•The many adverse health consequences of cigarette smoking are undeniable•Long-term smokers have functional impairments enhancing the risk of severe COVID-19•The role of active smoking in COVID-19 progression remains controversial•Additional research is needed to clarify the interplay between active smoking and SARS-CoV-2 infection Although both virulence and pathogenicity of SARS-CoV-2 have considerably declined over time, the number of coronavirus disease 2019 (COVID-19) cases and the consequent clinical burden remain substantial worldwide, thus persuading the World Health Organization (WHO) to reiterate the status of public health emergency of international concern for this pathology. One of the pivotal aspects in the managed care of COVID-19 encompasses the identification of subjects at enhanced risk of developing severe and /or critical illness since an early and targeted treatment may contribute to lower the clinical, social, and healthcare burden of this life-threatening condition. A recent meta-analysis published by Vardavas and colleagues [[1]Vardavas CI Mathioudakis AG Nikitara K Stamatelopoulos K Georgiopoulos G Phalkey R et al.Prognostic factors for mortality, intensive care unit and hospital admission due to SARS-CoV-2: a systematic review and meta-analysis of cohort studies in Europe.Eur Respir Rev. 2022; 31220098Crossref PubMed Scopus (8) Google Scholar], including 88 cohort studies with both gender- and age-adjusted information from nearly 7 million European participants, has corroborated the straightforward concept that the most predictive factors of unfavorable disease progression are male sex and obesity, along with a kaleidoscope of comorbidities such as chronic obstructive pulmonary disease (COPD), cardiovascular disease, heart failure, cancer, diabetes, renal and liver impairment, dementia, and immunosuppression. Although this conclusion is certainly not surprising and supports the findings of many other similar publications converging to identify these and other possible genetic, clinical, and environmental factors as key determinants of unfavorable prognosis, there is still an open debate about the role played by additional conditions, one of the most disputed of which is undoubtedly smoking. In the first early meta-analysis that we published in this journal in 2020 [[2]Lippi G Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).Eur J Intern Med. 2020; 75: 107-108Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar], which included only 5 studies and 1399 Chinese COVID-19 patients, we failed to find a significant association between active (cigarette) smoking and the risk of developing severe COVID-19 illness (pooled odds ratio [OR], 1.69; 95%CI, 0.41-6.92; p=0.254). Notably, after the publication of our meta-analysis, Simons et al. also performed a living rapid evidence review with Bayesian meta-analyses (233 studies included) [[3]Simons D Shahab L Brown J Perski O. The association of smoking status with SARS-CoV-2 infection, hospitalization and mortality from COVID-19: a living rapid evidence review with Bayesian meta-analyses (version 7).Addiction. 2021; 116: 1319-1368Crossref PubMed Scopus (148) Google Scholar]. They found that current smokers had a lower risk of SARS-CoV-2 infection compared with never smokers (relative risk [RR], 0.74; 95% CI, 0.58-0.93], also evidencing that the data linking current smoking with hospitalization (RR, 1.06; 0.82-1.35), higher disease severity (RR, 1.25; 0.85-1.93), and mortality (RR, 1.22; 95%CI, 0.78-1.94) were inconclusive. Another large cohort study published by Chen et al. [[4]Chen UI Xu H Krause TM Greenberg R Dong X Jiang X. Factors Associated With COVID-19 Death in the United States: Cohort Study.JMIR Public Health Surveill. 2022; 8: e29343Crossref PubMed Scopus (3) Google Scholar], reporting data on ∼1.2 million adult participants followed from February 1 to August 31, 2020, revealed that current smokers had an over 30% lower risk of COVID-19-related death (hazard ratio (HR), 0.57; 95%CI, 0.49-0.67). These results, especially those of our former meta-analysis, were fiercely contested by a number of subsequent letters, even in different journals, attempting to evidence some flaws in calculations and conclusions. Although stirring up further controversies or directly replying is out of the scope of this article, and while we are not willing here to specifically address some justified – along with others clearly biased – considerations, we have been offered the opportunity to provide here a two-year recap of the many controversies emerged around the role played by smoking in influencing the clinical course of SARS-CoV-2 infection. The best starting point is reporting the outcome of recent (large) studies and meta-analyses. The most recent meta-analysis that we could find about this topic has been published by Gallus and colleagues (including 320 publications) [[5]Guo FR. A flaw on a meta-analysis of smoking and the severity of COVID-19: the association should have been endorsed.J Public Health (Oxf). 