Advertisement

No double-edged sword and no doubt about the relation between smoking and COVID-19 severity

      At the beginning of March 2020, with the publication of the first Chinese epidemiological studies on the determinants of a severe form of COVID-19, tobacco smoking consistently appeared as one of the most important avoidable risk factors for a poorer prognosis [
      • Gorini G.
      • Clancy L.
      • Fernandez E.
      • Gallus S.
      Smoking history is an important risk factor for severe COVID-19.
      ,
      • Vardavas C.I.
      • Nikitara K.
      COVID-19 and smoking: a systematic review of the evidence.
      ]. COVID-19 was going to be added to the long list of diseases caused by smoking and was becoming the latest key argument to recommend avoiding tobacco use and quitting smoking [
      • Gorini G.
      • Clancy L.
      • Fernandez E.
      • Gallus S.
      Smoking history is an important risk factor for severe COVID-19.
      ,
      • Cattaruzza M.S.
      • Zagà V.
      • Gallus S.
      • D'Argenio P.
      • Gorini G.
      Tobacco smoking and COVID-19 pandemic: old and new issues. A summary of the evidence from the scientific literature.
      ,

      Simons D, Perski O, Brown J. Covid-19: the role of smoking cessation during respiratory virus epidemics. March 20, 2020. Available online at: https://blogs.bmj.com/bmj/2020/03/20/covid-19-the-role-of-smoking-cessation-during-respiratory-virus-epidemics/ (last access: 20 March 2020).

