Hurricane Katrina victims. Am J Health Educ 2008; 39:91-4..

During social isolation and stay-at-home orders, active smokers expose non-smokers to second-hand smoke. Secondhand smoke can cause smoking similar damage ²⁷27. U.S. Department of Health and Human Services. The health consequences of involuntary exposure to tobacco smoke: a report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services; 2006., including increased ACE-2 expression ⁸8. Brake SJ, Barnsley K, Lu W, McAlinden KD, Eapen MS, Sohal SS. Smoking upregulates angiotensin-converting enzyme-2 receptor: a potential adhesion site for novel coronavirus SARS-CoV-2 (Covid-19). J Clin Med 2020; 9:E841.. One cannot rule out the emission of aerosols containing the virus, especially in ESDs, which operate at lower temperatures. More studies are necessary to determine the extent of impacts of secondhand smoke on COVID-19 transmission and progression.

Gas exchange, lung function, and blood circulation, processes directly affected in COVID-19, improve quickly after smoking cessation ¹⁰10. U.S. Department of Health and Human Services. Smoking cessation: a report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services; 2020.. Quitting smoking and avoiding exposure to tobacco smoke and vapors can have a positive impact, reducing the risk involved in COVID-19 and smoking.

Acknowledgments

The authors wish to thank the Brazilian Health Regulatory Agency (Anvisa), the Oswaldo Cruz Foundation (Fiocruz), the Heart Institute, Clinical Hospital, School of Medicine, University of São Paulo (InCor/HC/FMUSP), and the Brazilian National Research Council (CNPq). The article expresses the sole opinions and ideas of the authors based on the currently available scientific evidence and does not represent any guidelines or institutional opinions on the part of Anvisa, InCor/HC/FMUSP, Fiocruz, the Brazilian Ministry of Health, or the Brazilian government.

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