2020; 42: 653-654Crossref PubMed Scopus (2) Google Scholar]. Notably, the authors found a positive relationship between current smoke and disease severity (OR, 1.35; 95%CI, 1.22-1.48) and mortality (OR, 1.32; 95%CI 1.20-1.45), but not with hospitalizations (1.08; 95%CI 0.98-1.19), which implicitly underlines that the link between current smoking and clinical severity is not so straightforward. However, the correlation was seemingly clearer with former smoking since a positive relationship was found with all three endpoints (OR between 1.16-1.46). Similar conclusions emerged from another meta-analysis by Patanavanich et al. [[6]Lo E Lasnier B. Active smoking and severity of coronavirus disease 2019 (COVID-19): The use of significance testing leads to an erroneous conclusion.Eur J Intern Med. 2020; 77: 125-126Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar], where the authors could found estimate a marginally significant association between current smoking and COVID-19-related mortality (OR, 1.26; 95%CI, 1.01-1.58), which, however, turned out to be no longer significant in people living in high-income countries (OR 1.14; 95%CI, 0.91-1.43). As concerns post- (or long) COVID, Tsampasian et al. highlighted a relatively modest association between higher risk of this condition and smoking status (OR, 1.10; 95%CI, 1.07-1.13) [[7]Tsampasian V Elghazaly H Chattopadhyay R Debski M Naing TKP Garg P et al.Risk Factors Associated With Post-COVID-19 Condition: A Systematic Review and Meta-analysis.JAMA Intern Med. 2023; (Mar 23Epub ahead of print)e230750https://doi.org/10.1001/jamainternmed.2023.0750Crossref PubMed Scopus (1) Google Scholar]. In another meta-analysis where the authors explored the role of potential predictors of venous thromboembolism in patients with COVID-19 [[8]Agarwal G Hajra A Chakraborty S Patel N Biswas S Adler MK et al.Predictors and mortality risk of venous thromboembolism in patients with COVID-19: systematic review and meta-analysis of observational studies.Ther Adv Cardiovasc Dis. 2022; 1617539447221105013Crossref PubMed Scopus (5) Google Scholar], smoking history was paradoxically associated with a lower risk of thrombotic events (OR, 0.71; 95%CI, 0.54-0.93). In one of the largest epidemiological studies ever published so far on this matter, which included over 28 million French inhabitants [[9]Semenzato L Botton J Drouin J Baricault B Bertrand M Jabagi MJ et al.Characteristics associated with the residual risk of severe COVID-19 after a complete vaccination schedule: A cohort study of 28 million people in France.Lancet Reg Health Eur. 2022; 19100441PubMed Google Scholar], Semenzato et al. failed to find a significant association between smoking and COVID-19-related hospitalization (OR, 1.03; 95%CI, 0.91-1.16) or in-hospital death (OR, 1.01; 95%CI, 0.75-1.37). This is not really surprising as the existence of a negative association between current smoking and risk of severe COVID-19 illness was confirmed in other epidemiological investigations such as that published by Galanti et al. (RR for hospital admission, 0.60; 95%CI, 0.47-0.76; RR for intensive care, 0.43; 95%CI, 0.21-0.89) [[10]Galanti MR Andersson F Caspersen IH Peña S Karvonen S Magnus P et al.Current tobacco use and COVID-19 diagnoses in a cohort of adult clients of public dental clinics in Sweden.Sci Rep. 2023; 13: 1204Crossref PubMed Scopus (2) Google Scholar]. Even in the large study published by Piasecki et al. [[11]Piasecki TM Smith SS Baker TB Slutske WS Adsit RT Bolt DM et al.Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.Nicotine Tob Res. 2022 Sep 7; (Epub ahead of print): ntac201https://doi.org/10.1093/ntr/ntac201Crossref Google Scholar], former but not current smoking emerged as a predictive factor for severe outcomes in patients hospitalized with COVID-19. Importantly, using serum cotinine levels (i.e., a more validated tool for establishing current smoking status than self-reporting use), Tomaselli et al. identified a lower rate of positive SARS-CoV-2 serology among current smokers compared to never/former smokers [[12]Tomaselli V Ferrara P Cantone GG Romeo AC Rust S Saitta D et al.The effect of laboratory-verified smoking on SARS-CoV-2 infection: results from the Troina sero-epidemiological survey.Intern Emerg Med. 2022; 17: 1617-1630Crossref PubMed Scopus (0) Google Scholar]. The abovenoted results affirm that a simple conclusion that current smoking increases the risk of clinical deterioration in COVID-19 is largely unsupported according to the currently available scientific evidence. The challenging biological relationship between cigarette smoke and COVID-19 has also been addressed in some interesting works. For example, Aliee et al. reported that the expression of angiotensin-converting enzyme 2 (ACE2; the main SARS-CoV-2 host receptor) in the nasal mucosa does not differ between current and never smokers, thus highlighting that enhanced cell penetration of SARS-CoV-2 is unlikely in the former class of subjects [[13]Aliee H Massip F Qi C Stella de Biase M van Nijnatten J Kersten ETG et al.Determinants of expression of SARS-CoV-2 entry-related genes in upper and lower airways.Allergy. 