      ]. However, Lippi and Henry [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ] published in the European Journal of Internal Medicine a meta-analysis with an unequivocal title: “Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19)”. In this meta-analysis, based on five Chinese studies, the authors reported a pooled odds ratio (OR) for COVID-19 progression of 1.69 (95% confidence interval, CI, 0.41-6.92) for smokers versus non-smokers. This study enjoyed widespread visibility in the scientific literature, as well as the lay press and various online social networks. It has been cited, posted or tweeted, particularly by researchers or subjects financially supported by the tobacco industry.
      On 30 April 2020, Guo [
      • Guo F.R.
      Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): an update of a meta-analysis.
      ] published a commentary on Tobacco Induced Diseases, showing that the meta-analysis by Lippi and Henry [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ] contained several mistakes in data collection. Guo did a meta-analysis using correct figures from the same five studies and obtained an OR of 2.20 (95% CI, 1.31-3.67).
      We double-checked the two meta-analyses and agree with all the criticism raised by Guo [
      • Guo F.R.
      Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): an update of a meta-analysis.
      ]. We feel justified in drawing attention to a number of mistakes and debatable choices made by Lippi and Henry in their review [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ], which were only partially addressed by Guo [
      • Guo F.R.
      Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): an update of a meta-analysis.
      ]. With reference to the study by Guan and colleagues [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ], Lippi and Henry's meta-analysis considered the OR for severity at admission, but, as shown in Table 1, they misreported that they had considered the OR for a composite outcome, i.e. requiring intensive care unit (ICU) admission or mechanical ventilation, or death (mistake 1). The decision to consider the OR for severity at admission (OR: 1.51; 95% CI 0.97-2.36) instead of for the composite outcome (OR: 2.60; 95% CI 1.45-4.66) is highly debatable (debatable choice 1), since the composite outcome, not surprisingly defined as the primary endpoint by Guan and colleagues [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ], seems a more reliable and objective measure of the progression of the disease.
      Then too, Lippi and Henry [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ] considered the OR for current smokers versus non-smokers (former and never smokers combined; debatable choice 2). However - at least when the information is available - it is preferable to compare the risk of ever (current and former smokers) versus never smokers (from information provided by Guan et al. [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ] one can estimate an OR of 1.87; 95% CI 1.25-2.82) or current versus never smokers (OR: 1.59; 95% CI, 1.01-2.49). In fact, given that a large proportion of ex-smokers quit smoking because of smoking-related conditions [
      • Gallus S.
      • Muttarak R.
      • Franchi M.
      • et al.
      Why do smokers quit?.
      ], the inclusion of ex-smokers in the reference category would bias any possible effect of current smokers.
      For the same reason, the inclusion in the meta-analysis of the study by Huang and colleagues [
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China..
      ], providing estimates for current versus non-smokers, is debatable too (debatable choice 3). For this study the correct number of non-severe patients is 28 (not 31; mistake 2) and the corresponding OR is 0.27 (95% CI, 0.01-5.62), not 0.30 (95% CI, 0.01-6.26; mistake 3) [
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China..
      ]. The choice of univariate estimate for Liu and colleagues’ study [
      • Liu W.
      • Tao Z.W.
      • Wang L.
      • et al.
      Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease.
      ] (OR: 12.19; 95% CI, 1.76-84.31) instead of multivariate estimate (OR: 14.29; 95% CI, 1.58-25.00) is also debatable (debatable choice 4). It is not by chance, in fact, that the multivariate result was reported by Liu and colleagues in the Abstract [
      • Liu W.
      • Tao Z.W.
      • Wang L.
      • et al.
      Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease.
      ]. The study by Yang and colleagues [
      • Yang X.
      • Yu Y.
      • Xu J.
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ] gives the number of non-severe patients (i.e. survivors) as 20, not 18 (mistake 4). More importantly, the correct OR - also reported by Guo [
      • Guo F.R.
      Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): an update of a meta-analysis.
      ] - is 0.11 (95% CI, 0.01-2.50) not 3.03 (95% CI, 0.14-68.71; mistake 5). Finally, in the study by Zhang and colleagues [
      • Zhang J.J.
      • Dong X.
      • Cao Y.Y.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan.
      ], the number of severe patients is 58 not 60 (mistake 6). Thus, the corresponding OR is 7.30 (95% CI, 0.34-154.96) not 7.05 (95% CI, 0.33-149.60; mistake 7).
      The worrying number of mistakes and debatable choices in the Lippi and Henry paper [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ] is not the only problem. The main concern is their use of a non-standard method to compute meta-analytic figures [
      • Patanavanich R.
      • Glantz S.A.
      Smoking is Associated with COVID-19 progression: a meta-analysis.
      ,
      • Lo E.
      • Lasnier B.
      Active smoking and severity of coronavirus disease 2019 (COVID-19): the use of significance testing leads to an erroneous conclusion.
      ]. As well explained also in a rebuttal letter by Lo and Lasnier [
      • Lo E.
      • Lasnier B.
      Active smoking and severity of coronavirus disease 2019 (COVID-19): the use of significance testing leads to an erroneous conclusion.
      ], the model Lippi and Henry used [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ] has fundamental flaws which result in incorrect uncertainty intervals. We re-analyzed the same (incorrect) ORs used in their meta-analysis [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ] but with standard procedures in R (metagen package) and found the same fixed-effects point estimate for the OR. However, we found a slimmer 95% CI, giving a significant figure (OR: 1.69; 95% CI, 1.11-2.58). Also excluding the study by Guan and colleagues [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ] from the meta-analysis, we still found a significant pooled estimate (OR: 4.59; 95% CI, 1.23-17.15). Accordingly, Carmona-Bayonas [
      • Carmona Bayonas A.
      • Jimenez-Fonseca P.
      • Sánchez-Arraez A.
      • Álvarez-Manceñido F.
      • Castañón E.
      Does active smoking worsen Covid-19?.
      ] used a Bayesian random-effects model to find a 95% posterior probability of the disease following a worse course in a smoker compared to a non-smoker.
      Moreover, the comments of other researchers on the Lippi and Henry meta-analysis [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ], including the warning to be cautious, taking published data as only preliminary [
      • Garufi G.
      • Carbognin L.
      • Orlandi A.
      • Tortora G.
      • Bria E.
      Smoking habit and hospitalization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related pneumonia: the unsolved paradox behind the evidence.
      ] and recommending a correct interpretation of pooled estimates from studies with potential limitations [
      • Sánchez J.J.
      • Acevedo N.
      • Guzmán E.
      Active smoking and severity of coronavirus disease 2019 (COVID-19): differences in measurement of variables could cause errors in the results.
      ], are common sense. However, in this case they are superfluous since they rely on properly conducted meta-analyses.
      Lippi and colleagues replied to the comments by Garufi and colleagues [
      • Garufi G.
      • Carbognin L.
      • Orlandi A.
      • Tortora G.
      • Bria E.
      Smoking habit and hospitalization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related pneumonia: the unsolved paradox behind the evidence.
      ], with a letter to the editor entitled “Active smoking and COVID-19: a double-edged sword” [
      • Lippi G.
      • Sanchis-Gomar F.
      • Henry B.M.
      Active smoking and COVID-19: a double-edged sword.
      ]. The letter reported the results from two additional studies [
      • Petrilli C.M.
      • Jones S.A.
      • Yang J.
      • et al.
      Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City.
      ,
      CDC COVID-19 Response Team
      Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12-March 28, 2020.
      ], apparently in favor of the hypothesis that there was no relation between smoking and COVID-19 progression. However, Lippi and colleagues overlooked some other findings from the same studies which contrast with their hypothesis. For instance, from the article by Petrilli et al. [
      • Petrilli C.M.
      • Jones S.A.
      • Yang J.
      • et al.
      Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City.
      ], Lippi and colleagues reported the crude OR for current versus non-smokers as 0.63 (95% CI, 0.40-1.00), without mentioning that the study found inconclusive results for ever smokers, with a multivariate OR of 0.89 (95% CI, 0.65-1.21) [
      • Petrilli C.M.
      • Jones S.A.
      • Yang J.
      • et al.
      Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City.
      ]. In addition, Lippi et al. [
      • Lippi G.
      • Sanchis-Gomar F.
      • Henry B.M.
      Active smoking and COVID-19: a double-edged sword.
      ] reported that in the Centers for Disease Control and Prevention (CDC) COVID-19 Response Team study [
      CDC COVID-19 Response Team
      Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12-March 28, 2020.
      ] the proportion of current smokers among ICU patients was nearly half that among non-ICU patients, the crude OR of ICU for current versus non smokers being 0.51 (95% CI, 0.19-1.36). But again they did not mention that former smokers were 7.2% of ICU patients and 4.4% of non-ICU patients, corresponding to a crude OR of 1.70 (95% CI, 1.07-2.70). More importantly, when considering all the participants in that study (not only hospitalized, but also non-hospitalized patients, who were excluded in Lippi and colleagues’ estimates [
      • Lippi G.
      • Sanchis-Gomar F.
      • Henry B.M.
      Active smoking and COVID-19: a double-edged sword.
      ]), the OR for ever versus never smokers from the CDC COVID-19 Response Team study [
      CDC COVID-19 Response Team
      Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12-March 28, 2020.
      ] was 2.60 (95% CI, 1.82-3.73) [
      • Patanavanich R.
      • Glantz S.A.
      Smoking is Associated with COVID-19 progression: a meta-analysis.
      ].
      The latest systematic review, published in pre-print on 23 May 2020, clarified the role of smoking in COVID-19 severity and mortality, summarizing the main findings so far [

      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. (version 3). May 23, 2020; Qeios ID: UJR2AW.4; https://doi.org/10.32388/UJR2AW.4.

      ]. It examined 22 studies reporting disease severity in hospitalized patients according to smoking status. The meta-analysis included only three fair-quality studies. Current smokers were at higher risk of more severe disease than never smokers (RR: 1.37; 95% CI, 1.07-1.75). There was no significant difference between former and never smokers (RR: 1.51; 95% CI, 0.82-2.80).
      Another recent meta-analysis included 19 studies for a total of 11,590 COVID-19 patients [
      • Patanavanich R.
      • Glantz S.A.
      Smoking is Associated with COVID-19 progression: a meta-analysis.
      ]. Of these, 30% of ever smokers experienced disease progression, compared with 18% of non-smokers (OR: 1.91, 95% CI, 1.42-2.59). Results were similar for current versus never smokers (OR: 1.91; 95% CI, 1.10-3.29), but based on only five studies [
      • Patanavanich R.
      • Glantz S.A.
      Smoking is Associated with COVID-19 progression: a meta-analysis.
      ].
      In conclusion, the meta-analysis by Lippi and Henry [
      • Lippi G.
      • Henry B.M.
      Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
      ] suffers from a surprising number of errors, resulting in misleading conclusions. It is the only review so far indicating no relation between smoking and COVID-19 severity. There are now at least 17 further studies in subsequent meta-analyses [
      • Patanavanich R.
      • Glantz S.A.
      Smoking is Associated with COVID-19 progression: a meta-analysis.
      ,

      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. (version 3). May 23, 2020; Qeios ID: UJR2AW.4; https://doi.org/10.32388/UJR2AW.4.

      ] that provide definite evidence of a direct relationship between tobacco smoking and COVID-19 severity and progression.
      Given the self-declared lack of competing interest of these authors, we are confident that the paper is the result of an unfortunate series of honest errors, with no intentional misconduct. The authors, not experts in tobacco control, were probably not aware of the serious, far-reaching potential consequences of their erroneous results, statements and conclusions. In fact, they were – and are still - giving the tobacco industry and its advocates a chance to raise doubts about the evidence that smoking worsens COVID-19 progression and prognosis. Unfortunately, this has substantially reduced the efficacy of the tobacco control community's claims to support smoking cessation in the COVID-19 era.

      Declaration of Competing Interest

      None to declare.

      Acknowledgments

      We thank Dr. Paolo D'Argenio, TobaccoEndgame, Italy (https://tobaccoendgame.it/), Prof. Maria Sofia Cattaruzza, La Sapienza University, Rome, Italy, and Dr. Vincenzo Zagà, President of the Italian Society for Tobaccology (SITAB; https://www.tabaccologia.it/) for their suggestions and comments. We also want to thank our teams for their editorial and biostatistical support: Dr. Giulia Carreras, ISPRO, Florence, Italy; Elisa Borroni and Dr. Cristina Bosetti, Mario Negri Institute, Milan, Italy. We are grateful to J.D. Baggott for language editing.

      Funding

      None.