2022; 77: 690-694Crossref PubMed Scopus (0) Google Scholar]. In another experimental study, Tomchaney et al. found that mice exposed to cigarette smoke displayed reduced levels of ACE2 in bronchial and alveolar epithelial cells, while such treatment was also effective in lowering SARS-CoV-2 replication in Calu-3 cells [[14]Tomchaney M Contoli M Mayo J Baraldo S Li S Cabel CR et al.Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease.BMC Pulm Med. 2021; 21: 275Crossref PubMed Scopus (6) Google Scholar]. In support of these findings, another work published by Porter et al. showed that cigarette smoke extracts may be modestly effective in enhancing the expression of full-length ACE2 on primary human differentiated bronchial epithelial cells [[15]Porter LM Guo W Crozier TW Greenwood EJ Ortmann B Kottmann D et al.Cigarette smoke preferentially induces full length ACE2 expression in differentiated primary human airway cultures but does not alter the efficiency of cellular SARS-CoV-2 infection.Heliyon. 2023; 9: e14383Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], but does not significantly modify airway cell infection by SARS-CoV-2. Interestingly, Dormoy et al. postulated that nicotinic acetylcholine receptors (nAChRs) might act as SARS-CoV-2 co-receptors [[16]Dormoy V Perotin JM Gosset P Maskos U Polette M Deslée G. Nicotinic receptors as SARS-CoV-2 spike co-receptors?.Med Hypotheses. 2022; 158110741Crossref PubMed Scopus (6) Google Scholar]; nicotine may hence act as an inhibitor of cell entry by competing with SARS-CoV-2 for cell surface receptors. This hypothesis has been addressed in an experimental study, where the authors administered nicotine in drinking water to hACE2 mice, observing a lower probability of SARS-CoV-2 RNA expression and pathology in their brain [[17]Letsinger AC Ward JM Fannin RD Mahapatra D Bridge MF Sills RC et al.Nicotine exposure decreases likelihood of SARS-CoV-2 RNA expression and neuropathology in the hACE2 mouse brain but not moribundity.Sci Rep. 2023; 13: 2042Crossref PubMed Scopus (0) Google Scholar]. On the other hand, in another study, nicotine was found to have no significant cytoprotective activity against infection of Vero E6 cells challenged with SARS-CoV-2 [[18]Zheng F Lian E Ramirez G McAlister C Zhou S Zhang W et al.Nicotine has no significant cytoprotective activity against SARS-CoV-2 infection.PLoS One. 2022; 17e0272941Crossref Scopus (1) Google Scholar]. Although the number of randomized trials that have assessed the role of nicotine replacement therapy (NRT) in modulating the risk of severe COVID-19 illness remains negligible, the findings of the study published by Piasecki et al. deserve to be mentioned [[11]Piasecki TM Smith SS Baker TB Slutske WS Adsit RT Bolt DM et al.Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.Nicotine Tob Res. 2022 Sep 7; (Epub ahead of print): ntac201https://doi.org/10.1093/ntr/ntac201Crossref Google Scholar]. Briefly, the authors found that the mortality rate of COVID-19 smokers prescribed with NRT was nearly half than those who did not use NRT (i.e., 4.5 vs. 7.7%; OR, 0.64; 95%CI, 0.50-0.82). Importantly, Muralidharan et al. studied the acute impact of short exposure to cigarette smoke extract and/or alcohol on SARS-CoV-2 infection of ciliated human bronchial epithelial cells of healthy subjects [[19]Muralidharan A Bauer CD Katafiasz DM Strah HM Siddique A Reid SP et al.Synergistic Detrimental Effects of Cigarette Smoke, Alcohol, and SARS-CoV-2 in COPD Bronchial Epithelial Cells.Pathogens. 