      References

        • Gorini G.
        • Clancy L.
        • Fernandez E.
        • Gallus S.
        Smoking history is an important risk factor for severe COVID-19.
        Blog Tob Control. 2020; (Available online at:) (020/04/05/smoking-history-is-an-important-risk-factor-for-severe-COVID-19/)
        • Vardavas C.I.
        • Nikitara K.
        COVID-19 and smoking: a systematic review of the evidence.
        Tob Induc Dis. 2020; 18: 20https://doi.org/10.18332/tid/119324
        • Cattaruzza M.S.
        • Zagà V.
        • Gallus S.
        • D'Argenio P.
        • Gorini G.
        Tobacco smoking and COVID-19 pandemic: old and new issues. A summary of the evidence from the scientific literature.
        Acta Biomed. 2020; 91: 106-112https://doi.org/10.23750/abm.v91i2.9698
      1. Simons D, Perski O, Brown J. Covid-19: the role of smoking cessation during respiratory virus epidemics. March 20, 2020. Available online at: https://blogs.bmj.com/bmj/2020/03/20/covid-19-the-role-of-smoking-cessation-during-respiratory-virus-epidemics/ (last access: 20 March 2020).

        • Lippi G.
        • Henry B.M.
        Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).
        Eur J Intern Med. 2020; 75 (Epub 2020 Mar 16): 107-108https://doi.org/10.1016/j.ejim.2020.03.014
        • Guo F.R.
        Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): an update of a meta-analysis.
        Tob Induc Dis. 2020; 18: 37https://doi.org/10.18332/tid/121915
        • Guan W.J.
        • Ni Z.Y.
        • Hu Y.
        • et al.
        Clinical characteristics of coronavirus disease 2019 in China.
        N Engl J Med. 2020; 382: 1708-1720https://doi.org/10.1056/NEJMoa2002032
        • Gallus S.
        • Muttarak R.
        • Franchi M.
        • et al.
        Why do smokers quit?.
        Eur J Cancer Prev. 2013; 22: 96‐101https://doi.org/10.1097/CEJ.0b013e3283552da8
        • Huang C.
        • Wang Y.
        • Li X.
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China..
        Lancet. 2020; 395: 497‐506https://doi.org/10.1016/S0140-6736(20)30183-5
        • Liu W.
        • Tao Z.W.
        • Wang L.
        • et al.
        Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease.
        Chin Med J. 2020; 133: 1032‐1038https://doi.org/10.1097/CM9.0000000000000775
        • Yang X.
        • Yu Y.
        • Xu J.
        • et al.
        Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
        Lancet Respir Med. 2020; 8: 475‐481https://doi.org/10.1016/S2213-2600(20)30079-5
        • Zhang J.J.
        • Dong X.
        • Cao Y.Y.
        • et al.
        Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan.
        China. Allergy. 2020; (10.1111/all.14238)https://doi.org/10.1111/all.14238
        • Patanavanich R.
        • Glantz S.A.
        Smoking is Associated with COVID-19 progression: a meta-analysis.
        Nicotine Tob Res. 2020; (ntaa082)https://doi.org/10.1093/ntr/ntaa082
        • 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; S0953-6205 (30188-6)https://doi.org/10.1016/j.ejim.2020.05.003
        • Carmona Bayonas A.
        • Jimenez-Fonseca P.
        • Sánchez-Arraez A.
        • Álvarez-Manceñido F.
        • Castañón E.
        Does active smoking worsen Covid-19?.
        Eur J Intern Med. 2020; S0953-6205https://doi.org/10.1016/j.ejim.2020.05.038
        • Garufi G.
        • Carbognin L.
        • Orlandi A.
        • Tortora G.
        • Bria E.
        Smoking habit and hospitalization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related pneumonia: the unsolved paradox behind the evidence.
        Eur J Intern Med. 2020; S0953-6205 (30163-1)https://doi.org/10.1016/j.ejim.2020.04.042
        • Sánchez J.J.
        • Acevedo N.
        • Guzmán E.
        Active smoking and severity of coronavirus disease 2019 (COVID-19): differences in measurement of variables could cause errors in the results.
        Eur J Intern Med. 2020;
        • Lippi G.
        • Sanchis-Gomar F.
        • Henry B.M.
        Active smoking and COVID-19: a double-edged sword.
        Eur J Intern Med. 2020; S0953-6205: 30182-30185https://doi.org/10.1016/j.ejim.2020.04.060
        • Petrilli C.M.
        • Jones S.A.
        • Yang J.
        • et al.
        Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City.
        medRxiv. 2020;
        • CDC COVID-19 Response Team
        Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 - United States, February 12-March 28, 2020.
        MMWR Morb Mortal Wkly Rep. 2020; 69: 382-386https://doi.org/10.15585/mmwr.mm6913e2
      2. 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. (version 3). May 23, 2020; Qeios ID: UJR2AW.4; https://doi.org/10.32388/UJR2AW.4.