2023; 12: 498Crossref PubMed Scopus (0) Google Scholar], and found that viral titers were only increased in cells treated with both compounds but not with cigarette smoke extract or alcohol alone, thus emphasizing that cigarette smoke may only play a subsidiary role in the pathogenesis of COVID-19. Accordingly, the biological evidence that cigarette smoke alone would enhance the risk of infection and/or unfavorable disease progression remains weak, at best. Overall, one important aspect that must be highlighted is that clinical studies and meta-analyses published in different periods should not be directly compared since the epidemiology and clinical burden of COVID-19 have both considerably changed over time due to the emergence of new viral variants, widespread vaccination, earlier and more accurate diagnosis, improved therapeutic management and even human habits. For example, Sarich et al. conducted an interesting meta-analysis about smoking behaviors before and after the onset of the COVID-19 pandemic [[20]Sarich P Cabasag CJ Liebermann E Vaneckova P Carle C Hughes S et al.Tobacco smoking changes during the first pre-vaccination phases of the COVID-19 pandemic: A systematic review and meta-analysis.EClinicalMedicine. 2022; 47101375Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar], reporting that not only was the rate of people smoking during the pandemic lower than before (i.e., around 13% less), but 21% of smokers admitted to having decreased the use of tobacco, while 27% reported an increase. The human population has also changed throughout these past 3 years, whereby most of the nearly 7 million deaths caused by COVID-19 involved older people [[21]Sorrell JM. Losing a Generation: The Impact of COVID-19 on Older Americans.J Psychosoc Nurs Ment Health Serv. 2021; 59: 9-12Crossref PubMed Scopus (8) Google Scholar]. Thus, a straightforward translation of findings between different publications is profoundly misleading. The synergy between cigarette smoke and pre-existing morbid conditions is another aspect that needs to be highlighted. Irrespective of the long-term harms directly related to cigarettes and second-hand smoke, such as cancer and cardiovascular disease, smoking also generates a number of acute unfavorable consequences on health, thus aggravating an already compromised status. Thus, at this point, it is certainly challenging to dissect the acute effects on SARS-CoV-2 infection of smoking per se from its negative impact on other co-morbidities or conditions known to enhance the risk of severe COVID-19 illness. For example, He et al. reported that smoking had a strong interaction with the number of comorbidities in influencing COVID-19 severity [[22]He Y He Y Hu Q Yang S Li J Liu Y et al.Association between smoking and COVID-19 severity: A multicentre retrospective observational study.Medicine (Baltimore). 2022; 101: e29438Crossref PubMed Scopus (1) Google Scholar]. In conclusion, we believe that providing a biased view based on preconceived notions does not help science and medicine. Smoking remains the leading cause of preventable morbidity and mortality worldwide, but struggling to find a robust relationship between current cigarette smoking and the risk of developing SARS-CoV-2 infection and/or severe COVID-19 illness is an almost illusory and even counterproductive enterprise, more or less like negating the side effects of the vaccines. Providing preconceived medical theories and unsubstantiated scientific assumptions can only pave the way for the spread of negative beliefs and behaviors. This is exactly what we should avoid. Transparent communication is the key to delivering a trustworthy message. The unfavorable consequences of cigarette smoking are paramount and indisputable. A recent retrospective analysis has estimated that active smoking and exposure to secondhand smoke have caused nearly 21 million premature (and otherwise preventable) deaths in the US during the past 50 years [[23]Onor IO Stirling DL Williams SR Bediako D Borghol A Harris MB et al.Clinical Effects of Cigarette Smoking: Epidemiologic Impact and Review of Pharmacotherapy Options.Int J Environ Res Public Health. 2017; 14: 1147Crossref PubMed Scopus (67) Google Scholar]. It has also been recently demonstrated that active smoking may enhance the risk of developing adverse events after COVID-19 vaccination [[24]Ponticelli D Losa L Campagna D Magliuolo R Vitale A Cacciapuoti D et al.Smoking habits predict adverse effects after mRNA COVID-19 vaccine: Empirical evidence from a pilot study.Public Health. 2023; 219: 18-21Crossref PubMed Scopus (0) Google Scholar]. The evidence that quit smoking is perhaps one of the best things that one could ever do for his/her health is certainly inalienable and should foster the development of anti-smoking campaigns, especially among the youth, who may then experience the largest burden of long-term unfavorable health consequences. Nonetheless, we also emphasize here that the potential role of current smoking in influencing the clinical course of COVID-19 remains controversial and may even be confounded by synergistic effects, e.g., long-term smokers may actually develop a kaleidoscope of conditions - namely COPD and cardiovascular disease - that per se influence the prognosis of SARS-CoV-2 infection. All authors have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work.